What changed in this filing

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Item 1A. Risk Factors

2024-02-08 compared with 2023-11-07 · 48 added, 12 removed, 918 unchanged (6% of the section changed)

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• our ability to obtain and maintain sufficient quantities of raw material supplies to build or maintain our product candidate supplies or otherwise operate our in-house manufacturing facility;

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• our ability to obtain and maintain sufficient quantities of materials and supplies to conduct our clinical trials, such as comparative, control and/or standard of care therapies including chemotherapeutic agents that are currently in short supply in the industry;

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Moreover, should there

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be an issue with the design of a clinical trial, our results may be impacted.

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By example, the FDA may determine that larger trials, Phase 3 trials, randomized and controlled clinical trials, or clinical trials designed to replicate results found in our registrational or pivotal trials are required before we may file a BLA or before the FDA will approve a marketing application;

• we may fail to reach an agreement with regulators or IRBs regarding the scope, design, or implementation of our clinical trials, and the FDA or comparable foreign regulatory authorities may require changes to our study designs that make further study impractical or not financially prudent;

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• we may fail to reach an agreement with regulators or IRBs regarding the scope, design, or implementation of our clinical trials, and the FDA or comparable foreign regulatory authorities may require changes to our study designs or study data analysis that may make further study impractical or not financially prudent;

• regulators may ultimately disagree with the design or our conduct of our preclinical studies or clinical trials, finding that they do not support product candidate approval;

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Significant delays relating to any preclinical or clinical trials also could shorten any periods during which we may have the exclusive right to commercialize our product candidates or allow our competitors to bring products to market before we do and impair our ability to successfully

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commercialize our product candidates and may harm our business and results of operations.

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As a result, topline data should be viewed with caution until the final data are available.

Further, others, including regulatory agencies, may not accept or agree with our assumptions, estimations, calculations, conclusions or analyses or may interpret or weigh the importance of data differently, which could impact the value of the particular program, the approvability or commercialization of the particular drug candidate or drug and our company in general.

Further, others, including regulatory agencies, may not accept or agree with our assumptions, estimations, calculations, conclusions or analyses or may request different calculations or analysis than conducted and may interpret or weigh the importance of data differently, which could impact the value of the particular program, the approvability or commercialization of the particular drug candidate or drug and our company in general.

In addition, the information we may publicly disclose regarding a particular study or clinical trial is based on what is typically extensive information, and you or others may not agree with what we determine is the material or otherwise appropriate information to include in our disclosure, and any information we determine not to disclose may ultimately be deemed significant with respect to future decisions, conclusions, views, activities or otherwise regarding a particular drug, drug candidate or our business.

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If any of these occur, our business, financial condition, results of operations, stock price and prospects may be materially harmed.

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Moreover, the development of our product candidates for use in combination with another product or product candidate may present challenges that are not faced for single agent product candidates.

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Our lead product candidate is RP1.

A key part of our strategy is to pursue clinical development of RP1 and additional product candidates, including RP2 and RP3.

A key part of our strategy is to pursue clinical development of RP1 and additional product candidates, including RP2 and, when appropriate RP3.

Developing, obtaining marketing approval for, and commercializing additional product candidates will require substantial additional funding and will be subject to the risks of failure inherent in medical product development.

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Even if we obtain regulatory approval for our product candidates, any such approval may be subject to limitations, including with respect to the approved indications or patient populations, which could impair our ability to successfully commercialize our product candidates.

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We are not permitted to market or promote or sell any of our product candidates before we receive regulatory approval from the FDA or comparable foreign regulatory authorities, and we may never receive such regulatory approval for any of our product candidates.

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In addition, approval policies, regulations, or the type and amount of clinical data necessary to gain approval may change during the course of a product candidate’s clinical development and may vary among jurisdictions and there may be varying interpretations of data obtained from preclinical studies or clinical trials, any of which may cause delays or limitations in the approval or a decision not to approve an application.

These regulatory requirements may require us to amend our clinical trial protocols, conduct additional preclinical studies or clinical trials that may require regulatory or IRB approval, or otherwise cause delays in the approval or rejection of an application.

These regulatory requirements may require us to amend our clinical trial protocols, conduct additional preclinical studies or clinical trials that may require regulatory or IRB approval, require additional or different analysis of clinical data or otherwise cause delays in the approval or rejection of an application.

For example, in February 2023, we received a response from the FDA following submission of our draft statistical analysis plan in September 2022, which raised a number of points and recommendations requiring further discussion.

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Serious adverse events or

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undesirable side effects caused by our product candidates could cause us, IRBs, and other reviewing entities or regulatory authorities to interrupt, delay, or halt clinical trials and could result in a more restrictive label or the delay or denial of regulatory approval by the FDA or comparable foreign regulatory authorities.

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While physicians may choose to prescribe products for uses that are not described in the product’s labeling and for uses that differ from those tested in clinical trials and approved by the regulatory authorities, we are prohibited from marketing

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and promoting the products for indications and uses that are not specifically approved by the FDA.

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If the FDA or comparable foreign regulatory authorities become aware of new safety information after approval of any of our product candidates, they may withdraw approval, issue public safety alerts, require labeling changes or establishment of a REMS or similar strategy, impose significant restrictions on a product’s indicated uses or

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marketing, or impose ongoing requirements for potentially costly post approval studies or post-market surveillance.

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• injunctions or the imposition of civil or criminal penalties, including imprisonment.

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Any of these events could prevent us from achieving or maintaining market acceptance of the particular product candidate, if approved, or could substantially increase the costs and expenses of commercializing such product, which in turn could delay or prevent us from generating significant revenues from its marketing and sale.

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Obtaining foreign marketing approvals and

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compliance with foreign regulatory requirements could result in significant delays, difficulties and costs for us and could delay or prevent the introduction of our products in certain countries.

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If their product candidates are shown to be safer or more effective than ours, our commercial opportunity may be reduced or eliminated.

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The development and commercialization of cancer immunotherapy products is characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary rights.

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The establishment and development of

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commercial capabilities, including compliance plans, to market any products we may develop will be expensive and time consuming and could delay any product launch, and we may not be able to successfully develop this capability.

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Only one oncolytic immunotherapy, T-

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Vec, has received FDA approval to date.

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• the safety, efficacy, and other potential advantages over, and availability of, alternative treatments already used or that may later be approved;

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• distribution and use restrictions imposed by the FDA or comparable foreign regulatory authorities with respect to our product candidates or to which we agree as part of a REMS or voluntary risk management plan;

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If any of the assumptions proves to be

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inaccurate, the actual markets for our product candidates could be smaller than our estimates of the potential market opportunities.

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We are not profitable and have incurred losses in each period since our inception.

For the three months ended September 30, 2023 and 2022, we reported a net loss of $60.0 million and $43.1 million, respectively.

At September 30, 2023, we had an accumulated deficit of $595.1 million.

For the three months ended December 31, 2023 and 2022, we reported a net loss of $51.1 million and $39.7 million, respectively.

At December 31, 2023, we had an accumulated deficit of $646.2 million.

We expect to continue to incur significant losses for the foreseeable future, and we expect these losses to increase as we continue our research and development of, and seek marketing approvals for, RP1, our other product candidates and any additional product candidates we may develop.

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We have no products approved for commercial sale, have not generated any revenue from product sales, and do not anticipate generating any revenue from product sales until after we have received marketing approval for the commercial sale of

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a product candidate, if ever.

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Our operations have consumed substantial amounts of cash since inception.

At September 30, 2023, our cash and cash equivalents and short-term investments were $496.8 million.

At December 31, 2023, our cash and cash equivalents and short-term investments were $466.4 million.

We expect to continue to spend substantial amounts to continue the clinical and preclinical development of RP1 and our other product candidates.

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• the timing of, and the costs involved in, obtaining marketing approvals for RP1 and our other product candidates if clinical trials are successful;

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• the success of any collaborations;

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Until we can generate sufficient product revenue to finance our cash requirements, which we may never do, we expect to finance our future cash needs through a combination of public or private equity offerings, debt financings, collaborations, strategic alliances, licensing arrangements and other marketing or distribution arrangements.

Based on our current operating plan, we expect that our existing cash and cash equivalents and short-term investments, as of September 30, 2023 will enable us to fund operations into the second half of calendar 2025.

Based on our current operating plan, we expect that our existing cash and cash equivalents and short-term investments, as of December 31, 2023 will enable us to fund operations into the second half of calendar 2026.

We have based this estimate on assumptions that may prove to be wrong, and we could exhaust our available capital resources sooner than we expect.

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The steps we have taken to protect our proprietary rights may not be adequate to preclude misappropriation of our proprietary information, use by third parties of our products or infringement of our intellectual property rights, both inside and outside of the United States.

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Our pending applications cannot be enforced against third parties practicing the inventions claimed in such applications unless and until a patent issues from such applications.

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The disclosure

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of our trade secrets or the independent development of our trade secrets by a competitor or other third party would impair our competitive position and may materially harm our business, financial condition, results of operations, stock price and prospects.

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We also may develop our product candidates in combination with

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products developed by additional companies that are covered by patents or licenses held by those entities to which we do not have a license.

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If our relationships with BMS, Regeneron, or any future collaborator or supplier are not successful, we may be delayed in completing the development of our product candidates.

We have entered into arrangements with BMS and Regeneron as part of our clinical development for RP1, RP2 and RP3 for where nivolumab or cemiplimab, respectively, are intended to be used for these clinical programs.

BMS is providing nivolumab, its anti-PD-1 therapy, for use in our ongoing IGNYTE Phase 1/2 trials with RP1, our Phase 1/2 clinical trial with RP2 and our Phase 1 and Phase 2 clinical trials with RP3 where we intend to use nivolumab and may potentially do so for other clinical trials in the future;

Regeneron is providing cemiplimab, its anti-PD-1 therapy, for use in our ongoing CERPASS Phase 2 clinical trial and may potentially do so for other clinical trials in the future.

We have entered into arrangements with BMS and Regeneron as part of our clinical development for our product candidates where nivolumab or cemiplimab, respectively, are intended to be used for these clinical programs.

BMS is providing nivolumab, its anti-PD-1 therapy, for use in our ongoing IGNYTE Phase 1/2 trials with RP1 and our Phase 1/2 clinical trial with RP2 where we intend to use nivolumab and may potentially do so for other clinical trials in the future;

Regeneron is providing cemiplimab, its anti-PD-1 therapy, for use in our CERPASS Phase 2 clinical trial and may potentially do so for other clinical trials in the future.

We may also enter into agreements with additional companies for the supply of anti-PD-1 therapies for use in the development of RP1 and our other product candidates, similar to our agreement with Roche.

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The success of any collaboration arrangements may depend on the efforts and activities of our

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collaborators.

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If we do not receive the funding we expect under the agreements, our development of our product candidates could be delayed and we may need additional resources to develop our product candidates and our product platform.

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Additionally, if any future collaborator of ours is involved in a business combination, the collaborator might de-emphasize or terminate development or commercialization of any product candidate it licenses to us.

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we may not be able to, or may be delayed in our efforts to, successfully commercialize our product candidates, or we or they may be subject to regulatory

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enforcement actions.

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We must also receive FDA approval for the use of any new manufacturers for clinical or commercial supply, including our own manufacturing facility.

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A failure to comply with the applicable regulatory requirements, including periodic regulatory inspections, may result in regulatory enforcement actions against us (including fines and civil and criminal penalties, including imprisonment) suspension or restrictions of production, injunctions, delay or denial of product approval or supplements to approved products, clinical holds or termination of clinical trials, warning or untitled letters, regulatory authority communications warning the public about safety issues with the product candidate, refusal to permit the import or export of the products, product seizure, detention, or recall, operating restrictions, suits under the civil False Claims Act, corporate integrity agreements, consent decrees, withdrawal of product approval, environmental or safety incidents and other liabilities.

If the safety of any quantities supplied is compromised due to our manufacturing failures to adhere to applicable laws or for other reasons, we may not be able to obtain regulatory approval for or successfully commercialize our product candidates.

The transition of our manufacturing operations to our new facility may result in further delays or expenses, and we may not experience the anticipated operating efficiencies.

The transition of our manufacturing operations to, and operating and maintaining, our own manufacturing facility may result in further delays or expenses, and we may not experience the anticipated operating efficiencies.

Our approximately 63,000 square foot manufacturing facility in Framingham, Massachusetts is now fully operational.

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Risks related to legal and compliance matters

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We face potential product liability exposure, and if successful claims are brought against us, we may incur substantial liability and have to limit the commercialization of any approved products and/or our product candidates.

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We are also subject to other laws and regulations governing our international operations, including regulations administered by the governments of the United States and the United Kingdom and authorities in the European Union, including applicable import and export control regulations, economic

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sanctions on countries and persons, anti-money laundering laws, customs requirements and currency exchange regulations, collectively referred to as the trade control laws.

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As a result of these and other new proposals, we may determine to change our current manner of operation, provide additional benefits or change our contract arrangements, any of which could have a material adverse effect on our business, financial condition, results of operations, stock price and prospects.

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Our employees, independent contractors, consultants, commercial partners, principal investigators, CMOs, or CROs may engage in misconduct or other improper activities, including noncompliance with regulatory standards and requirements, which could have a material adverse effect on our business.

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Although there are some exemptions for clinical trial data and health information, the CCPA may impact our business activities and increase our compliance costs and potential

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In addition, it is anticipated that the California Privacy Rights Act, or CPRA, which became operative on January 1, 2023, will expand the CCPA, including by expanding consumers’ rights with respect to certain sensitive personal data.

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If we are not able to effectively expand our organization by hiring qualified new employees and expanding our groups of consultants and contractors, we may not be able to successfully implement the tasks necessary to further develop and commercialize RP1 and our other product candidates and, accordingly, may not achieve our research, development and commercialization goals.

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Our future success depends on our ability to retain our key employees and consultants, and to attract and motivate highly qualified personnel.

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Our business and operations could suffer in the event of system failures or unauthorized or inappropriate use of or access to our systems.

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In the ordinary course of business, we collect, receive, store, process, generate, use, transfer, disclose, make accessible, protect, secure, dispose of, transmit, and share (collectively, processing) sensitive information, including personal data, proprietary and confidential business data, trade secrets, intellectual property, data we collect about trial participants in connection with clinical trials, and sensitive third-party data.

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• the level of expenses related to the development of RP1 and our other product candidates or clinical development programs;

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• the results of our efforts to discover, develop, acquire or in-license additional product candidates or drugs;

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• the timing and outcomes of clinical and preclinical studies for RP1 and our other product candidates or competing product candidates;

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• competition from existing and potential future products that compete with RP1 and our other product candidates, and changes in the competitive landscape of our industry, including consolidation among our competitors or partners;

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Sales of a substantial number of shares of our common stock in the public market could cause our stock price to fall.

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If our existing stockholders sell, or indicate an intention to sell, substantial amounts of our common stock in the public market after the expiration of contractual or legal restrictions on resale lapse, the market price of our common stock could decline.

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• retention of key employees, the loss of key personnel, and uncertainties in our ability to maintain key business relationships;

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• risks and uncertainties associated with the other party to such a transaction, including the prospects of that party, their regulatory compliance status, and their existing products or product candidates and marketing approvals;

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Although we do not currently operate in Russia, Ukraine, Israel or territories under Hamas control, if these conflicts broaden it may impact countries or territories in which we do operate or intend to operate, which could have a negative impact on our ability to achieve our objectives or timelines.

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The increasing focus on environmental sustainability and social initiatives could increase our costs, harm our reputation and adversely impact our financial results.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-Q

Item 1A. Risk Factors