As filed with the Securities and Exchange Commission on January 27, 2023.

Registration No. 333-260565

UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549

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Amendment No. 12

to

FORM S-1
REGISTRATION STATEMENT
UNDER
THE SECURITIES ACT OF 1933

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Intensity Therapeutics, Inc.

(Exact name of registrant as specified in its charter)

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61 Wilton Road, 3rd Floor
Westport, CT 06880
Telephone: (203) 221-7381
(Address, including zip code, and telephone number, including area code, of registrant’s principal executive offices)

_______________________________________________

Lewis H. Bender
Chief Executive Officer
61 Wilton Road, 3rd Floor
Westport, CT 06880
Telephone: (203) 221-7381
(Name, address, including zip code, and telephone number, including area code, of agent for service)

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Copies to:

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Approximate date of commencement of proposed sale to the public: As soon as practicable after this registration statement becomes effective.

If any of the securities being registered on this form are to be offered on a delayed or continuous basis pursuant to Rule 415 under the Securities Act of 1933, check the following box. ☐

If this form is filed to register additional securities for an offering pursuant to Rule 462(b) under the Securities Act, check the following box and list the Securities Act registration statement number of the earlier effective registration statement for the same offering. ☐

If this form is a post-effective amendment filed pursuant to Rule 462(c) under the Securities Act, check the following box and list the Securities Act registration statement number of the earlier effective registration statement for the same offering. ☐

If this form is a post-effective amendment filed pursuant to Rule 462(d) under the Securities Act, check the following box and list the Securities Act registration statement number of the earlier effective registration statement for the same offering. ☐

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, or a smaller reporting company. See the definitions of “large accelerated filer,” “accelerated filer” and “smaller reporting company” in Rule 12b-2 of the Exchange Act. (Check one).

If an emerging growth company, indicate by checkmark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided to Section 7(a)(2)(B) of the Securities Act. ☐

The Registrant hereby amends this Registration Statement on such date or dates as may be necessary to delay its effective date until the Registrant shall file a further amendment which specifically states that this Registration Statement shall thereafter become effective in accordance with Section 8(a) of the Securities Act of 1933 or until the Registration Statement shall become effective on such date as the Commission, acting pursuant to said Section 8(a), may determine.

The information in this preliminary prospectus is not complete and may be changed. These securities may not be sold until the registration statement filed with the Securities and Exchange Commission is effective. This preliminary prospectus is not an offer to sell these securities nor does it seek an offer to buy these securities in any jurisdiction where the offer or sale is not permitted.

This is our initial public offering. We are offering 1,777,778 shares of our common stock, par value $0.0001 per share (“Common Stock”). Prior to this offering, there has been no public market for our Common Stock. The initial public offering price for our Common Stock is expected to be $4.50 per share.

We have applied to list our Common Stock on the Nasdaq Capital Market under the symbol “INTS,” which listing is a condition to this offering. However, no assurance can be given that our application will be approved and that our Common Stock will ever be listed on Nasdaq. If our listing application is not approved by Nasdaq, we will not be able to consummate the offering and will terminate this offering.

Unless otherwise indicated or the context otherwise requires, references in this prospectus to the “Company”, “we”, “us” and “our” refer to Intensity Therapeutics, Inc.

We are an “emerging growth company” as that term is used in the Jumpstart Our Business Startups Act of 2012 and, as such, may elect to comply with certain reduced public company reporting requirements. See the section entitled “Prospectus Summary — Implications of Being an Emerging Growth Company” in this prospectus.

Investing in our securities involves a high degree of risk. Before buying any of our securities, you should carefully read the discussion of the material risks of investing in our securities under the heading “Risk Factors” beginning on page 9 of this prospectus.

Neither the Securities and Exchange Commission nor any state securities commission has approved or disapproved of these securities or passed on the adequacy or accuracy of this prospectus. Any representation to the contrary is a criminal offense.

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(1)      See “Underwriting” beginning on page 130 of this prospectus for additional information regarding the compensation and reimbursement of expenses payable to the underwriters. We have also agreed to issue to the underwriters warrants to purchase up to 7% of the shares of Common Stock sold in this offering.

The underwriters have an option to purchase up to 266,666 additional shares of Common Stock from us at the initial public offering price less the underwriting discounts and commissions. The underwriters can exercise this option at any time and from time to time within 45 days from the date of this prospectus.

Certain of our existing stockholders have indicated an interest in purchasing an aggregate of up to $2,500,000 of Common Stock in this offering at the initial public offering price per share of Common Stock and on the same terms as other purchasers in this offering. However, because indications of interest are not binding agreements or commitments to purchase, the underwriters may determine to sell more, fewer or no Common Stock in this offering to any of these stockholders, or any of these stockholders may determine to purchase more, fewer or no Common Stock in this offering. The underwriters will receive the same underwriting discount on any Common Stock purchased by these stockholders as they will on any other securities sold to the public in this offering.

Delivery of the shares of our Common Stock will be made on or about             , 2023.

Book Running Manager

The Benchmark Company

The date of this Prospectus is             , 2023.

TABLE OF CONTENTS

You should rely only on the information contained in this prospectus or in any free writing prospectus we may authorize to be delivered or made available to you. We have not, and the underwriters have not, authorized anyone to provide you with different information. If anyone provides you with different or inconsistent information, you should not rely on it. We are offering to sell, and seeking offers to buy, our securities only in jurisdictions where offers and sales are permitted. The information in this prospectus is accurate only as of the date of this prospectus, regardless of the time of delivery of this prospectus or any sale of our securities.

For investors outside the United States: We have not, and the underwriters have not, done anything that would permit this offering or possession or distribution of this prospectus in any jurisdiction where action for that purpose is required, other than in the United States. Persons outside the United States who come into possession of this prospectus must inform themselves about, and observe any restrictions relating to, the offering of our securities and the distribution of this prospectus outside the United States.

Market and Other Industry Data

Unless otherwise indicated, market data and certain industry forecasts used throughout this prospectus were obtained from various sources, including internal surveys, market research, consultant surveys, publicly available information and industry publications and surveys. Industry surveys, publications, consultant surveys and forecasts generally state that the information contained therein has been obtained from sources believed to be reliable, but that the accuracy and completeness of such information is not guaranteed. Such data and industry forecasts involve a number of assumptions and limitations and they are necessarily subject to a high degree of uncertainty and risk due to a variety of factors, including those described in the sections entitled “Risk Factors” and “Cautionary Note Regarding Forward-Looking Statements” and elsewhere in this prospectus. These and other factors could cause results to differ materially from those expressed in these publications and reports.

Trademarks and Other Intellectual Property Rights

We own or have rights to trademarks or trade names that we use in connection with the operation of our business, including our corporate names, tag-lines, logos and website names. In addition, we own or have the rights to patents, copyrights, trade secrets and other proprietary rights that protect our service offerings. Solely for convenience, some of the copyrights, trade names and trademarks referred to in this prospectus are listed without their ©, ® and ™ symbols, but we will assert, to the fullest extent under applicable law, our rights to our copyrights, trade names and trademarks.

RISK FACTORS

You should carefully consider the risks described below before buying shares in Intensity Therapeutics, Inc. These are risks and uncertainties that management believes are most likely to be material and therefore are important for an investor to consider. Our business operations and results may also be adversely affected by additional risks and uncertainties not presently known to us, or which are currently deemed immaterial, or which are similar to those faced by other companies in the pharmaceutical industry or business in general. If any of the following risks or uncertainties actually occurs, our business, financial condition, results of operations, or cash flows would likely suffer. In that event, the value of our stock could decline, perhaps significantly.

Risks Related to Our Business, Financial, and Investment Conditions

The market price of our Common Stock may be highly volatile, and you could lose all or part of your investment.

The trading price of our Common Stock is likely to be volatile. Upon the consummation of this offering, we will have a relatively small public float due to the relatively small size of this offering, the ownership percentage of our executive officers and directors, and greater than 5% stockholders. As a result of our small public float, our Common Stock may be less liquid and have greater stock price volatility than the common stock of companies with broader public ownership.

Our stock price could be subject to wide fluctuations in response to a variety of other factors, which include:

•        whether we achieve our anticipated corporate objectives;

•        changes in financial or operational estimates or projections;

•        termination of the lock-up agreement or other restrictions on the ability of our stockholders and other security holders to sell shares after this offering; and

•        general economic or political conditions in the United States or elsewhere.

In addition, the stock market in general, and the stock of clinical stage biotechnology companies in particular, has experienced extreme price and volume fluctuations that have often been unrelated or disproportionate to the operating performance of these companies. Such rapid and substantial price volatility, including any stock run-up, may be unrelated to our actual or expected operating performance and financial condition or prospects, making it difficult for prospective investors to assess the rapidly changing value of our stock. This volatility may prevent you from being able to sell your securities at or above the price you paid for your securities. If the market price of our Common Stock after this offering does not exceed the initial public offering price, you may not realize any return on your investment in us and may lose some or all of your investment.

We are a clinical-stage biotechnology company with a limited operating history and have not generated any revenue to date from product sales.

We are a clinical-stage, pre-commercial company with only a limited operating history upon which to base an evaluation of our current business and future prospects and how we will respond to competitive, financial or technological challenges. Biotechnology product development is a highly speculative undertaking and involves a substantial degree of risk. We were incorporated under the laws of the State of Delaware in November 2012. Since inception, we have focused substantially all of our efforts and financial resources on raising capital and developing our initial product candidates. We have no products approved for commercial sale and therefore have never generated any revenue from product sales, and we do not expect to do so in the foreseeable future. We have not obtained regulatory approvals for any of our product candidates. Consequently, the revenue-generating potential of our business is unproven and uncertain. Even if our product candidates receive regulatory approval, we may be unable to successfully introduce and market them at prices that would permit us to operate profitably.

We have incurred significant operating losses since our inception and anticipate that we will incur continued losses for the foreseeable future.

To date, we have financed our operations primarily through an initial investment from our founder and the issuance and sale of Common Stock, our convertible preferred stock and convertible debt notes, to outside investors in private equity financings. From our inception through September 30, 2022, we raised an aggregate of $32.1 million

of gross proceeds from such transactions. As of September 30, 2022, our cash and cash equivalents were $0.7 million. During November 2022, the Company raised an additional $2.25 million with convertible notes. We have incurred net losses in each year since our inception, and we had an accumulated deficit of $37.1 million as of September 30, 2022. For the nine months ended September 30, 2022 and 2021, and for the years ended December 31, 2021 and December 31, 2020, we reported net losses of $6.1 million, $5.5 million, $7.9 million, and $6.0 million, respectively. The report of our independent registered public accounting firm for the year ended December 31, 2021 included herein contains an explanatory paragraph indicating that there is substantial doubt as to our ability to continue as a going concern as a result of recurring losses from operations and negative cash flows.

We expect to continue to incur significant expenses and operating losses over the next several years and for the foreseeable future. Substantially all of our operating losses have resulted from costs incurred in connection with our research and development programs and from general and administrative costs associated with our operations. We expect our research and development expenses to significantly increase in connection with the commencement and continuation of clinical trials of our product candidates. In addition, if we obtain marketing approval for our product candidates, we will incur significant sales, marketing and manufacturing expenses. Once we are a public company, we will incur additional costs associated with operating as a public company. As a result, we expect to continue to incur significant and increasing operating losses for the foreseeable future. Because of the numerous risks and uncertainties associated with developing biotechnology products, we are unable to predict the extent of any future losses or when we will become profitable, if at all. Even if we do become profitable, we may not be able to sustain or increase our profitability on a quarterly or annual basis. Our prior losses, combined with expected future losses, have had and will continue to have an adverse effect on our stockholders’ deficit and working capital.

If we fail to establish and maintain an effective system of internal control, we may not be able to report our financial results accurately or to prevent fraud. Any inability to report and file our financial results accurately and timely could harm our reputation and adversely impact the future trading price of our securities.

Effective internal control is necessary for us to provide reliable financial reports and prevent fraud. However, because of our limited resources, there are limited controls over information processing. We have material weaknesses due to (1) a lack of segregation of duties, since we have a limited administrative staff, and (2) Information Technology matters regarding user access that aggregate to a material weakness. Our management is composed of a small number of individuals resulting in a situation where limitations on segregation of duties exist. We have focused our segregation of duties to ensure that the actual payments are performed separately from the accounting staff, and the Chief Executive Officer performs a robust review of the financial statements on a monthly basis. All accounting entries and the creation of financial statements, however, are performed by a single person. To remedy this situation, we would need to hire additional staff. In August 2021, we hired a Chief Financial Officer to add a layer of supervision and control. Currently, we are unable to hire additional staff to facilitate greater segregation of duties but will reassess its capabilities after completion of the Offering. We are also working to institute policies and procedures that would eliminate our Information Technology weaknesses related to user access. These procedures include the recent implementation of a Virtual Private Network (VPN) and Multi-Factor Authentication (MFA) on all computers involved with financial transactions.

Our small size and internal control deficiencies may adversely affect our financial condition, results of operation and access to capital. If we cannot provide reliable financial reports or prevent fraud, we may not be able to manage our business as effectively as we would if an effective control environment existed, and our business and reputation with investors may be harmed.

The report by our auditors includes a paragraph that states that substantial doubt exists about the Company’s ability to continue as a going concern.

The report of our independent registered public accounting firm for the year ended December 31, 2021 included herein contains an explanatory paragraph indicating that there is substantial doubt as to our ability to continue as a going concern as a result of recurring losses from operations and negative cash flows. We do not have a history of earnings and, as a result, substantial doubt exists about our ability to continue as a going concern. Further, without the proceeds of this offering, we do not have sufficient cash to continue with our business plan for the next 12 months. Also, at any time on or after May 18, 2022, the holders of at least two-thirds of the then outstanding shares of Series A Preferred Stock may elect to cause the Company to redeem all, but not less than all, of the shares of Series A Preferred Stock at a redemption price per share of $2.00, or $10,000,000 in total. Through the date of this filing, these shareholders have not exercised this option.

Our continued operations are dependent on our ability to complete equity or debt financings or generate profitable operations. Such financings may not be available or may not be available on reasonable terms. Our financial statements do not include any adjustments that may result from the outcome of this uncertainty. If we are unable to

obtain adequate funding from this proposed offering or in the future, or if we are unable to generate revenue to achieve and sustain profitability, we may not be able to continue as a going concern. We believe that there is substantial doubt as to whether we can raise sufficient funding in order for us to continue operations.

Even if we consummate this offering, we will need to raise substantial additional funding. If we are unable to raise capital when needed, we would be forced to delay, reduce or eliminate some or all of our product development programs or commercialization efforts.

The development of biotechnology products is capital-intensive and we expect our expenses to significantly increase in connection with our ongoing activities, particularly as we continue our ongoing clinical trials or initiate future trials and pursue the research and development of, and seek marketing approval for, our product candidates. Our future capital requirements will depend on and could increase significantly as a result of many factors, including:

•        our research and product development programs, including clinical studies;

•        the timing and costs of our various U.S. and foreign regulatory filings, obtaining approvals, and complying with regulations;

•        the timing and costs associated with developing manufacturing operations;

•        the timing of product commercialization activities, including marketing and distribution arrangements;

•        the timing and costs involved in preparing, filing, prosecuting, defending, and enforcing intellectual property rights; and

•        the impact of competing technological and market developments.

We expect that the net proceeds from this offering, together with our existing cash and cash equivalents and investments will be sufficient to fund our operations and capital expenditure requirements through March 31, 2024. Accordingly, we will need to obtain substantial additional funding to continue our operations. We cannot guarantee that future financing will be available in sufficient amounts or on terms acceptable to us, if at all. Moreover, the terms of any financing may adversely affect the holdings or the rights of our stockholders and the issuance of additional securities, whether equity or debt, by us, or the possibility of such issuance, may cause the market price of our shares to decline. The sale of additional equity or convertible securities would dilute all of our stockholders. The incurrence of indebtedness would result in increased fixed payment obligations and we may be required to agree to certain restrictive covenants, such as limitations on our ability to incur additional debt, limitations on our ability to acquire, sell or license intellectual property rights and other operating restrictions that could adversely impact our ability to conduct our business. We could also be required to seek funds through arrangements with collaborators or otherwise at an earlier stage than otherwise would be desirable and we may be required to relinquish rights to some of our technologies or product candidates or otherwise agree to terms unfavorable to us, any of which may have a material adverse effect on our business, operating results and prospects. Any additional fundraising efforts may also divert our management from their day-to-day activities, which may adversely affect our ability to develop and commercialize our product candidates.

If we are unable to raise capital when needed or on attractive terms, we would be forced to delay, reduce or eliminate certain of our research and development programs or future commercialization efforts, and may be unable to expand our operations or otherwise capitalize on our business opportunities, as desired, which could materially affect our business, financial condition and results of operations.

We are largely dependent upon the success of our new intratumoral technology, which will require additional development before we may be able to seek regulatory approval and may never receive regulatory approval or be successfully commercialized.

The Intensity Therapeutics Technology, a platform for the creation of products to improve treatment of cancer patients, is our only technology. Our entire focus has been on developing, commercializing, and ultimately obtaining regulatory authorizations and approvals of product candidates using this technology. We have invested, and we expect to continue to invest, significant efforts and financial resources in its development. Our ability to generate meaningful revenue, which may not occur for the foreseeable future, if ever, will depend heavily on the successful development, regulatory approval and commercialization of our technology. If we are unable to develop the Intensity Therapeutics Technology, obtain regulatory approval, and sell products using the technology, we will not generate operating revenue or become profitable, and we may be forced to terminate or cease operations.

We have not completed clinical trials on any forms of cancer, and we are subject to risks and challenges that may prevent or delay the completion of our clinical trials.

We have only two clinical trials in progress. One on-going study is a multi-cohort clinical trial testing our product candidate alone or combined with Keytruda® or with Yervoy®. The other study is a randomized Phase 2 study in presurgical breast cancer. Our program is in the early stage. Approximately 200 patients have been enrolled in our clinical trials as of December 31, 2022. We have not demonstrated any survival benefit compared to an active control group in a statistically significant and meaningful manner. We have not demonstrated sufficient safety of any product candidate for FDA approval. Our largest dose on any given day so far has been 244mL containing 122 mg of cisplatin and 24.4 mg of vinblastine sulfate. We have no indication that higher doses or any dose will be safe or effective.

We intend to conduct clinical trials for multiple indications, and it may take several years to complete the testing of our product candidates and technology for the indications for which we wish to obtain approval. Failure or delay can occur at any stage of development, for many reasons, including:

•        any pre-clinical or clinical test may fail to produce results satisfactory to the FDA or foreign regulatory authorities and preclude us from testing in humans;

•        pre-clinical or clinical data can be interpreted in different ways, which could delay, limit, or prevent regulatory approval;

•        negative or inconclusive results from a pre-clinical study or clinical trial or adverse medical events during a clinical trial could cause a pre-clinical study or clinical trial to be repeated or a program to be terminated, even if other studies or trials relating to the program are successful;

•        the FDA or foreign regulatory authorities can place a clinical hold on a trial if, among other reasons, it finds that patients enrolled in the trial are or would be exposed to an unreasonable and significant risk of illness or injury;

•        changes in regulatory agency policies during the period in which we are developing a system, or the period required for review of any application for regulatory agency approval;

•        our clinical trials may not demonstrate the safety and efficacy of any system or result in marketable products;

•        the FDA or foreign regulatory authorities may request additional clinical trials, including more than one Phase 3 trial, relating to any potential NDA submissions;

•        the FDA or foreign regulatory authorities may change their approval policies or adopt new regulations that may negatively affect or delay our ability to bring a system to market or require additional clinical trials; and

•        a system may not be approved for all the requested indications.

We face significant competition from other biotechnology and pharmaceutical companies, and our operating results will suffer if we fail to compete effectively.

The biopharmaceutical industry is characterized by intense competition and rapid innovation. We face competition from major pharmaceutical, specialty pharmaceutical and biotechnology companies among others with respect to INT230-6 and will face similar competition with respect to any product candidates that we may seek to develop or commercialize in the future. We compete in pharmaceutical, biotechnology and other related markets that develop immune-oncology therapies for the treatment of cancer. There are other companies working to develop new drugs, immunotherapies and other approaches for the treatment of cancer including divisions of large pharmaceutical and biotechnology companies of various sizes. Many of our competitors have substantially greater financial, technical and other resources, such as larger research and development staff and experienced marketing and manufacturing organizations and well-established sales forces. Smaller or early-stage companies may also prove to be significant competitors, particularly as they develop novel approaches to treating disease indications that our product candidates are also focused on treating. Established pharmaceutical companies may also invest heavily to accelerate discovery and development of novel therapeutics or to in-license novel therapeutics that could make the product candidates that we develop obsolete. Mergers and acquisitions in the biotechnology and pharmaceutical industries may result in even more resources being concentrated in our

competitors. Competition may increase further as a result of advances in the commercial applicability of technologies and greater availability of capital for investment in these industries. Our competitors, either alone or with collaborative partners, may succeed in developing, acquiring or licensing on an exclusive basis drug or biologic products that are more effective, safer, more easily commercialized or less costly than our product candidates or may develop proprietary technologies or secure patent protection that we may need for the development of our technologies and products. We believe the key competitive factors that will affect the development and commercial success of our product candidates are efficacy, safety, tolerability, reliability, convenience of use, price and reimbursement.

There are a number of companies trying to develop intratumoral therapies. However, most of our competitors are currently focused on intratumoral treatment approaches that stimulate immune cells to achieve inflammation rather than directly killing a tumor. This shift to a pure immune-oncology (IO) treatment has reopened the investigations into intratumoral approaches focusing on activating local immune response. Amgen markets a novel genetically modified oncolytic viral-based immunotherapeutic, talimogene laherparepvec (T-Vec), that has been approved for IT use in cutaneous melanoma. While T-Vec is approved solely for local treatment of localized cutaneous melanoma, the drug has not been shown to improve overall survival or have any effect on distal metastases, which will be a critical factor to broader use. Another viral based system is being developed by Replimune. RP1 is Replimune’s genetically modified herpes simplex type 1 virus that is designed to directly destroy tumors and to generate an anti-tumor immune response. This product is being evaluated in a Phase 1/2, open label, multicenter, dose escalation and expansion, first-in-human (FIH) clinical study to evaluate the safety and tolerability, biodistribution, shedding, and preliminary efficacy of RP1 alone and in combination with nivolumab in adult subjects with advanced and/or refractory solid tumors. The IGNYTE Study, which started in 2017, includes a dose escalation phase for single agent RP1, an expansion phase with a combination of RP1 and nivolumab and a Phase 2 portion in specified tumor types for the combination therapy. Dose escalation of RP1 by intratumoral injection in superficial tumors and in visceral tumors. The objective of this viral approach is to transfect the granulocyte-macrophage colony-stimulating factor gene into the tumor microenvironment to recruit a local inflammatory response that would promote a systemic immune response.

Oncosec Immunotherapies Inc. is developing cytokine-based intratumoral immunotherapies to stimulate the body’s immune system to target and attack cancer. The Company built a clinical pipeline utilizing their primary technology, TAVO™ (tavokinogene telseplasmid), as a potential treatment for multiple cancer indications either as a monotherapy or in combination with leading checkpoint inhibitors. TAVO is DNA-based interleukin-12 (IL-12), a naturally occurring protein in the body with immune-stimulating functions. TAVO is administered directly into the tumor using the Company’s proprietary electroporation (EP) gene delivery system, which employs a series of momentary energy pulses. Those pulses are designed to increase the permeability of the cell membrane and facilitate uptake of IL-12 coded DNA into cells.

Other local treatment approaches being explored by companies such as Merck also attempt to recruit the immune system cells into the local tumor microenvironment with intratumoral delivery of other agents. Data on several other intratumorally-delivered agents such as STING agonists, RIG-1, and TLR9 have been presented at major cancer conferences.

Our belief is that our competitors have formulated their products without consideration of the inability of water-based products to be well absorbed into a tumor’s lipophilic, high-pressure microenvironment. Attempts at the stimulation of an inflammatory response or efforts to attract immune cells into a hostile live, rapidly growing tumor still pose a number of challenges. Accordingly, there remains a continued unmet need for the development of direct IT therapies for solid tumors that provide high local killing efficacy coupled with nontoxic systemic anti-cancer effects. We believe we have created a product candidate having the necessary physical and chemical properties to overcome the local delivery challenges. Evidence shows the mechanism of tumor killing achieved by our drug candidate also leads to systemic immune activation in certain cancers.

We anticipate competing with other companies that are focused on treating disease indications that our product candidates are also focused on treating. A competitor may develop technologies focused on the same disease pathway as our technology or may focus on treating the targeted disease in a completely different manner. To the extent a new drug is developed that is more efficacious than any product candidate developed by us, this could reduce or negate the need for our product candidate. In addition, while we believe our product candidates may be used in conjunction with existing or emerging standard of care (SOC) in certain disease indications, as companies continue to improve upon existing standard of care, more efficacious drug therapies could become available, reducing or completely negating the benefit of our product candidates. Our competitors may also include companies that are or will be developing therapies for the same therapeutic areas that we are targeting within our early pipeline.

Even if we are successful in achieving regulatory approval to commercialize a product candidate ahead of our competitors, our future pharmaceutical products may face direct competition from generic and other follow-on drug products. Any of our product candidates that may achieve regulatory approval in the future may face competition from generic products earlier or more aggressively than anticipated, depending upon how well such approved products perform in the U.S. prescription drug market. Our ability to compete also may be affected in many cases by insurers or other third-party payors seeking to encourage the use of generic products. Generic products are expected to become available over the coming years. Even if our product candidates achieve marketing approval, they may be priced at a significant premium over competitive generic products, if any have been approved by then.

In addition to creating the 505(b)(2) NDA pathway, the Hatch-Waxman Amendments to the federal Food, Drug, and Cosmetic Act (FDCA) authorized the FDA to approve generic drugs that are the same as drugs previously approved for marketing under the NDA provisions of the statute pursuant to ANDAs. An ANDA relies on the preclinical and clinical testing conducted for a previously approved reference listed drug (“RLD”), and must demonstrate to the FDA that the generic drug product is identical to the RLD with respect to the active ingredients, the route of administration, the dosage form, and the strength of the drug and also that it is “bioequivalent” to the RLD. The FDA is prohibited by statute from approving an ANDA when certain marketing or data exclusivity protections apply to the RLD. If any such competitor or third party is able to demonstrate bioequivalence without infringing our patents, then this competitor or third party may then be able to introduce a competing generic product onto the market.

We cannot predict the interest of potential follow-on competitors or how quickly others may seek to come to market with competing products, whether approved as a direct ANDA competitor or as a 505(b)(2) NDA referencing one of our future drug products. If the FDA approves generic versions of our drug candidates in the future, should they be approved for commercial marketing, such competitive products may be able to immediately compete with us in each indication for which our product candidates may have received approval, which could negatively impact our future revenue, profitability and cash flows and substantially limit our ability to obtain a return on our investments in those product candidates.

Even if we obtain regulatory approval of our product candidates, the availability and price of our competitors’ products could limit the demand and the price we are able to charge for our product candidates. We may not be able to implement our business plan if the acceptance of our product candidates is inhibited by price competition or the reluctance of physicians to switch from existing methods of treatment to our product candidates, or if physicians switch to other new drug or biologic products or choose to reserve our product candidates for use in limited circumstances. For additional information regarding our competition, see “Business — Competition.”

The COVID-19 pandemic has spread worldwide and may affect our ability to initiate and complete current or future preclinical studies or clinical trials, disrupt regulatory activities or have other adverse effects on our business and operations. In addition, this pandemic has caused substantial disruption in the financial markets and may adversely impact economies worldwide, both of which could result in adverse effects on our business and operations.

The COVID-19 pandemic, which began in December 2019 and has spread worldwide, has caused many governments to implement measures to slow the spread of the outbreak through quarantines, travel restrictions, heightened border scrutiny, and other measures. The outbreak and government measures taken in response have also had a significant impact, both direct and indirect, on businesses and commerce, as worker shortages have occurred; supply chains have been disrupted; facilities and production have been suspended; and demand for certain goods and services, such as medical services and supplies, has spiked, while demand for other goods and services, such as travel, has fallen. The future progression of the outbreak and its effects on our business and operations are uncertain. We and our contract manufacturing organizations or clinical sites, or CMOs, and contract research organizations, or CROs, may face disruptions that may affect our ability to initiate and complete preclinical studies or clinical trials or raise capital to finance our business.

Our prospects for obtaining additional financing, as needed, are uncertain and our failure to obtain needed financing could affect our ability to pursue future growth.

Even if this offering is successful, we will need to raise additional funds in the future to develop or enhance our product candidates, to fund expansion, to conduct additional clinical trials and to fund general operating expenses. For example, with regard to our Phase 3 sarcoma study (IT-03) and Phase 2/3 early-stage breast cancer study (IT-04), we expect that the proceeds from this offering will be sufficient to allow us to obtain regulatory authorizations to proceed for these trials. However, the proceeds from this offering will be insufficient to enable us to finish these trials, and we will need to raise additional funding in order to complete these trials. There is no assurance that additional financing will be available on terms favorable to us, or at all. If additional funds are raised through the issuance of equity or convertible debt securities, the percentage ownership of our stockholders would be reduced, and these securities might

have rights, preferences, or privileges senior to those of our current stockholders. If adequate funds are not available on acceptable terms, our ability to fund our expansion, take advantage of unanticipated opportunities, develop or enhance services or products, or otherwise respond to competitive pressures would be significantly limited.

Inadequate funding for the FDA, the SEC and other government agencies could hinder their ability to hire and retain key leadership and other personnel, prevent new products and services from being developed or commercialized in a timely manner or otherwise prevent those agencies from performing normal business functions on which the operation of our business may rely, which could negatively impact our business.

The ability of the FDA to review and approve new products can be affected by a variety of factors, including government budget and funding levels, ability to hire and retain key personnel and accept the payment of user fees, and statutory, regulatory, and policy changes. Average review times at the agency have fluctuated in recent years as a result. In addition, government funding of the SEC and other government agencies on which our operations may rely, including those that fund research and development activities, is subject to the political process, which is inherently fluid and unpredictable.

Disruptions at the FDA and other agencies may also slow the time necessary for new products to be reviewed and/or approved by necessary government agencies, which would adversely affect our business. For example, over the last several years, the U.S. government has shut down several times and certain regulatory agencies, such as the FDA and the SEC, have had to furlough critical employees and stop critical activities.

Separately, the FDA has announced its commitment to achieving timely reviews of applications for medical products during the COVID-19 pandemic in line with its user fee performance goals; however, the FDA may not be able to continue its current pace and review timelines could be extended, including where a pre-approval inspection or an inspection of clinical sites is required and due to the COVID-19 pandemic and travel restrictions FDA is unable to complete such required inspections during the review period. On March 10, 2020, the FDA announced its intention to postpone most inspections of foreign manufacturing facilities, and on March 18, 2020, the FDA temporarily postponed routine surveillance inspections of domestic manufacturing facilities. Subsequently, on July 10, 2020, the FDA announced its intention to resume certain on-site inspections of domestic manufacturing facilities subject to a risk-based prioritization system. The FDA intends to use this risk-based assessment system to identify the categories of regulatory activity that can occur within a given geographic area, ranging from mission critical inspections to resumption of all regulatory activities. Additionally, on April 15, 2021, the FDA issued a guidance document in which the FDA described its plans to conduct voluntary remote interactive evaluations of certain drug manufacturing facilities and clinical research sites. According to the guidance, the FDA intends to request such remote interactive evaluations in situations where an in-person inspection would not be prioritized or deemed mission-critical, or where direct inspection is otherwise limited by travel restrictions, but where the FDA determines that remote evaluation would still be appropriate. Regulatory authorities outside the U.S. may adopt similar restrictions or other policy measures in response to the COVID-19 pandemic and may experience delays in their regulatory activities. If a prolonged government shutdown occurs, or if global health concerns continue to prevent the FDA or other regulatory authorities from conducting their regular inspections, reviews, or other regulatory activities, it could significantly impact the ability of the FDA to timely review and process our regulatory submissions, which could have a material adverse effect on our business. Further, upon completion of this offering and in our operations as a public company, future government shutdowns could impact our ability to access the public markets and obtain necessary capital in order to properly capitalize and continue our operations.

Risks Related to FDA and Foreign Regulatory Approval

Clinical development involves a lengthy, complex and expensive process, with an uncertain outcome, and the results of preclinical studies and early-stage clinical trials of our product candidates may not be predictive of the results of later-stage clinical trials.

The development and approval process in the United States may take many years, require substantial resources, and may never lead to the approval of any of our product candidates by the FDA for use in the United States. To obtain the requisite regulatory approvals to commercialize any product candidates, we must demonstrate through extensive preclinical studies and clinical trials that our product candidates are safe and effective in humans. Clinical testing is expensive and can take many years to complete, and its outcome is inherently uncertain. In particular, the general approach for FDA approval of a new drug is dispositive data from one or two adequate and well-controlled, Phase 3 clinical trials of the relevant drug in the relevant patient population. Phase 3 clinical trials typically involve hundreds of patients, have significant costs and take years to complete. A product candidate can fail at any stage of testing, even after observing promising signals of activity in earlier preclinical studies or clinical trials. The results of preclinical studies and early clinical trials of our product

candidates may not be predictive of the results of later-stage clinical trials. In addition, initial success in clinical trials may not be indicative of results obtained when such trials are completed. There is typically an extremely high rate of attrition from the failure of product candidates proceeding through clinical trials. Product candidates in later stages of clinical trials may fail to show the desired safety and efficacy profile despite having progressed through preclinical studies and initial clinical trials. A number of companies in the biotechnology and biopharmaceutical industries have suffered significant setbacks in advanced clinical trials due to lack of efficacy or unacceptable safety issues, notwithstanding promising results in earlier trials. Most product candidates that commence clinical trials are never approved as therapeutic products, and there can be no assurance that any of our future clinical trials will ultimately be successful or support further clinical development of INT230-6 or any of our other product candidates. Product candidates that appear promising in the early phases of development may fail to reach the market for several reasons, including:

•        preclinical studies or clinical trials may show the product candidates to be less effective than expected (e.g., a clinical trial could fail to meet its primary endpoint(s)) or to have unacceptable side effects or toxicities;

•        failure to establish clinical endpoints that applicable regulatory authorities would consider clinically meaningful;

•        failure to receive the necessary regulatory approvals;

•        manufacturing costs, formulation issues, pricing or reimbursement issues, or other factors that make a product candidate uneconomical; and

•        the proprietary rights of others and their competing products and technologies that may prevent one of our product candidates from being commercialized.

In addition, differences in trial design between early-stage clinical trials and later-stage clinical trials make it difficult to extrapolate the results of earlier clinical trials to later clinical trials. Moreover, clinical data are often susceptible to varying interpretations and analyses, and many companies that have believed their product candidates performed satisfactorily in clinical trials have nonetheless failed to obtain marketing approval of their products.

Additionally, we expect that some of our trials will be open-label studies, where both the patient and investigator know whether the patient is receiving the investigational product candidate as a monotherapy or in combination with an existing approved drug. Most typically, open-label clinical trials test only the investigational product candidate and sometimes do so at different dose levels. Open-label clinical trials are subject to various limitations that may exaggerate any therapeutic effect as patients in open-label clinical trials are aware when they are receiving treatment. In addition, open-label clinical trials may be subject to an “investigator bias” where those assessing and reviewing the physiological outcomes of the clinical trials are aware of which patients have received treatment and may interpret the information of the treated group more favorably given this knowledge. Therefore, it is possible that positive results observed in open-label trials will not be replicated in later placebo-controlled trials.

In addition, the standards that the FDA and comparable foreign regulatory authorities use when regulating our product candidates require judgment and can change, which makes it difficult to predict with certainty how they will be applied. Although we are initially focusing our efforts on development of small-molecule drug products, we may in the future pursue development of biological products, which could make us subject to additional regulatory requirements. Any analysis we perform of data from preclinical and clinical activities is subject to confirmation and interpretation by regulatory authorities, which could delay, limit or prevent regulatory approval. We may also encounter unexpected delays or increased costs due to new government regulations. Examples of such regulations include future legislation or administrative action, or changes in FDA policy during the period of product development and FDA regulatory review. We cannot predict whether legislative changes will be enacted, or whether FDA or foreign regulations, guidance or interpretations will be changed, or what the impact of such changes, if any, may be. The FDA may also require a panel of experts, referred to as an Advisory Committee, to deliberate on the adequacy of the safety and efficacy data to support approval. The opinion of the Advisory Committee, although not binding, may have a significant impact on our ability to obtain approval of any product candidates that we develop.

We may seek to conduct clinical trials in foreign countries, as well as in the United States. If we continue to seek to conduct clinical trials in foreign countries or pursue marketing approvals in foreign jurisdictions, we must comply with numerous foreign regulatory requirements governing, among other things, the conduct of clinical trials, manufacturing and marketing authorization, pricing and third-party reimbursement. The foreign regulatory approval process varies among countries and may include all of the risks associated with FDA approval described above as

well as risks attributable to the satisfaction of local regulations in foreign jurisdictions. Moreover, the time required to obtain approval from foreign regulatory agencies may differ from that required to obtain FDA approval. Approval by the FDA does not ensure approval by regulatory authorities outside the United States and vice versa.

Successful completion of clinical trials is a prerequisite to submitting a marketing application to the FDA and similar marketing applications to comparable foreign regulatory authorities, for each product candidate and, consequently, the ultimate approval and commercial marketing of any product candidates. We may experience negative or inconclusive results, which may result in our deciding, or our being required by regulators, to conduct additional clinical studies or trials or abandon some or all of our product development programs, which could have a material adverse effect on our business.

We will likely need separate regulatory approvals for every therapeutic agent or combination of compounds that we intend to develop and market using our technology.

Although many drugs have been approved by the FDA for use as therapeutic agents, regulatory approval is likely required in the United States for the combined enhancer component with the drug component(s) and the specific indication, dose, and route of administration of the therapeutic agent or agents used in our system.

We will likely need to obtain separate regulatory approvals for products using our technology with every therapeutic agent or combination of compounds used with our system that we intend to market. All the manufacturing facilities used to manufacture components or assemble our system must be inspected and meet legal requirements. Securing regulatory approval requires the submission of extensive pre-clinical and clinical data and other supporting information for each proposed therapeutic indication to establish to the FDA’s satisfaction the product’s safety, efficacy, potency, and purity for each intended use. The pre-clinical testing and clinical trials of any products using our technology with any therapeutic agent or compound we use must comply with the regulations of the FDA and other federal, state, and local government authorities in the United States. Clinical development is a long, expensive, and uncertain process and is subject to delays. We may encounter delays or rejections for various reasons, including our inability to enroll enough patients to complete our clinical trials. Moreover, approval policies or regulations may change. If we do not obtain and maintain regulatory approval for our system and our use of therapeutic agents, our results of operations will be harmed.

Failure to obtain, or delay in obtaining, regulatory approvals would likely have a material adverse effect on our business, financial condition and results of operations.

During its development, our product candidates and technology will be subject to extensive and rigorous government regulation by the U.S. Food and Drug Administration (FDA) and possibly other foreign regulatory agencies. The FDA regulates the research, development, pre-clinical and clinical testing, manufacture, safety, effectiveness, record keeping, reporting, labeling, storage, approval, advertising, promotion, sale, distribution, import, and export of pharmaceutical and medical device products. Failure to comply with FDA and other applicable regulatory requirements, either before or after product approval, may subject us to administrative or judicially imposed sanctions.

We are not permitted to market products made using our technology in the United States unless and until we obtain regulatory approval from the FDA.

To market the product candidate in the United States, we must submit to the FDA and obtain FDA approval of a New Drug Application (NDA). An investigational new drug (IND) application is the first step in the regulatory process. Under an IND, a Company develops a drug in the hopes of someday submitting to FDA the NDA to permit marketing of the drug. An NDA must be supported by extensive clinical and preclinical data, as well as extensive information regarding chemistry, manufacturing, and controls (CMC) to demonstrate the safety and effectiveness of the applicable product candidate. Regulatory approval of an NDA is not guaranteed. The number and types of preclinical studies and clinical trials that will be required varies depending on the product candidate, the disease or condition that the product candidate is designed to target, and the regulations applicable to any product candidate. Despite the time and expense associated with preclinical and clinical studies, failure can occur at any stage and we could encounter problems that cause us to repeat or perform additional preclinical studies, CMC studies or clinical trials. The FDA and similar foreign authorities could delay, limit or deny approval of a product candidate for many reasons, including because they:

•        may not deem a product candidate to be adequately safe and effective;

•        may not find the data from preclinical studies, CMC studies, and clinical trials to be sufficient to support a claim of safety and efficacy;

•        may interpret data from preclinical studies, CMC studies, and clinical trials significantly differently than we do;

•        may not approve the manufacturing processes or facilities associated with our product candidates;

•        may change approval policies (including with respect to our product candidates’ class of drugs) or adopt new regulations; or

•        may not accept a submission due to, among other reasons, the content or formatting of the submission.

Delays in FDA approval could be costly to us and prevent us from commercializing our product candidates effectively.

The regulatory review and approval process is lengthy, expensive, and inherently uncertain. As part of the U.S. Prescription Drug User Fee Act, the FDA has a goal to review and act on a percentage of all submissions in a given time frame. The general review goal for a drug application is ten to twelve months for a standard application and six months for a priority review application. The FDA’s review goals are subject to change and it is unknown whether the review of an NDA filing for any of our product candidates will be completed within the FDA’s review goals or will be delayed. Moreover, the duration of the FDA’s review may depend on the number and types of other NDAs that are submitted to the FDA around the same time. The development and approval process may take many years, require substantial resources, and may never lead to the approval of a product. Failure to obtain or delays in obtaining regulatory approvals may:

•        adversely affect the commercialization of our current technology or any products that we develop in the future;

•        impose additional costs on us;

•        diminish any competitive advantages that may be attained; and

•        adversely affect our ability to generate revenues.

We have received one Fast Track Designation, and may continue to seek Breakthrough Therapy Designations or other Fast Track Designations from the FDA, for certain of our product candidates in certain indications, but receipt of either such designation may not actually lead to a faster development or regulatory review or approval process.

In 2018, we received Fast Track Designation by the FDA to use INT230-6 in metastatic triple negative breast cancer for patients whose cancer has progressed following one or two prior drug treatments. We may continue to seek Breakthrough Therapy Designation or Fast Track Designation for our product candidates or for other indications.

A breakthrough therapy is defined as a product that is intended, alone or in combination with one or more other products, to treat a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. For products that have been designated as breakthrough therapies, interaction and communication between the FDA and the sponsor of the trial can help to identify the most efficient path for clinical development while minimizing the number of patients placed in ineffective control regimens. Products designated as breakthrough therapies by the FDA can also be eligible for accelerated approval.

Designation as a breakthrough therapy is within the discretion of the FDA. Accordingly, even if we believe one of our product candidates meets the criteria for designation as a breakthrough therapy, the FDA may disagree and instead determine not to make such designation. In any event, the receipt of a Breakthrough Therapy Designation for a product candidate may not result in a faster development process, review or approval compared to products considered for approval under conventional FDA procedures and does not assure ultimate approval by the FDA. In addition, even if one or more of our product candidates qualify as breakthrough therapies, the FDA may later decide that the products no longer meet the conditions for qualification and rescind the breakthrough designation.

If a product is intended for the treatment of a serious or life-threatening condition and the product demonstrates the potential to address unmet medical needs for this condition, the product sponsor may apply for Fast Track Designation. The FDA has broad discretion whether or not to grant this designation, so even if we believe a particular product candidate is eligible for this designation, we cannot assure you that the FDA would decide to grant it. Even

though we have received Fast Track Designation to use INT230-6 in certain indications, or if we receive Fast Track Designation for other drug products or indications, we may not experience a faster development process, review or approval compared to conventional FDA procedures. The FDA may withdraw Fast Track Designation if it believes that the designation is no longer supported by data from our clinical development program.

If we encounter difficulties enrolling patients in our clinical trials, our clinical development activities could be delayed or otherwise adversely affected.

We may experience difficulties in patient enrollment in our clinical trials for a variety of reasons. The timely completion of clinical trials in accordance with their protocols depends, among other things, on our ability to enroll a sufficient number of patients who remain in the trial until its conclusion. The enrollment of patients depends on many factors, including:

•        the patient eligibility and exclusion criteria defined in the protocol;

•        the size of the patient population required for analysis of the trial’s primary endpoints;

•        the proximity of patients to trial sites;

•        the design of the trial;

•        our ability to recruit clinical trial investigators with the appropriate competencies and experience;

•        our ability to obtain and maintain patient consents; and

•        the risk that patients enrolled in clinical trials will drop out of the trials before completion.

In addition, our clinical trials will compete with other clinical trials for product candidates that are in the same therapeutic areas as our product candidates, and this competition will reduce the number and types of patients available to us, because some patients who might have opted to enroll in our trials may instead opt to enroll in a trial being conducted by one of our competitors. Since the number of qualified clinical investigators is limited, we expect to conduct some of our clinical trials at the same clinical trial sites that some of our competitors use, which will reduce the number of patients who are available for our clinical trials in such clinical trial site.

Delays in patient enrollment may result in increased costs or may affect the timing or outcome of our future clinical trials, which could prevent completion of these trials and adversely affect our ability to advance the development of our product candidates.

We will rely on third parties to conduct certain of the preclinical research and any clinical trials for products using our technology, and if those third parties perform in an unsatisfactory manner, it may harm our business.

We do not currently have the ability to independently conduct any clinical trials. We intend to rely on CROs and clinical trial sites to ensure the proper and timely conduct of our preclinical studies and clinical trials, and we expect to have limited influence over their actual performance. We rely upon CROs to monitor and manage data for our clinical programs, as well as the execution of future preclinical studies. We expect to control only certain aspects of our CROs’ activities. Nevertheless, we will be responsible for ensuring that each of our preclinical studies and clinical trials is conducted in accordance with the applicable protocol, legal, regulatory and scientific standards, and our reliance on the CROs does not relieve us of our regulatory responsibilities.

We and our CROs are required to comply with the good laboratory practices, or GLPs, and GCPs, which are regulations and guidelines enforced by the FDA and comparable foreign regulatory authorities in the form of International Conference on Harmonization guidelines for any of our product candidates that are in preclinical and clinical development. The regulatory authorities enforce GCPs through periodic inspections of trial sponsors, principal investigators and clinical trial sites. Although we rely on CROs to conduct GCP-compliant clinical trials, we remain responsible for ensuring that each of our GLP preclinical studies and clinical trials is conducted in accordance with its investigational plan and protocol and applicable laws and regulations. If we or our CROs fail to comply with GCPs, the clinical data generated in our clinical trials may be deemed unreliable, and the FDA or comparable foreign regulatory authorities may require us to perform additional clinical trials before approving our marketing applications. Accordingly, if our CROs fail to comply with these regulations or fail to recruit a sufficient number of subjects, we may be required to repeat clinical trials, which would delay the regulatory approval process.

Our reliance on third parties to conduct clinical trials will result in less direct control over the management of data developed through clinical trials than would be the case if we were relying entirely upon our own staff. Communicating with CROs and other third parties can be challenging, potentially leading to mistakes as well as difficulties in coordinating activities. Such parties may:

•        have staffing difficulties;

•        fail to comply with contractual obligations;

•        experience regulatory compliance issues; or

•        undergo changes in priorities or become financially distressed.

These factors may adversely affect the willingness or ability of third parties to conduct our clinical trials and may subject us to unexpected cost increases that are beyond our control. If our CROs do not successfully carry out their contractual duties or obligations, fail to meet expected deadlines, or fail to comply with regulatory requirements, or if the quality or accuracy of the clinical data they obtain is compromised due to the failure to adhere to our clinical protocols or regulatory requirements or for any other reasons, our clinical trials may be extended, delayed or terminated, and we may not be able to obtain regulatory approval for, or successfully commercialize, any product candidate that we develop. As a result, our financial results and the commercial prospects for any product candidate that we develop would be harmed, our costs could increase, and our ability to generate revenue could be delayed. While we will have agreements governing their activities, our CROs will not be our employees, and we will not control whether or not they devote sufficient time and resources to our future clinical and preclinical programs. These CROs may also have relationships with other commercial entities, including our competitors, for whom they may also be conducting clinical trials, or other drug development activities which could harm our business. We face the risk of potential unauthorized disclosure or misappropriation of our intellectual property by CROs, which may reduce our trade secret protection and allow our potential competitors to access and exploit our proprietary technology.

If our relationship with any of these CROs terminates, we may not be able to enter into arrangements with alternative CROs or do so on commercially reasonable terms. Switching or adding additional CROs involves substantial cost and requires management time and focus. In addition, there is a natural transition period when a new CRO commences work. As a result, delays occur, which can negatively impact our ability to meet our desired clinical development timelines. While we intend to carefully manage our relationships with our CROs, there can be no assurance that we will not encounter challenges or delays in the future or that these delays or challenges will not have a negative impact on our business, financial condition and prospects.

In addition, principal investigators for our clinical trials may serve as scientific advisors or consultants to us from time to time and receive compensation in connection with such services. Under certain circumstances, we may be required to report some of these relationships to the FDA. The FDA may conclude that a financial relationship between us and a principal investigator has created a conflict of interest or otherwise affected interpretation of the trial. The FDA may therefore question the integrity of the data generated at the applicable clinical trial site and the utility of the clinical trial itself may be jeopardized. This could result in a delay in approval, or rejection, of our marketing applications by the FDA and may ultimately lead to the denial of marketing approval of our product candidates.

Even if products using our technology are approved by the FDA or any other regulatory agency, we will be subject to additional ongoing regulatory obligations and oversight in the U.S. and other countries where we obtain approval.

For example, we may be subject to limitations on the approved indicated uses for which the product may be marketed or to the conditions of approval, or requirements for potentially costly post-marketing testing, including Phase 4 clinical trials, and surveillance to monitor the safety and efficacy of the product candidate. In addition, if the FDA approves a product candidate, the manufacturing processes, labeling, packaging, distribution, adverse event reporting, storage, advertising, promotion, and recordkeeping for the product will be subject to extensive and ongoing regulatory requirements. These requirements include submissions of safety and other post-marketing information and reports, registration, and continued compliance with FDA Current Good Manufacturing Processes (CGMPs), good clinical practices (GCPs), and good laboratory practices, which are regulations and guidelines enforced by the FDA for all products in clinical development and for any clinical trials that we conduct post-approval. In addition, post-marketing requirements for our product candidates may include implementation of a Risk Evaluation and Mitigation Strategies (REMS) to ensure that the benefits of the product outweigh its risks. A REMS may include a Medication Guide, a patient package insert, a communication plan to healthcare professionals, and/or other elements

to assure safe use of the product. Compliance with all these requirements, and any other requirements imposed upon us by U.S. or overseas regulators, could be costly to us, and failure to comply with these requirements could cause us to lose any marketing approval that we may have obtained, subject us to sanctions and jeopardize our ability to commercialize our product candidates.

Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with any third-party manufacturers or manufacturing processes, or failure to comply with regulatory requirements, may result in, among other things:

•        refusals or delays in the approval of applications or supplements to approved applications;

•        refusal of a regulatory authority to review pending market approval applications or supplements to approved applications;

•        restrictions on the marketing or manufacturing of the product, withdrawal of the product from the market or voluntary or mandatory product recalls or seizures;

•        fines, warning letters, or holds on clinical trials;

•        import or export restrictions;

•        injunctions or the imposition of civil or criminal penalties;

•        restrictions on product administration, requirements for additional clinical trials, or changes to product labeling, or REMS programs; or

•        recommendations by regulatory authorities against entering into governmental contracts with us.

Even if we obtain regulatory approval for our product candidates using our technology in the United States, our ability to market a product would be limited to those uses that are approved for that product.

The FDA closely regulates the post-approval marketing and promotion of drugs, including standards and regulations for direct-to-consumer advertising, dissemination of off-label information, industry-sponsored scientific and educational activities, and promotional activities involving the Internet. Drugs may be marketed only for the approved indications and in accordance with the provisions of the approved label. In the United States, we intend to seek approval for products for various types of cancer. If the FDA approves any drug application, our ability to market and promote a product would be limited to the indication tested for a specific disease, so even with FDA approval, products using our technology may only be promoted in this limited market. Physicians may prescribe legally available drugs for uses that are not described in the product’s labeling, and that differ from those tested by us and approved by the FDA. Such off-label uses are common across medical specialties, including oncology. Physicians may believe that such off-label uses are the best treatment for many patients in varied circumstances. The FDA does not regulate the behavior of physicians in their choice of treatments. The FDA does, however, impose stringent restrictions on manufacturers’ communications regarding promotion of approved drug products for off-label use, and FDA approval may otherwise limit our sales practices and our ability to promote, sell, and distribute a product. Thus, we may only market products using our technology, if approved by the FDA, for its approved indication and we could be subject to enforcement action for off-label marketing.

Further, if there are any modifications to an approved product, including changes in indications, labeling, or manufacturing processes or facilities, we may be required to submit and obtain FDA approval of a new or supplemental NDA, which may require us to develop additional data or conduct additional preclinical studies and clinical trials. Failure to comply with these requirements can result in regulatory enforcement actions and adverse publicity.

If future clinical trials are unsuccessful, significantly delayed or not completed, we may not be able to market products for other indications or our technology.

If we do not obtain required approvals in other countries in which we aim to market our product candidates, we will not be able to export or sell the products in those markets, which will limit our sales opportunities.

Obtaining and maintaining regulatory approval of our product candidates in one jurisdiction does not guarantee that we will be able to obtain or maintain regulatory approval in any other jurisdiction, while a failure or delay in obtaining regulatory approval in one jurisdiction may have a negative effect on the regulatory approval process in others. For example, even if the FDA grants marketing approval of a product candidate, similar foreign regulatory authorities must also approve the manufacturing, marketing and promotion of the product candidate in those countries.

Approval and licensure procedures vary among jurisdictions and can involve requirements and administrative review periods different from, and greater than, those in the United States, including additional preclinical studies or clinical trials as clinical trials conducted in one jurisdiction may not be accepted by regulatory authorities in other jurisdictions.

Our lack of experience conducting clinical trials outside the United States and Canada may negatively impact the approval process in foreign countries where we intend to seek approval for the products using our technology. We have not previously conducted multi-national clinical trials.

If we are unable to obtain and maintain required approval from one or more foreign jurisdictions where we would like to sell products using our technology, we will be unable to market products as intended, our international market opportunity will be limited, and our results of operations will be harmed.

If no product candidates using our technology are approved by the FDA or other regulatory body, third-party payors in the United States or anywhere will not reimburse the use of our product candidates. Even if approval is obtained, inadequate reimbursement may harm results of operations.

Following regulatory approval, we intend to seek reimbursement by third-party payors for the products created by our technology. There are no assurances that third-party payors in the United States or other countries will agree to cover the cost of products using our technology at all or at rates that are adequate to cover actual costs. Further, third-party payors may deny reimbursement if they determine that our product candidates are not used in accordance with established payor protocols regarding cost effective treatment methods or are used outside their approved indication or for forms of cancer not specifically approved by the FDA or other foreign regulatory bodies in the future. Without reimbursement, physicians, hospitals, and other healthcare providers may be less likely to prescribe our product candidates thereby harming our results of operations. Without adequate reimbursement, we may not be able to successfully commercialize systems.

Risks Related to Manufacturing, Commercialization, and Market Acceptance of Products made using our Technology

We intend to rely on third parties to produce clinical and commercial supplies of our product candidates.

We do not own or operate facilities for drug manufacturing, storage and distribution, or testing. We are dependent on third parties to manufacture the clinical supplies of our current and any future product candidates. The facilities used by our contract manufacturers to manufacture our product candidates must be approved by the FDA pursuant to inspections that will be conducted after we submit our NDA to the FDA. We do not control the manufacturing process of, and are completely dependent on, our contract manufacturing partners for compliance with the cGMP requirements, for manufacture of both active drug substance and finished drug product. If our contract manufacturers cannot successfully manufacture material that conforms to our specifications and the strict regulatory requirements of the FDA or others, we will not be able to secure and/or maintain regulatory approval for our product candidates. In addition, we have no control over the ability of our contract manufacturers to maintain adequate quality control, quality assurance and qualified personnel. If the FDA or a comparable foreign regulatory authority does not approve these facilities for the manufacture of our product candidates or if it withdraws any such approval in the future, we may need to find alternative manufacturing facilities, which would significantly impact our ability to develop, obtain regulatory approval for or market our product candidates, if approved. Any significant delay in the supply of a product candidate, or the raw material components thereof, for an ongoing clinical trial due to the need to replace a third-party manufacturer could considerably delay completion of our clinical trials, product testing and potential regulatory approval of our product candidates.

We also intend to rely on third-party manufacturers to supply us with sufficient quantities of our product candidates to be used, if approved, for commercialization. We do not yet have a commercial supply agreement for commercial quantities of drug substance or drug product. If we are not able to meet market demand for any approved product, it would negatively impact our ability to generate revenue, harm our reputation, and could have an adverse effect on our business and financial condition.

Further, our reliance on third-party manufacturers entails risks to which we would not be subject if we manufactured product candidates ourselves, including:

•        inability to meet our product specifications and quality requirements consistently;

•        delay or inability to procure or expand sufficient manufacturing capacity;

•        issues related to scale-up of manufacturing;

•        costs and validation of new equipment and facilities required for scale-up;

•        our third-party manufacturers may not be able to execute our manufacturing procedures and other logistical support requirements appropriately;

•        our third-party manufacturers may fail to comply with cGMP requirements and other inspections by the FDA or other comparable regulatory authorities;

•        our inability to negotiate manufacturing agreements with third parties under commercially reasonable terms, if at all;

•        breach, termination or nonrenewal of manufacturing agreements with third parties in a manner or at a time that is costly or damaging to us;

•        reliance on single sources for drug components;

•        lack of qualified backup suppliers for those components that are currently purchased from a sole or single-source supplier;

•        our third-party manufacturers may not devote sufficient resources to our product candidates;

•        we may not own, or may have to share, the intellectual property rights to any improvements made by our third-party manufacturers in the manufacturing process for our product candidates;

•        operations of our third-party manufacturers or suppliers could be disrupted by conditions unrelated to our business or operations, including the bankruptcy of the manufacturer or supplier; and

•        carrier disruptions or increased costs that are beyond our control.

In addition, if we enter into a strategic collaboration with a third party for the commercialization of our current or any future product candidates, we will not be able to control the amount of time or resources that they devote to such efforts. If any strategic collaborator does not commit adequate resources to the marketing and distribution of our product candidates, it could limit our potential revenues.

Any of these events could lead to clinical trial delays or failure to obtain regulatory approval, or impact our ability to successfully commercialize our current or any future product candidates once approved. Some of these events could be the basis for FDA action, including injunction, request for recall, seizure, or total or partial suspension of production.

We purchase components for our product candidates from third parties, some of which may be sole-source suppliers.

Our product candidate is comprised of three key ingredients, the excipient (referred to as SHAO) and two active, commercially available pharmaceutical ingredients cisplatin and vinblastine sulphate. Currently each of the three ingredients and our product candidate are single sourced. While we are aware of other suppliers for the two active ingredients, those suppliers have not been qualified as yet. We also have identified other producers of both the SHAO excipient and the product candidate. We manufacture SHAO using Curia in Albany, New York and INT230-6 at Curia in Glasgow, Scotland. We have only qualified Curia to produce SHAO and INT230-6 at this time. We control the manufacturing processes for SHAO and INT230-6, and we have all information on the production of the molecule and product candidate; however, it would take several months to qualify a new supplier or suppliers. We purchase the cisplatin from Johnson Matthey in West Deptford, New Jersey. Johnson Matthey is the developer of cisplatin and one of the world’s largest producer of cisplatin. We have only qualified Johnson Matthey. We purchase vinblastine sulphate from Minakem located in Mont-Saint-Guibert, Belgium. We have only qualified Minakem as a supplier of our vinblastine sulphate. It would take several months to quality new vendors for cisplatin and vinblastine sulfate.

We rely and expect to continue to rely completely on third parties to manufacture key components of our preclinical, clinical trial and commercial product candidate supplies. The development and commercialization of any of our product candidates could be stopped, delayed or made less profitable if those third parties fail to provide us with sufficient quantities of such product supplies or fail to do so at acceptable quality levels, including in accordance with applicable regulatory requirements or contractual obligations, and our operations could be harmed as a result. The components of our product candidates, including enhancers, drugs, and excipients, must be manufactured and assembled in accordance with approved manufacturing and predetermined performance specifications and must meet CGMP and quality systems requirements. Some states also have similar regulations. Many of the other components of our product candidates may

be manufactured by sole-source suppliers that may have proprietary manufacturing processes. If we need to find a new source of supply, we may face long interruptions in obtaining necessary components for our product candidates, in obtaining FDA or foreign regulatory agency approval of these components and in establishing the manufacturing process, which could jeopardize our ability to supply products using our technology to the market.

We have not entered into long term manufacturing and supply agreements with any producers.

We intend to pursue agreements with contract manufacturers to produce the components and drug products that we will use in the future for the commercialization of products that make using of our technology, as well as for labeling and finishing services. We may not be able to enter into such arrangements on acceptable terms or at all. Components of our product candidates are currently manufactured for us in small quantities for use in our preclinical and clinical studies. We will require significantly greater quantities to commercialize any given product. We may not be able to find alternate sources of comparable components. If we are unable to obtain adequate supplies of components from our existing suppliers or need to switch to an alternate supplier and obtain FDA or other regulatory agency approval of that supplier, commercialization of our product candidates may be delayed. If we are unable to obtain sufficient compounds and labeling services on acceptable terms, or if we should encounter delays or difficulties in our relationships with our current and future suppliers or if our current and future suppliers of each component do not comply with applicable regulations for the manufacturing and production of drugs, our business, financial condition, and results of operations may be materially harmed.

If we cannot successfully purchase or produce the drugs used in the manufacture of our product candidates, our ability to develop and commercialize products using our technology would be impaired.

To manufacture the therapeutic agents on our own, we would first have to develop a manufacturing facility that complies with FDA requirements and regulations to produce each therapeutic agent we choose to manufacture. Developing these resources would be an expensive and lengthy process and would have a material adverse effect on our revenues and profitability. We have no manufacturing history and we may not be able to scale up or demonstrate manufacture of commercial quantities, in a cost-effective manner, or in compliance with the regulatory requirements applicable to such manufacturing. Additionally, we may have difficulty obtaining other components for the system from our third-party suppliers in a timely manner or at all which may adversely affect our ability to conduct timely clinical trials in the United States and elsewhere to obtain regulatory approval, and our ability to deliver our product candidates to purchasers.

Our current and future relationships with investigators, health care professionals, consultants, third-party payors, and customers will be subject to applicable healthcare regulatory laws, which could expose us to penalties.

Our business operations and current and future arrangements with investigators, healthcare professionals, consultants, third-party payors, patient support, charitable organizations and customers may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations. These laws regulate the business or financial arrangements and relationships through which we conduct our operations, including how we research, market, sell, and distribute our product candidates for which we obtain marketing approval. Such laws include, among others: he federal Anti-Kickback Statute, the federal false claims laws, including the False Claims Act, the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, or HITECH, and their implementing regulations, the federal Physician Payments Sunshine Act, federal consumer protection and unfair competition laws and analogous state and foreign laws and regulations, such as state antikickback and false claims laws, which may apply to our business practices. For additional information regarding the regulatory regime under which we operate, see “Business — Government Regulation.”

Efforts to ensure that our current and future business arrangements with third parties will comply with applicable healthcare laws and regulations will involve substantial costs. It is possible that governmental authorities will conclude that our business practices do not comply with current or future statutes, regulations, agency guidance or case law involving applicable healthcare laws. If our operations are found to be in violation of any of these or any other health regulatory laws that may apply to us, we may be subject to significant penalties, including the imposition of significant civil, criminal and administrative penalties, damages, monetary fines, disgorgement, individual imprisonment, possible exclusion from participation in Medicare, Medicaid and other federal healthcare programs or similar programs in other countries or jurisdictions, contractual damages, reputational harm, diminished profits and future earnings, additional reporting requirements and oversight if we become subject to a corporate integrity agreement or similar agreement and curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our

legislative amendments to the statute, will remain in effect through 2029 unless additional Congressional action is taken. The Coronavirus Aid, Relief, and Economic Security Act, or CARES Act, which was signed into law on March 27, 2020, designed to provide financial support and resources to individuals and businesses affected by the COVID-19 pandemic, suspended these reductions from May 1, 2020 through December 31, 2020, and extended the sequester by one year, through 2030. In addition, in January 2013, the American Taxpayer Relief Act of 2012 was signed into law, which, among other things, further reduced Medicare payments to several providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years. Additionally, on March 11, 2021, President Biden signed the American Rescue Plan Act of 2021 into law, which eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single-source and innovator multiple-source drugs, beginning January 1, 2024. These laws may result in additional reductions in Medicare, Medicaid and other healthcare funding.

Moreover, payment methodologies may be subject to changes in healthcare legislation and regulatory initiatives. For example, CMS may develop new payment and delivery models, such as bundled payment models. In addition, recently there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their commercial products, which has resulted in several Congressional inquiries and proposed and enacted state and federal legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for pharmaceutical products. For example, on July 24, 2020 and September 13, 2020, the Trump administration announced several executive orders related to prescription drug pricing and importation. As a result, the FDA also released a final rule in September 2020, effective November 30, 2020, providing guidance for states to build and submit importation plans for drugs from Canada. Further, in November 2020, the U.S. Department of Health and Human Services, or HHS, finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law. The implementation of the rule has been delayed by the Biden administration from January 1, 2022 to January 1, 2023 in response to ongoing litigation. The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers, the implementation of which have also been delayed by the Biden administration until January 1, 2023. The CMS also issued an interim final rule that establishes a Most Favored Nation, or MFN, Model for Medicare Part B drug payments. This regulation would substantially change the reimbursement landscape as it bases Medicare Part B payment for 50 selected drugs on prices in foreign countries instead of average sales prices (ASP) and establishes a fixed add-on payment in place of the current 6 percent (4.3 percent after sequestration) of ASP. The MFN drug payment amount is expected to be lower than the current ASP-based limit because U.S. drug prices are generally the highest in the world. On December 28, 2020, the U.S. District Court in Northern California issued a nationwide preliminary injunction against implementation of the interim final rule. On January 13, 2021, in a separate lawsuit brought by industry groups in the U.S. District Court for the District of Maryland, the government defendants entered a joint motion to stay litigation on the condition that the government would not appeal the preliminary injunction granted in the U.S. District Court for the Northern District of California and that performance for any final regulation stemming from the MFN Model interim final rule shall not commence earlier than sixty (60) days after publication of that regulation in the Federal Register. In December 2020, CMS issued a final rule implementing significant manufacturer price reporting changes under the Medicaid Drug Rebate Program, including regulations that affect manufacturer-sponsored patient assistance programs subject to pharmacy benefit manager accumulator programs and Best Price reporting related to certain value-based purchasing arrangements. On May 21, 2021, an industry group sued CMS, claiming that the change to the Best Price rule exceeds CMS’s statutory authority and is contrary to the Medicaid Rebate statute. This litigation is ongoing. It is unclear to what extent these new regulations will be implemented and to what extent these regulations or any future legislation or regulations by the Biden administration will have on our business, including our ability to generate revenue and achieve profitability.

Outside the United States, ensuring coverage and adequate payment for a product also involves challenges. Pricing of prescription pharmaceuticals is subject to government control in many countries. Pricing negotiations with government authorities can extend well beyond the receipt of regulatory approval for a product and may require a clinical trial that compares the cost-effectiveness of a product to other available therapies. The conduct of such a clinical trial could be expensive and result in delays in commercialization.

In the European Union, pricing and reimbursement schemes vary widely from country to country. Some countries provide that products may be marketed only after a reimbursement price has been agreed. Some countries may require the completion of additional studies that compare the cost-effectiveness of a particular product candidate to currently available therapies or so-called health technology assessments, in order to obtain reimbursement or pricing approval. For example, the European Union provides options for its member states to restrict the range of products for which their

national health insurance systems provide reimbursement and to control the prices of medicinal products for human use. European Union member states may approve a specific price for a product or they may instead adopt a system of direct or indirect controls on our profitability for placing the product on the market. Other member states allow companies to fix their own prices for products, but monitor and control prescription volumes and issue guidance to physicians to limit prescriptions. Recently, many countries in the European Union have increased the amount of discounts required on pharmaceuticals and these efforts could continue as countries attempt to manage healthcare expenditures, especially in light of the severe fiscal and debt crises experienced by many countries in the European Union.

We expect that these and other healthcare reform measures that may be adopted in the future may result in more rigorous coverage criteria and in additional downward pressure on the price that we receive for any approved drug, which could have an adverse effect on demand for our product candidates. Any reduction in reimbursement from Medicare or other government programs may result in a similar reduction in payments from private payors. The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability or commercialize our product candidates. For additional information on healthcare reform, see “Business — Government Regulation — Healthcare reform.”

Rapid technological developments in treatment methods for cancer and competition with other forms of cancer treatments could affect our ability to achieve meaningful revenues or profit.

Competition in the cancer treatment industry is intense. Products made using our technology will compete with all forms of cancer treatments that are alternatives to the “gold standard” treatment of surgical resection. Many of our competitors have substantially greater resources and considerable experience in conducting clinical trials and obtaining regulatory approvals. If these competitors develop more effective, more affordable products, or if treatment methods achieve earlier product development, our revenues or profitability will be substantially reduced.

The loss of key personnel could adversely affect our business.

The loss of any of our key members could delay our ability to develop the technology, conduct preclinical research, conduct clinical research, obtain FDA approval, or introduce products using our technology commercially and, ultimately, our ability to generate revenues and profits. Competition for experienced personnel is intense. If we cannot retain our current personnel or attract additional experienced personnel, our ability to compete could be adversely affected.

We are dependent on the services of our Chief Executive Officer, Lewis H. Bender, for the future success of our business. The loss of the services of Mr. Bender could have an adverse effect on our business, financial condition and results of operations. If that should occur, until we find another person to act as our chief executive officer, our operations could be suspended. In that event it is possible you could lose your entire investment.

Two of our Executive Officers are engaged in other business activities and have a conflict in determining how much time to devote to our affairs. Their failure to devote sufficient time to our business could have a negative impact on our operations.

Two of our executive officers, Rebecca Drain, our Vice President of Regulatory Affairs and Quality, and Dr. Ian B. Walters, our Vice President and Chief Medical Officer, had their employment agreements terminated during fiscal year 2022. Ms. Drain signed a consulting agreement, pursuant to which she is obligated to spend no more than four hours per week working for us. We are currently negotiating a services agreement pursuant to which we anticipate Dr. Walters will dedicate up to three hours of his time per week to providing services to the Company. Neither Ms. Drain nor Dr. Walters are required to, and will not, commit full time to our affairs.

Ms. Drain and Dr. Walters are engaged in several other business endeavors. These other engagements result in a conflict of interest in allocating their time between our operations and the other businesses in which they are engaged. Their failure to devote time to our business could have an adverse impact on our business, results of operations and financial condition. It is possible that the demands on Ms. Drain and Dr. Walters from other obligations could increase with the result that they would no longer be able to devote sufficient time to the management of our business. In addition, Ms. Drain and Dr. Walters may not be able to allocate sufficient time for conducting our business if the demands of managing our business increase substantially beyond current levels. In addition, Ms. Drain’s and Dr. Walters’ engagements may result in other conflicts of interest between their obligations to the Company and our shareholders and their other obligations. Should such conflicts arise, there can be no assurance that Ms. Drain or Dr. Walters would act in the best interest of the Company, or that any of these conflicts would be resolved in a manner favorable to the Company and our shareholders.

Risks Related to Patents, Trade Secrets, and Proprietary Rights

Our success depends in part on our ability to obtain patents, maintain trade secret protection, operate without infringing on the proprietary rights of third parties, and commercialize our technology prior to the expiration of our patent protection.

We have three U.S. patents and one pending U.S. patent application. We have 12 foreign patents, including one European patent, validated in 27 countries. We have four pending foreign patent applications. We have registered trademarks and know-how. While we have patents and filed patent applications covering composition of matter, use and methods, only 15 patents have issued. Due to the uncertainty of the patent prosecution process, there are no guarantees that our pending patent applications or any future applications will result in the issuance of a patent. Even if we are successful in obtaining more U.S. patents and new patents in other countries, there is no assurance that our patents will be upheld if later challenged or will provide significant protection or commercial advantage. For example, given the uncertain situation in Eastern Europe, we cannot assure that our Russian patent will not be lost, given that payments necessary to maintain the patent may be unavailable in future years without the risk of international sanctions. Because of the length of time and expense associated with bringing new medical drugs and devices to the market, the healthcare industry has traditionally placed considerable emphasis on patent and trade secret protection for significant new technologies. Other parties may challenge our patents, patent claims or patent applications licensed or issued to us or may design around technologies we have patented, licensed or developed.

Patent terms may be inadequate to protect our competitive position on our product candidates for an adequate amount of time.

Patents have a limited lifespan. In the United States, if all maintenance fees are timely paid, the natural expiration of a patent is generally 20 years from its earliest U.S. non-provisional filing date. Various extensions such as patent term adjustments and/or extensions, may be available, but the life of a patent, and the protection it affords, is limited. Even if patents covering our product candidates are obtained, once the patent life has expired, we may be open to competition from competitive products, including biosimilars. Given the amount of time required for the development, testing and regulatory review of new product candidates, patents protecting such candidates might expire before or shortly after such candidates are commercialized. As a result, our owned and licensed patent portfolio may not provide us with sufficient rights to exclude others from commercializing products similar or identical to ours.

If we do not obtain patent term extension and data exclusivity for any product candidates we may develop, our business may be materially harmed.

Depending upon the timing, duration and specifics of any FDA marketing approval of any product candidates we may develop, one or more of our U.S. patents may be eligible for limited patent term extension under the Drug Price Competition and Patent Term Restoration Action of 1984 Hatch-Waxman Amendments. The Hatch-Waxman Amendments permit a patent extension term of up to five years as compensation for patent term lost during the FDA regulatory review process. A patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval, only one patent may be extended and only those claims covering the approved drug, a method for using it, or a method for manufacturing it may be extended. However, we may not be granted an extension because of, for example, failing to exercise due diligence during the testing phase or regulatory review process, failing to apply within applicable deadlines, failing to apply prior to expiration of relevant patents, or otherwise failing to satisfy applicable requirements. Moreover, the applicable time period or the scope of patent protection afforded could be less than we request. If we are unable to obtain patent term extension or term of any such extension is less than we request, our competitors may obtain approval of competing products following our patent expiration, and our business, financial condition, results of operations, and prospects could be materially harmed.

Companies in the medical drug/device industry may use intellectual property infringement litigation to gain a competitive advantage.

In the United States, patent applications filed in recent years are confidential for 18 months, while older applications are not publicly available until the patent issues. As a result, even after the products using our technology are introduced to the market, there is no guarantee that we will be able to avoid patent infringement claims, whether such claims are ultimately held to have merit. Litigation may be necessary to enforce any patents issued or assigned

to us or to determine the scope and validity of third-party proprietary rights. Litigation could be costly and could divert our attention from our business. There are no guarantees that we will receive a favorable outcome in any such litigation. If a third-party claims that we infringed its patents, any of the following may occur:

•        we may become liable for substantial damages for past infringement if a court decides that our product candidates infringe upon a competitor’s patent;

•        a court may prohibit us from selling or licensing our product candidates without a license from the patent holder, which may not be available on commercially acceptable terms or at all, or which may require us to pay substantial royalties or grant cross-licenses to our patents; and

•        we may have to redesign our product candidate so that it does not infringe upon others’ patent rights, which may not be possible or could require substantial funds or time.

If a third party violates our intellectual property rights, we may be unable to enforce our rights because of our limited resources.

Use of our limited funds to enforce or to defend our intellectual property rights or to defend against legal proceedings alleging infringement of third party proprietary rights may also affect our financial condition adversely. If others file patent applications with respect to inventions for which we already have applications pending, we may be forced to participate in interference proceedings declared by the U.S. Patent and Trademark Office to determine priority of invention, which could also be costly and could divert our attention from our business. Because of the extensive time required for development, testing and regulatory review of a potential product, it is possible that, before the any product can be commercialized, any related patent may expire or remain in force for only a short period following commercialization, thereby reducing any advantages of the patent. Not all our U.S. patent rights will have corresponding patent rights effective in Europe or other foreign jurisdictions.

Similar considerations will apply in any other country where we may prosecute patent applications, may be issued patents, or may decide not to pursue patent protection relating to our technology. The laws of foreign countries may not protect our intellectual property rights to the same extent as do laws of the United States.

We protect our trade secrets and proprietary knowledge in part through confidentiality agreements with employees, consultants, and other parties. However, certain consultants, advisors and third parties with whom we have business relationships, and to whom in some cases we have disclosed or will disclose trade secrets and other proprietary knowledge, may also provide services to other parties in the medical device industry, including companies, universities, and research organizations that are developing competing products.

In addition, some employees may eventually seek employment with, and become employed by, our competitors. We cannot be assured that consultants, employees, and other third parties with whom we have entered into confidentiality agreements will not breach the terms of such agreements by improperly using or disclosing our trade secrets or other proprietary knowledge or that we will have adequate remedies for any such breach.

Trade secret protection does not prevent independent discovery of the technology or proprietary information or use of the same.

Competitors may independently duplicate or exceed our technology in whole or in part. If we are not successful in maintaining the confidentiality of our technology, the loss of trade secret protection or know-how relating to our technology will significantly impair our ability to commercialize our product candidates, and our value and results of operations will be harmed. Similar considerations apply in any other foreign country where we receive approval. Since we do not yet have valid issued patents for the products using our technology in some countries, our ability to successfully commercialize our technology in those countries may be harmed.

Risks Related to Products Liability

We may be the subject of product liability claims or product recalls, and we may be unable to maintain insurance adequate to cover potential liabilities.

Our business exposes us or may in the future expose us to potential liability risks that may arise from the testing, manufacture, marketing, sale and use of products using our technology. In addition, because certain products using the new technology are intended for use in patients with cancer, there is an increased risk of death among the patients treated with our system which may increase the risk of product liability lawsuits. We may be subject to claims

against us even if the injury is due to the actions of others. For example, if the medical personnel that use our product candidates on patients are not properly trained or are negligent in the use of our product candidates, the patient may be injured through the use of our product candidates, which may subject us to claims. Were such a claim asserted we would likely incur substantial legal and related expenses even if we prevail on the merits. Claims for damages, whether or not successful, could cause delays in clinical trials and result in the loss of physician endorsement, adverse publicity and/or limit our ability to market and sell the system, resulting in loss of revenue. In addition, it may be necessary for us to recall products that do not meet approved specifications, which would also result in adverse publicity, as well as resulting in costs connected to the recall and loss of revenue. A successful products liability claim, or product recall would have a material adverse effect on our business, financial condition and results of operations. We currently carry product liability and clinical trial insurance coverage, but it may be insufficient to cover one or more large claims.

Risks Related to Our Securities and This Offering

If our listing application for our Common Stock is not approved by Nasdaq, we will not be able to consummate the offering and will terminate this offering.

We have applied to have our Common Stock listed on Nasdaq under the symbol “INTS,” which listing is a condition to this offering. No assurance can be given that our application will be approved and that our Common Stock will ever be listed on Nasdaq. If our listing application is not approved by Nasdaq, we will not be able to consummate the offering and will terminate this offering. Failure to have our Common Stock listed on Nasdaq would make it more difficult for our stockholders to dispose of our Common Stock and more difficult to obtain accurate price quotations on our Common Stock. Our ability to issue additional securities for financing or other purposes, or otherwise to arrange for any financing we may need in the future, may also be materially and adversely affected if our Common Stock is not traded on a national securities exchange.

We are an “emerging growth company” as defined in the JOBS Act and a “smaller reporting company” as defined in the Securities Exchange Act of 1934, as amended, or the Exchange Act, and will be able to avail ourselves of reduced disclosure requirements applicable to emerging growth companies and smaller reporting companies, which could make our securities less attractive to investors and adversely affect the market price of our securities.

We are an “emerging growth company,” as defined in the Jumpstart Our Business Startups Act of 2012, or the JOBS Act. We will remain an emerging growth company until the earlier of (i) the last day of the fiscal year in which we have total annual gross revenues of $1.07 billion or more; (ii) the last day of the fiscal year following the fifth anniversary of the date of the completion of this offering; (iii) the date on which we have issued more than $1 billion in nonconvertible debt during the previous three years; or (iv) the date on which we are deemed to be a large accelerated filer under the rules of the Securities and Exchange Commission, which means the market value of our Common Stock that is held by non-affiliates exceeds $700 million as of the prior June 30. For so long as we remain an emerging growth company, we are permitted and intend to rely on exemptions from certain disclosure requirements that are applicable to other public companies that are not emerging growth companies. These exemptions include:

•        not being required to comply with the auditor attestation requirements of Section 404 of the Sarbanes-Oxley Act of 2002, or Section 404;

•        not being required to comply with any requirement that may be adopted by the Public Company Accounting Oversight Board regarding mandatory audit firm rotation or a supplement to the auditor’s report providing additional information about the audit and the financial statements;

•        providing only two years of audited financial statements in addition to any required unaudited interim financial statements and a correspondingly reduced “Management’s Discussion and Analysis of Financial Condition and Results of Operations” disclosure;

•        reduced disclosure obligations regarding executive compensation; and

•        exemptions from the requirements of holding a nonbinding advisory vote on executive compensation and shareholder approval of any golden parachute payments not previously approved. In this prospectus, we have not included all of the executive compensation-related information that would be required if we were not an emerging growth company.

We may choose to take advantage of some, but not all, of the available exemptions. We have taken advantage of reduced reporting burdens in this prospectus. In particular, we have provided only two years of audited financial statements and have not included all of the executive compensation information that would be required if we were not

an emerging growth company. We cannot predict whether investors will find our securities less attractive if we rely on these exemptions. If some investors find our securities less attractive as a result, there may be a less active trading market for our securities and the price of our securities may be more volatile.

In addition, the JOBS Act provides that an emerging growth company can take advantage of an extended transition period for complying with new or revised accounting standards. This allows an emerging growth company to delay the adoption of certain accounting standards until those standards would otherwise apply to private companies. We have elected to use the extended transition period for new or revised accounting standards during the period in which we remain an emerging growth company; however, we may adopt certain new or revised accounting standards early.

We are also a “smaller reporting company” as defined in the Exchange Act. We may continue to be a smaller reporting company even after we no longer qualify as an emerging growth company. We may take advantage of certain of the scaled disclosures available to smaller reporting companies until the fiscal year following the determination that our voting and non-voting Common Stock held by non-affiliates is more than $250 million measured on the last business day of our second fiscal quarter, or our annual revenues are more than $100 million during the most recently completed fiscal year and our voting and non-voting Common Stock held by non-affiliates is more than $700 million measured on the last business day of our second fiscal quarter.

So long as we qualify as an “emerging growth company” or a “smaller reporting company,” we may elect not to provide you with certain information, including certain financial information and certain information regarding compensation of our executive officers, that we would otherwise have been required to provide in filings we make with the SEC, which may make it more difficult for investors and securities analysts to evaluate our company. Further, as mentioned above, so long as we qualify as an “emerging growth company” our independent registered public accounting firm will not be required to provide an attestation report on the effectiveness of our internal control over financial reporting, which may increase the risk that material weaknesses or significant deficiencies in our internal control over financial reporting go undetected. We cannot predict if investors will find our securities less attractive because we may rely on these exemptions. If some investors find our securities less attractive as a result, there may be a less active trading market for our securities, and the price of our securities may be more volatile and may decline.

Substantial influence will remain with our management and major stockholder, which could delay or prevent a change of control or cause us to take actions in conflict with the intent of our stockholders.

Immediately following the completion of this offering, and disregarding any shares of Common Stock that they purchase in this offering, the existing holdings of our executive officers, directors, principal stockholders and their affiliates will represent beneficial ownership, in the aggregate, of up to approximately 69% of our outstanding Common Stock. We anticipate that our President and CEO will be our largest overall shareholder following the completion of this offering, beneficially owning up to approximately 25% of our outstanding Common Stock. These stockholders, if they act together, will be able to influence our management and affairs and the outcome of matters submitted to our stockholders for approval, including the election of directors and any merger, consolidation or sale of all or substantially all of our assets. These stockholders acquired their shares of Common Stock for substantially less than the price of the shares of Common Stock being acquired in this offering, and these stockholders may have interests with respect to their Common Stock that are different from those of investors in this offering. The concentration of voting power among these stockholders may have an adverse effect on the price of our Common Stock.

An active trading market for our securities may not develop, and you may not be able to resell your shares at or above the initial public offering price.

Prior to this offering, there has been no public market for shares of our Common Stock. Although we anticipate that our Common Stock will be approved for listing on The Nasdaq Capital Market, or Nasdaq, an active trading market for our shares may never develop or be sustained following this offering. The initial public offering price of our Common Stock will be determined through negotiations between us and the underwriters. This initial public offering price may not be indicative of the market price of our Common Stock after this offering. In the absence of an active trading market for our Common Stock, investors may not be able to sell their Common Stock at or above the initial public offering price or at the time that they would like to sell.

The price of our Common Stock may be volatile and fluctuate substantially, which could result in substantial losses for purchasers of our Common Stock in this offering.

Our stock price is likely to be volatile. The stock market in general and the market for biotechnology companies in particular have experienced extreme volatility. Due to our history of losses as well as a variety of factors, many of which are outside of our control and may be difficult to predict, our quarterly and annual operating results may fluctuate

significantly in the future. This variability and unpredictability could also result in our failing to meet the expectations of industry or financial analysts or investors for any period. If our revenue or operating results fall below the expectations of analysts or investors or below any forecasts we may provide to the market, or if the forecasts we provide to the market are below the expectations of analysts or investors, the price of our Common Stock could decline substantially.

Further, investors in our Common Stock may experience a decrease, which could be substantial, in the value of their stock for reasons unrelated to our operating performance or prospects, and could lose part or all of their investment. The price of our Common Stock could be subject to wide fluctuations in response to a number of factors, including those described elsewhere in this prospectus and others such as:

•        variations in our operating performance and the performance of our competitors;

•        actual or anticipated fluctuations in our quarterly or annual operating results;

•        publication of research reports by securities analysts about us or our competitors or our industry;

•        announcements by us, our competitors or our vendors of significant contracts, acquisitions, joint marketing relationships, joint ventures or capital commitments;

•        our failure or the failure of our competitors to meet analysts’ projections or guidance that we or our competitors may give to the market;

•        additions and departures of key personnel;

•        strategic decisions by us or our competitors, such as acquisitions, divestitures, spin-offs, joint ventures, strategic investments or changes in business strategy;

•        the passage of legislation or other regulatory developments affecting us or our industry;

•        speculation in the press or investment community;

•        changes in accounting principles;

•        terrorist acts, acts of war or periods of widespread civil unrest;

•        natural disasters and other calamities; and

•        changes in general market and economic conditions.

As a result of this volatility, you may not be able to sell your Common Stock at or above the initial public offering price.

If you purchase our Common Stock in this offering, you will incur immediate and substantial dilution in the book value of your shares.

You will suffer immediate and substantial dilution in the net tangible book value of the Common Stock you purchase in this offering. Based on the initial public offering price of $4.50 per share, purchasers of Common Stock in this offering will experience immediate dilution of $4.21 per share in net tangible book value of the Common Stock, assuming the conversion of all preferred shares. In addition, investors purchasing Common Stock in this offering will contribute 21.0% of the total amount invested by stockholders since inception but will only own 10.1% of the shares of Common Stock outstanding. In the past, we issued options and other securities to acquire Common Stock at prices significantly below the initial public offering price. To the extent these outstanding securities are ultimately exercised, investors purchasing Common Stock in this offering will sustain further dilution. See “Dilution” for a more detailed description of the dilution to new investors in the offering.

Participation in this offering by certain of our existing stockholders would reduce the available public float for our shares.

Certain of our existing stockholders have indicated an interest in purchasing an aggregate of up to $2,500,000 of shares of Common Stock in this offering at the initial public offering price and on the same terms as other purchasers in this offering. If certain of our existing stockholders are allocated all or a portion of the shares in which they have indicated an interest in this offering and purchase any such shares, such purchases would reduce the available public float for our shares because such stockholders would be restricted from selling the shares by a lock-up agreement entered into with us or our underwriters and/or by restrictions under applicable securities laws. As a result, any purchase of shares by such stockholders in this offering may reduce the liquidity of our Common Stock relative to what it would have been had these shares been purchased by investors that were not previously associated with us.

CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS

This prospectus contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this prospectus, including statements regarding our strategy, future operations, future financial position, future revenue, projected costs, prospects, plans, objectives of management and expected market growth are forward-looking statements. These statements involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements.

The words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “will,” “project,” “would” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. These forward-looking statements include, among other things, statements about:

•        the initiation, timing, progress and results of future preclinical studies and clinical trials, and our research and development programs;

•        our need to raise additional funding before we can expect to generate any revenues from product sales;

•        our plans to develop and commercialize our product candidates;

•        the timing or likelihood of regulatory filings and approvals;

•        the ability of our research to generate and advance additional product candidates;

•        the implementation of our business model, strategic plans for our business, product candidates and technology;

•        our commercialization, marketing and manufacturing capabilities and strategy;

•        the rate and degree of market acceptance and clinical utility of our system;

•        our competitive position;

•        our intellectual property position;

•        developments and projections relating to our competitors and our industry;

•        our ability to maintain and establish collaborations or obtain additional funding;

•        our expectations related to the use of proceeds from this offering; and

•        our estimates regarding expenses, future revenue, capital requirements and needs for additional financing.

We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make. We have included important factors in the cautionary statements included in this prospectus, particularly in the “Risk Factors” section, that could cause actual results or events to differ materially from the forward-looking statements that we make. Our forward-looking statements do not reflect the potential impact of any future acquisitions, mergers, dispositions, joint ventures or investments that we may make. You should read this prospectus completely and with the understanding that our actual future results may be materially different from what we expect. We do not assume any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

You should read this prospectus and the documents that we have filed with the SEC as exhibits to the registration statement, of which this prospectus is a part, with the understanding that our actual future results, levels of activity, performance and events and circumstances may be materially different from what we expect. We qualify all forward-looking statements by these cautionary statements.

USE OF PROCEEDS

We estimate that the net proceeds from the sale of our Common Stock in this offering will be approximately $6.1 million, based upon an assumed initial public offering price of $4.50 per share, the price set forth on the cover page of this prospectus, and after deducting underwriting discounts and commissions and estimated offering expenses payable by us. If the underwriters’ option to purchase additional shares of our Common Stock is exercised in full, we estimate that the net proceeds from the offering will be approximately $7.2 million.

We intend to use the net proceeds from this offering for the following purposes:

•        approximately 5% toward initiating/conducting a Phase 3 sarcoma study (IT-03);

•        approximately 10% toward initiating/conducting a Phase 2/3 early-stage breast cancer studies (IT-04);

•        approximately 40% toward our current clinical trials and related operations, including costs associated with the manufacturing of SHAO and INT230-6 for our clinical trials, conducting/completing our existing clinical programs, and maintaining our IND with the FDA, CTA with Health Canada as well as other regulatory filings with other countries;

•        approximately 5% toward development of our second product candidate, INT33X; and

•        approximately 40% toward general corporate purposes and working capital.

With regard to our Phase 3 sarcoma study (IT-03) and Phase 2/3 early-stage breast cancer study (IT-04), we expect that the proceeds from this offering will be sufficient to allow us to obtain regulatory authorizations to proceed for these trials. However, the proceeds from this offering will be insufficient to enable us to finish these trials, and we will need to raise additional funding in order to complete these trials. Based on our current plans, we believe that our existing cash and cash equivalents, together with the anticipated net proceeds to us from this offering, will enable us to fund our operations and capital expenditure requirements through March 31, 2024.

We will have broad discretion over how to use the net proceeds we receive from this offering. The expected uses of net proceeds from this offering represents our intentions based upon our current plans and business conditions, which could change in the future as our plans and business conditions evolve. The amounts and timing of our actual expenditures may vary significantly depending on numerous factors, including the progress of our development, the status of and results from preclinical and clinical trials, and any unforeseen cash needs.

DIVIDEND POLICY

We have not declared or paid any cash dividends on our capital stock since our inception. In the near term we intend to retain future earnings, if any, to finance the operation and expansion of our business and do not anticipate paying any cash dividends to holders of Common Stock in the foreseeable future.

CAPITALIZATION

The following table sets forth our cash and cash equivalents and consolidated capitalization as of September 30, 2022:

•        on an actual basis;

•        on a pro forma basis to give effect to:

•        the automatic conversion of 8,249,719 outstanding shares of our preferred stock into an aggregate of 8,249,719 shares of our Common Stock upon the closing of this offering. The Series A, Series B, and Series C shareholders have consented to the conversion of the preferred shares into common shares following an IPO raising gross proceeds of at least $8.0 million in the aggregate at a price of at least $4.00 per share of Common Stock offered. The Company does not intend to proceed with the offering unless the preferred stock is converted into Common Stock upon completion of the offering;

•        35,744 additional shares of Series C Preferred Stock that are issued as a result of the proposed offering price of shares of Common Stock being offered hereby being below the $5.75 issuance price of the Series C Preferred Stock. These shares will be converted into 35,744 shares of our Common Stock upon the closing of this offering;

•        the conversion of a convertible note into an aggregate of 654,490 shares of our Common Stock upon the closing of this offering, which is based on unpaid principal and accrued but unpaid interest as of September 30, 2022 at a conversion price of $3.15 per share. The convertible note and accrued interest is converted upon completion of an IPO of at least $8.0 million; and

•        the filing and effectiveness of our amended and restated certificate of incorporation, which will occur immediately prior to the consummation of this offering; and

•        and on a pro forma as adjusted basis, giving effect to our issuance and sale of shares of Common Stock in this offering at an assumed initial public offering price of $4.50 per share (the price set forth on the cover page of this prospectus), after deducting estimated underwriting discounts and commissions and estimated offering expenses payable by us, and the application of the proceeds as described under the section entitled “Use of Proceeds”. The pro forma as adjusted cash and cash equivalents of approximately $7.9 million includes the gross proceeds of the IPO, less commissions, less the cash needed for the remaining expenses related to the issuance of the IPO shares.

This table should be read in conjunction with the other information contained in this prospectus, including “Use of Proceeds,” “Management’s Discussion and Analysis of Financial Condition and Results of Operations” and our consolidated financial statements and related notes appearing elsewhere in this prospectus.

The information set forth in the table excludes:

•        $2,250,000 of convertible notes that were issued in November 2022;

•        1,702,500 shares of our Common Stock issuable upon the exercise of stock options outstanding as of September 30, 2022 under our 2013 Stock and Option Plan, or the 2013 Plan, at a weighted average exercise price of $4.18 per share; of these, 1,336,250 were exercisable at a weighted average exercise price of $3.77 per share;

•        2,797,500 shares of our Common Stock were reserved for future issuance under the 2013 Plan; however, these shares are no longer available for issuance since the 2021 Plan became effective;

•        646,500 shares of our Common Stock reserved and available for future issuance upon exercise of the Company’s outstanding warrants, as of September 30, 2022 at a weighted average exercise price of $3.00 per share; of these 619,750 were exercisable at a weighted average exercise price of $2.90 per share;

•        124,444 shares of Common Stock underlying the Underwriter Warrants; and

•        3,000,000 shares of our Common Stock that became available for future issuance under the 2021 Plan, which became effective November 12, 2021.

Unless otherwise indicated, all information contained in this prospectus assumes no exercise by the underwriters of their option to purchase additional shares and no exercise of any other options or warrants.

DILUTION

If you invest in our Common Stock in this offering, your ownership interest will be diluted immediately to the extent of the difference between the initial public offering price per share of our Common Stock and the pro forma as adjusted net tangible book value per share of our Common Stock after this offering.

Our historical net tangible book value (deficit) as of September 30, 2022 was ($14.2 million), or ($2.08) per share of our Common Stock. Our historical net tangible book value (deficit) is the amount of our total tangible assets less our total liabilities and preferred stock, which is not included within our stockholders’ (deficit) equity. Historical net tangible book value per share represents historical net tangible book value (deficit) divided by the 6,820,211 shares of our Common Stock outstanding as of September 30, 2022. This calculation of historical net tangible book value (deficit) includes $2.0 million in convertible notes and $10.0 million in Series A preferred stock, both of which convert into Common Stock following an initial public offering (IPO) with gross proceeds of at least $8.0 million. The Series A, Series B, and Series C shareholders have consented to convert their preferred shares into common shares following an IPO with gross proceeds of at least $8.0 million in the aggregate and a price of at least $4.00 per share of Common Stock offered. The Company does not intend to proceed with the offering unless the preferred stock is converted into Common Stock upon completion of the offering.

The pro forma data in the table below is derived from our balance sheet as of September 30, 2022 and is presented on a pro forma basis after giving effect to the conversion of our preferred stock into 8,249,719 shares of our Common Stock, the issuance and conversion to shares of Common Stock of 35,744 additional shares of Series C Preferred Stock as a result of the proposed offering price of shares of Common Stock being offered hereby being below the $5.75 issuance price of Series C Preferred Stock and the issuance of 654,490 shares of our Common Stock upon the conversion of a convertible note and accrued interest as of September 30, 2022 at a conversion price of $3.15 per share, each of which is expected to occur at the closing of this offering. Our pro forma net tangible book value (deficit) as of September 30, 2022 was $(2.2) million, or $(0.14) per share of our Common Stock. Our pro forma net tangible book value (deficit) is the amount of our total tangible assets less our total liabilities. Pro forma net tangible book value per share represents pro forma net tangible book value (deficit) divided by the 15,760,164 shares of our Common Stock outstanding as of September 30, 2022 after giving effect to these pro forma adjustments.

After giving effect to the receipt of the estimated net proceeds from our sale of Common Stock in this offering, assuming an initial public offering price of $4.50 per share (the price set forth on the cover of this prospectus), after deducting the underwriting discount and other estimated offering expenses payable by us, our pro forma as-adjusted net tangible book value as of September 30, 2022 would have been approximately $5.1 million, or $0.29 per share. This represents an immediate increase in pro forma as adjusted net tangible book value per share of $0.43 to existing stockholders and immediate dilution to new investors in this offering of $4.21 per share. The following table illustrates this dilution per share. Dilution represents the difference between the amount per share paid by investors in this offering and the pro forma as-adjusted net tangible book value per share of our Common Stock immediately after this offering.

If the underwriters fully exercise their option to purchase additional shares of Common Stock, pro forma as-adjusted net tangible book value after this offering would increase by approximately $0.06 per share, and there would be an immediate dilution of approximately $4.15 per share to new investors based on the assumed initial public offering price of $4.50 per share, and after deducting underwriting discounts and commissions and estimated offering expenses payable by us. If any shares are issued upon exercise of outstanding options or warrants, you will experience further dilution.

The dilution information discussed above is illustrative only and will change based on the actual initial public offering price and other terms of this offering determined at pricing. A $1.00 increase (decrease) in the assumed initial public offering price of $4.50 per share of Common Stock, would decrease (increase) our pro forma as-adjusted net tangible book value after giving effect to the offering by $1.653 million, assuming no change to the number of shares of our Common Stock offered by us as set forth on the cover page of this prospectus, and after deducting estimated underwriting discounts and commissions and estimated expenses payable by us.

Each increase of 200,000 in the number of shares offered by us would increase our pro forma as-adjusted net tangible book value by $0.8 million, increase the pro forma as-adjusted net tangible book value per share after this offering by $0.05 and decrease the dilution per share to new investors by $0.05, assuming the assumed public offering price remains the same and after deducting the estimated underwriting discounts and commissions and estimated expenses payable by us. Each decrease of 200,000 in the number of shares offered by us would decrease our pro forma as-adjusted net tangible book value by $0.8 million, decrease the pro forma as-adjusted net tangible book value per share after this offering by $0.05 and increase the dilution per share to new investors by $0.05, assuming the assumed public offering price remains the same and after deducting the estimated underwriting discounts and commissions and estimated expenses payable by us.

The following table presents, on a pro forma as-adjusted basis, as described above, the differences between the existing stockholders on a pro forma basis and the purchasers of shares of Common Stock in this offering with respect to the number of shares of Common Stock purchased from us, the total consideration paid, and the average price paid per share at an assumed public offering price of $4.50 per share (the price set forth on the cover page of this prospectus):

____________

*        Certain of our existing stockholders have indicated an interest in purchasing an aggregate of up to $2,500,000 of shares of Common Stock in this offering at the initial public offering price and on the same terms as other purchasers in this offering. The presentation in this table regarding ownership by existing stockholders does not give effect to any purchases in this offering by such stockholders.

The table above assumes no exercise of the underwriters’ option to purchase additional shares in this offering. If the underwriters’ option to purchase additional shares is exercised in full with respect to the Common Stock, the number of shares of our Common Stock held by existing stockholders would be reduced to 88.5% of the total number of shares of our Common Stock outstanding after this offering, and the number of shares of Common Stock held by new investors participating in this offering would be increased to 11.5% of the total number of shares of our Common Stock outstanding after this offering.

The number of shares of our Common Stock to be outstanding after this offering is based on 18,268,347 shares of Common Stock, which includes 6,820,211 shares of our Common Stock outstanding as of January 13, 2023, plus 8,249,719 shares of our Common Stock issued upon the conversion of our preferred stock, plus 33,588 additional shares of Series C Preferred Stock issued and converted into common stock as a result of the proposed offering price of shares of Common Stock being offered hereby being below the $5.75 issuance price of Series C Preferred Stock and 1,387,051 shares of our Common Stock that would be issued on the convertible notes and an assumed amount of accrued interest at a conversion price of $3.15 per share, plus 1,777,778 shares of our common stock offered in this offering and excludes:

•        2,088,500 shares of our Common Stock issuable upon the exercise of stock options outstanding as of January 13, 2023 under the 2013 Plan and the 2021 Plan at a weighted average exercise price of $4.24 per share. Of these, 1,423,750 are exercisable at January 13, 2023 at a weighted average exercise price of $3.81 per share;

•        2,797,500 shares of our Common Stock were reserved for future issuance under the 2013 Plan; however, these shares are no longer available for issuance since the 2021 Plan became effective;

•        775,500 shares of our Common Stock reserved and available for future issuance upon exercise of the outstanding warrants, as of January 13, 2023 at a weighted average exercise price of $3.25 per share. Of these, 664,750 are exercisable at January 13, 2023 at a weighted average exercise price of $3.01 per share;

•        124,444 shares of Common Stock underlying the Underwriter Warrants; and

•        2,852,700 shares of our Common Stock that became available for future issuance under the 2021 Plan, effective November 12, 2021. This includes the original 3,000,000 authorized shares plus an additional 238,700 shares authorized effective January 1, 2023.

Unless otherwise indicated, all information contained in this prospectus assumes no exercise by the underwriters of their option to purchase additional shares and no exercise of any other options or warrants.

To the extent that outstanding options are exercised or shares are issued under our 2021 Plan, you will experience further dilution. In addition, we may choose to raise additional capital due to market conditions or strategic considerations, even if we believe that we have sufficient funds for our current or future operating plans. To the extent that additional capital is raised through the sale of equity or convertible debt securities, the issuance of these securities may result in further dilution to our stockholders.

The conversion of the 8,249,719 shares of preferred stock and the conversion of the convertible notes into 1,387,051 shares is contingent upon this IPO being at least $8.0 million in aggregate. The Company does not intend to proceed with the offering unless the preferred stock and convertible note is converted into Common Stock upon completion of this offering.

MANAGEMENT’S DISCUSSION AND ANALYSIS OF
FINANCIAL CONDITION AND RESULTS OF OPERATIONS

The following discussion and analysis of our financial condition and results of operations should be read together with our financial statements and related notes and other financial information appearing elsewhere in this prospectus. This discussion and analysis contains forward-looking statements that involve risk, uncertainties and assumptions. See the section entitled “Cautionary Note Regarding Forward-Looking Statements” in this prospectus. Our actual results could differ materially from those anticipated in the forward-looking statements as a result of many factors, including those discussed in “Risk Factors” and elsewhere in this prospectus.

Unless otherwise indicated or the context otherwise requires, references in this prospectus to the “Company”, “we”, “us” and “our” refer to Intensity Therapeutics, Inc.

Overview

We are a clinical-stage biotechnology company whose treatment approach addresses both the regional and systemic nature of a patient’s cancer. We are currently conducting Phase 2 clinical trials with one study using our lead product candidate in late-stage disease and another study in early stage breast cancer. Our first clinical trial has dosed 110 patients through December 31, 2022. This clinical trial uses our lead product candidate INT230-6 alone; in combination with Merck’s Keytruda (pembrolizumab) for patients with advanced solid malignancies including pancreatic, bile duct, squamous cell, and non-MSI high colon cancers; and in combination study with Bristol Myers Squibb’s Yervoy (ipilimumab) for patients with breast cancer, liver cancer, and advanced sarcoma.

Our second clinical trial (the INVINCIBLE Study or IT-02) is testing INT230-6 in early stage breast cancer for patients not suitable for presurgical chemotherapy. The study enrolled 91 subjects; enrollment is now complete. This clinical trial is a Phase 2 randomized, window of opportunity for patients who are ineligible or chose not to have presurgical chemotherapy. The primary endpoint is to understand whether INT230-6 can reduce the patient’s cancer by measuring the proportion of patients who achieve a complete cell cycle arrest compared to no treatment (the current standard of care) or a saline injection. Reduction of cancer is defined as a lowering of the proportion of cells staining positive for Ki67, a widely used marker of cancer cell proliferation. Another endpoint will be to understand the percentage of necrosis that can be achieved in tumors ranging from 1.5 to 5 cm in longest diameter following treatment with one dose of INT230-6, which set by the tumor’s diameter.

Since our inception in 2012, our operations have included business planning, hiring personnel, raising capital, building our intellectual property portfolio, and performing both research and development on our product candidates. We currently have incurred net losses since inception and expect to incur net losses in the future as we continue our research and development activities. To date, we have funded our operations primarily through approximately $34.3 million of sales of our common stock, preferred stock and convertible notes. As of September 30, 2022, we had approximately $0.7 million of cash and cash equivalents. In November 2022 the Company raised an additional $2.25 million with the issuance of convertible notes. Since our inception we have incurred significant operating losses. We incurred net losses of $7.9 million and $6.0 million for the years ended December 31, 2021 and 2020, respectively, and net losses of $6.1 million and $5.5 million for the nine months ended September 30, 2022 and 2021, respectively. As of September 30, 2022, December 31, 2021, September 30, 2021, and December 31, 2020, we had an accumulated deficit of approximately $37.1 million, $31.1 million, $28.7 million and $23.2 million, respectively. We expect to incur significant expenses and operating losses for the next several years. See “Funding Requirements” below.

We expect our expenses to increase as we continue to:

•        Initiate Phase 3 programs in sarcoma and/or breast cancer;

•        Complete our current Phase 2 programs;

•        Advance our preclinical research and bring new product into clinical development;

•        Incur manufacturing costs for additional GMP batches of our product candidates and enhancer molecules;

•        Seek regulatory approvals for any of our product candidates that successfully complete clinical trials;

•        Hire additional personnel;

•        Expand our operational, financial, and management systems;

•        Invest in measures to protect our existing and new intellectual property;

•        Establish a sales, marketing, medical affairs, and distribution infrastructure to commercialize any product candidates for which we may obtain marketing approval and intend to commercialize; and

•        Operate as a public company.

Due to numerous risks and uncertainties associated with biopharmaceutical product development and the economic and developmental uncertainty arising from the COVID-19 pandemic, we may be unable to accurately predict the timing or magnitude of all expenses. Our ability to ultimately generate revenue to achieve profitability will depend heavily on the development, approval, and subsequent commercialization of our product candidates. If we fail to become profitable or are unable to sustain profitability on a continuing basis, then we may be unable to continue our operations at planned levels and be forced to reduce or terminate our operations.

As a result, we will need substantial additional funding to support our continuing operations and pursue our growth strategy. Until such time as we can generate significant revenue from product sales, if ever, we expect to finance our operations through the sale of equity, debt financing, or other capital sources, which may include collaborations with other companies or other strategic transactions. We may not be able to raise additional funds or enter into such other agreements or arrangements when needed on favorable terms, or at all. If we fail to raise capital or enter into such agreements as and when needed, we would have to significantly delay, reduce, or eliminate the development and commercialization of one or more of our product candidates.

Components of Results of Operations

Revenue

To date, we have not generated any revenue from product sales and we do not expect any revenue from the sale of product in the foreseeable future. If our development efforts for any of our product candidates are successful and result in regulatory approval, then we may generate revenue in the future from product sales. We cannot predict if, when, or to what extent we will generate revenue from the commercialization and sale of any of our product candidates. We may never succeed in obtaining regulatory approval for any of our product candidates.

Research and Development Costs

Salaries and Payroll Taxes

Salaries and payroll taxes include Company employees involved in our pre-clinical research and clinical trials. This includes medical officers, project management, manufacturing staff and research scientists. The payroll taxes include all government required payments such as social security and unemployment taxes.

Fringe Benefits

We offer a partially funded health insurance and dental insurance plan. We maintain a defined contribution plan for all employees age 21 and older who have completed one year of service. This 401K plan makes a matching contribution equal to 100% of an employee’s contribution, up to 3% of an employee’s eligible earnings.

Research Costs

Research costs include:

•        Pre-clinical research

•        Manufacture of new enhancer compounds,

•        Manufacture and labelling of GMP product candidate

•        Product candidate stability testing of GMP batches

•        Costs due to clinical trial sites for patient care

•        Other clinical trial costs such as shipping, storage, and analytical testing

Scientific Consulting

Scientific consulting are costs related to non-employees involved in research. This category includes: statistical analysis, clinical trial operations, development of product manufacturing techniques, and internet research related to oncology and chemistry issues that may impact our preclinical or clinical research.

Stock-Based Compensation

Stock-based compensation is the expense related to stock options granted to our employees and warrants granted to our independent consultants who work in the research aspects.

General and Administrative Costs

Salaries and Payroll Taxes

Salaries and payroll taxes includes Company employees who are involved in fund raising, management, and our financial administration. The payroll taxes include all government required payments such as social security and unemployment taxes.

Fringe Benefits

We offer a partially funded health insurance and dental insurance plan. We maintain a defined contribution plan for all employees age 21 and older who have completed one year of service. This 401K plan makes a matching contribution equal to 100% of an employee’s contribution, up to 3% of an employee’s eligible earnings.

Legal

Legal costs relate primarily to our corporate administration. All legal costs relate to expenses for our outside corporate law firm.

Patent and Trademark

Patent and Trademark are the legal costs and filing costs to establish and maintain patents in 37 countries.

Insurance

Insurance includes: directors and officers insurance, workers compensation insurance, product liability insurance, business insurance, employee and cyber liability insurance.

Facilities and Rent

Facilities and rent is the cost of maintaining our office facility in Westport, Connecticut.

Investor Relations

Investor relations are costs paid to outside consultants to develop the materials to present to prospective investors, and to arrange meetings with potential investors.

Accounting Services

Accounting services include the cost of our independent auditors for our annual audit, quarterly reviews, and services related to the filing of our registration statement on Form S-1. This category also includes costs related to the preparation of income tax returns, and the cost of maintain our accounting system.

Other

Other general and administrative costs include such items as office supplies, computer related costs, bank fees, public relations costs, recruiting costs and conferences.

Stock-Based Compensation

Stock-based compensation is the expense related to stock options granted to our employees and warrants granted to our independent consultants who work in the general and administrative aspects.

Other income

We earned interest income on our cash balances. All investments are in U.S. Treasury bills and bank certificates of deposit.

We received a refundable Connecticut Research and Development tax credit and a Federal Research and Development tax credit that is recoverable through a refund of Social Security taxes paid by us.

Results of Operations

The following table summarizes our results of operations for the years ended December 31, 2021 and 2020 and the nine months ended September 30, 2022 and 2021 (in thousands):

Year Ended December 31, 2021 Compared to Year Ended December 31, 2020

Research and Development expenses increased by 16.0%. Salaries and wages were higher in 2021 primarily because we hired our Senior Vice President of Clinical Development in October 2020. Research costs increased because our IT-02 study was conceived and implemented in 2020, including patient enrollment. Our IT-03 Phase 3 study began to be designed in late 2020 and continued forward in 2021. Our IT-01 study continued to generate data, but with enrollment restricted by COVID restrictions at our clinical trial sites.

General and Administrative expenses increased from approximately $1.2 million to approximately $2.2 million primarily due to our preparation for an IPO. The increase in General and Administrative Legal and Accounting services in particular, increased due to the preparation for an IPO. Other cost includes Nasdaq fees and printing costs related to our registration statements.

Nine Months Ended September 30, 2022 Compared to Nine Months Ended September 30, 2021

Research and Development expense decreased by 4.0%. Study IT-01 costs decreased by 17% as enrollment in this multi-year study was concluded in the second quarter of 2022. This decrease in IT-01 was partially offset by increases in the other studies.

General and Administrative expenses increased from approximately $1.2 million to $1.9 million primarily due legal and accounting expenses incurred related to Company’s proposed IPO. The increase in consulting services mostly relates to the Chief Financial Officer position which began in August 2021.

Liquidity and Capital Resources

Our financial statements have been prepared assuming we will continue as a going concern. The Company has incurred losses from operations and negative cash flows that raise substantial doubt about our ability to continue as a going concern.

Since our inception, we have not generated any revenue from product sales and have incurred significant operating losses. We expect to continue to incur significant expenses and operating losses for the foreseeable future as we advance the clinical development of our product candidates. We expect that our research and development and general and administrative costs will continue to increase significantly, including in connection with conducting clinical trials for our product candidates, developing our manufacturing capabilities and building and qualifying our manufacturing facility to support clinical trials and commercialization and providing general and administrative support for our operations, including the cost associated with operating as a public company. As a result, we will need additional capital to fund our operations, which we may obtain from additional equity or debt financings, collaborations, licensing arrangements or other sources.

We do not currently have any approved products and have never generated any revenue from product sales. We have financed our operations primarily through an initial investment from our founder and the issuance and sale of convertible debt notes, Common Stock and our convertible preferred stock to outside investors in private equity financings. From our inception through September 30, 2022, we raised an aggregate of approximately $32.1 million of gross proceeds from such transactions. As of September 30, 2022, our cash and cash equivalents were $0.7 million.

The following table summarizes the net cash provided by (used for) operating activities, investing activities and financing activities for the periods indicated (in thousands):

Operating Activities

Net cash used in operating activities for the year ended December 31, 2021 was $6,826,863, primarily consisting of a net loss of $7,895,600 as we incurred expenses associated with our clinical programs. In addition, we had non-cash charges of $719,822 for stock-based compensation of options and warrants granted to employees and consultants. Net cash used in operating activities as also impacted by expenses related to our preparation for an IPO.

Net cash used in operating activities for the year ended December 31, 2020 was $5,370,192, primarily consisting of a net loss of $6,030,480 as we incurred expenses associated with our clinical programs. In addition, we had non-cash charges of $555,488 for stock-based compensation of options and warrants granted to employees and consultants. Net cash used in operating activities was also impacted by the increase in accrued patient care costs as enrollment expanded.

Net cash used in operating activities for the nine months ended September 30, 2022 and 2021 was $3,842,663 and $3,957,900, respectively.

For the nine months ended September 30, 2022, the net loss of $6,071,556 was offset primarily by $541,333 in the non-cash charge for stock-based compensation expense and a $1,609,986 increase in accounts payable and accrued expenses. For the nine months ended September 30, 2021, the net loss of $5,494,482 was offset primarily by the $464,139 in the non-cash charge for stock-based compensation expense and a $1,065,416 increase in accounts payable and accrued expenses.

Investing Activities

There was no cash provided by investing activities in 2021 or the first nine months of 2022 and 2021 since all funds were in cash accounts, not investments.

Net cash provided by investing activities for the year ended December 31, 2020 was $4,564,813, which was attributable to maturities of short term investments exceeding the purchase of short term investments.

Financing Activities

Net cash provided by financing activities for the year ended December 31, 2021 was $2,000,000 from the issuance of a convertible note plus $50,000 payment of the receivable related to a prior year Common Stock purchase.

Net cash provided by financing activities for the year ended December 31, 2020 was $6,292,633 consisting primarily from the sale of Series C preferred stock.

Financing activities for the nine months ended September 30, 2021 consisted of receipt of the final payment on a shareholder note of $50,000 and proceeds from the issuance of a convertible note for $2,000,000. There were no financing activities for the nine months ended September 30, 2022.

Off-Balance Sheet Arrangements

We did not have during the periods presented, and we do not currently have, any off-balance sheet arrangements, as defined under SEC rules.

Seasonality

Our business experiences limited seasonality.

Contractual Obligations, Commitments and Contingencies

The following table provides our significant commitments and contractual obligations as of September 30, 2022:

JOBS Act Accounting Election

We are an “emerging growth company,” as defined in the Jumpstart Our Business Startups Act of 2012, or the JOBS Act. Under the JOBS Act, emerging growth companies can delay adopting new or revised accounting standards issued subsequent to the enactment of the JOBS Act until such time as those standards apply to private companies. We have irrevocably elected not to avail ourselves of this exemption from new or revised accounting standards and, therefore, will be subject to the same new or revised accounting standards as other public companies that are not emerging growth companies.

Subject to certain conditions set forth in the JOBS Act, if, as an “emerging growth company”, we choose to rely on such exemptions we may not be required to, among other things, (i) provide an auditor’s attestation report on our system of internal controls over financial reporting pursuant to Section 404, (ii) provide all of the compensation disclosure that may be required of non-emerging growth public companies under the Dodd-Frank Wall Street Reform and Consumer Protection Act, (iii) comply with any requirement that may be adopted by the PCAOB regarding mandatory audit firm rotation or a supplement to the auditor’s report providing additional information about the audit and the financial statements (auditor discussion and analysis), and (iv) disclose certain executive compensation related items such as the correlation between executive compensation and performance and comparisons of the CEO’s compensation to median employee compensation. These exemptions will apply for a period of five years following the completion of our initial public offering or until we are no longer an “emerging growth company,” whichever is earlier.

Critical Accounting Policies and Estimates

Our management’s discussion and analysis of financial condition and results of operations is based on our financial statements, which have been prepared in accordance with accounting principles generally accepted in the United States, or U.S. GAAP. The preparation of our financial statements and related disclosures requires us to make estimates and assumptions that affect the reported amounts of assets and liabilities, costs and expenses, and the disclosure of contingent assets and liabilities in our financial statements. These items are monitored and analyzed by us for changes in facts and circumstances, and material changes in these estimates could occur in the future. We base our estimates on historical experience, known trends and events, and on various other factors that we believe are reasonable under the circumstances, the results of which form the basis for making judgments about the carrying values of assets and liabilities that are not readily apparent from other sources. We evaluate our estimates and assumptions on an ongoing basis. Our actual results may materially differ from these estimates under different assumptions or conditions.

While our significant accounting policies are described in more detail in the notes to our financial statements included elsewhere in this prospectus, we believe that the following accounting policies are those most significant to the judgments and estimates used in the preparation of our consolidated financial statements.

Accrued Research and Development Expenses

Research and development costs are expensed as incurred. We record the estimated patient care costs as services are provided but not yet invoiced and include these costs in the accrued expenses in the balance sheet and within research other expense in the statement or operations.

BUSINESS

Business Overview

Intensity Therapeutics, Inc. is a clinical stage biotechnology company passionately committed to applying scientific leadership in the field of localized cancer reduction leading to anti-cancer immune activation. Our new approach involves the direct injection into tumors of a unique product created from our DfuseRxSM discovery platform. Our technology and products are distinct from all other cancer treatments — essentially a new weapon in the war on cancer.

Intratumoral (IT) treatment approaches are not new; however, current and past IT methods fail to address the key fact that a tumor’s lipophilic, high fat and pressurized microenvironment does not effectively absorb water-based products. Prior and current IT treatments formulated their product candidates as aqueous products (regardless of the mechanism or approach), current competitor IT efforts attempt to stimulate an inflammatory response or to attract immune cells into a hostile live tumor. However, the fundamental challenge of IT treatment is drug delivery.

Accordingly, there remains a continued unmet need for the development of direct IT therapies for solid tumors that provide high local killing efficacy coupled with nontoxic systemic anti-cancer effects. We believe we have created such a product candidate — one with the necessary physical and chemical properties to overcome the local delivery challenge. Our data also shows the mechanism of tumor killing achieved by our drug candidate also leads to systemic immune activation in certain cancers. The tumor is unfavorable to treatments for systemic products especially in metastatic disease. Systemic chemotherapy delivers low cytotoxic agent concentrations and drugs do not reach hypoxic areas. Immunotherapy is hindered by the tumor’s ability to exclude immune cells. Cytokines produced by live cancer cells in prevent Antigen Preventing Cell (APC) recognition. However, using our delivery science following direct injection the tumor is saturated with killing agents — the cancer cells die — including cells in areas away from blood vessels (hypoxic zones). The cell membranes remain intact, quality antigen is released, and the tumor is now favorable to entry by APCs and T-cells. This process is shown in Figure 1 below.

Figure 1 Mechanism of tumor killing and immune activation

Tumors have poor vascularization and can prevent immune cells from entering. Following injection of our highly diffusive and cell penetrating product candidate, the tumor’s cancer cells die but their membranes remain intact. Antigen is created and APCs as well as T-cells can infiltrate the tumor (image from January 2018 Tuberculosis and Respiratory Diseases 81(1):29.

Our platform creates patented anti-cancer product candidates comprising active anti-cancer agents and amphiphilic molecules. Amphiphilic means multi-loving, and these molecules have two distinct structural components: one part of the molecule is soluble in water and the other is soluble in fat or oils. Certain amphiphilic compounds when mixed with medicinal agents allow those compounds to also become soluble in both fat and water.

Our lead product candidate, INT230-6, consists of two proven anti-cancer cytotoxic agents, cisplatin and vinblastine sulfate, mixed in water with the amphiphilic molecule 8-((2-hydroxybenzoyl)amino)octanoate (referred to as SHAO). The product is packaged in a single vial. The anti-cancer agents, cisplatin and vinblastine sulfate, used in our product candidate are both generic versions of the compounds. These agents are available to purchase in bulk

supply commercially. The United States Food & Drug Administration (the “FDA”) previously approved both drugs as intravenous agents for several types of cancers. Cisplatin was first approved in 1978 for testicular cancer. Per the product labeling, cisplatin’s approved indications include treatment of testicular, ovarian and bladder cancer. The drug is also used widely in several other cancers including pancreatic and bile duct cancer. Vinblastine sulfate was approved in 1965. Per the product labeling, vinblastine sulfate’s approved indications include treatment of generalized Hodgkin’s disease, lymphocytic lymphoma, advanced carcinoma of the testis, and Kaposi’s sarcoma. The drug is also used in breast and lung cancer. In 2017, we initiated a Phase 1/2 dose escalation study with INT230-6 in the United States under an investigational new drug application (“IND”) authorized by the FDA and in Canada following receipt of a no objection letter from Health Canada. The study, IT-01, is exploring the safety and efficacy of INT230-6 in patients with refractory or metastatic cancers. We completed the Phase 1 dose escalation portion of this study and completed enrollment of the phase 2 portion in June 2022. We are currently finishing the close-out and data analysis of the trial, which consists of several different cohorts. One arm of the trial tests our drug candidate in a variety of cancers. Another arm of the trial combined our product candidate with Merck’s Keytruda® (pembrolizumab) in 4 cancer types and another cohort tested our drug candidate with Bristol-Myers Squibb’s drug Yervoy® (ipilimumab) in 3 cancer types. We are also evaluating INT230-6 in another Phase 2 study (the INVINCIBLE study) in Canada as a treatment for early-stage breast cancer prior to surgery. A Phase 3 study in sarcoma (INVINCIBLE 3) is in process of initiating and a follow-on phase 2/3 registration studies in early stage breast cancer is also being planned.

We believe that our drug candidate has achieved clinical proof-of-concept (POC). This means that there is sufficient availability of human clinical data confirming that the concept of a direct intratumoral injection in certain tumor types is feasible and that further investigation is reasonably likely to lead to drug approval and commercialization. We believe clinical POC has been achieved based on the broad range of data that we have generated from our preclinical experiments and clinical trials. Data shows that INT230-6 disperses widely throughout injected tumors, is absorbed well, penetrates and delivers the potent agents into tumor cells to kill them and activates a systemic immune response to fight the cancer. Our treatment approach utilizes intratumoral administration of INT230-6 to selectively induce tumor cell death and elicit an innate and adaptive anti-tumor immune response. Following injection of our product candidate, the tumors become highly necrotic, meaning that cancer cells die. After injection of INT230-6, tumors also become more amenable to immune cell infiltration. The tumor-killing process creates antigens, which are substances from the patient’s tumor that improve the recognition of the cancer by immune cells. While our product candidate is administered directly into the tumor, we have also observed in our preclinical studies and in our clinical trials that injections of INT230-6 can lead to a systemic immune response that attacks distal, uninjected tumors, a result known as an “abscopal” effect. Data generated in our trials show that our patented and patent pending drugs can extend life with less toxicity than is observed when these drugs are used by their normal route of administration, intravenously (IV).

Between the metastatic study IT-01 and the INVINCIBLE study we have enrolled over 200 patients as of December 31, 2022.

Our Pipeline

Our pipeline shown below is focused on realizing the full potential of INT230-6 in metastatic and local disease settings to help cancer patients with major unmet medical need. Together with our collaboration partners Merck and Bristol-Myers Squibb, we are exploring the use of our product candidate across multiple cancer types (including those types that do not normally respond to immunotherapy) and “hot” tumors (cancer types that are more likely to respond to immunotherapy). Within study IT-01 we are evaluating INT230-6 with Keytruda as treatment for pancreatic cancer, colon cancer, bile duct cancer and squamous cell cancer. Also, within IT-01 we are evaluating INT230-6 in combination with Yervoy for the treatment of sarcoma, breast cancer and liver cancer. In the Phase 2 randomized INVINCIBLE study, a collaboration with the Ottawa Hospital Research Institute, INT230-6 alone is also being used as treatment in early-stage breast cancer.

Based on survival data generated to date in sarcoma subjects, we have also designed a Phase 3 program to test our drug candidate in soft tissue sarcoma and are designing phase 2/3 registration studies in early-stage breast cancer. Further, in 2018, we received Fast Track Designation by the FDA to use INT230-6 in metastatic triple negative breast cancer for patients whose cancer has progressed following one or two prior drug treatments. The FDA has reviewed our Phase 2/3 development plan for the sarcoma indication. We plan to use the proceeds from this offering to initiate our Phase 2/3 and 3 programs.

We also continue to research and test new formulations for improved immune activating properties. Preclinical testing is in process, and we conducted a number of animal experiments and identified promising product candidates such as INT33X.

Figure 2 Pipeline

In addition, we plan to continue to research and test new product candidates with improved immune activating properties. Through research studies conducted in animals, we have identified a promising product candidate currently designated as INT33X. We believe that the INT33X product candidate development program will most likely lead to the creation of new patents and other intellectual property. As disclosed in the Use of Proceeds section of this prospectus, we anticipate spending a portion of the proceeds that we receive from this offering to conduct preclinical experiment work and fund the drafting of the new patents related to INT33X. As part of our development program for INT33X, we will first conclude our on-going research studies in mice, after which we will finalize the exact product candidate composition before proceeding with clinical development. We expect that we will be able to complete the discover portion of this work in 2023.

Our Strengths

•        Experienced Oncology Pharmaceutical Development Management Team.    Our CEO, Lewis H. Bender, has over 29 years of experience in the development of drugs using novel delivery technologies. While at Emisphere (a company purchased for $1.8 billion by Novo Nordisk in 2020), where he held many positions including CEO, Mr. Bender developed expertise in cGMP manufacturing, preclinical and clinical testing, biotech financing, quality assurance and drug development. He has taken products from research to Phase 3 testing and helped to create the commercial drug semaglutide branded as Rybelsus for type 2 diabetes that uses amphiphilic molecules to enhance diffusion of peptides across the gut. Mr. Bender also worked in manufacturing at Roche. Our Chief Medical Officer, Ian B. Walters. MD, has more than 20 years of clinical development experience and helped to test over 30 clinical compounds helped five products gain FDA approval including the multi-billion dollar drugs Opdivo® and Yervoy® (trademarks of Bristol-Myers Squibb). He is a clinical and translational scientist with research experience at the Rockefeller University, Bristol-Myers Squibb and Millennium. Our Chief Financial Officer, James M. Ahlers, has over 25 years working building life science businesses. He has been CFO of Intarcia Pharmaceuticals and has raised capital through equity, debt and complex structured instruments, including initial public offerings. Our Executive Responsible for Clinical Development, Brian Schwartz MD, has significant experience in drug development in both the biotechnology and pharmaceutical industries. Dr. Schwartz most recently served as Chief Medical Officer and head of Research and Development of ArQule, Inc. where he served as a key member of the management team and spearheaded a number of preclinical and clinical drug development programs in oncology and rare diseases. Dr. Schwartz received his medical degree from the University of Pretoria, South Africa, practiced medicine, and worked at the University of Toronto prior to his career in the biopharmaceutical industry. Dr Schwartz currently serves as a board member a number of biotech companies. Our Vice President of Project Management, Steve Innaimo, has over 20 years of experience from Bristol Myers Squibb, with expertise in all aspects of logistics and project management software. Our Principal Accounting Officer and Controller, John Wesolowski CPA has experience in public accounting at KPMG, with over 30 years of private and public controller experience including 18 years in the controller office at Yale University.

•        Proprietary Drug Discovery platform, DfuseRxSM with Product Patent Protection in 38 Countries.    Since our inception, we have conducted research using our discovery platform. Our technology platform allows us to identify novel product formulations and test the products’ activity in animal or test tube models of cancer. Using our platform technology, we have evaluated several formulations comprising various amphiphilic molecules that act as cancer cell penetration enhancers. We have tested formulations using our technology with many potent, anti-cancer drugs (with different mechanisms of action) in various combinations under several conditions to discover our lead product candidate. Our product candidates have a robust intellectual property position with 15 issued patents (3 issued in the US) and the ability to enforce our claims in 38 countries including the U.S. and all external major pharmaceutical markets. Four foreign patent applications are pending.

•        Partnerships with World Leading Oncology Research Organizations and Major Pharmaceutical Companies

•        The National Cancer Institute (NCI) Research Agreement.    In May 2014, we were awarded a Collaboration Research and Development Agreement (CRADA) by the National Institute of Health’s National Cancer Institute. The CRADA was with the Vaccine Branch under the leadership of Dr. Jay Berzofsky. The research sought to understand the mechanism of action of INT230-6 and test the drug in several models in the NCI’s laboratories. The program resulted in a peer-reviewed publication titled Intratumorally delivered formulation, INT230-6, containing potent anti-cancer agents induces protective T-cell immunity and memory, which appeared in the journal OncoImmunology 2019 Vol 8 No 10; 15 and that was jointly authored by us and the NCI. The data for the paper was generated entirely by the NCI in their laboratories and reported the critical role of T-cells in promoting complete tumor regression using our drug candidate and that INT230-6 was synergistic with anti-PD-1 (programmed death receptor 1) and anti-Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) antibodies.

•        Merck Partnership.    In June 2019, we entered into an agreement with Merck to evaluate the combination of INT230-6 and KEYTRUDA® (pembrolizumab), Merck’s anti-PD-1 therapy, in patients with advanced solid malignancies, including pancreatic, bile duct, squamous cell and non-MSI high colon cancers. We dosed our first patient in this combination study in October 2019 and, through December 31, 2022, 30 patients in total have been dosed. After nearly two years of dosing a combination of Keytruda and INT230-6 we see comparable safety to INT230-6 monotherapy. In addition, there have been only three grade 3 immune-related adverse events reported in patients receiving the combination of INT230-6 with Keytruda. Please see Table 1 in the “Results from IT-01 Phase 1/2 Clinical Trial” portion of our “Business” section on page 67 of this prospectus for more information.

•        Bristol Myers Squibb Partnership.    In April 2020, we entered into a clinical trial collaboration agreement with Bristol Myers Squibb to evaluate the safety and efficacy of our product candidate INT230-6 with BMY’s CTLA-4 immune checkpoint inhibitor Yervoy® (ipilimumab). This combination is being evaluated in patients with breast cancer, liver cancer, and advanced sarcoma. Through December 31, 2022, we have dosed 18 patients in this combination arm. There have been only one grade 3 immune-related adverse event (colitis) reported in the combination of INT230-6 and ipilimumab. Please see Tables 1 and 2 in the “Results from IT-01 Phase 1/2 Clinical Trial” portion of our “Business” section on page 67 of this prospectus for more information.

•        Clinical Collaborations with World Leading Academic Hospitals in the US and Canada.    To conduct our Phase 1/2 trial we have partnered with experienced clinicians at leading academic institutions in the US and Canada to test the safety and efficacy of our lead product candidate. The hospitals include Johns Hopkins Sydney Kimmel Cancer Center, Temple University’s Fox Chase Cancer Center, UMASS Memorial Hospital, The University of Southern California’s Norris & HOAG Hospitals, Columbia Presbyterian, the University of Toronto’s Princess Margaret Hospital and Houston Methodist.

•        The INVINCIBLE study, with Canadian Centers of Cancer Research: the Ottawa Hospital Research Institute and the Ontario Institute of Cancer Research (OICR).    In March 2021, we began this Phase 2 Randomized, Window of Opportunity trial evaluating clinical and biological effects of intratumoral INT230-6 against no treatment (the standard of care) in early-stage breast cancer awaiting surgery. The primary endpoint is the proportion of patients who achieve a complete cell cycle arrest, defined as a reduction in the proportion of cells staining positive for Ki67, a widely used marker of cancer cell proliferation.

•        Clinical Data Demonstrates the Anti-Cancer Activity in Humans in Multiple Cancers of Our Lead Product Candidate.    INT230-6 has already generated solid evidence of activity as a single agent in clinical studies. Localized and abscopal effects have been observed in several patients. Tumor regressions with killing of the cancer cells is widely observed in injected lesions. Many patients who had exhausted all approved treatments for their type of cancer benefited from our product candidate. Our clinicians have reported tumor stabilization, tumor shrinkage, long periods without new tumors forming, a size reduction of un-injected tumors and a reduction in disease symptoms. These results are observed in combination with low toxicity over a period of several months and even well after our treatment has completed.

•        Increased Survival Observed in Metastatic Disease.    Preliminary data presented at the American Society of Clinical Oncology (ASCO) 2022 indicates patients receiving INT230-6 appear to live longer compared to historical data for subjects in Phase 1 basket studies as reported in the literature.

•        Acceptable Safety Profile of the New Drug/Treatment Approach to Date.    As of December 31, 2022, there have been 820 injections of INT230-6 into 238 tumors, including 502 injections into visceral tumors deep in the body. Injection locations include the pancreas, liver, lung, and lymph nodes. No maximum tolerated dose has been reached. In our study IT-01 in metastatic patients most adverse events are minor grade 1 or 2; a total of 10 patients out of 110 (9.1%) have had a grade 3 event. The primary grade 3 events have been pain, anemia, rash, fatigue vomiting, dehydration and dizziness. There has been one grade 4 adverse event, a decrease in the number of neutrophils, the most common type of white blood cell that contributes toward the healing of damaged tissues and resolving infections. There have been no grade 5 adverse events up to our recommended maximum doses. Please see Table 1 and 2 in the “Results from IT-01 Phase 1/2 Clinical Trial” portion of our “Business” section on page 67 of this prospectus for more information. We believe the safety profile consists of mainly low grade related adverse events because the drug primarily stays in the tumor and the potent agents do not disperse throughout the body. Measurement of the amount of the drugs seen in the blood (pharmacokinetics or PK) indicates that more than 95% of the drug that is dosed remains in the tumor.

•        Fast Track Designation from FDA for INT230-6 in Triple Negative Breast Cancer.    On April 17, 2019, we announced that the FDA granted Fast Track Designation to our development program evaluating INT230-6 for the treatment of patients with relapsed or metastatic triple negative breast cancer (mTNBC) who have failed at least two prior lines of therapy. This important regulatory designation is based on the promising data observed to date from use of INT230-6 in our breast cancer research. This Fast-Track Designation (FTD) allows us to work more closely with the FDA to develop our new cancer treatment approach most effectively and efficiently for the indication reviewed by the FDA. The FTD may help us determine other potential indications or uses to pursue for INT230-6 in breast cancer.

•        Phase 3 Program Sarcoma Study Designed and Discussed with FDA.    Given the positive preliminary data on survival seen in our metastatic study in sarcoma patients, in August 2021 we requested a meeting with the FDA to discuss our Phase 3 program. The FDA granted us a meeting date and we met with FDA on October 14, 2021. We presented our existing sarcoma data and discussed our protocol synopsis. At the conclusion of that meeting, we believe there was alignment with FDA on the Phase 3 patient population, control groups and overall statistical design. We initiated drafting of the Phase 3 protocol based on that meeting. We have contacted contract research organizations to help manage the trial. The Phase 3 trial can only begin after final review and approval of the protocol and other IND documents by FDA. Depending on funding, we anticipate that the study could begin (assuming an acceptable FDA review and no disruptions) in 2023.

•        A Results-Oriented Organization.    We are committed to reporting data generated from our clinical trials and presenting such data at medical conferences. We were selected for three posters and two discussion sessions at ASCO in June 2022. We also had several new data presentations in the fourth quarter of 2022. Two presentations were made at the annual Society for Immunotherapy of Cancer (SITC) in early November. The first presentation was of INT230-6 alone or in combination with Keytruda and the other presentation was new data from the INVINCIBLE study made by Professor Angel Arnaout M.D. from

the Ottawa Hospital Research Institute . Also, at SITC Professor Jacob S. Thomas M.D. from USC presented the latest data from our clinical trial testing INT230-6 alone or the combination of INT230-6 and Keytruda. At the Connective Tissue Oncology Society (CTOS) meeting in mid-November (held live in Vancouver BC Canada) Professor Christian Meier M.D. from Johns Hopkins’ Sydney Kimmel Cancer Center made an oral presentation on our results using INT230-6 alone or in combination with Yervoy in a highly refractory sarcoma patient population. Finally, in December 2022, new results in presurgical breast cancer from the INVINCIBLE study were made at the San Antonio Breast Cancer Symposium (SABCS). The data was selected for a Spotlight oral discussion session. In the session an independent academic clinical oncologist from the University Texas (UT) presented live the study design and newest results to a large audience. Dr. Arnaout from the Ottawa Hospital was then invited onto to the podium to answer questions about the study results.

We anticipate initiation of our Phase 3 programs as well as the selection of a next generation product candidate in 2023 (pending funding). Clinical manuscripts containing results from our on-going studies are in draft.

•        A Company Focused on Reaching the Market with its Lead Product Candidate.    We are focused. To reach the market our product candidate requires a significant amount of work including animal safety studies, toxicology studies, communication with regulatory authorities, manufacturing development, quality testing, assay development, manufacturing scale up, production, and stability testing all of which has been conducted. We are now preparing for the last portion of development — Phase 3 clinical trial testing. We have navigated to this point by being nimble and allocating resources properly with the objective of generating the data necessary to advance our product candidate and technology platform forward under the best circumstances possible.

Our Strategy

We believe our approach may overcome some of the inherent problems of treating cancer with less toxicity. We intend to apply our deep understanding of novel drug delivery to create a range of new direct killing and immune-activating products candidates while focusing on our lead clinical program. If successful, we hope to fundamentally change the way cancer is treated for multiple cancer types in both the metastatic and presurgical disease settings.

We seek to build a company that develops and commercializes a new medicine and treatment methodology. By applying a disciplined focus on product development, we seek to transform the lives of cancer patients and change the very essence of cancer treatment.

Our objective is for patients to overcome their cancer without harm, to live a long life with high quality and to eliminate the fear of disease recurrence. We maintain a culture of high integrity that embraces the patient and their caregivers. A simple strategy: taking care of the patient will benefit all stakeholders.

Key elements of our strategy include:

•        Focus our resources to aggressively pursue the research and development of our novel medicine to transform patient lives.

•        To always remember that taking care of and benefiting the patient is the most important element to being successful.

•        Manage costs well by outsourcing research and development to qualified, academic, private or government laboratories or hospitals to leverage outside expertise while always maintaining our know-how, skill sets and intellectual property.

•        Build an internal team of experienced industry veterans that can work independently and who know how to get the product development job done.

•        Create a large body of rigorous data, publications, presentations, collaborations and training materials.

•        Continuously find better methods to communicate to the medical community and patients of the power of our new approach.

•        Continue our commitment to precision medicine and personalized care for each and every patient.

•        Assure that our technology is fully understood, explored, and used as designed.

Market Opportunities for Our Product Candidates

The development of a tumor is a complex biological process involving uncontrolled cellular division and growth. Cancer arises from mutations in our own cells. When such cellular alterations happen the immune system often cannot distinguish between cancer and healthy cells. Cancer cells adapt to evade and thwart immune cells in several ways and can thus grow unchecked.

According to the American Cancer Society, in 2022 there will be an estimated 1.9 million new cancer cases diagnosed and 609,360 cancer deaths in the United States. Cancer is the second most common cause of death in the U.S. after heart disease. According to the American Society of Clinical Oncology’s journal, the ASCO Post, the national cost of cancer care in the United States is expected to rise to $246 billion by 2030. As healthcare costs in general continue to escalate, expenses due to cancer are a major contributing factor.

Metastatic Disease

The overwhelming, unmet medical need is better treatment of solid tumors; 90% of cancer patient deaths are due to solid tumors. Unfortunately, even with the best new therapeutic agents, the long-term survival rates for inoperable or metastatic cancer are extremely low (often single digits) and toxicity (the collateral damage to the patient’s health) is debilitating.

Five-year Survival Percentage Rates for Metastatic, Late Stage Cancers

____________

*        For cancers that have moved to distal sites

From data sources: Surveillance, Epidemiology, and End Results National Cancer Institute, SEER 5-Year Relative Survival Rates, 2011–2017

In late stage, metastatic disease, tumors often become resistant to all therapies, even after the agents have provided some efficacy benefit. The reality today for many cancer types is that if the disease is detected late, most treatments are highly toxic and few approaches provide patients with much hope of long term survival. Even with good outcomes, whether by surgical, chemical, radiative or ablation methods, the treatment is invasive, has severe side effects, damages the body and is mentally demanding on patients and their families.

Local Disease

Today, the annual number of interventional oncology procedures in the U.S. alone are estimated in the millions. For example, the majority of breast cancer tumors identified are local to the breast or are regional. As a result, there are 170,000 lumpectomies performed in the U.S. each year. Dr. Roshni Rao, Chief, Breast surgery program, at New York-Presbyterian/Columbia University Medical Center wrote in the Cancer Letter that “although lumpectomy is the best option for many breast cancer patients, with 170,000 procedures performed annually, it is not perfect. All too often, a post-operative pathology report shows that while the surgeon may have removed the entire tumor, a second surgical procedure is needed to clean up lingering cancer cells. Known as re-excision, it occurs in roughly 20% to 25% of cases, on average. It is critical for surgeons and their patients to have access to the latest innovations, once demonstrated effective by clinical research, be used wherever and whenever possible.” Our drug candidate’s potential to kill cancer quickly prior to surgery and engage an anti-cancer immune response may provide a higher percentage of patients a greater five year event-free survival for a number of tumor types.

Breast Cancer

About 1 in 8 U.S. women (about 13%) will develop invasive breast cancer over the course of her lifetime. An estimated 287,850 new cases of invasive breast cancer are expected to be diagnosed in women in the U.S. during 2022, along with 51,400 new cases of non-invasive (in situ) breast cancer. Breast cancer is the most commonly diagnosed cancer among American women. In 2022, it was estimated that about 30% of newly diagnosed cancers in women would be breast cancers. Breast cancer became the most common cancer globally as of 2021, accounting for 12% of all new annual cancer cases worldwide, according to the World Health Organization.

Approximately 11-17% of breast cancers test negative for estrogen receptors (ER), progesterone receptors (PR), and excess human epidermal growth factor receptor 2 (HER2) protein, qualifying them as triple negative. TNBC is considered to be more aggressive and have a poorer prognosis than other types of breast cancer, mainly because there are fewer available targeted medicines. Patients typically receive chemotherapy. According to a study published in the Journal of Clinical Oncology, patients who fail two lines of therapy for TNBC typically progress within nine weeks. Those who have failed three lines progress within four weeks.

Sarcoma

Soft tissue sarcoma is a broad term for cancers that start in soft tissues (muscle, tendons, fat, lymph and blood vessels, and nerves). These cancers can develop anywhere in the body but are found mostly in the arms, legs, chest, and abdomen. There are many types of soft tissue tumors, and not all of them are cancerous.

There are many types of sarcoma; however, the three most common are bone sarcoma (referred to as osteosarcoma), leiomyosarcoma and liposarcoma. Leiomyosarcoma is a type of sarcoma that grows in the smooth muscles. The smooth muscles are also in the hollow organs of the body, including the intestines, stomach, bladder, and blood vessels. In females, there is also smooth muscle in the uterus. When sarcoma is metastatic prognosis is poor; even with chemotherapy, half of people diagnosed with metastatic disease die within 15 months. Each year, 12,000 people in the U.S. are diagnosed with soft tissue sarcomas. About 3,000 patients have bone sarcomas.

Cancer Treatment

There is a high unmet medical need for improved cancer treatments. Currently, early detection coupled with surgery and systemic chemotherapy is the most effective treatment against most cancers. For metastatic disease, systemic chemotherapy represents the backbone of treatment for many cancers. However, chemotherapeutic resistance often results in therapeutic failure and eventually death. Not only is chemotherapy often ineffective for cancers that exhibit such resistance, but this approach is also highly toxic for many patients (Cancer Cell Int. 2015; 15:71). Almost all of the current anti-cancer drug therapies load drug throughout the entire body including classic chemotherapy before surgery (neoadjuvant), after surgery (adjuvant), targeted therapy, antibodies or antibody drug conjugates, liposomal or nanoparticle delivered drugs. Many cancer cells in tumors are located away from blood vessels (referred to have hypoxic regions) and systemic administration is ineffective at delivering the needed amounts of the medicine to all parts of the tumor. Thus, a significant limitation of the current anti-cancer treatments is proper drug delivery. Another challenge for systemic approaches is poor absorption or cellular mechanisms in the cancer cell to remove the drugs.

Immunotherapy

There has been much media and news reporting about the promise of immunotherapy in treating cancer. These novel product candidates are designed mobilize an immune system to attack the cancer. The field of cancer immunotherapy has become the primary focus of treatment for many tumor types. There is significant interest from pharmaceutical companies, physicians and patients in advancing new, immune-based treatment concepts. For the first time, some patients having a variety of formerly fatal cancers are experiencing long term survival benefit. Immunotherapy has shown promise against the most mutated cancers such as melanoma, renal cell carcinoma, squamous cell carcinomas and a subset of lung cancers. Often these new immune stimulating drugs work in patients having high levels of specific markers, such as the percentage of a protein on the surface of the cancer cell known as PD-L1 or the number of genetic mutations that may have caused the cancer referred to as a tumor’s mutational burden.

Unfortunately, immunotherapy has not worked well for the majority of solid tumor types, including the deadliest cancers such as sarcoma, pancreatic cancer, of the majority of colon cancers, triple negative breast cancer and brain cancer. Sometimes when using immunotherapies, the immune system has trouble distinguishing cancer from normal tissue and attacks healthy cells. Thus, the immune therapies induce side effects. To enable more patients to benefit from immunotherapy, new technologies that are able to improve recognition of the cancer by the immune system, or disrupt the tumor’s ability to evade immune cells, are critical and strongly needed.

Challenges Facing Current Treatments

We believe that an effective cancer treatment must overcome three major problems.

1.       The diverse nature of the disease:    In most patients, there are two populations of the cancer with different physical properties. The local component is comprised of the well-defined, visual large tumors, seen in x-ray or imaging scans, that invade organs and tissue. The systemic aspect is comprised of cells circulating or implanted throughout the body. Essentially cancer is often simultaneously both microscopic (unseen) and macroscopic (seen).

2.      Unreachable parts of tumors:    Current methods of delivering cancer drugs either orally or intravenously (IV) do not reach many portions of tumors due to a lack of blood supply. These areas are referred to as hypoxic (low oxygen) regions. These areas of the tumor can also impede the influx of immune cells. IV or system dosing of cytotoxic agents suppresses the systemic immune system (Mathios et al, STM 2016) and reduces the potential of immunotherapies.

3.      Lack of immune cell recognition and activation by tumor processes to evade:    Immune cells have difficulty recognizing/distinguishing cancer cells from normal cells. Cancer also can cloak itself from the immune cells and create barriers to reduce their influx into the tumor.

Our Treatment Approach

Our treatment concept pioneers a new approach to treating cancer — kill tumors in the body (in situ) to create from the patient’s own cancer a recognizable, high-quality material (referred to as antigen) for better immune cell engagement against the cancer (immunological cell kill).

Our new treatment concept is to diffuse potent drugs throughout the tumor to saturate the tumor with strong killing agents. The active agents themselves used in our product candidate also have properties that improve immune recognition of the cancer. At the right dose our product candidates can completely saturate an injected tumor delivering high concentrations of drug into the cancer cells and killing the tumor. This process removes the cancer’s cloaking system, decreases the barriers to immune influx and activates a body-wide anti-cancer immune response to attack the uninjected tumors and unseen metastases. Our clinical data suggests that not all tumors need be injected for long term disease control.

Through our novel, drug treatment technology, we hope to transform the lives of patients with cancer. Our objectives are to increase patient longevity, reduce side effects, remove the fear of treatment, empower the patient, and minimize the risk of disease recurrence.

INT230-6, Our Lead Product Candidate

Our product candidate, INT230-6, consists of two proven anti-cancer cytotoxic agents mixed with a penetration enhancing amphiphilic molecule (SHAO), the chemical structure of which is shown in figure 3 below. When injected into tumors, INT230-6 can kill the tumors. Our safety studies show that if the drug is (accidently) injected into healthy tissue there is no observation of damage. The drug agents enter the blood stream at low doses. The unique amphiphilic SHAO compound formulated product candidate increases the dispersion of the drug throughout the tumor following intratumoral injection. Our technology is novel and unique. For those familiar with drug delivery technologies in cancer, it is important to note that our product candidate is not a liposome, not a nanoparticle nor an emulsion. INT230-6 is a 100% water-based formulation with tissue dispersion properties that do not destroy cancer cell membranes. We are not aware of any previous anti-cancer drug or prior intratumoral preparation with similar characteristics.

Figure 3 chemical structure of SHAO

The SHAO molecule facilitates drug dispersion throughout the tumor. The molecule allows the tumor to absorb the killing agents and facilitates their diffusion into the cancer cells. Once in the cancer cell one drug cisplatin binds the DNA and causes the cell apoptosis (death) whereas the other agent, vinblastine sulfate, destroys the cell’s tubulin to shut down replication. Data in humans suggests that when administered at the proper drug dose to tumor volume ratio, a significant portion of the injected tumor can be killed on a single dose. In addition, there is evidence (in both animals and humans) that for certain cancers there is an activation of the immune system.

Our intratumoral (IT) technology is different than other IT approaches in four important ways:

1)      We recognized that the composition of a tumor is highly unfavorable to direct injection of water-based products because the tumor has a high fat content and is under surrounding pressure. To be effective, an IT drug must disperse, be absorbed by the tumor and enter the cancer cell. Without our unique formulation chemistry water soluble drugs are not readily dispersed or absorbed by a tumor.

2)      Our delivery technology is based on a proven science that uses amphiphilic molecules to transport drugs through tissue. The active drug agents in our lead product candidate (cisplatin and vinblastine sulfate) are established, commercial, potent killing agents with immune stimulating properties that as of now are only sold as IV products. Both cisplatin and vinblastine sulfate have dual direct killing and immune activating mechanisms of action. Cisplatin binds to DNA to cause apoptotic cell death and also attracts and binds T-cells via TL9 receptors. Vinblastine sulfate destroys tubulin to stop replication and also induces dendritic cell maturation.

3)      Unlike other IT products, our product candidates have multiple opportunities well beyond skin tumors, such as melanoma. Our lead product candidate, INT230-6, has shown the ability to kill tumors deep in the body such as in the liver, lung, and peritoneum. The product candidate has also demonstrated ability to kill tumors from several cancer types with abscopal effects and increased overall survival.

4)      Our product candidate has potential to kill tumors quickly and could be used before surgery immediately after diagnosis or for treatment of cancers where there are no therapeutic agents or suitable local treatments available.

INT230-6 in Animals

Our first research studies in mice were conducted with organizations that provide services under contract, referred to as contract research organizations (CROs). Our Company collaborated with the Vaccine Branch of the National Cancer Institute (NCI) in Bethesda, MD. The research with the NCI was established after the National Institutes of Health awarded our Company a cooperative research and development agreement (CRADA). The program was quite successful and culminated with the publication of a paper in July 2019 that we jointly authored with the NCI. In that publication we reported that INT230-6 treatment resulted in regression from baseline in 100% of the tumors and complete response in up to 90%. Experiments showed a critical role of T-cells in promoting complete tumor regression. Mice with complete response were protected from subcutaneous and intravenous re-challenge of cancer cells. Thus, immunological T-cell memory was induced by INT230-6.

As part of our own research, we formulated cisplatin in water without the SHAO and added a noncolloidal dye. When injected into a human pancreatic tumor grown in a mouse model, we observed that the water formulation of the drug without the SHAO was not absorbed in the tumor. The liquid mostly leaked from the tumor. However, the formulation that incorporated SHAO was readily and rapidly absorbed by the tumor in a dose dependent manner as shown in figure 4 below.

Figure 4 Comparison of drug dispersion/absorption in tumors with and without our DfuseRx technology.

Dense human pancreatic cancer BXPC-3 tumors were grown in severe combined immunodeficiency mice. Injections using a metered pump of the cisplatin with dye in water were compared to INT230-6 with dye. Fourteen mice were treated. INT230-6 is well absorbed and distributed throughout tumors (right side images) compared to the drug alone in water which leaks out (left side images). Data published in the International Journal of Molecular Sciences June 2020 doi.org/10.3390/ijms21124493.

In addition to formulation experiments we conducted growth inhibition experiments using large tumors (>300 mm3) and treated with low drug doses. Typically, research conducted by other companies developing cancer products use small tumors (25 to 100 mm3). Such companies also often use large drug doses in their studies with drug amounts that are five to fifty-fold above our dose amounts. Our product candidate can completely eradicate murine tumors, an effect that is termed a complete response (CR). Most competitors show only a slowing down of the tumor’s growth rate over time.

INT230-6 regresses tumors over time as shown in figure 5 panel A and extends animal life compared to the drugs given alone intratumorally at the same dose without our technology. In addition, our drug candidate shows superior efficacy given intratumorally compared to dosing the drugs intravenously. Often animals with a CR are permanently protected against the cancer. This means upon re-inoculation with the same cancer new tumors do not grow. The protective effect happens whether the cancer cells are reinoculated under the skin or administered intravenously indicating a broad systemic immune protection.

Through our research collaboration with the NCI, we generated data regarding the mechanism of action for our lead product candidate. INT230-6 shows direct tumor killing and immune cell activation. The direct tumor cell death is caused by action of the two potent agents (cisplatin and vinblastine sulfate). Data generated to date indicates infiltration of dendritic cells into the tumor which can present antigen to activate CD8 and CD4 immune T-cells against the cancer. Survival and tumor eradication are mostly driven by CD8+ T-cells. Thus, our product candidate generates high quality, vaccine-like antigen from the attenuated tumors to promote the immune activation. The Company also published data showing increases in dendritic cells, macrophage, T-cells and Natural Killer (NK) cells 10 days after intratumoral treatment in mouse colon tumors. Selective immune depletion of CD4 and CD8 abrogates the therapeutic effect. Figure 5 panel B that shows the influx of various immune cell into the tumor microenvironment.

The scope of the NCI studies was to assess growth inhibition, survival and immune activation. Naïve mice were SC challenged with 1 × 106 C26 cells into the right flank. Vehicle or INT230-6 (0.5 mg/ml cisplatin, 0.1 mg/ml vinblastine sulfate, 10 mg/ml IT-006 cell penetration enhancer) were intratumorally (IT) administered into 300 mm3 (approx. 8.5 mm in diameter, 100 μl/400 mm3 C26 tumor) SC tumors (n = 10/group) for 5 sequential days (day 0 to 4) and tumor growth was monitored. The fraction 5/10 indicates the number of complete responders. The log rank test indicates a significant difference between the groups (p<0.0001).

Figure 5 Mouse data showing tumor reduction and immune activation

In Panel A on the left, 100% of animals receiving INT230-6 treatment for 5 days have a slight increase followed by a decrease from baseline, with 50% of animals having a complete response compared to no treatment controls with no decrease or complete responders (data generated by the NCI see OncoImmunology 2019 Vol 8 No 10; 15). Panel B cell staining shows an increase in the immune infiltrates. Data from Int. J. Mol. Sci. 2020, 21, 4493.

INT230-6 is Synergistic with Checkpoint Blockade

Nature has created checkpoints on the immune system to regulate the activity of the immune cells. These pathways are crucial for self-tolerance to prevent the immune system from attacking healthy cells indiscriminately. Large pharmaceutical companies such as Merck, Roche, AstraZeneca, Pfizer and Bristol Myers Squibb (BMS) have developed new types of anti-cancer anti-body drugs with the ability to modify and block the checkpoints on the immune system.

Our results show strong benefit in regressing tumors with the combination of INT230-6 and checkpoint inhibitors which leads to improve survival. The data showed the combination of our product candidate with either anti-PD-1 or CTLA-4 antibodies in a dual tumor (metastatic) cancer mouse resulted in additive benefit. The data was generated by our partners at the National Cancer Institute and under our CRADA and published (OncoImmunology 2019 Vol 8 No 10; 15).

Preclinical Good Laboratory Practice (GLP) Safety of INT230-6

During a pre-meeting in 2014 with FDA we reached agreement on an accelerated safety and manufacturing program. We successfully completed the needed tasks to begin clinical testing that included conducting pharmacology studies (showing activity of the drug), toxicology studies in two animal species, analytical methods development, manufacturing scale up, and regulatory submissions. All these steps were completed by 2015. The data showed that the use of SHAO did not change or increase the toxicity of cisplatin or vinblastine sulfate. Analytical results showed the two drugs remain unchanged chemically when INT230-6 is stored properly, which is in a standard freezer at -20°C.

Pre-Clinical Regulatory Interactions

In the United States, the U.S. Food and Drug Administration (FDA) regulates drug and device products under the Federal Food, Drug, and Cosmetic Act and its implementing regulations. The primary mode of action for our product candidate is expected to be attributable to the two drug components. Since our product candidate consists of small molecules, the FDA’s Center for Drug Evaluation and Research has primary jurisdiction over our product candidate’s pre-market development and review. Please see the section entitled “Risk Factors” for a description of some of the uncertainties regarding the timing or outcome of the regulatory approval process relating to our technology. We have been working closely with the Division of Oncology 1 (DO1), which is responsible for breast, gynecologic, and genitourinary cancers. We are working with the Division of Oncology 3 (DO3) to conduct a Phase 3 clinical trial of INT230-6 in patients with sarcomas.

As noted above, we met formally with the FDA (DO1) in a pre-investigational new drug application (pre-IND (as defined below)) Type B meeting in August 2014 and then completed the agreed upon preclinical safety program on INT230-6. We filed our investigational new drug application (“IND”) application and held a meeting with senior FDA officials in November 2016. In December 2016 FDA provided us a “Study May Proceed” letter.

We also met formally with the Canadian regulatory agency Health Canada (HC) in a preclinical trial application (CTA) meeting in 2016. We filed the CTA and held meetings with senior HC officials. Health Canada provided us a “No Objection” letter in early 2017. As we have progressed our study, we filed several amendments since 2017 and have received “No Objection Letters” each time from Health Canada. We have been treating patients continuously under both our IND and CTA since May 2017.

The regulatory agencies agreed to permit setting the drug dose based on tumor volumes rather than using alternatives such as dose based on a patient’s height and weight. Our belief is that using the patients’ total tumor burden instead of body size is a more personalized and precise approach to ensure that patients receive an appropriate dose for their unique cancer burden. Better dosing could lead to maximized efficacy with minimized side effects. In our clinical trial, tumor volume is calculated from radiographic imaging on target tumors at baseline. Dose for a given tumor is set based on its size.

IT-01 Phase 1/2 Clinical Trials

Our first study (IT-01), which began in 2017, is entitled “A Phase 1/2 Safety Study of Intratumorally Administered INT230-6 in Adult Subjects with Advanced Refractory Cancers”. The study design permits our product candidate to be tested in several different cancer patient populations with dosing into both superficial e.g. squamous cell, thyroid, breast, head and neck, lymphoma, melanoma and deep body tumors such as those found in pancreatic, liver, colon, bile duct, sarcoma, and chordoma cancers. The clinical trial seeks to determine the safety and potential efficacy of dosing INT230-6 directly into several types of cancers. We have tested our product candidate in 19 different tumor types. The Phase 1 portion of the study completed in July 2020 and the phase 2 enrollment completed in June 2022.

Study, IT-01, is listed on clinicaltrials.gov; NCT03058289. The hospitals that enrolled patients in the United States are: the Sydney Kimmel Cancer Center at Johns Hopkins, The Fox Chase Cancer Center at Temple University, the Norris Cancer Center, LA County and HOAG Presbyterian Hospitals of the University of Southern California medical system, the UMASS Memorial in Worchester Massachusetts, Columbia Presbyterian in New York, the Princess Margaret Hospital which is part of the University Health Network in Toronto, and the Houston Methodist.

Since the initial regulatory submissions, we have made six amendments to the IT-01 protocol. The most recent amendment simplified setting dose and eliminated blood collection for pharmacokinetic evaluation as dose escalation was completed and focus is now on the Phase 2 expansion cohorts including 4 cohorts with Merck’s Keytruda® (pembrolizumab) and 3 cohorts with Bristol Myers Squibb’s Yervoy® (ipilimumab). A schematic of the Phase 2 study’s three final dosing cohorts is shown in figure 6 below.

Figure 6 Schema of the 3 final dosing groups for the metastatic study IT-01.

Clinical Collaborations

Merck Partnership

On June 25, 2019, we announced entering into an agreement with Merck Sharpe and Dohme to evaluate the combination of our lead product candidate INT230-6 and KEYTRUDA® (pembrolizumab), Merck’s anti-PD-1 (programmed death receptor-1) therapy, in patients with advanced solid malignancies including pancreatic, bile duct, squamous cell and non-MSI high colon cancers. Keytruda annual sales in 2020 are tracking to exceed over $12 billion. INT230-6 is highly synergistic with anti-PD-1 antibodies in mice. Survival and tumor response are significantly increased using the combination. One squamous cell carcinoma patient in our monotherapy study, who was recommend for arm and shoulder amputation prior to beginning INT230-6, received 4 doses of INT230-6 from March to July of 2018. That patient had a following treatment with pembrolizumab, (outside of our study) and subsequently had a complete response.

On October 31, 2019, we announced that the first patient has been dosed with a combination of INT230-6, and Keytruda. The combination is being studied in a series of cohorts within our ongoing Phase 1/2 international clinical study (NCT03058289). On March 30, 2020, we announced successful completion of the safety lead in portion of the IT-01 KEYNOTE A10 study arm (NCT03058289) that is testing the combination for safety. The cohort treated seven patients with different types of advanced cancers that were amenable to superficial injections including triple negative breast cancer (n=3) Merkel cell carcinoma, chordoma, desmoid tumor, and soft tissue sarcoma. Patients’ tumors were treated every two weeks for 5 doses with INT230-6 in combination with 200 mg of Keytruda every three weeks. All seven patients completed the 28-day dose limiting toxicity (DLT) evaluation period with no DLTs or drug-related serious adverse events. The safety profile appears to be similar to INT230-6 monotherapy. Following completion of the dosing of INT230-6, patients continued Keytruda monotherapy for up to 2 years. Scans were collected regularly on patients to evaluate the efficacy of the combination. In the study cohort dosing INT230-6 with Keytruda as of September 30, 2022, there was a total of three grade 3 treatment related adverse immune events reported; one episode of a gamma glutamyltransferase increase, one rash and one aspartate amino tranferase increase. Please see Table 1 in the “Results from IT-01 Phase 1/2 Clinical Trial” portion of our “Business” section on page 67 of this prospectus for more information. There were only 3 of those same immune events of grade 1 along with one grade 2 hypothyroidism and a grade even of systemic inflammatory response syndrome. All patients recovered.

The study steering committee, which is comprised of the principal investigators, reviewed the safety data and approved dosing into deep tumors and authorized initiation of the Phase 2 studies. The KEYNOTE A10 Phase 2 studies are enrolling patients with pancreatic cancer, microsatellite stable colorectal cancer and cholangiocarcinoma. These cancers are typically immunologically cold and historically non-responsive to immunotherapies. We also plan to test the combination in squamous cell carcinoma patients who have already failed a PD1/PDL1 agent.

Pursuant to our agreement with Merck, we are the sponsor of the clinical trial and are responsible for the costs of conducting it, and Merck will supply KEYTRUDA® for use in the clinical trial at no charge to us. The agreement does not provide for any milestone payments, royalties or other compensation to be paid to either party. The agreement provides for joint ownership of any inventions, clinical data and results solely generated in the combination portion of the clinical trial that relate to the combined use of the two drugs. Merck will solely own any inventions generated in the clinical trial that relate solely to KEYTRUDA® and all data resulting from testing performed by third parties engaged by and on behalf of Merck for some samples collected during the clinical trial. We will solely own any inventions generated in the clinical trial that relate solely to INT230-6, clinical data resulting from the use of INT230-6 as a monotherapy, and from all data resulting from testing performed by or on behalf of us on samples collected during the clinical trial. The term of the agreement will continue until delivery of the final report for the clinical trial, provided that either party may terminate the agreement due to the other party’s uncured material breach, a violation of anti-corruption obligations, patient safety concerns, regulatory action that prevents supply of such party’s compound, or such party’s termination of its compound’s development or withdrawal of its compound’s regulatory approval. Enrollment in the study was completed in June of 2022. Merck could have terminated the agreement if we failed to make any changes to the clinical trial protocol regarding the use of KEYTRUDA® that would have been requested by Merck in good faith to address any concern raised by Merck that KEYTRUDA® was being used in the clinical trial in an unsafe manner. No such concerns were raised by Merck and the study team is drafting the final report.

Bristol Myers Squibb (BMS) Partnership

On April 14, 2020, we announced that we had entered into a clinical trial collaboration agreement with Bristol Myers Squibb Company. The program evaluates the safety and efficacy of our lead product INT230-6, in combination with Bristol Myers Squibb’s Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) immune checkpoint inhibitor Yervoy® (ipilimumab). The combination is being evaluated in patients with breast cancer, liver cancer and advanced sarcoma in Phase 2 cohorts within IT-01, our ongoing Phase 1/2 clinical trial. We sponsor and conduct the clinical trial and Bristol Myers Squibb supplies Yervoy for use in the study. Yervoy is an immunotherapy approved in melanoma and in combination with nivolumab in other indications as well. The most common severe immune-mediated adverse reactions from Yervoy (ipilimumab) are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of Yervoy.

Yervoy sold nearly $1.040 billion in the first six months of 2022 and primarily treats melanoma or kidney cancer. In 2018, Dr. James Allison won the Nobel Prize for recognizing that a protein on immune cells named CTLA-4 stopped immune cells from fighting cancer. Dr. Allison helped develop Yervoy to block CTLA-4 and unleash immune cells against cancer. Yervoy is quite potent, but has a relatively high percentage of severe side effects. We believe that improved recognition of cancer by the immune system, which our product candidate enables, may reduce the toxicities of the immune regulating agents and boost efficacy.

In the Yervoy combination arm of our trial, INT230-6 injections are given every 2 weeks for 5 sessions at fixed maximal dose into superficial or deep tumors, unlimited number of tumors to be treated per session with retreatment once every 9 weeks for two years. Yervoy (ipilimumab) is dosed concurrently starting at Day 1 every 3 weeks for four treatments for selected cancer types breast, liver and sarcoma. The types of cancers being evaluated in the combination arm of our study with Yervoy are sarcoma, liver and breast cancers. We are comparing our drug candidate alone to the combination in each of the cancer types. As of June 30, 2022, there have been only two treatment related adverse events one treatment related immune adverse event of grade 3 in the combination of INT230-6 with Yervoy (colitis). Please see Table 1 in the “Results from IT-01 Phase 1/2 Clinical Trial” portion of our “Business” section on page 67 of this prospectus for more information.

Pursuant to our agreement with BMS, we will sponsor, conduct and fund the Phase 1/2 trial, and BMS is obligated to supply Yervoy to us for no cost. The agreement does not provide for any milestone payments, royalties or other compensation to be paid to either party. The agreement provides for joint ownership of any inventions, clinical data and results solely generated in the combination portion of the clinical trial that relate to the combined use of the two drugs. BMS will solely own any inventions generated in the clinical trial that relate solely to Yervoy and all data resulting from testing performed by third parties engaged by and on behalf of BMS for some samples collected during the clinical trial. We will solely own any inventions generated in the clinical trial that relate solely to INT230-6, clinical data resulting from the use of INT230-6 as a monotherapy, and from all data resulting from testing performed by or on behalf of us on samples collected during the clinical trial. After the completion of the Phase 1/2 trial, we are obligated to provide BMS with a final report of the data resulting from the trial. Our agreement with BMS will terminate upon the completion of the Phase 1/2 trial, the delivery of a final report containing the data resulting from the combination cohort of Yervoy and INT230-6. Either party may terminate the agreement upon a material breach by the other party that remains uncured following written notice of such breach or upon certain bankruptcy events. In addition, either party may terminate the agreement immediately upon written notice if such party reasonably deems it necessary in order to protect the safety, health or welfare of subjects enrolled in the Phase 1/2 trial, or if a clinical issue arises with respect to INT230-6 or Yervoy that adversely impacts the ability to conduct the Phase 1/2 trial.

IT-02 (The INVINCIBLE Study)

In March 2021, we began this Phase 2 Randomized, Window of Opportunity trial evaluating clinical and biological effects of intratumoral INT230-6 against no treatment (the standard of care) in early stage breast cancer patients awaiting surgery. The primary endpoint is the proportion of patients who achieve a complete cell cycle arrest, defined as a reduction in the proportion of cells staining positive for Ki67, a widely used marker of cancer cell proliferation. The study design is shown in the figure 7 below. According to our estimates using the National Cancer Database (NCBD), approximately 39% of diagnosed with breast cancer nearly 100,000 patients have no therapeutic treatment following diagnosis. Women undergoing surgery typically wait approximately 2 to 5 weeks to have the procedure.

The trial is a two-part Phase 2, randomized, open label, multi-center study that has completed enrollment of 91 patients with early-stage breast cancer. In part 1 twenty-nine patients were randomized 2:1 to treatment or no treatment. Those in treatment, received either up to three doses of INT230-6 on days 1, 8 and 15 post diagnosis or no treatment, the current standard of care (SOC) prior to resection. Part 2 of the study randomized patients 2:1 to one injection of either INT230-6 or saline solution. The Study is being conducted under the direction and supervision of Principal Investigator, Dr. Angel Arnout. Dr. Arnout is performing all those responsibilities assigned to principal investigators for personal performance by applicable Health Canada (HC) regulations. The study is evaluating the various responses in the tumors compared to the standard of care or a placebo. The primary endpoint is the proportion of patients who achieve a reduction in the proportion of cells staining positive for Ki67, a widely used marker of cancer cell proliferation, as assessed by immunohistochemistry. Other important endpoints are the percent of tumor death (necrosis) achieved comparted to placebo injection. The Ottawa Hospital will conduct subject enrollment and treatment and evaluate clinical responses, OICR will analyze subject immune responses and conduct biomarker analyses and Ozmosis will manage the data and study in Canada. Intensity will fund the trial and provide INT230-6 supply. Our agreement with OICR, the Ottawa Hospital Research Institute and Dr. Arnout does not provide for any milestone payments, royalties or other compensation to be paid to any party. The agreement provides that each party will solely own any inventions generated in the clinical trial that relate solely to intellectual property owned by that party. Any party may terminate the agreement upon notification that the trial has completed, any party has committed a material breach of the agreement or upon certain bankruptcy events.

Figure 7: Schema for the INVINCIBLE Study in Ontario, Canada

Results from IT-01 Phase 1/2 Clinical Trial

Safety

The Phase 1/2 study has been treating refractory patients, who have failed multiple lines of therapy since May of 2017. Sixty-seven (67) subjects were treated in the Phase 1 escalation portion of study IT-01, which is now complete. The results of the escalation portion, which included up to 175 mL per session every two weeks, indicated a favorable safety profile of INT230-6, with only 8 patients experiencing grade 3 related adverse events in Phase 1. The most frequent related adverse events include localized tumor related pain. The Company has annually submitted safety data from all clinical trials to the FDA and Health Canada. Both regulatory agencies have reviewed the data and have permitted the Company to continue all clinical development programs without comment on safety. The majority of treatment related adverse events have been low grade (grade 1 or 2). As of December 31, 2022, a total of 10 patients out of 110 (9.1%) have had at least one grade 3 related adverse event in study IT-01. The primary grade 3 events have been pain, anemia, rash, fatigue vomiting, dehydration and dizziness. There has been one grade 4 adverse event, a decrease in the number of neutrophils, the most common type of white blood cell that contributes toward the healing of damaged tissues and resolving infections. There have been no grade 5 treatment related adverse events reported. See Tables below for the frequency and severity of adverse events in study IT-01.

Table 1 — Study IT-01 Treatment Related Adverse Events (Grade 3 or Higher)

Study IT-01 Treatment Related Emergent Adverse Events (Grade 3 or Higher)(1)

____________

(1)      Except as otherwise noted, adverse events listed are Grade 3. The grading of adverse events uses the Common Terminology Criteria for Adverse Events (CTCAE) dictionary, which is a method to categorize adverse events across all clinical trials of five grades; Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life threatening; Grade 5 death.

*        Indicates a sarcoma patient.

Table 2 — Study IT-01 Serious Treatment Related Adverse Events

Study IT-01 Serious Treatment Related Adverse Events(1)

____________

(1)      The protocol defines certain criteria by which an adverse event of any grade may be deemed to be “serious.” This is done to help guide treatment.

Even though our product candidate is dosed directly into the tumor, a key element of safety is to observe how much drug enters the bloodstream. Toxicities are linked to the circulating levels of the active agents in the blood. We measure circulating concentrations of the three main ingredients, SHAO, cisplatin (as platinum metal) and vinblastine sulfate, in the blood. This type of data is referred to as pharmacokinetics or PK. Data that measured the circulating levels of the key ingredients has been generated from the ongoing study in metastatic patients. The amount of vinblastine sulfate seen in plasma of patients is much lower than a lesser dose given IV. Cisplatin is reduced to metal rapidly and is challenging to measure in blood even for IV dosing. A measurement of vinblastine sulfate provides a better understanding of the PK.

In our study vinblastine plasma concentrations increase proportional to the amount of drug administered. In essence the concentration of vinblastine seen in the blood increase proportional to the dose given intratumorally. See figure 8 panel A. This effect is independent of the cancer type and highly reproducible. As would be expected the amount of the vinblastine seen in the plasma when given intratumorally is less than 5% of the blood concentrations had the drug been

given intravenously. Dosing 80 mL of our drug candidate intratumorally contains 8 mg of vinblastine sulfate and results in ~6.8 nanograms of vinblastine in blood plasma at one hour post dose at 6 hours the amount has dropped to about 2.2 ng/mL. Publications show the plasma concentration of a standard dose of vinblastine sulfate (6.5mg for an averaged sized person) can be estimated to be 72 nanograms per mL (ng/mL) at 1 hour (Owelien J. Cancer Res 8/1977). See figure 8 panel B. We estimate from other studies 240 ng/mL at 6 hours for an IV dose of 5.1 mg (Links, M., Cancer Investigation Volume 17, 1999 -issue 7479-485). The blood plasma concentration profile for of vinblastine at various doses indicates that >95% and perhaps 99% of the drug remains or degrades in the tumor post injection. This drug retention in the tumor spares the patient the side effects of circulating drug. Indeed, the low observed plasma levels of the potent agents following INT230-6 dosing correlates with the low grade of side effects observed. Thus, INT230-6 compares favorably to the toxicities normally associated with cisplatin and vinblastine sulfate when given intravenously at comparable doses.

Figure 8 Free vinblastine (VIN) levels in blood plasma over time for intratumorally (IT) administered INT230-6 compared to IV dosing.

Cytotoxic components in INT230-6 have minimal systemic exposure and short half-life. Most of the active drug remains in the tumor as a result INT230-6 appears to have favorable safety data to date.

RECIST

A standard way to measure how well a cancer patient responds to a treatment is based on whether tumors shrink, stay the same, or get bigger. Efficacy assessments for evaluating changes in tumor size in clinical trials are typically conducted with standardized oncology response criteria, for example, Response Evaluation Criteria in Solid Tumors known as RECIST or a newer version 1.1 (RECIST 1.1). There are additional guidelines for immunotherapeutic trials (iRECIST). These criteria measure the change in longest diameter of tumors to assess drug response. An increase in longest diameter of > 20% is considered progressive disease. The rationale behind this is that tumors should generally become smaller. The main benefit of iRECIST is to afford physicians the opportunity to confirm progression with a follow up scan of the tumors 1 to 2 months later. However, both RECIST 1.1 and iRECIST criteria were designed only to assess response to systemic therapies.

Our study initially employed RECIST 1.1, and subsequently, iRECIST methods for determining the efficacy of INT230-6. INT230-6 induced tumor regression in both injected and non-injected lesions in several patients. We have reported data at major medical conferences (ASCO 2021) to indicate that RECIST methodology may not be a good measure of clinical benefit for intratumoral INT230-6.

RECIST 1.1 and iRECIST are not ideal for use with our intratumoral immune based therapy for several reasons. First, the evaluation of injected tumors is complicated by the amount of INT230-6 repeatedly injected and retained in the tumor. Prior to the first efficacy scan, during the first two months (after 5 sessions) of INT230-6 treatment, patients would have received depending on the cohort a dose volume of drug injected into the tumor equivalent to 25% to 250% of the tumor’s volume. As noted above, our data shows a significant percentage of INT230-6 is retained in the tumor, which can increase the tumor size. Second, there is the possibility for immune infiltration. The influx of immune cells also increases tumor size.

Tumor Death (Necrosis)

Investigators report significant necrosis (reduced contrast uptake in the CT image) in many injected tumors including adrenocortical, breast, chordoma, colon, head and neck (H&N), lung, sarcoma and squamous cell. Figure 9 below is an example of a squamous cell tumor that became necrotic by the 2 month scan. The darker contrast of the tumors indicated that significant necrosis of the tumor occurred following treatment.

Figure 9 showing that INT230-6 induces tumor necrosis (death) in the injected tumors.

The patient in these images had a squamous cell carcinoma. His cancer continued to progress after 2 surgeries, radiation, and chemotherapy. The patient enrolled in our study in January 2018 with two 10 cm3 deep tumor nodules in his upper arm muscle. The hospital recommended total arm and shoulder amputation. This subject received 4 intratumoral injections equal to 100% of his 2 tumors’ volume. The drug was dosed at ratio of 1 mL per 4 cc of tumor. In the red circle in the left panel there is bright contrast indicating active cancer. At the first scan on May 15, 2018, there was an increase in tumor size, significant necrosis (lack of contrast) and inflammation observed (right panel). The patient received a few doses of Keytruda treatment and had a complete response. This patient has retained his arm and shoulder and is alive as of the last follow up visit in 2021.

Abscopal Effects

In the metastatic study several subjects showed tumor size reduction of non-injected lesions in lymph nodes, liver, lung, perineum, and retroperitoneal areas (i.e. abscopal effects to visceral lesions). The apparent abscopal effect was seen primarily in patients that received a dose greater than 40% of their total tumor burden. Abscopal effect rates may be even higher than known. No tumors under 1 cm in diameter were reported. In addition, many tumors above 1 cm were not followed or reported. We are capturing images from all subjects to be able to determine the true abscopal effect in all subjects at a future time. Figure 10 below shows uninjected tumor diameter changes over time of patients with confirmed reports of abscopal effects.

Figure 10 Change in longest diameter of uninjected tumors over time (abscopal effects).

Tumor Diameter and Corresponding Volume

For injected tumors, changes in longest diameter often do not correlate with changes in volume. Dosing is completed just prior to their first scan when the increase in tumor diameter is most likely to be highest. As noted above, RECIST measurements of whether a patient’s cancer is stable, decreasing or progressing are based on the changes in the tumor’s longest diameter. An increase in longest diameter above a threshold would indicate progression. In figure 11, the graph on the left shows the change in individual tumors’ longest diameter over time. The graph on the right shows the same tumor’s volume over time. Tumors in many patients treated with INT230-6 can show an increase or no change in longest diameter with a decrease of the corresponding tumor’s volume. There is also a much greater volume decrease than expected for the slight decrease in longest diameter. In some cases, tumors can become cystic, which on imaging looks like a large increase as was the case with subject 004-002. The increase in size was seen on scans until the cystic tumor was drained. These data provide further evidence that RECIST may not be a good indication of efficacy for INT230-6.

Figure 11 Using INT230-6 may increase tumor’s longest diameter while decreasing the tumor’s volume.

In the left figure each color represents the change in diameters of an individual patient’s group of tumors. In the right figure the same color represents that same patient’s change in tumor volumes.

Visualizing a change in 3 dimensions also shows the limitations of using RECIST methods for determining efficacy for intratumoral INT230-6. Figure 12 shows the scan of a sarcoma patient’s tumor pre- and post-dosing. The longest diameter declines by 15%, while the second longest diameter declines 42%. Using RECIST criteria, this patient would have been classified as having stable disease, whereas the World Health Organization, which uses the two longest diameters, would classify this patient as having had a partial response, which is a better outcome.

Figure 12 Change in two longest diameters of an injected sarcoma tumor at the base of the spine.

We do not believe that RECIST measurements (longest diameter) effectively capture efficacy.

Data below supports a hypothesis that INT230-6 increases survival in refractory cancer patients. As a result, given the issues with RECIST criteria noted above we believe survival, the FDA’s gold standard efficacy endpoint, is a better measure of our drug candidate’s performance than RECIST methods.

Survival — Phase 1 Basket Studies

The primary objectives of Phase 1 trials are to define the safety or toxicity profile of a new drug and to determine the dose for further evaluation in Phase 2 trials. Patients enrolled in Phase 1 are therefore placed at risk of toxicity, in exchange for an undefined and limited clinical benefit. Furthermore, patients who are considered for Phase 1 trials may be regarded as vulnerable because their physical condition may be deteriorating due to advanced cancer malignancy for which no further standard treatment options exist. Efficacy is not usually the primary objective. Most patients in Phase 1 studies have low survival expectations that ranges from 3 to 8 months depending on the type of cancer and patient’s incoming health. (see Chau, N., BMC Cancer volume 11, Article number: 426 2011).

Over the past two decades the development of a prognostic score to predict survival of patients treated in Phase 1 studies has been completed and validated by the Royal Marsden Hospital (RMH) in the United Kingdom. The score, which ranges from 0 to 3, is highly correlated of overall survival (OS) outcomes. A score of 0 suggests longest potential survival and a 3 worst. Many studies show that subjects enrolled in Phase 1 have survival of under 6 months when RMH scores greater than or equal to 1.

In our study IT-01 patients were enrolled whose cancer progressed following treatment using all approved and some experimental therapies suitable for their specific disease. Forty-three (43%) of patients had previous had an IV form of a platinum-based drug including cisplatin. Forty-four percent (44%) had previously received an anti-PD-1 antibody. Efficacy data from 64 patients enrolled in IT-01 through December 31, 2022 is available from patients receiving INT230-6 alone (referred to as monotherapy). Efficacy data from 30 patients receiving INT230-6 in combination with Keytruda are also available through December 31, 2022. The median number of prior therapies in this population was 4 with a range of 0 to 10 treatments (not including surgery or radiation). As of December 31, 2022, there have been over 820 different tumor injections conducted over the course of the trial with over 502 being into visceral deep tumors.

Study IT-01 is a Phase 1/2 dose escalation (i.e. the phase 1 basket portion) and phase 2 (expansion of specified cancer types). These types of studies are primarily testing safety in the phase 1 and determining whether there is an efficacy signal in the expansion compared to historical data. There is no control arm in IT-01 and no randomization. Therefore, there is no comparator to determine the significance of any given endpoint. Patients receiving a dose above a certain percentage of their total tumor burden (TTB) (more than 40%) had a statistically significantly longer survival than patients who received less than 40%. The subjects receiving a dose >40% of their total incoming tumor burden also lived much longer than would be expected for patients in a Phase 1/2 basket study. This indicates a potentially active drug. Given the small size of the population, the heterogeneity of the cancers and variability of the incoming tumor burdens, the high and low dose groups may have been different in a way that we could not measure. We observed a strong signal in just sarcoma patients; however, this Phase 2 population size was also too small to properly assess effectiveness of INT230-6. As a result, we have determined that overall survival, an endpoint that is generally acceptable to FDA for cancer clinical trials for drug development to treat metastatic disease, is the most appropriate metric to prove efficacy of our drug candidate. Study IT-01 also indicates that soft tissue sarcoma, at tumor type with high unmet medical need, would be a suitable disease for a large Phase 3 trial.

In our metastatic study survival appears to be impacted by the total dose a patient received relative to number and size of their tumors. Patients receiving a higher percentage of drug (mL) relative to their total tumor burden (cm3) (TTB) remained on study longer regardless of the cancer type. A patient’s total tumor burden is calculated by adding up the volumes of all reported tumors. Simply stated, the more drug given to more tumors, the more likely a subject would be alive longer, though not all tumors need be treated. Killing more of a patient’s cancer is beneficial.

The probability of survival for a given population can be plotted. Figure 13 below illustrates the survival for all monotherapy INT230-6 subjects with total tumor burdens between 2 cm3 and 700 cm3. See Table below for the patient population.

INT230-6 monotherapy population (n=64) in Study IT-01 (as of December 31, 2022)

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a        Others include: Adrenocortical carcinoma, Anal, Bladder, Cervical, Eccrine, Lung, Metastatic Cancer of Unknown Primary, Pseudomyxoma peritonei, Renal, and Thyroid.

Treating only with our drug candidate, approximately 50% of patients would be expected to be alive at one year (blue curve) with a median overall survival (mOS) expected of 361 days. Subjects dosed an amount of INT230-6 that was less than 40% of their total tumor burden (TTB) had a mOS of 96 days. This result is shown in the purple curve and is comparable to survival expected in historical Phase 1 basket studies (See Chau, N., BMC Cancer volume 11, Article number: 426 2011). Patients that received a dose of INT230-6 to greater than 40% of their total tumor burden had a ~63% chance of being alive at 1 year and the median overall survival has not been reached. The Hazard Ratio of the green to orange curves was 0.088 with a Confidence Interval (0.035, 0.226). These results indicate that survival improves for those dosed to >40% of their total tumor burden compared to those receiving under 40%. While were no differences statistically in the two populations with regards to incoming tumor burden; the sample size is small and the average values for the blue curve was lower. More data from larger randomized controlled in a specific cancer population is required to understand efficacy.

Figure 13 Kaplan Meier Estimates of Survival Dosing INT230-6 alone as of December 31, 2022

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*        Exploratory analysis of dose relative to total tumor burden (TTB or TB) was conducted. Many tumors, including all under 1 cm in diameter, were not reported and so total tumor burden is likely underestimated.

The survival of the combination of INT230-6 and Keytruda tested in a different cancer patient population (see table below) indicates the median overall survival has not been reached for enrolled patients meeting the inclusion criteria (n=24) following 173 days of median overall follow-up. The combination data also compare favorably to history data from basket studies of patients with these types of refractory cancers who have failed multiple lines of therapy; however, the data is still immature and the sample size small at the time of the data cut-off.

Patient Population:

Total enrolled patients dosed at least once INT230-6 with Keytruda (n=30) (December 31, 2022)

Biomarker Analysis

A cancer cell’s surface expresses a unique set of proteins specific to the patient and their cancer type. Certain immune cells can “read” the cell surface to create a patient-specific immune response. However, as noted above, live cancer cells can send signals that can block the immune cells from entering the tumor. There is a constant “cat and mouse” battle between the cancer cell and the immune system.

Other local treatments such as radiation or ablation destroy the cell surface. Our technology disperses potent killing agents throughout tumors and enables the potent killing agents to diffuse into the cancer cell without damage to the cell membrane. When the tumor’s cancer cells are no longer alive, the ability of the immune system to identify the cancer and mount a response can be increased.

We collect tumor tissue before and after dosing of our drug candidate from patients injected tumors. We analyze for live and dead cancer cells (referred to as necrotic cells). Our data shows that our drug candidate can kill cancer cells quickly and activate an immune response. We have observed these effects in multiple cancers.

Methods used

Pre-clinical experiments showed that to kill substantial amounts of the tumor would require a dose into the tumor of at least 1 mL of our drug candidate per 4 cubic centimeters of tumor volume with 1 mL for 2 or 3 cc being preferred. INT230-6 injections were conducted on the first treatment cycle’s first day (referred to as C1D0) and on the fourteenth day (C1D14). Pre and post-dose biopsies from the same injected tumor were obtained on C1D0 and again 28 days later just prior to the 3rd dose on the first day of the second treatment cycle (C2D0). To determine the percentage of viable tumor cells and necrotic (dead) cancer cells pre and post two treatments, we conducted analysis on the collected tissue following haemotoxylin and eosin (H&E) staining. H&E tissue analysis helps identify different types of cells and provides important information about the pattern, shape, and structure of cells in a tissue sample.

For many patients, we observed substantial reductions of cancer following the two injections of INT230-6 alone. Below are data on cell killing and immune activation from the two cancer types, breast cancer and sarcoma, for which we are planning Phase 3 programs. We also use immunohistochemistry (IHC) staining to help assess cancer and various immune cell populations, as well as the degree of cancer cell proliferation in the treated tumors.

Results from Breast Cancer Tissue

Several patients with breast cancer have been enrolled throughout the metastatic study. In figure 14, which shows tissue taken from a breast cancer patient (002-022) below, the pre-dose (C1D0) samples stained positive (dark purple) for significant amounts of cancer throughout the sample. However, 28 days later (C2D0), there was almost no cancer observed in the collected tissue. Magnification is 400µ.

Figure 14 Images from match pair biopsied tissue samples pre and post two INT230-6 injections:

Markers of Cancer Cell Proliferation

There are different rates at which cancer can grow. Highly aggressive cancers have high levels of certain proliferation markers. One such marker is Ki67, a protein found on highly proliferative cells. From the same collected biopsy samples staining was conducted to assess Ki67 in each sample using a validated commercial in vitro diagnostic (IVD) that identifies proliferating cells in all active phases of the cancer’s cell cycle. Both a manual assessment by a pathologist and an automatic image analyzer were used to report values. Results of Ki-67 assessments are shown in the table below.

Summary of H&E, tissue analysis and injected tumor volumes in matched pair biopsy samples from 3 triple negative metastatic breast cancer subjects from study IT-01

In addition to the substantial reduction of viable cancer cells observed, Ki 67 was reduced significantly. This means the residual cancer is replicating more slowly.

While there are several publications on Ki67 as a predictor of clinical benefit in presurgical settings, the reduction of proliferation markers such as Ki67 is not yet an FDA-recognized approvable endpoint for a drug. However, the percentage of change in pathological complete response rate (pCR) defined as the absence of cancer following surgery or major pathological response (MPR) in a tumor following resection defined as less than or equal to 10% of residual cancer have both been recognized by FDA as surrogate endpoints to support accelerated approval for neoadjuvant treatment in certain cancers. The INVINCIBLE study will help us to determine whether the addition of INT230-6 to an existing or modified neoadjuvant (presurgical) treatment regimen may increase pCR or MPR and reduce toxicities in neoadjuvant cancer subjects.

Immune Response in Breast Cancer Tissue

In preclinical studies, we have shown that our technology reduces the tumor and causes the influx of immune cells (in theory by creating antigen from the dying or dead cancer cells). The below images from a breast cancer patient confirm that this effect also occurs in humans. Applying a special set of stains to the biopsied tissue enables the measurement of immune cells inside the tumor. We observe infiltrating immune cells in the tumor. In figure 15 (below) the first panel (Image A) there is extensive cancer as the blue color seen is for 4´,6-diamidino-2-phenylindole, a blue-fluorescent DNA stain (DAPI) and the marker of live and proliferating cancer. The green and yellow colored

cells are of immune cells. The second panel (Image B) shows that at 28 days after the first dose there is a markedly reduced amount of live cancer (no blue stain) indicating significant cancer cell death has occurred. These results are consistent with the H&E results shown above. In addition, the green/yellow stained cells, representing CD4 and CD8 anti-cancer T-cells, are increased dramatically throughout the entire tissue. The dead cancer can no longer prevent the immune cells from infiltrating the entire tissue.

Figure 15 IHC Staining of breast cancer tissue for immune cell infiltration pre and post dosing of INT230-6

Results from Sarcoma Tissue

Several patients with metastatic soft tissue sarcomas have been enrolled in the study. As was seen with breast cancer and multiple other tumor types, there were substantial reductions of cancer in sarcoma patients. An example of this type of result is shown in figure 16. Image A is the stained tissue sample (pre-dose) that shows significant cancer (dark purple cells) throughout the tissue sample. Image B is the stained tissue sample taken on day 28 after two doses of INT230-6 (day 0 and day 14) that shows significant reduction in the cancer (Magnification 3.7x).

Figure 16 Images from match pair biopsied soft tissue sarcoma subject 010-001 pre and post two INT230-6 injections

To confirm the H&E results, we measured DAPI and activated T-cells from a sarcoma tumor. The results again confirm that for this tumor type this is also a substantial reduction of tumor cells as shown by the decrease in the blue DAPI marker post INT230-6 treatment. As was seen in other tumor types, figure 17 shows the influx for sarcoma patients into the tumor of CD4 and CD8 T-cells at 28 following the first dose as seen in Images A and B.

Figure 17 Staining of biopsied sarcoma tumor tissue pre and post dosing of INT230-6

Results of the H&E analysis as well as the multiplex IHC staining show substantial cancer cell reduction, decreases in proliferation, and increased immune infiltration after INT230-6 dosing. The totality of the date indicate the drug has the ability to kill cancer and increase the immune response in multiple cancer types.

INT230-6 Efficacy in Soft Tissue Sarcoma

Sarcomas are a rare and heterogeneous group of solid tumors derived from mesenchymal origin. Although single agent or combination anthracycline-based chemotherapy provides some benefit for the treatment of advanced sarcomas, prognosis is still unfavorable with median overall survival of 12 – 16 months and there is significant unmet medical need. By the time subjects fail approved therapies and enter Phase 1 studies patients’ median overall survival is typically 3 – 8 months (see Subbiah, V Scientific Reports | 6:35448 | DOI: 10.1038/srep35448) depending on certain risk factors such those found in the RMHI score.

As of December 31, 2022, 29 patients with sarcoma were treated in study IT-01. Enrolled subjects receiving INT230-6 had a median of 3 (0, 8) prior therapies, median age of 64 and 13% were ECOG 0, 80% ECOG 1. Those receiving the combination with ipilimumab had a median of 4 (0, 9) prior therapies, median age of 64 and 38% were ECOG 0, with 62% ECOG 1.

The sarcoma types was Leiomyosarcoma, Liposarcoma, pleomorphic sarcomas, chondrosarcoma, chordoma, spindle cell sarcoma, fibrosarcoma, osteosarcoma, myofibroblastic sarcoma, desmoid type, and Kaposi sarcoma. The INT230-6 dose delivered at a single visit was up to 242 mL (112 mg of cisplatin, 24.2 mg of vinblastine sulfate) into one or more tumors. The VIN given exceeded the typical 5.1 mg starting IV dose for an average size person. The CIS given was equivalent to a typical IV dose. Safety in sarcoma population remained favorable. The most common treatment-related adverse events (TRAEs) in evaluable monotherapy subjects were localized pain, fatigue, decreased appetite, nausea, most of which were low grade. Please see Table 1 in the “Results from IT-01 Phase 1/2 Clinical Trial” portion of our “Business” section on page 67 of this prospectus for more information.

We compared our Phase 1/2 basket study survival data in soft tissue sarcoma (“STS”) to overall survival data generated from three published clinical Phase 1/2 basket trials in sarcoma. In our trial, IT-01, fifteen (15) STS patients received only INT230-6 monotherapy and 11 have received the combination with ipilimumab. The 3 studies used were:

•        Jones Cancer Chemother Pharmacol (2011) 68:423–429, Clinical benefit of early phase clinical trial participation for advanced sarcoma patients.

•        Cassier et. al., Annals of Oncology 25: 1222–1228, 2014 Outcome of patients with sarcoma and other mesenchymal tumours participating in phase I trials: a subset analysis of a European Phase I database.

•        Subbiah et. al., Scientific Reports | 6:35448 2016, Evaluation of Novel Targeted Therapies in Aggressive Biology Sarcoma Patients after progression from US FDA approved Therapies.

Each of these publications report use of the Royal Marsden Hospital index (RMHI). As noted above the RMHI is validated score predictive of overall survival for cancer patients in basket studies. A subject obtains 1 point depending on their number of metastatic sites, pre-dose plasma lactase dehydrogenase level and albumin concentrations. Each of the 3 studies report the median overall survival results for subjects for various RMHI values as shown in the table below.

Median OS in Phase 1 Basket studies

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*        44% of Subbiah study subjects had a RMHI score of 0 versus 26% in Sponsor’s study IT-01

Though the sarcoma subtype mix between the 3 literature study populations is not matched exactly, mOS from the Jones, Cassier and Subbiah studies are similar. Subbiah reports the overall survival of sarcoma patients for a given RMHI score (Figure 18 below) from the publication shows the strong correlation between RMHI score and overall survival.

Figure 18 Overall Survival based on RMHI in soft tissue sarcoma (Subbiah data)

We were able to estimate the RMHI score in our study for each patient receiving only INT230-6. Subjects in our study primarily had a RMHI score of 1 (33%) or 2 (40%). To be more confident that we are matching the population when comparing our drug to the Subbiah population, we created a synthetic Kaplan-Meier (KM) curve from the Subbiah dataset that approximated our patients’ RMHI score distribution (Figure 19 below). We chose Subbiah as the dataset since this study reported the longest survival of the 3 Sarcoma studies and would be the most conservative historical control data.

Our drug is dosed based on a patient’s total measured volumetric tumor burden. From our mouse studies we found that a dose volume to tumor volume ratio of 1 to 4 could nearly saturate a tumor. The average total tumor burden of patients entering the trial was 200cc. However, when our study was initiated, the dose was limited to 5 mL per month to establish the maximum tolerated dose and generate safety data. This early dose proved to be inadequate to treat most tumors. As a result, most early patients were under treated and the survival seen early in the study was typical of survival rates normally seen in phase 1 basket trials. As we moved through the dose escalation phase of our trial and generated favorable safety data, the dose amount frequency and loading into the tumor was escalated.

No maximum tolerated dose was established. Empirically, we have determined that if a drug volume equal to 40% of the total reported tumor burden was administered over 5 sessions every two weeks, patients showed evidence of clinical efficacy as overall survival increased. Survival at one year for sarcoma patients in a Phase 1/2 (Subbiah n=56) is 28%. For all INT230-6 patients receiving only INT230-6 in our Phase 1/2 (n=15) survival at 1 year is 56%. However, for INT230-6 only patients having more than 40% of their total tumor burden treated survival at 1 year is 79%. For the combination (n=14) with ipilimumab the survival increases at 1 year to 90% and the median overall survival has not been reached with a median follow up is 287 days. For the INT230-6 monotherapy STS patients (N=15) our median OS is 21.4 months with

a confidence interval of 6.4 to 42.0 months (this dataset includes those subjects underdosed with considerably less than 40% of their total tumor burden). In those subjects receiving a dose greater than or equal to 40% of their total tumor burden (N=11), the OS is 23.6 months, and the confidence interval is 21.4 to 42.0 months.

We plotted the KM control derived from the Subbiah basket trial matched to our RMHI scores for all INT230-6 monotherapy patients and for those receiving a dose equal to 40% of their total tumor burden. Compared to the control the Hazard Ratio (HR) for all STS patients administered solely INT230-6 through 500 days is 0.507 and the Confidence Interval (CI) is (0.273, 0.942). The p-value is 0.0318. For STS patients administered INT230-6 monotherapy at >40% of total tumor burden, the HR is 0.363 with CI (0.187 to 0.705). The p-value is 0.0028. See figure 19.

Figure 19:  Survival of INT230-6 monotherapy vs. historical control in comparable population of RMHI scored basket study sarcoma patients

Estimates of sarcoma subject survival using INT230-6 based on dose per total tumor burden (TTB) from study IT-01

Efficacy Results from IT-02 (The INVINCIBLE Study)

Tissue taken via biopsy from tumor in our metastatic study IT-01 shows that viable cancer cells are significantly reduced. However, in our INVINCIBLE study, surgeons also removed the entire breast cancer tumor following INT230-6 injection. In the INVINCIBLE study when dosed at a ratio proportionate to the tumor’s volume, at the San Antonio Breast Cancer Symposium in December 2022 we showed that up to 100% of an entire tumor greater than 3 cm can be killed on a single dose.

This result is seen in figure 20 panel A. An ER+PR+HER2+ 3.9 cm grade 3 invasive ductal breast cancer tumor was treated on day 1 with 7.4 cc of INT230-6. Seven days later with another 14.8 cc. The tumor was then resected another seven days later. In panel B, a ER+PR+Her2- 4.4 cm diameter invasive lobular breast cancer tumor was treated with one dose of 21.3 mL of INT230-6, then resected 20 days later. The INT230-6 was able to kill 85% of the ductal tumor. However, in the second panel, the drug was able to diffuse throughout the entire tumor. The boundary of the tumor is shown by the black dotted lines and the red dotted lines show the extent of the necrosis. Pathology conducted on the excised tumor showed that there was only a small percentage of viable cancer cells in one area of the 4.4 cm tumor after a single dose of INT230-6 of 21. 4 mL. More than 95% of the tumor was necrotic (dead) or ghost cells (cells without nucleus). These images show that diffusion distance is proportional to the amount given on a single dose.

In part 2, the treatment group had a highly statistically significant increase in necrosis (tumor death) compared to the saline control group (17% for the treatment group versus 1.3% for the saline control group, p=0.0041). For tumors with diameter of 2.6 cm or higher in longest diameter the treatment group had an even larger difference in necrosis than the saline control group (30% for the treatment group vs. 0.25% for the saline control group, p=0.039). Of subjects with tumors over 3 cm in longest diameter, 100% of the treatment group experienced necrosis, whereas only 5 of 20 subjects in the saline control group experienced any necrosis. The highest saline control group necrosis level was only 10% and was only found in one subject. In the study three (3), INT230-6 treatment subjects had a major pathological response (MPR), which is defined as having less

than or equal to 10% residual cancer in the tumor. The control group had zero (0) subjects achieve MPR (n=29). The p-value is 0.042 for MPR rate of drug vs. control for the entire study. The MPR-achieving subjects all had tumors of 2.9 cm in diameter or higher. There were 21 subjects in the drug-treatment group that had tumors with diamaters of 2.9 cm or higher. This translates to an MPR rate of 14.3% for the larger-sized tumor population. MPR is being considered by FDA as an accelerated approval endpoint for certain cancers as MPR has been associated with increased event-free survival. Analysis of the immune activation from part 2 is on-going. Part 1 showed INT230-6 induced immunological response in those receiving drug.

Through December 31, 2022, we have enrolled 91 patients. Nine patients in part 1 of the study were untreated. Part 1 enrolled 30 patients (one consented patient failed screening). Part 1 evaluated safety and dose. Part 2 enrolled an additional 61 patients, although some patients failed screening. We shall compare tissue taken from a biopsy at the time of diagnosis with tissue taken after surgery on the entire tumor to conduct efficacy and immunological evaluations. As discussed above, the percentage of residual cancer was significantly lowered in subjects that receive the drug compared to no treatment or a saline injection. The surgery proceeded without any delay or changes for those receiving drug compared to the control. Safety was favorable.

We are continuing to evaluate (A) the change complete cell cycle arrest as measured by Ki67 — a proliferation marker (part 2 only), (B) type of cell death (apoptotic, etc.), (C) immune response in tumors, (D) systemic immune response by T cell repertoire analysis and I patient reported outcomes.

Enrollment has been rapid. Patients are highly interested in a product that can destroy the majority of their tumor rapidly while waiting for their surgery and with the possibility to induce a systemic anti-cancer immune response. Surgery has not been delayed or made more difficult by the INT230-6 IT treatment. Adverse events are minimal — mainly transient, low-grade pain at the injection site. Large amounts of necrosis can be induced across multiple breast cancer subtypes with 1 or 2 doses.

The INVINCIBLE study will provide data to help the design of pivotal studies in the neoadjuvant or pre-surgical settings. In addition, INVINCIBLE results should help to set dosing regimens based on tumor diameter in our Phase 3 metastatic studies.

Figure 20 Showing the extent of the entire tumor and the area of dead cancer for various doses of drug; greater than 95% of the total tumor volume was killed by a single 21.3 cc injection of INT230-6.

In the above figure the entire breast tumor has been removed. The black dotted line shows the extent of the tumor, and red dotted line shows the extent of the necrotic (dead cancer) after treatment with INT230-6. For a given tumor diffusion distance and thus tumor killing is proportional to the amount of drug dosed. Both tumors shown with high grade (3) proliferative tumors.

Evidence of Efficacy and Immune activation

An analysis of differential gene expression comparing pre-and post-treated tumor tissue samples in the control group compared to the drug treated group showed that over 200 more immune related genes were activated pre- and post-treatment compared to the controls. As shown in Figure 21 below within the tumor there was a relative increase in abundance of CD4 T naïve and B and NK cells post treatment. Within the tumor microenvironment compartment (the space between cancer cells) there was a relative increase in abundance of CD8 memory T, CD4 naïve and B cells

post-treatment. Further analysis with immune profiling of blood is pending. This immune profiling (T-Cell repertoire) will determine whether a systemic activation of CD4+ and CD8+ T-cells has occurred. Generating an anti-cancer T-cell response from a patient’s own tumors could offer long term protection against disease recurrence.

Figure 21 Relative abundance levels of immune cells present in the breast cancer tumor compared to current standard of care (no treatment controls.

Each bar demonstrates the immune cell abundance in a patient separated by cancer subtype

Part 1 demonstrated feasibility, safety and tolerability of presurgical IT injections in breast cancer patients. Preliminary data show histologic evidence of up to 95% tumor necrosis in varying biologic subtypes including lobular carcinoma. Further analysis with Ki67 and residual cancer burden scoring is pending.

Planned Phase 3 Trials

Metastatic Sarcoma

Given the positive data on survival seen in our metastatic study in sarcoma patients, we plan to conduct a single Phase 3 study in 2nd/3rd line treatment for locally advanced, recurrent, inoperable, or metastatic non-diffuse soft tissue sarcoma with overall survival as the primary endpoint. The current Phase 3 study design plans to enroll subjects who will be randomized 2 to 1 to either INT230-6 for 5 doses Q2 weeks with maintenance dosing every 9 weeks for 2 years or the standard of care. The three drugs most used for soft tissue sarcoma will be the control SOC at the investigator’s choice depending on the type of sarcoma. Our Phase 3 study is designed to be 90% powered to detect a difference Hazard Value of 0.65 in overall survival between the INT230-6 treatment group and the control group with 331 patients enrolled (2:1 randomization to either INT230-6 treatment or control therapy). The study will have 2 interim data reviews to determine efficacy. The first interim analysis is planned when 50% of the required events (deaths) for the final analysis has occurred and the second analysis will be at 75%. Futility will also be tested as part of the interim analysis. A protocol synopsis was developed and submitted to the FDA. On October 14, 2021, we met with FDA to discuss the Phase 3 protocol and reached alignment on the Phase 3 study design, patient population and statistical approach.

Figure 22 shows the survival curves from five recent Phase 3 studies using now approved standard of care drugs for sarcoma. The figure also shows the expected Phase 3 survival for 1) the blended control based on the likely mix of sarcoma types (green curve) and 2) the expected INT230-6 Phase 3 survival curve that was generated based on our clinical results in sarcoma (navy blue curve). The references showing the Phase 3 data for the standard of care controls are; for trabectadin: Patel S, et. Cancer. 2019 Aug 1;125(15):2610-2620; for eribulin: Schöffski et. al. Lancet. 2016 Apr 16;387(10028):1629-37; and for pazopanib: van der Graaf et. al. Lancet. 2012 May 19;379(9829):1879-86.

It is notable that despite different regimens and sarcoma subtype distributions, the overall survival is consistent for the current standard of care drugs. Our Phase 2 program enrolled sarcoma patients with mixed subtypes whose cancer progressed despite a median of 3 prior treatments. We plan to enroll a similar mix of sarcoma patients; in Phase 3, however, no patient will have progressed on more than 2 treatments. Thus, patients in our planned Phase 3 study will be healthier than those treated in our Phase 2 study. Over 25% of patients in our Phase 2 study were

underdosed. In the planned Phase 3 study such a high percentage of underdosed patients will be less likely. Patients in the planned Phase 3 program shall also receive long term maintenance treatment of INT230-6 every 9 weeks, which mostly did not occur in our Phase 2 program.

Figure 22 the expected Phase 3 study schema comparing INT230-6 to the approved 2nd or 3rd line standard of care drugs

The current Phase 3 design reviewed together with FDA proposes an endpoint of overall survival in a subset of advanced soft tissue sarcoma patients. In addition, we proposed 2 interim analyses; the first at 50% and the second at 75% of total events (266 deaths) needed for the final analysis. We plan to enroll 2 subjects in the INT230-6 group per one subject of any of the three used drugs for each patient’s type of advanced soft tissue sarcoma. INT230-6 will be dosed every 2 weeks for 5 doses with maintenance every 12 weeks. The SOC drugs will be dosed at their approved regimens.

Triple Negative Breast Cancer

•        In 2021, over 270,000 patients were expected to be diagnosed with breast cancer;

•        Of these, ~11-17% of tumors found in breast cancer patients will not test positive for any of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), or progesterone receptor (PR) proteins, and thus will be classified as triple negative tumors;

•        TNBC is commonly found in younger patients (<50), African American and Hispanic women, and patients with a BRCA1 mutation (~70% of BRCA patients are triple negative); and

•        TNBC tends to be more aggressive, i.e., higher grade, relative to other forms of breast cancer with limited treatment options, highlighting a high degree of unmet need in this patient population.

Pre-surgical (Neoadjuvant) Triple Negative Breast

In November 2020, we met with FDA to discuss use of our drug prior to surgery for breast cancer patients at high risk of disease recurrence such as those with triple negative breast cancer for potential accelerated approval.

The FDA instituted its Accelerated Approval Program to allow for earlier approval of drugs that treat serious conditions, and that fill an unmet medical need based on a surrogate endpoint. A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit. The use of a surrogate endpoint can considerably shorten the time required prior to receiving FDA approval. The surrogate endpoint we discussed with pathological complete response.

Preoperative or neoadjuvant systemic chemotherapy, once reserved for patients with locally advanced breast cancer in whom the goal was to render large breast cancers operable, has become increasingly common. There are several potential reasons to consider neoadjuvant treatment for early-stage breast cancer. Giving chemotherapy preoperatively

permits breast conservation in some patients who would otherwise require mastectomy and may improve cosmesis, or the preservation or restoration of physical appearance, in existing candidates for breast conservation. Preoperative therapy also provides a real-time evaluation of tumor response to permit discontinuation of ineffective therapy. Finally, the neoadjuvant setting offers investigators the unique opportunity to examine modulation of tissue, imaging, and other biomarkers from the time of biopsy to the time of definitive breast surgery following preoperative systemic therapy.

Pathological complete response (pCR) is an accepted FDA criteria for triple negative breast cancer. pCR is defined as the absence of residual invasive and in situ cancer on hematoxylin and eosin (H&E) evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy.

On July 26, 2021, the FDA approved pembrolizumab (brand name Keytruda) for high-risk, early-stage, triple-negative breast cancer in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. FDA granted accelerated approval to pembrolizumab for this indication in November 2020.

The efficacy of pembrolizumab in combination with neoadjuvant chemotherapy followed by surgery and continued adjuvant treatment with pembrolizumab as a single agent was investigated in KEYNOTE-522, a randomized, multicenter, double-blind, placebo-controlled trial conducted in patients with newly diagnosed previously untreated high-risk early-stage triple-negative breast cancer. Patients were enrolled regardless of tumor PD-L1 expression. Patients were randomized (2:1) to pembrolizumab in combination with chemotherapy or placebo in combination with chemotherapy. The main efficacy outcome measures were pathological complete response rate and event free survival. The pathological complete response rate was only 63% for patients who received pembrolizumab in combination with chemotherapy compared with 56% for patients who received chemotherapy alone. However, that was good enough for approval. At the same time, in Keynote 522 eighty percent (80%) of patients had a grade 3 or higher adverse event and 0.6% of patients died from the treatment.

As shown in Figure 20 above from the INVINCIBLE study INT230-6 can cause >95% of a large tumor to become necrotic on a single dose without toxicity other than minor pain at the injection site. Combining one or two doses upfront of INT230-6 with the standard of care neoadjuvant therapy (pembrolizumab with anthracycline, cyclophosphamide and taxane) could potentially increase the pCR rate significantly to allow for accelerated approval. Further use of INT230-6 may allow for the elimination of the anthracycline or cyclophosphamide and could reduce the toxicity of current chemotherapy regimen while obtaining an increase in pCR. The data on percent tumor necrosis form the INVINCIBLE study will indicate how much necrosis can be induced upfront. Follow receipt of the data from the INVINCIBLE study we plan to request another meeting with FDA to review a phase 3 trial in neoadjuvant breast cancer with pCR as the endpoint.

Metastatic Triple Negative Breast Cancer.

The FDA designation of INT230-6 for Fast Track was made in 2018 as response to our proposed development program evaluating INT230-6 for the treatment of patients with relapsed or metastatic triple negative breast cancer.

Metastatic TNBC patients have a poor prognosis, with a median overall survival of 13.3 months with treatment first line. Recently approved treatments including Lynparza (PARP inhibitor) and Tecentriq (PD-L1 inhibitor). Those treatments target a specific subset of patients, with BRCA1/2 and PD-L1 positive markers, respectively. Our target population would be more inclusive.

Continuing chemotherapy treatment until disease progression is currently the standard of care for patients with metastatic TNBC, with no preferred chemotherapy regimens established at this time. Gilead presented data at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #1080) for second line use of sacituzumab (Trodelvy). Sacituzumab extended median overall survival to 10.9 months versus 4.9 months with chemotherapy (HR: 0.51; 95% CI: 0.28-0.91).

With a small sample size in study IT-01 INT230-6 either as monotherapy or with pembrolizumab has shown in refractory metastatic breast cancer (all types) a median overall survival of 12 months (n=9), and in subset of just m TNBC subjects, a median overall survival of approximately 12.5 months.

INT230-6 Phase 2/3 study design would consist of metastatic TNBC patients whose cancer has progressed following 1 to 2 lines of prior therapy. The Phase 2 study would be approximately 60 patients with INT230-6 arm and a control arm cohort design of patients using investigators choice of therapy. The endpoints would be median overall survival. Patients would receive 5 doses of INT230-6 every two weeks delivered IT with a maintenance dosing. The protocol will be designed to allow us to determine, within 12 months following completion of enrollment, whether INT230-6 has the potential to offer clinical benefit. A combination of INT230-6 with a checkpoint antibody

(e.g. pembrolizumab or ipilimumab) within the randomized Phase 2 may be considered. From the results of the ongoing Phase 2, the company would make a strategic decision to use either monotherapy or combination with a checkpoint and size the final study accordingly. Phase 3 would be randomized 2 to 1 against investigators choice of treatment. Additional subjects could be added to the Phase 2 portion to complete the Phase 3 program. A clinical phase 2/3 program in metastatic breast will be initiated post-initiation of the sarcoma phase 3 study.

Government Regulation

The FDA and other regulatory authorities at federal, state and local levels, as well as in foreign countries, extensively regulate, among other things, the research, development, testing, manufacture, quality control, import, export, safety, effectiveness, labeling, packaging, storage, distribution, record keeping, approval, advertising, promotion, marketing, post-approval monitoring and post-approval reporting of drugs such as those we are developing. We, along with our vendors, collaboration partners, CROs and contract manufacturers, will be required to navigate the various preclinical, clinical, manufacturing and commercial approval requirements of the governing regulatory agencies of the countries in which we wish to conduct studies or seek approval of our product candidate. The process of obtaining regulatory approvals of drugs and ensuring subsequent compliance with appropriate federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources.

In the United States, where we are initially focusing our product development, the FDA regulates drugs under the federal Food, Drug, and Cosmetic Act (FDCA) and its implementing regulations. Drug products are also subject to other federal, state and local statutes and regulations. Our product candidate is early-stage and has not been approved by the FDA for marketing in the United States.

The process required by the FDA before our product candidate is approved for therapeutic indications and may be marketed in the United States generally involves the following:

•        completion of extensive preclinical studies in accordance with applicable regulations, including studies conducted in accordance with Good Laboratory Practice, or GLP, requirements;

•        submission to the FDA of an IND, which must become effective before clinical trials may begin and must be updated annually or when significant changes are made;

•        approval by an Institutional Review Board, or IRB, or independent ethics committee at each clinical trial site before each trial may be initiated;

•        performance of adequate and well-controlled clinical trials in accordance with Good Clinical Practice, or GCP requirements and other clinical trial-related regulations to establish the safety and efficacy of the proposed drug product candidate for its intended purpose;

•        preparation and submission to the FDA of a New Drug Application (NDA) after completion of all pivotal trials;

•        a determination by the FDA of its receipt of an NDA, to file the application for review;

•        satisfactory completion of one or more FDA pre-approval inspections of the manufacturing facility or facilities where the product will be produced to assess compliance with current Good Manufacturing Practice requirements, or CGMPs, to assure that the facilities, methods and controls are adequate to assure the drug product’s identity, strength, quality and purity;

•        potential FDA audit of the clinical trial sites that generated the data in support of the NDA;

•        payment of user fees for FDA review of the NDA; and

•        FDA review and approval of the NDA, including consideration of the views of any FDA advisory committee, prior to any commercial marketing or sale of the drug product in the United States.

Preclinical and clinical trials for drug products

Before testing any drug in humans, the product candidate must undergo rigorous preclinical testing. Preclinical studies include laboratory evaluations of chemistry, formulation and stability, as well as in vitro and animal studies to assess safety and in some cases to establish the rationale for therapeutic use. The conduct of preclinical studies is subject to federal and state regulations and requirements, including GLP requirements for safety and toxicology studies. The results of the preclinical studies, together with manufacturing information and analytical data must be submitted to the

•        Phase 2 — Phase 2 clinical trials typically involve administration of the investigational product to a limited patient population with a specified disease or condition to evaluate the preliminary efficacy, optimal dosages and dosing schedule and to identify possible adverse side effects and safety risks. Multiple Phase 2 clinical trials may be conducted to obtain information prior to beginning larger and more expensive Phase 3 clinical trials.

•        Phase 3 — Phase 3 clinical trials typically involve administration of the investigational product to an expanded patient population to further evaluate dosage, to provide statistically significant evidence of clinical efficacy and to further test for safety, generally at multiple geographically dispersed clinical trial sites. These clinical trials are intended to establish the overall risk/benefit ratio of the investigational product and to provide an adequate basis for product approval. Generally, one or two adequate and well-controlled Phase 3 clinical trials are required by the FDA for approval of an NDA.

Post-approval trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial marketing approval. These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication and are commonly intended to generate additional safety data regarding use of the product in a clinical setting. In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA.

Progress reports detailing the results of the clinical trials, among other information, must be submitted at least annually to the FDA and written IND safety reports must be submitted to the FDA and the investigators fifteen days after the trial sponsor determines the information qualifies for reporting for serious and unexpected suspected adverse events, findings from other studies or animal or in vitro testing that suggest a significant risk for human participants exposed to the investigational product and any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure. The sponsor must also notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible but in no case later than seven calendar days after the sponsor’s initial receipt of the information.

Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the drug characteristics of the product candidate and finalize a process for manufacturing the drug product in commercial quantities in accordance with CGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the product candidate and manufacturers must develop, among other things, methods for testing the identity, strength, quality and purity of the final drug product. Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life and to identify appropriate storage conditions for the product candidate.

New Drug Applications (NDA) Submission and Review by the FDA

We intend to seek data exclusivity or market exclusivity for INT230-6. Assuming successful completion of the required clinical testing, the results of the preclinical studies and clinical trials, together with detailed information relating to the product’s chemistry, manufacture, controls and proposed labeling, among other things, are submitted to the FDA as part of an NDA requesting approval to market the product for one or more indications. An NDA is a request for approval to market a new drug for one or more specified indications. The NDA must include all relevant data available from pertinent pre-clinical and clinical studies, including negative or ambiguous results as well as positive findings, together with detailed information relating to the product’s chemistry, manufacturing, controls, and proposed labeling, among other things. Data may come from company-sponsored clinical trials intended to test the safety and efficacy of a product’s use or from a number of alternative sources, including studies initiated by investigators. To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and efficacy of the investigational product to the satisfaction of the FDA. FDA approval of an NDA must be obtained before a chemical drug may be marketed in the United States.

In addition, under the Pediatric Research Equity Act, or PREA, an NDA or supplement to an NDA must contain data to assess the safety and effectiveness of the drug product candidate for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective. The Food and Drug Administration Safety and Innovation Act requires that a sponsor who is planning to submit a marketing application for a drug product that includes a new clinically active component, new indication, new dosage form, new dosing regimen or new route of administration submit an initial Pediatric Study Plan

(PSP) within sixty days after an end-of-Phase 2 meeting or as may be agreed between the sponsor and FDA. The FDA may grant deferrals for submission of pediatric data or full or partial waivers. Unless otherwise required by regulation, PREA does not apply to any drug product for an indication for which orphan designation has been granted.

The FDA reviews all submitted NDAs before it accepts them for filing, and may request additional information rather than accepting the NDA for filing. The FDA must make a decision on accepting an NDA for filing within 60 days of receipt, and such decision could include a refusal to file by the FDA. Once the submission is accepted for filing, the FDA begins an in-depth substantive review of the NDA. The FDA reviews an NDA to determine, among other things, whether the product is safe and effective and whether the facility in which it is manufactured, processed, packaged or held meets standards designed to assure the product’s continued identity, strength, quality and purity. Under the goals and polices agreed to by the FDA under the Prescription Drug User Fee Act, or PDUFA, the FDA targets ten months, from the filing date, in which to complete its initial review of an original NDA and respond to the applicant, and six months from the filing date of an original NDA filed for priority review. The FDA does not always meet its PDUFA goal dates for standard or priority NDAs, and the review process is often extended by FDA requests for additional information or clarification.

Further, under PDUFA, as amended, each NDA must be accompanied by a substantial user fee, and the sponsor of an approved NDA is also subject to an annual program fee for each approved drug product. FDA adjusts the PDUFA user fees on an annual basis. Fee waivers or reductions may be available in certain circumstances, including a waiver of the application fee for the first application filed by a small business. Additionally, no user fees are assessed on NDAs for products designated as orphan drugs, unless the product also includes a non-orphan indication.

The FDA may refer an application for a new drug product to an advisory committee. An advisory committee is a panel of independent experts, including clinicians and other scientific experts, which reviews, evaluates and provides a recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

Before approving an NDA, the FDA typically will inspect the facility or facilities where the product is manufactured. The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications. Additionally, before approving an NDA, the FDA may inspect one or more clinical trial sites to assure compliance with GCP and other requirements and the integrity of the clinical data submitted to the FDA.

The FDA also may require submission of a Risk Evaluation and Mitigation Strategy, or REMS, as a condition for approving the NDA to ensure that the benefits of the product outweigh its risks. The REMS could include medication guides, physician communication plans, assessment plans, and/or elements to assure safe use, such as restricted distribution methods, patient registries, or other risk-minimization tools.

After evaluating the NDA and all related information, including the advisory committee recommendation, if any, and inspection reports regarding the manufacturing facilities and clinical trial sites, the FDA may issue an approval letter or a Complete Response Letter. A Complete Response Letter indicates that the review cycle of the application is complete and the application is not ready for approval. A Complete Response Letter will usually describe all of the deficiencies that the FDA has identified in the NDA, except that where the FDA determines that the data supporting the application are inadequate to support approval, the FDA may issue the Complete Response Letter without first conducting required inspections, testing submitted product lots, and/or reviewing proposed labeling. In issuing the Complete Response Letter, the FDA may recommend actions that the applicant might take to place the NDA in condition for approval, including requests for additional information or clarification. Even with submission of this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval. If and when those conditions have been met to the FDA’s satisfaction, the FDA will typically issue an approval letter. An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications.

Even if the FDA approves a product, depending on the specific risk(s) to be addressed, the FDA may limit the approved indications for use of the product, require that contraindications, warnings or precautions be included in the product labeling, require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess a product’s safety after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution and use restrictions or other risk management mechanisms under a REMS, which can materially affect the potential market and profitability of the product. The FDA may prevent or

new indications or for a new patient population that would require new clinical data to demonstrate safety or effectiveness. The FDA may then approve the new product for all or some of the label indications for which the RLD has been approved, or for any new indication sought by the Section 505(b)(2) applicant, as applicable.

In seeking approval of an NDA or a supplement thereto, the NDA sponsor is required to list with the FDA each patent with claims that cover the sponsor’s product or an approved method of using the product. Upon approval of an NDA, each of the patents listed in the application for the drug is published in the FDA publication Approved Drug Products with Therapeutic Equivalence Evaluations, commonly known as the Orange Book. When an ANDA applicant submits its application to the FDA, the applicant is required to certify to the FDA concerning any patents listed in the Orange Book for the RLD, except for patents covering methods of use for which the follow-on applicant is not seeking approval. To the extent a Section 505(b)(2) applicant is relying on studies conducted for an already approved product, such an applicant is also required to certify to the FDA concerning any patents listed for the approved product in the Orange Book to the same extent that an ANDA applicant would.

Specifically, any applicant who subsequently files an ANDA or 505(b)(2) NDA that references the drug listed in the Orange Book must certify to the FDA that with respect to each published patent, (i) the required patent information has not been filed by the original applicant of the RLD; (ii) the listed patent already has expired; (iii) the listed patent has not expired, but will expire on a specified date and approval is sought after patent expiration; or (iv) the listed patent is invalid, unenforceable or will not be infringed by the manufacture, use or sale of the new product. These are known as Paragraph I, II, III, and IV certifications, respectively.

If a Paragraph I or II certification is filed, the FDA may make approval of the application effective immediately upon completion of its review. If a Paragraph III certification is filed, the approval may be made effective on the patent expiration date specified in the application, although a tentative approval may be issued before that time. If an application contains a Paragraph IV certification, a series of events will be triggered, the outcome of which will determine the effective date of approval of the ANDA or 505(b)(2) application.

A certification that the new product will not infringe the RLD’s listed patents or that such patents are invalid is called a Paragraph IV certification. If the follow-on applicant has provided a Paragraph IV certification to the FDA, the applicant must also send notice of the Paragraph IV certification to the NDA and patent holders for the RLD once the applicant’s NDA has been accepted for filing by the FDA. The NDA and patent holders may then initiate a legal challenge to the Paragraph IV certification. The filing of a patent infringement lawsuit within 45 days of their receipt of a Paragraph IV certification automatically prevents the FDA from approving the ANDA or 505(b)(2) NDA until the earlier of 30 months after the receipt of the Paragraph IV notice, expiration of the patent or a decision in the infringement case that is favorable to the ANDA or 505(b)(2) applicant. Alternatively, if the listed patent holder does not file a patent infringement lawsuit within the required 45-day period, the follow-on applicant’s ANDA or 505(b)(2) NDA will not be subject to the 30-month stay.

In addition, under the Hatch-Waxman Amendments, the FDA may not approve an ANDA or 505(b)(2) NDA until any applicable period of non-patent exclusivity for the referenced RLD has expired. These market exclusivity provisions under the FDCA also can delay the submission or the approval of certain applications. The FDCA provides a five-year period of non-patent marketing exclusivity within the United States to the first applicant to gain approval of an NDA for a drug containing a new chemical entity. A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance. During the exclusivity period, the FDA may not accept for review an ANDA or a 505(b)(2) NDA submitted by another company for another version of such drug where the applicant does not own or have a legal right of reference to all the data required for approval. However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement.

The FDCA also provides three years of marketing exclusivity for an NDA, 505(b)(2) NDA or supplement to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, for example, new indications, dosages or strengths of an existing drug. This three-year exclusivity covers only the conditions of use associated with the new clinical investigations and does not prohibit the FDA from approving follow-on applications for drugs containing the original active agent. Five-year and three-year exclusivity also will not delay the submission or approval of a traditional NDA filed under Section 505(b)(1) of the FDCA. However, an applicant submitting a traditional NDA would be required to either conduct or obtain a right of reference to all of the preclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.

Patent Term Extension

After NDA approval, owners of relevant drug patents may apply for up to a five-year patent term extension. The allowable patent term extension is calculated as half of the drug’s testing phase — the time between when the IND becomes effective and NDA submission — and all of the review phase — the time between NDA submission and approval, up to a maximum of five years. The time can be shortened if FDA determines that the applicant did not pursue approval with due diligence. The total patent term after the extension may not exceed 14 years. For patents that might expire during the application phase, the patent owner may request an interim patent extension. An interim patent extension increases the patent term by one year and may be renewed up to four times. For each interim patent extension granted, the post-approval patent extension is reduced by one year. The director of the Patent and Trademark Office (PTO) must determine that approval of the drug covered by the patent for which a patent extension is being sought is likely. Interim patent extensions are not available for a drug for which an NDA has not been submitted.

Other regulatory matters

Manufacturing, sales, promotion and other activities of drug products following approval, where applicable, or commercialization are also subject to regulation by numerous regulatory authorities in the United States in addition to the FDA, which may include the Centers for Medicare & Medicaid Services, or CMS, other divisions of the Department of Health and Human Services, or HHS, the Department of Justice, the Drug Enforcement Administration, the Consumer Product Safety Commission, the Federal Trade Commission, the Occupational Safety & Health Administration, the Environmental Protection Agency and state and local governments and governmental agencies.

Other healthcare laws

Healthcare providers, physicians, and third-party payors will play a primary role in the recommendation and prescription of any products for which we obtain marketing approval. Our business operations and any current or future arrangements with third-party payors, healthcare providers and physicians may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which we develop, market, sell and distribute any drugs for which we obtain marketing approval. In the United States, these laws include, without limitation, state and federal anti-kickback, false claims, physician transparency, and patient data privacy and security laws and regulations, including but not limited to those described below.

•        The federal Anti-Kickback Statute, which prohibits, among other things, persons and entities from knowingly and willfully soliciting, offering, paying, receiving or providing any remuneration (including any kickback, bribe, or certain rebate), directly or indirectly, overtly or covertly, in cash or in kind, to induce or reward, or in return for, either the referral of an individual for, or the purchase, order or recommendation of, any good or service, for which payment may be made, in whole or in part, under a federal healthcare program such as Medicare and Medicaid; a person or entity need not have actual knowledge of the federal Anti-Kickback Statute or specific intent to violate it in order to have committed a violation. Violations are subject to civil and criminal fines and penalties for each violation, plus up to three times the remuneration involved, imprisonment, and exclusion from government healthcare programs;

•        The federal civil and criminal false claims laws, including the civil False Claims Act, or FCA, which prohibit individuals or entities from, among other things, knowingly presenting, or causing to be presented, to the federal government, claims for payment or approval that are false, fictitious or fraudulent; knowingly making, using, or causing to be made or used, a false statement or record material to a false or fraudulent claim or obligation to pay or transmit money or property to the federal government; or knowingly concealing or knowingly and improperly avoiding or decreasing an obligation to pay money to the federal government. Manufacturers can be held liable under the FCA even when they do not submit claims directly to government payors if they are deemed to “cause” the submission of false or fraudulent claims. In addition, the government may assert that a claim that includes items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the civil False Claims Act. The FCA also permits a private individual acting as a “whistleblower” to bring actions on behalf of the federal government alleging violations of the FCA and to share in any monetary

recovery. When an entity is determined to have violated the federal civil False Claims Act, the government may impose civil fines and penalties for each false claim, plus treble damages, and exclude the entity from participation in Medicare, Medicaid and other federal healthcare programs;

•        The federal civil monetary penalties laws, which impose civil fines for, among other things, the offering or transfer or remuneration to a Medicare or state healthcare program beneficiary if the person knows or should know it is likely to influence the beneficiary’s selection of a particular provider, practitioner, or supplier of services reimbursable by Medicare or a state health care program, unless an exception applies;

•        The Health Insurance Portability and Accountability Act of 1996, or HIPAA, imposes criminal and civil liability for knowingly and willfully executing a scheme, or attempting to execute a scheme, to defraud any healthcare benefit program, including private payors, knowingly and willfully embezzling or stealing from a healthcare benefit program, willfully obstructing a criminal investigation of a healthcare offense, or falsifying, concealing or covering up a material fact or making any materially false statements in connection with the delivery of or payment for healthcare benefits, items or services. Similar to the federal Anti-Kickback Statute, a person or entity need not have actual knowledge of the statute or specific intent to violate it in order to have committed a violation;

•        HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, or HITECH, and their respective implementing regulations, imposes, among other things, specified requirements on covered entities and their business associates relating to the privacy and security of individually identifiable health information including mandatory contractual terms and required implementation of technical safeguards of such information. HITECH also created new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates in some cases, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions;

•        The Physician Payments Sunshine Act, enacted as part of the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively, the ACA, imposed new annual reporting requirements for certain manufacturers of drugs, devices, biologics, and medical supplies for which payment is available under Medicare, Medicaid, or the Children’s Health Insurance Program, for certain payments and “transfers of value” provided to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members. In addition, many states also require reporting of payments or other transfers of value, many of which differ from each other in significant ways, are often not pre-empted, and may have a more prohibitive effect than the Sunshine Act, thus further complicating compliance efforts. Effective January 1, 2022, these reporting obligations will extend to include transfers of value made in the previous year to certain non-physician providers such as physician assistants and nurse practitioners;

•        Federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers; and

•        Analogous state and foreign laws and regulations, such as state anti-kickback and false claims laws, which may apply to sales or marketing arrangements and claims involving healthcare items or services reimbursed by non-governmental third party-payors, including private insurers, and may be broader in scope than their federal equivalents; state and foreign laws require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government or otherwise restrict payments that may be made to healthcare providers; state and foreign laws that require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers, and restrict marketing practices or require disclosure of marketing expenditures and pricing information; state and foreign laws that govern the privacy and security of health information in some circumstances. These data privacy and security laws may differ from each other in significant ways and often are not pre-empted by HIPAA, which may complicate compliance efforts.

The distribution of drug products is subject to additional requirements and regulations, including extensive record-keeping, licensing, storage and security requirements intended to prevent the unauthorized sale of pharmaceutical products.

The scope and enforcement of each of these laws is uncertain and subject to rapid change in the current environment of healthcare reform, especially in light of the lack of applicable precedent and regulations. Federal and state enforcement bodies have recently increased their scrutiny of interactions between healthcare companies and healthcare providers, which has led to a number of investigations, prosecutions, convictions and settlements in the healthcare industry. It is possible that governmental authorities will conclude that our business practices do not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations. If our operations are found to be in violation of any of these laws or any other related governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, imprisonment, disgorgement, exclusion from government funded healthcare programs, such as Medicare and Medicaid, reputational harm, additional oversight and reporting obligations if we become subject to a corporate integrity agreement or similar settlement to resolve allegations of non-compliance with these laws and the curtailment or restructuring of our operations. If any of the physicians or other healthcare providers or entities with whom we expect to do business are found to be not in compliance with applicable laws, they may be subject to similar actions, penalties and sanctions. Ensuring business arrangements comply with applicable healthcare laws, as well as responding to possible investigations by government authorities, can be time- and resource-consuming and can divert a company’s attention from its business.

Coverage and Reimbursement

In the United States and markets in other countries, patients who are prescribed treatments for their conditions and providers performing the prescribed services generally rely on third-party payors to reimburse all or part of the associated healthcare costs. Thus, even if a product candidate is approved, sales of the product will depend, in part, on the extent to which third-party payors, including government health programs in the United States such as Medicare and Medicaid, commercial health insurers and managed care organizations, provide coverage, and establish adequate reimbursement levels for, the product. In the United States, no uniform policy of coverage and reimbursement for drug products exists among third-party payors. Therefore, coverage and reimbursement for drug products can differ significantly from payor to payor. The process for determining whether a third-party payor will provide coverage for a product may be separate from the process for setting the price or reimbursement rate that the payor will pay for the product once coverage is approved. Third-party payors are increasingly challenging the prices charged, examining the medical necessity, and reviewing the cost-effectiveness of medical products and services and imposing controls to manage costs. Third-party payors may limit coverage to specific products on an approved list, also known as a formulary, which might not include all of the approved products for a particular indication.

In order to secure coverage and reimbursement for any product that might be approved for sale, a company may need to conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity and cost-effectiveness of the product, in addition to the costs required to obtain FDA or other comparable regulatory approvals. Additionally, companies may also need to provide discounts to purchasers, private health plans or government healthcare programs. Nonetheless, product candidates may not be considered medically necessary or cost effective. A decision by a third-party payor not to cover a product could reduce physician utilization once the product is approved and have a material adverse effect on sales, our operations and financial condition. Additionally, a third-party payor’s decision to provide coverage for a product does not imply that an adequate reimbursement rate will be approved. Further, one payor’s determination to provide coverage for a product does not assure that other payors will also provide coverage and reimbursement for the product, and the level of coverage and reimbursement can differ significantly from payor to payor.

The containment of healthcare costs has become a priority of federal, state and foreign governments, and the prices of products have been a focus in this effort. Governments have shown significant interest in implementing cost-containment programs, including price controls, restrictions on reimbursement and requirements for substitution of generic products. Adoption of price controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limit a company’s revenue generated from the sale of any approved products. Coverage policies and third-party payor reimbursement rates may change at any time. Even if favorable coverage and reimbursement status is attained for one or more products for which a company or its collaborators receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future.

American Rescue Plan Act of 2021 into law, which eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single-source and innovator multiple-source drugs, beginning January 1, 2024. These laws may result in additional reductions in Medicare, Medicaid and other healthcare funding.

Moreover, payment methodologies may be subject to changes in healthcare legislation and regulatory initiatives. For example, CMS may develop new payment and delivery models, such as bundled payment models. In addition, recently there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their commercial products, which has resulted in several Congressional inquiries and proposed and enacted state and federal legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for pharmaceutical products. For example, on July 24, 2020 and September 13, 2020, the Trump administration announced several executive orders related to prescription drug pricing and importation. As a result, the FDA also released a final rule in September 2020, effective November 30, 2020, providing guidance for states to build and submit importation plans for drugs from Canada. Further, in November 2020, the U.S. Department of Health and Human Services, or HHS, finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law. The implementation of the rule has been delayed by the Biden administration from January 1, 2022 to January 1, 2023 in response to ongoing litigation. The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers, the implementation of which have also been delayed by the Biden administration until January 1, 2023. The CMS also issued an interim final rule that establishes a Most Favored Nation, or MFN, Model for Medicare Part B drug payments. This regulation would substantially change the reimbursement landscape as it bases Medicare Part B payment for 50 selected drugs on prices in foreign countries instead of average sales prices (ASP) and establishes a fixed add-on payment in place of the current 6 percent (4.3 percent after sequestration) of ASP. The MFN drug payment amount is expected to be lower than the current ASP-based limit because U.S. drug prices are generally the highest in the world. On December 28, 2020, the U.S. District Court in Northern California issued a nationwide preliminary injunction against implementation of the interim final rule. On January 13, 2021, in a separate lawsuit brought by industry groups in the U.S. District Court for the District of Maryland, the government defendants entered a joint motion to stay litigation on the condition that the government would not appeal the preliminary injunction granted in the U.S. District Court for the Northern District of California and that performance for any final regulation stemming from the MFN Model interim final rule shall not commence earlier than sixty (60) days after publication of that regulation in the Federal Register. In December 2020, CMS issued a final rule implementing significant manufacturer price reporting changes under the Medicaid Drug Rebate Program, including regulations that affect manufacturer-sponsored patient assistance programs subject to pharmacy benefit manager accumulator programs and Best Price reporting related to certain value-based purchasing arrangements. On May 21, 2021, an industry group sued CMS, claiming that the change to the Best Price rule exceeds CMS’s statutory authority and is contrary to the Medicaid Rebate statute. This litigation is ongoing. It is unclear to what extent these new regulations will be implemented and to what extent these regulations or any future legislation or regulations by the Biden administration will have on our business, including our ability to generate revenue and achieve profitability.

On May 30, 2018, the Right to Try Act was signed into law. The law, among other things, provides a federal framework for certain patients to access certain investigational new drug products that have completed a Phase 1 clinical trial and that are undergoing investigation for FDA approval. Under certain circumstances, eligible patients can seek treatment without enrolling in clinical trials and without obtaining FDA permission under the FDA expanded access program. There is no obligation for a drug manufacturer to make its drug products available to eligible patients as a result of the Right to Try Act, but the manufacturer must develop an internal policy and respond to patient requests according to that policy.

Outside the United States, ensuring coverage and adequate payment for a product also involves challenges. Pricing of prescription pharmaceuticals is subject to government control in many countries. Pricing negotiations with government authorities can extend well beyond the receipt of regulatory approval for a product and may require a clinical trial that compares the cost-effectiveness of a product to other available therapies. The conduct of such a clinical trial could be expensive and result in delays in commercialization.

In the European Union, pricing and reimbursement schemes vary widely from country to country. Some countries provide that products may be marketed only after a reimbursement price has been agreed. Some countries may require the completion of additional studies that compare the cost-effectiveness of a particular product candidate

In addition, we may incur substantial costs in order to comply with current or future environmental, health and safety laws and regulations. Current or future environmental laws and regulations may impair our research, development or production efforts. In addition, failure to comply with these laws and regulations may result in substantial fines, penalties or other sanctions.

Government regulation of drugs outside of the United States

To market any product outside of the United States, we would need to comply with numerous and varying regulatory requirements of other countries regarding safety and efficacy and governing, among other things, clinical trials, marketing authorization or identification of an alternate regulatory pathway, manufacturing, commercial sales and distribution of our product candidates. For instance, in the European Economic Area, or the EEA (comprised of the 26 EU Member States plus Iceland, Liechtenstein and Norway, with the UK having left the EU in January of 2020), medicinal products must be authorized for marketing by using either the centralized authorization procedure or national authorization procedures.

•        Centralized procedure — If pursuing marketing authorization of a product candidate for a therapeutic indication under the centralized procedure, following the opining of the EMA’s Committee for Medicinal Products for Human Use, or, CHMP, the European Commission issues a single marketing authorization valid across the EEA. The centralized procedure is compulsory for human medicines derived from biotechnology processes or advanced therapy medicinal products (such as gene therapy, somatic cell therapy and tissue engineered products), products that contain a new active substance indicated for the treatment of certain diseases, such as HIV/AIDS, cancer, neurodegenerative disorders, diabetes, autoimmune diseases and other immune dysfunctions, viral diseases, and officially designated orphan medicines. For medicines that do not fall within these categories, an applicant has the option of submitting an application for a centralized marketing authorization to the EMA, as long as the medicine concerned contains a new active substance not yet authorized in the EEA, is a significant therapeutic, scientific or technical innovation, or if its authorization would be in the interest of public health in the EEA. Under the centralized procedure the maximum timeframe for the evaluation of an MAA by the EMA is 210 days, excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP. Accelerated assessment might be granted by the CHMP in exceptional cases, when a medicinal product is expected to be of a major public health interest, particularly from the point of view of therapeutic innovation. The timeframe for the evaluation of an MAA under the accelerated assessment procedure is 150 days, excluding clock stops.

•        National authorization procedures — There are also two other possible routes to authorize products for therapeutic indications in several countries, which are available for products that fall outside the scope of the centralized procedure:

•        Decentralized procedure — Using the decentralized procedure, an applicant may apply for simultaneous authorization in more than one EU country of medicinal products that have not yet been authorized in any EU country and that do not fall within the mandatory scope of the centralized procedure.

•        Mutual recognition procedure — In the mutual recognition procedure, a medicine is first authorized in one EU Member State, in accordance with the national procedures of that country. Following this, additional marketing authorizations can be sought from other EU countries in a procedure whereby the countries concerned recognize the validity of the original, national marketing authorization.

In the EEA, new products for therapeutic indications that are authorized for marketing (i.e., reference products) qualify for eight years of data exclusivity and an additional two years of market exclusivity upon marketing authorization. The data exclusivity period prevents generic or biosimilar applicants from relying on the preclinical and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar marketing authorization in the EU during a period of eight years from the date on which the reference product was first authorized in the EU. The market exclusivity period prevents a successful generic or biosimilar applicant from commercializing its product in the EU until ten years have elapsed from the initial authorization of the reference product in the EU. The ten-year market exclusivity period can be extended to a maximum of eleven years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.