What changed in this filing

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Item 1. Business

2025-05-22 compared with 2024-05-16 · 171 added, 186 removed, 508 unchanged (41% of the section changed)

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Our proprietary oncolytic immunotherapy product candidates are designed and intended to maximally activate the immune system against cancer.

Oncolytic immunotherapy is an emerging drug class, which we intend to establish as the second cornerstone of immune-based cancer treatments, alongside checkpoint blockade.

Oncolytic immunotherapy is an emerging drug class.

Oncolytic immunotherapy exploits the ability of certain viruses to selectively replicate in and directly kill tumors, as well as induce a potent, patient-specific, anti-tumor immune response.

Our product candidates incorporate multiple mechanisms into a practical “off-the-shelf” approach that is intended to maximize the immune response against a patient’s cancer and to offer significant advantages over other approaches to inducing anti-tumor immunity, including personalized vaccine approaches.

We believe that the bundling of multiple approaches for the treatment of cancer into single therapies may improve patient outcomes and simplify the development path of our product candidates.

Our proprietary RPx platform is based on a novel, engineered strain of herpes simplex virus 1, or HSV-1, backbone with payloads added to maximize immunogenic cell death and the induction of a systemic anti-tumor immune response.

Our RPx platform is intended to have unique dual local and systemic activity consisting of direct selective virus-mediated killing of the tumor resulting in the release of tumor-derived antigens and altering of the tumor microenvironment to ignite a strong and durable systemic response.

Our product candidates are expected to be synergistic with most established and experimental cancer treatment modalities, and, with an attractive safety profile our RPx platform is expected to have the versatility to be developed alone or combined with a variety of other treatment options.

We currently have three RPx product candidates in our portfolio, RP1 (vusolimogene oderparepvec), our lead product candidate, RP2 and RP3.

We believe that the bundling of multiple approaches for the treatment of cancer into single therapies will increase clinical efficacy and simplify the development path of our product candidates, while also improving patient outcomes.

Our proprietary RPx platform is based on a novel, engineered strain of herpes simplex virus 1, or HSV-1, backbone with payloads added that are intended to maximize immunogenic cell death and the induction of a systemic anti-tumor immune response.

The RPx platform is intended to have unique dual local and systemic activity consisting of direct selective virus-mediated killing of the tumor resulting in the release of tumor-derived antigens and altering of the tumor microenvironment to ignite a strong and durable systemic response.

Our product candidates are expected to be synergistic with most established and experimental cancer treatment modalities, and, with an attractive safety profile the RPx platform is expected to have the versatility to be developed alone or combined with a variety of other treatment options.

We currently have three RPx product candidates in our development pipeline, RP1 (vusolimogene oderparepvec), our lead product candidate, RP2 and RP3.

Although our fiscal year ends March 31st, our programs and program updates are reported on a calendar year basis.

We are conducting a number of clinical trials of RP1, both as a monotherapy and in combination with anti-PD-1 therapy, with a focus on establishing a major skin cancer franchise.

Our leading clinical trial of RP1 is our IGNYTE trial, a multi-cohort Phase 1/2 clinical trial being conducted in collaboration with Bristol Myers Squibb Company, or BMS, under which BMS has granted us a non-exclusive, royalty-free license to, and is supplying at no cost, its anti-PD-1 therapy, nivolumab, for use in combination with RP1.

The leading tumor specific cohort in the IGNYTE trial is our registration directed Phase 2 expansion cohort enrolling patients with anti-PD-1 failed cutaneous melanoma who are being treated with RP1 in combination with nivolumab.

In December 2023, we reported the full data set of 156 patients (140 patients from the registration-directed expansion cohort and 16 anti-PD1 failed cutaneous melanoma patients from the prior phase 2 cohort), by investigator assessment, with an overall response rate, or ORR, of 31.4% and a complete response rate, or CR, of 12%.

We are conducting a number of clinical trials of RP1, both as a monotherapy and in combination with anti-PD-1 therapy, with the goal of establishing a major skin cancer treatment franchise.

Our leading clinical trial of RP1 is referred to as the IGNYTE trial, which is a multi-cohort clinical trial being conducted in collaboration with Bristol Myers Squibb Company, or BMS, under which BMS has granted us a non-exclusive, royalty-free license to, and is supplying at no cost, its anti-PD-1 therapy, nivolumab, for use in combination with RP1.

The leading tumor specific cohort in the IGNYTE trial is our registration directed Phase 2 expansion cohort in anti-PD-1 failed cutaneous melanoma.

The anti-PD-1 failed melanoma cohort from the IGNYTE trial includes 140 patients who received RP1 in combination with nivolumab.

The primary analysis by independent central review was triggered once all patients had been followed for at least 12 months.

The topline results showed the overall response rate, or ORR, was 33.6% by modified RECIST 1.1 criteria, the primary endpoint as defined in the protocol, and 32.9% by RECIST 1.1 criteria, an additional analysis requested by the FDA.

Responses from baseline were highly durable with 85% of responses lasting more than 12 months.

The median duration of response from baseline was 27.6 months and the median duration of response from treatment initiation was 21.6 months.

RP1 combined with nivolumab continues to be well-tolerated, with mainly Grade 1-2 "on target" side effects, observed.

Following a Type C meeting with the U.S.

Food and Drug Administration, or FDA, a Phase 3 study design was agreed.

This confirmatory study, our IGNYTE-3 trial, is a randomized, controlled, multicenter, open-label Phase 3 clinical study comparing RP1 in combination with nivolumab versus physician's choice treatment for patients with unresectable Stage IIIb-IV cutaneous melanoma whose disease progressed on an anti PD-1 and an anti-CTLA-4 containing regimen (administered either as a combination regimen or in sequence) or who are not candidates for treatment with an anti-CTLA-4 therapy.

The FDA requested that the IGNYTE-3 trial be underway at the time of a BLA submission under the accelerated approval pathway and we plan to enroll patients into this trial in the second half of 2024.

The FDA also indicated that all responding patients in the IGNYTE anti-PD-1 failed cohort of melanoma patients should be followed for at least 6 months with assessments completed through independent central review using RECIST v1.1, in addition to modified RECIST used in the study.

Topline primary data from RP1 in combination with nivolumab in anti-PD-1 failed melanoma patients is expected in the second quarter of 2024 and we plan to submit a BLA for this cohort in the second half of 2024.

In our non-melanoma skin cancer, or NMSC, cohort of the IGNYTE clinical trial, we provided a data update in December 2023 from the first 30 patients with at least 6 months of follow up including patients with cutaneous squamous cell carcinoma, or CSCC, Merkel cell carcinoma, or MCC, basal cell carcinoma, and angiosarcoma in this cohort.

In September 2024, we presented the independently reviewed data from the IGNYTE trial, including key secondary endpoints and subgroup analysis as a late-breaking abstract during an oral session at the European Society for Medical Oncology, or ESMO.

Data presented at ESMO showed activity across all subgroups, including patients who had prior anti-PD-1 and anti-CTLA-4 treatment had an ORR of 27.7% and patients who had primary resistance to anti-PD-1 had an ORR of 35.9% by modified RECIST v1.1.

In November 2024, we presented a late-breaking abstract featuring the IGNYTE trial primary analysis that had been selected for oral presentation at the 39th Annual Meeting of the Society for Immunotherapy of Cancer (SITC 2024).

The data presented at SITC 2024 included further clinical subgroup and initial biomarker data from the IGNYTE trial.

In November 2024, we announced submission of a biologics license application, or BLA, to the FDA for RP1 (vusolimogene oderparepvec) in combination with nivolumab for the treatment of adult patients with advanced melanoma who have previously received an anti-PD-1 containing regimen and that the FDA has granted Breakthrough Therapy designation to RP1 in combination with nivolumab in the same setting.

The submission was made under the accelerated approval pathway.

The FDA accepted our BLA and granted priority review with a Prescription Drug User Fee Act, or PDUFA, goal date of July

The FDA recently completed their late-cycle review meeting and all manufacturing inspections for the BLA and we believe we remain on track for the July 22, 2025 PDUFA date.

In August 2024, we announced the dosing of the first patient in the IGNYTE-3 trial, or the I-3 trial, a confirmatory study design concept consisting of a 2-arm randomized Phase 3 clinical trial with physician's choice of treatment as a comparator arm in anti-PD-1 failed melanoma patients.

With over 100 sites planned globally and an expectation to enroll 400 patients, the I-3 trial will assess RP1 in combination with nivolumab in patients with advanced melanoma who have progressed on anti-PD-1 and anti-CTLA-4 therapies or are ineligible for anti-CTLA-4 treatment.

We continue to enroll patients in the I-3 trial.

In our non-melanoma skin cancer, or NMSC, cohort of the IGNYTE trial, we provided a data update in December 2023 from the first 30 patients with at least 6 months of follow up including patients with cutaneous squamous cell carcinoma, or CSCC, Merkel cell carcinoma, or MCC, basal cell carcinoma, and angiosarcoma in this cohort.

The data showed that treatment with RP1 in combination with nivolumab led to an ORR of 30% which is consistent with data from the anti-PD-1 failed melanoma cohort with approximately one-third of patients responding and 60% demonstrating clinical benefit.

combination of RP1 and nivolumab was well tolerated in this patient population with a safety profile consistent with the overall experience seen with this treatment regimen to date.

The combination of RP1 and nivolumab was well tolerated in this patient population with a safety profile consistent with the overall experience seen with this treatment regimen to date.

Enrollment remains open in this cohort.

Furthering development of our RP1 clinical candidate, we have open for enrollment a Phase 1b/2 clinical trial of single agent RP1 in solid organ transplant recipients with skin cancers, including CSCC, which is referred to herein as ARTACUS or the ARTACUS trial, which we believe to be potentially registrational (subject to discussion with regulatory authorities).

Furthering development of RP1, we have open for enrollment a Phase 1b/2 clinical trial of single agent RP1 in solid organ transplant recipients with skin cancers, including CSCC, which we refer to as the ARTACUS trial.

We believe that the ARTACUS trial will be potentially registrational (in its own right or, subject to discussion with regulatory authorities, following enrollment of additional patients, including as a potential label expansion after an initial approval of RP1 in a different indication).

We are currently enrolling up to 65 patients in the ARTACUS trial to assess the safety and efficacy of RP1 in liver, kidney, heart, lung, and hematopoietic cell transplant patients with skin cancers.

In November 2023 we presented initial data from the ARTACUS clinical trial of RP1 monotherapy in solid organ transplant recipients with skin cancers at the Society for Immunotherapy of Cancer’s, or SITC, 38th Annual Meeting.

The data included 23 evaluable patients with CSCC (n=20) and MCC (n=3), demonstrating an ORR of 34.8% with responses observed in 6 CSCC patients and 2 patients with MCC.

Additional biomarker data collected showed an increase in CD+8 T, a type of immune cell, and an increase in the expression of PD-L1, after treatment suggesting immune activation.

In November 2023 we presented initial data from the ARTACUS trial of RP1 monotherapy in solid organ transplant recipients with skin cancers at the Society for Immunotherapy of Cancer’s, or SITC, 38th Annual Meeting.

The data included 23 evaluable patients with CSCC (n=20) and MCC (n=3), demonstrating an ORR of 34.5% and a complete response, or CR, of 21%.

RP1 monotherapy was well tolerated in these patients and the safety profile was similar to that observed in our other RP1 clinical trials in patients who are not immune suppressed.

No immune-mediated adverse events or evidence of allograft rejection were observed.

This data was also presented during oral presentation at the American Association of Cancer Research, or AACR, 2024 Annual Meeting in April 2024.

We continue to enroll patients into this trial.

As reported in December, our randomized, controlled Phase-2 clinical trial of RP1 with CSCC, referred to as CERPASS or the CERPASS trial, under agreement with our partner Regeneron did not meet either of the two primary endpoints.

RP1 in combination with cemiplimab increased the CRR versus cemiplimab alone (38.1% vs.

25%, p=0.040), which was just short of the required threshold for statistical significance in this study.

The ORR was comparable between the two study groups (52.5% for RP1 plus cemiplimab vs.

51.4% for cemiplimab alone, p=0.692).

Notably, among the 83 patients with locally advanced disease, the complete response rate in the RP1 plus cemiplimab group was 48.1% versus 22.6% in the cemiplimab only group.

RP1 in combination with cemiplimab increased duration of response, or DOR, as compared to cemiplimab alone.

The CERPASS trial will continue as planned to assess DOR, progression free survival, or PFS, and overall survival, or OS, with greater maturity.

We are also developing or have been developing additional product candidates, RP2 and RP3, that have been further engineered to enhance anti-tumor immune responses and are intended to address additional tumor types, including traditionally less immune responsive tumor types.

No immune-mediated adverse events or evidence of allograft rejection were observed to result from RP1.

This data was also presented during oral presentation at the American Association of Cancer Research 2024 Annual Meeting in April 2024.

We continue to enroll patients into the ARTACUS trial.

As previously reported, our clinical trial of RP1 in patients with CSCC, which we refer to as the CERPASS trial, continues as planned to follow patients that were dosed in the trial.

We are also developing or are continuing to develop additional product candidates, RP2 and RP3, that have been further engineered to enhance anti-tumor immune responses and are intended to address additional tumor types, including traditionally less immune responsive tumor types.

In addition to the expression of GALV-GP R(-) and human GM-CSF as in RP1, RP2 has been engineered to express an antibody-like molecule intended to block the activity of CTLA-4, a protein that inhibits the full activation of an immune response, including to tumors.

RP3 has been engineered with the intent to further stimulate an anti-tumor immune response through activation of immune co-stimulatory pathways through the additional expression of the ligands for CD40 and 4-1BBL, as well as anti-CTLA-4 and GALV-GP R(-), but without the expression of GM-CSF.

We continue the development of our clinical candidate RP2 with a focus on establishing a rare cancer franchise.

Notably, as previously reported, from our Phase-1 clinical trial of RP2 alone and in combination with nivolumab, we have seen durable responses from a monotherapy cohort in a variety of difficult to treat tumors as well as in combination with anti-PD1 and in particular in patients with uveal melanoma, among other tumor types.

In November 2023, we presented updated data from a cohort of metastatic uveal melanoma patients during a Plenary Session at the 20th Annual International Society for Melanoma Research Congress.

The updated data showed RP2 led to an ORR of 29.4 percent (5 of 17 patients;

We continue the development of our product candidate RP2 with the goal of moving beyond skin cancers and aiming to treat the more prevalent tumor types commonly found in liver and lung metastasis and including those involving primary liver cancer.

In November 2023, we presented updated data from a cohort of mUM patients during a Plenary Session at the 20th Annual International Society for Melanoma Research Congress.

The updated data showed RP2 led to an ORR of 29.4% (5 of 17 patients;

one of the responding patients was treated with RP2 monotherapy and four of the responding patients were treated with RP2 combined with nivolumab), including responses in patients with liver, lung, and bone metastases.

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The most common grade 1 or 2 treatment related adverse events, or TRAEs, overall in both cohorts were pyrexia, chills, fatigue, hypotension and pruritis.

Six patients had grade 3 TRAEs, including two cases of hypotension and no patients had grade 4 or 5 TRAEs.

Based on the data in this population, we are near final in the development of a registrational clinical trial protocol with RP2 combined with nivolumab in advanced uveal melanoma following input from the FDA.

As previously announced, our development program in hepatocellular carcinoma, or HCC, that we are collaborating on with Roche for the supply of its currently approved drugs, atezolizumab and bevacizumab, has been limited to the 2L setting and will use RP2 rather than RP3.

The Phase 2 clinical trial with RP2 in anti-PD1/PD-L1 progressed HCC with RP2 combined with atezolizumab and bevacizumab is expected to initiate in the second half of 2024.

Although our RP2/3 development in squamous cell carcinoma of the head and neck and colorectal cancer, or CRC, have been discontinued, as previously announced, we are continuing to treat patients who were already in screening or enrolled in these trials before the trials were discontinued.

Six patients had grade 3 TRAEs, including two cases of hypotension.

There were no grade 4 or 5 TRAEs.

In June 2024, we presented that the disease control rate for this cohort of mUM patients was 58.8%.

We have initiated and are enrolling patients in a registration-directed study, or the REVEAL study, of RP2 in mUM patients who are immune checkpoints inhibitor-naive.

The REVEAL study is a randomized, phase 2/3 open label study to investigate the efficacy and safety of RP2 in combination with nivolunab vs.

ipilimumab in combination with nivolunab in immune checkpoint inhibitor naive adult patients with metastatic uveal melanoma.

We continue our signal finding trial of RP2 in combination with atezolizumab and bevacizumab in the 2L setting of patients with hepatocellular carcinoma, or HCC, in collaboration with Roche.

This Phase 2 clinical trial is currently open and enrollment is underway.

RP1, RP2 and RP3 are administered by direct injection into solid tumors, guided either visually or by ultrasound, computerized tomography or other imaging methods.

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Our product candidates are intended to act at several key points in the pathways involved in the initiation of an immune response.

Following direct injection into tumors, our viruses replicate in cancer cells and then lyse, or break them open, releasing tumor antigens, including neo-antigens specific to the patient, which could otherwise be hidden from the immune system.

Following direct injection into tumors, our viruses are intended to replicate in cancer cells and then lyse, or break them open, releasing tumor antigens, including neo-antigens specific to the patient, which could otherwise be hidden from the immune system.

This process of necrotic cell death releases intra-cellular markers of “danger,” the danger associated molecular patterns, or DAMPs, while the virus produces pathogen associated markers of danger, or PAMPs.

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Primed with the antigens, these T cells then proliferate and disperse systemically to seek and destroy cancer cells with the same antigen profile throughout the body, resulting in the potential destruction of distant tumor deposits.

To further augment these intended effects, our product candidates are genetically encoded with multiple potent, cell-killing and immune-stimulating proteins — in other words, our product candidates are “armed” with these therapeutic genes.

We believe that our ability to incorporate multiple mechanisms of action into a practical “off-the-shelf” approach to initiating or enhancing an anti-tumor immune response, including to neo-antigens, will offer significant advantages over the various approaches to immune activation that are currently in development, including personalized vaccine treatments.

Tumor neo-antigens are uniquely present in tumors, rather than normal tissue, because they result from the genetic changes that occur as cancer develops.

Unlike the antigens present in normal tissue, the immune system identifies neo-antigens as foreign.

As a result, the immune system is able to mount an immune response to tumor neo-antigens in the same way that it would to the antigens contained in disease-causing micro-organisms, which the immune system also identifies as foreign.

Researchers believe immune responses to tumor neo-antigens are particularly important in the immune system’s ability to combat cancer, and as a consequence various “personalized vaccine” approaches to generating immune responses to tumor neo-antigens are in development.

These approaches are generally both expensive and time consuming because a vaccine cannot be designed and manufactured until a tumor biopsy is taken and analyzed in the laboratory to identify the mutated tumor antigens that will be targeted by the treatment.

We also believe that our “off-the-shelf” approach may offer significant advantages over other approaches to anti-cancer immune activation that only target a single pathway of the immune system, as is the case with most of the other immuno-oncology therapies currently under development.

Importantly, our product candidates are intended to maximally activate an immune response against cancer, which we believe is the missing element needed to allow anti-PD-1 or anti-PD(L)-1 therapy to treat more patients and tumor types, unlike some other therapies that are intended to act by blocking additional defense mechanisms against an anti-tumor immune response once it has been initiated.

Our Oncolytic Immunotherapy platform and product candidates

Our current product candidate pipeline is summarized in the table below:

To further augment these intended effects, our product candidates are genetically encoded with multiple strong, cell-killing and immune-stimulating proteins — in other words, our product candidates are “armed” with these therapeutic genes.

The foundation of our oncolytic immunotherapy product candidates consists of a proprietary strain of HSV-1 that we have engineered to replicate selectively in tumors and to express a fusogenic glycoprotein, a protein that triggers the fusion of the membranes between cells.

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We believe that our development approach of further enhancing our product candidates with additional therapeutic proteins reduces clinical risk, as we are able to study the safety profile of each therapeutic protein that is intended to provide more potent anti-tumor immune effects.

We believe that our ability to incorporate multiple mechanisms of action into a practical “off-the-shelf”, or a pre-manufactured drug product, approach to initiating or enhancing an anti-tumor immune response, including to neo-antigens, will offer significant advantages over the various approaches to immune activation that are currently in development, including personalized vaccine treatments.

Tumor neo-antigens are uniquely present in tumors, rather than normal tissue, because they

result from the genetic changes that occur as cancer develops.

Unlike the antigens present in normal tissue, the immune system identifies neo-antigens as foreign.

Our Oncolytic Immunotherapy platform and product candidates

Our current product candidate pipeline is summarized in the table below:

Lead product candidate:

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We believe that the robust release of tumor antigens and the highly immunogenic tumor cell death intended to be caused by RP1 will further increase the previously observed synergy between oncolytic viruses and immune checkpoint blockade therapy.

RP1 Leading Indications

Our lead indication for our lead product candidate, RP1, is the potential treatment of advanced melanoma, which is currently under BLA review with the FDA.

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin.

Metastatic melanoma is the deadliest form of the disease and occurs when cancer spreads beyond the surface of the skin to other organs.

The incidence of melanoma has been increasing steadily for the last 30 years.

Globally, the World Health Organization estimates that by 2035, melanoma incidence will reach 424,102, with 94,308 related deaths.

We anticipate the commercial opportunity for RP1 to help improve the lives of patients with advanced melanoma is significant.

We estimate approximately 13,000 patients progress on or after PD-1 treatment annually in the U.S.

with approximately 80% of these patients eligible for treatment with RP1 in combination with nivolumab, if approved.

Importantly, we believe these treatments will take place in the outpatient setting, not require hospitalization and that nearly all of these patients are being treated in healthcare settings that have interventional radiology onsite or readily accessible, further supporting the anticipated rapid adoption of RP1.

Our following indications with our lead product candidate, RP1, include patients that develop skin cancers following a solid organ transplant.

Individuals who receive an organ transplant face a significantly higher risk, greater than 50 times higher, of developing skin cancer following the transplant.

These individuals are also on chronic immuno-suppressive treatments to reduce the risk of transplant rejection by their immune system.

Adding to this risk for these individuals, anti-PD-1/L1 based cancer treatment options, which are approved and/or used in other skin cancer settings carry a high risk of transplant rejection, potentially leaving these patients without many treatment options.

We are also investigating RP1 as a potential product candidate for the treatment of non-melanoma skin cancers, or NMSC, which is a collection of common cancer types which occurs mainly in fair-skinned populations.

About 80% of all NMSC are basal cell carcinomas, squamous cell carcinomas represent about 20%, with other diagnoses representing around 1% or less.

Pipeline product candidates:

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We expect that our RP2 product candidate will be used as monotherapy and/or in combination with other treatment approaches, including anti-PD-1 therapy, which, when used in combination, we believe will result in both synergy with the oncolytic immunotherapy and the expression of anti-CTLA-4 in the tumor.

We have designed our RP3 product candidate to express further immune-activating proteins that stimulate T cells, in addition to anti-CTLA-4 and GALV-GP R(-).

RP2 Leading Indication

Uveal melanoma, or mUM, represents the predominant primary intraocular malignancy among adults, comprising over 95% of cases.

Globally, the estimated annual incidence of mUM is approximately 4,800 individuals, with an estimated 1,700 new diagnoses occurring in the U.S.

Risk factors for developing mUM include fair skin, light-colored eyes, congenital ocular melanocytosis, melanocytoma, and the BAP1-tumour predisposition syndrome.

It is estimated that greater than about 90% of mUM cases develop metastatic liver tumors.

Historically, one-year survival rate of patients with distant metastases (such as liver metastases) is 15%, while reported median survival time is less than 1 year ranging from four to fifteen months.

RP2 is currently being investigated in a randomized , phase 2/3 open label study to investigate the efficacy and safety of RP2 in combination with nivolunab vs.

ipilimumab in combination with nivolunab in immune checkpoint inhibitor naive adult patients with metastatic uveal melanoma.

We have another product candidate in the portfolio as well and have designed our RP3 product candidate to express further immune-activating proteins that stimulate T cells, in addition to anti-CTLA-4 and GALV-GP R(-).

These immune activating proteins are the ligands for two immune co-stimulatory pathways responsible for T cell proliferation and/or activation, the CD40L and 4-1BBL pathways.

As previously announced, we have discontinued development of RP3 at this time.

Due to program prioritization we are currently not pursuing further development of RP3 at this time.

Intellectual property

We believe our rights under our issued patents and, anticipated future patents from our patent applications, will provide a competitive advantage.

Our success depends in part on our ability to obtain and maintain proprietary protection for our product candidates, technology and know-how, to operate without infringing the proprietary rights of others and to prevent others from infringing upon our proprietary rights.

infringing upon our proprietary rights.

Our policy is to seek to protect our proprietary position by, among other methods, filing United States and foreign patent applications related to our proprietary technology, inventions and improvements that are important to the development of our business.

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We continue to vigorously pursue advancement and defense of our patents and patent applications through the respective patent offices in which they are granted or pending throughout the world.

See " Risk Factors - Risk Related to Intellectual Property."

See " Risk factors - Risks Related to intellectual property."

The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained.

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Similar provisions are available in Europe and other foreign jurisdictions to extend the term of a patent that covers an approved drug.

In the future, if and when our products receive FDA approval, and if

and when patents grant, we expect to apply for patent term extensions on patents covering those products.

In the future, if and when our products receive FDA approval, and if and when patents grant, we expect to apply for patent term extensions on patents covering those products.

We plan to seek patent term extensions to any of our issued patents in any jurisdiction where these are available, however there is no guarantee that the applicable authorities, including the FDA in the United States, will agree with our assessment of whether such extensions should be granted, and if granted, the length of such extensions.

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• cancer vaccines including personalized vaccines and those targeting tumor neo-antigens;

• cell-based therapies, such as CAR-T, T cell receptor-based, and natural killer, or NK, cell therapies.

• cell-based therapies, such as TILs, CAR-T, T cell receptor-based, and natural killer cell therapies.

Our commercial opportunity will be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, have fewer side effects, are easier to administer or are less expensive alone or in combination with other therapies than any products that we may develop alone or in combination with other therapies, especially if these get to market sooner than our products.

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We therefore believe that our product candidates, if and when marketed, would largely complement rather than compete directly with some of these existing treatment options.

We do, however, expect to face direct and increasing competition from a number of companies that are also seeking to develop cancer therapies based on oncolytic viruses and other ways to prime the immune system, including neo-antigen vaccination.

We believe that our ability to successfully compete will depend, among other things, on our ability to:

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Manufacturing and suppliers

We have established an operations leadership team with what we believe is extensive experience in manufacturing biologics based on viruses, including oncolytic products and gene therapy products, and in the construction, validation, operation and approval of facilities for the manufacture and filling of complex biological products.

Our team has already developed a robust and reproducible manufacturing process for our product candidates.

We are also developing our product candidates for maximum practicality of use compared with some other oncolytic immunotherapies.

Traditionally, our third-party contract manufacturer in Europe had been responsible for the cGMP manufacture and filling of our product candidates for use in our clinical trials.

We have established our raw material supply chain for our product candidates as part of the process of establishing and qualifying our own manufacturing facility and intend to enter into commercial supply, collaboration or similar agreements as needed to continue to operate the in-house manufacturing of our product candidates for our clinical trials and, if approved, build commercial supply of our products.

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

We have completed the process of transferring the manufacturing of RP1, RP2 and RP3 from our third-party contract manufacturer.

Comparability analysis of RP1, RP2 and RP3 produced at our Framingham facility with the contract manufacturer material used in our clinical studies is complete.

The FDA and some European regulatory agencies have approved the use of material produced at Framingham in ongoing and future clinical trials.

We plan to operate our in-house manufacturing facility in order to secure our product candidates for our ongoing and planned clinical studies and, if approved, commercial launch and supply.

The facility has been designed to allow us to produce enough material to cover full global commercialization of all our current product candidates.

We have established an operations leadership team that we believe has extensive experience in manufacturing biologics based on viruses, including oncolytic products and gene therapy products and we operate our own in-house, approximately 63,000 square foot, U.S.

based manufacturing facility in Framingham, Massachusetts.

We operate our in-house manufacturing facility in order to secure our product candidates for our ongoing and planned clinical studies and, if approved, commercial launch and supply.

The facility has been designed to allow us to produce enough material to cover full global commercialization of all our product candidates that are currently in development.

The facility is intended to give us control over key aspects of the supply chain for our products and product candidates.

We recently completed a successful Type C meeting with the FDA that confirmed alignment on our chemistry, manufacturing, and controls, or CMC, plans to support our BLA submission for RP1 in the second half of 2024.

By establishing our own manufacturing facility, we aim to minimize or eliminate our reliance on contract manufacturing organizations, which typically have limited capacity at commercial scale and long-lead time to conduct manufacturing campaigns.

We believe that having control over the whole manufacturing process will allow us to reduce cycle times and cost of goods for commercial production and to shorten overall timelines for new product candidates in our development pipeline, as well as help us to develop drug formulations or presentations to simplify distribution and/or administration of future oncolytic immunotherapies.

We also believe that having a dedicated manufacturing facility will allow us to optimize commercial-scale processes and to ensure security of supply to support market launch and commercialization of our product candidates, if approved.

By controlling our own manufacturing facility, we aim to minimize or eliminate reliance on contract manufacturing organizations, which typically have limited capacity at commercial scale and long-lead time to conduct manufacturing campaigns.

We believe that having control over the whole manufacturing process, in the U.S., will allow us to reduce cycle times, cost of goods for commercial production, other potential political or territorial cost efficiencies, and to shorten overall timelines for new product candidates in our development pipeline, as well as help us to develop drug formulations or presentations to simplify distribution and/or administration of future oncolytic immunotherapies.

We also believe that having a dedicated manufacturing facility will allow us to optimize commercial-scale processes and to enhance security of supply to support market launch and commercialization of our product candidates, if approved.

While we do control our own manufacturing facility, we rely on industry suppliers for raw materials and other process supplies, such as single-use manufacturing components, formulation components, sterile filters, bioreactors and other consumable components.

Sales and marketing

None of our product candidates have been approved for sale.

If and when our product candidates receive marketing approval, we intend to commercialize them on our own in the United States and potentially with pharmaceutical or biotechnology partners in other geographies.

If and when our product candidates advance closer to marketing approval, we intend to commercialize them on our own in the United States and potentially with pharmaceutical or biotechnology partners in other geographies.

We may take different approaches to commercialization in different geographies.

We continue to build our in-house sales, marketing and commercialization capabilities with the addition of sales, marketing, trade and distribution, as well as other related expertise.

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Both parties will own the study data produced in the clinical trial, other than study data related solely to nivolumab, which will belong solely to BMS, or study data related solely to RP1, which will belong solely to us.

In January 2020, this agreement was expanded to cover an additional cohort of 125 patients with anti-PD-1 failed melanoma.

In January 2020, the agreement was expanded to cover an additional cohort of 125 patients with anti-PD-1 failed melanoma.

Unless earlier terminated, the agreement will remain in effect until (i) the completion of the clinical trial, (ii) all related clinical trial data have been delivered to both parties and (iii) the completion of any statistical analyses and bioanalyses contemplated by the clinical trial protocol or any analysis otherwise agreed upon by the parties.

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In April 2019, we entered into a separate agreement with BMS on terms similar to the terms set forth in the agreement described above, pursuant to which BMS will provide, at no cost to us, nivolumab for use in our Phase 1 clinical trial of RP2 in combination with nivolumab.

In May 2018, we entered into a Master Clinical Trial Collaboration and Supply Agreement with Regeneron.

Pursuant to the agreement we agreed to undertake one or more clinical trials with Regeneron for the administration of our product candidates in combination with cemiplimab, an anti-PD-1 therapy developed by Regeneron, across multiple solid tumor types.

The first of which, agreed in June 2018, is our ongoing clinical trial testing RP1 in combination with cemiplimab versus cemiplimab alone in patients with CSCC.

Each clinical trial will be conducted pursuant to an agreed study plan which, among other things, will identify the name of the sponsor and which party will manage the particular study, and include the protocol, the budget and a schedule of clinical obligations.

Pursuant to the terms of the agreement, each party granted the other party a non-exclusive license of their respective intellectual property and agreed to contribute the necessary resources needed to fulfill their respective obligations, in each case, under the terms of agreed study plans.

The Company does not expect any further reimbursements from Regeneron related to the initial study plan of June 2018 and the CERPASS trial.

The agreement contains representations, warranties, undertakings and indemnities customary for a transaction of this nature.

The agreement also contains certain time-based covenants that restrict us from entering into a third-party arrangement with respect to the use of our product candidates in combination with an anti-PD-1 therapy and that restrict Regeneron from entering into a third-party arrangement with respect to the use of cemiplimab in combination with an HSV-1 virus, in each case, for the treatment of a tumor type that is the subject of a clinical trial to which the covenants apply.

Unless otherwise mutually agreed in a future study plan, these covenants are only applicable to our ongoing Phase 2 clinical trial in CSCC.

The agreement may be terminated by either party if (i) there is no active study plan for which a final study report has not been completed and the parties have not entered into a study plan for an additional clinical trial within a period of time after the delivery of the most recent final study report or (ii) in the event of a material breach.

In December 2022, we entered into a Master Clinical Trial Collaboration and Supply Agreement with Roche in relation to our RP2 and RP3 programs in colorectal cancer, or CRC, and hepatocellular carcinoma, or HCC.

In December 2022, we entered into a Master Clinical Trial Collaboration and Supply Agreement with Roche in relation to our RP2 and RP3 programs in colorectal cancer, or CRC, and HCC.

Under the agreement, the companies intended to collaborate in 30 patient cohort signal finding studies in third-line, or 3L, CRC and in first- and second-line, or 1L and 2L, respectively, HCC.

Following our re-prioritization of our product development portfolio in December 2023, we have agreed with Roche to terminate the CRC collaboration and pursue the 2L cohort in HCC with RP2 only.

Roche has expressed its intent to continue to supply its currently approved drugs, atezolizumab and bevacizumab for the 2L cohort in HCC but is unlikely to share costs following our re-prioritization.

We are in discussions with Roche about revising these agreements following our changes to our RP2 and RP3 development plans.

Roche has continued to supply its currently approved drugs, atezolizumab and bevacizumab for the 2L cohort in HCC but is not sharing costs following our re-prioritization.

Under the terms of the initial agreement we retained the responsibility of operating the clinical trials as well as retaining all the rights to the development and commercialization of our product candidates.

The agreement may be terminated by either party upon sixty days prior written notice to the other party.

In July 2023, we entered into a Clinical Trial Collaboration and Supply Agreement with Incyte Corporation, or Incyte.

Under the agreement, the companies anticipate collaborating in a signal finding study in which Incyte will initiate and sponsor a clinical trial of INCB99280 (oral PD-L1 inhibitor) and RP1 in approximately 40 patients with unresectable, high risk CSCC in the neoadjuvant setting.

Under the terms of the agreement, we will supply Incyte with RP1 for the study and share costs of the study equally with Incyte.

The agreement may be terminated by either party upon (i) a material breach not reasonably cured within thirty days;

(ii) the discontinuation of development of its clinical drug candidate;

(iii) the unethical or illegal business practices of the other party;

or (iv) if the parties have not agreed on the protocol or budget within ninety days of the effective date of the agreement.

In addition, the Company may terminate the agreement upon the inappropriate or unsafe use of the RP1

product candidate.

As of March 31, 2024, we and Incyte had not yet agreed on the protocol or budget.

However, we and Incyte continue to discuss a potential protocol and neither party has triggered termination of the agreement in accordance with the termination right described in clause (iv) above.

The parties are evaluating potential collaboration efforts pending further CERPASS data readout of RP1 in combination with cemiplimab and additional data for Incyte's product candidate INCB99280.

Regulatory matters

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• FDA review and approval of the BLA to permit commercial marketing for particular indications for use.

The process in the European Union and other countries with developed regulatory regimes is broadly comparable.

The process in the European Union and other countries with developed regulatory regimes is broadly comparable save that there is no dedicated BLA route in Europe as a Marketing Authorisation, or MAA, covers both small molecules, and biologics and cell and gene therapies.

Preclinical studies and IND submission

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Such studies must generally be conducted in accordance with GLPs.

Prior to commencing the first clinical trial at a United States or other country’s investigational site with a product candidate, an IND sponsor must submit the results of the preclinical tests and preclinical literature, together with manufacturing information, analytical data, any available clinical data or literature, and proposed clinical study protocols among other things, to the FDA as part of an IND (or equivalent in other countries).

Recently, however, in the U.S., new methods of non-animal preclinical testing are being explored.

For instance, in 2025, FDA outlined a stepwise plan to reduce animal testing in preclinical safety studies with scientifically validated new approach methodologies, or NAMs, which may include organ-on-a-chip systems, computational modeling, and advanced in vitro assays, and other data.

Prior to commencing the first clinical trial at a United States or other country’s investigational site under and IND with a product candidate, an IND sponsor must submit the results of the preclinical tests and preclinical literature, together with manufacturing information, analytical data, any available clinical data or literature, and proposed clinical study protocols among other things, to the FDA as part of an IND (or equivalent in other countries).

Additional preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, may continue after the IND is submitted.

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Clinical trials

Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in accordance with federal regulations and GCP requirements, which include the requirements that all research subjects provide their informed consent in writing for their participation in any clinical trial, as well as review and approval of the study by an IRB.

the study by an IRB.

Investigators must also provide certain information to the clinical trial sponsors to allow the sponsors to make certain financial disclosures to the FDA.

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In general, for purposes of BLA approval, human clinical trials are typically conducted in three sequential phases, which may overlap, be divided, or be combined.

• Phase 1 — Trials are initially conducted in healthy human volunteers or subjects with the target disease or condition and test the product candidate for safety, dosage tolerance, structure-activity relationships, mechanism of action,

absorption, metabolism, distribution, and excretion.

If possible, Phase 1 trials may also be used to gain an initial indication of the activity of the product candidate.

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Typically, two Phase 3 trials are required by the FDA for product approval.

Under some limited circumstances, however, approval may be based upon a single adequate and well-controlled clinical trial plus confirmatory evidence or a single large multicenter trial without confirmatory evidence.

Under some limited circumstances, however, approval may be based upon a single adequate and

well-controlled clinical trial plus confirmatory evidence or a single large multicenter trial without confirmatory evidence.

Additional kinds of data may also help to support a BLA, such as patient experience data and real-world evidence.

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For genetically targeted products and variant protein targeted products intended to address an unmet medical need in one or more patient subgroups with a serious or life threatening rare disease or condition, the FDA may allow a sponsor to rely upon data and information previously developed by the sponsor or for which the sponsor has a right of reference, that was submitted previously to support an approved application for a product that incorporates or utilizes the same or similar genetically targeted technology or a product that is the same or utilizes the same variant protein targeted drug as the product that is the subject of the application.

More recently, a program was established whereby a platform technology that is incorporated within or utilized by an approved drug or biologic product may be designated as a platform technology, provided that certain conditions are met, in which case development and approval of subsequent products using such technology may be expedited.

More recently, a program was established whereby a platform technology that is incorporated within or utilized by an approved drug or biologic product may be designated as a platform technology, provided that certain conditions are met and provided that the technology is considered a platform technology under FDA's definition, in which case development and approval of subsequent products using such technology may be streamlined.

Further, under certain circumstances, manufacturers and sponsors of investigational biopharmaceutical product candidates can provide access to the product candidates to certain qualifying patients outside of clinical trials.

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In relation to the clinical trial in the United Kingdom and in so far as trials will be conducted in other countries with a view to obtaining a marketing authorization from the Medicines and Healthcare products Regulatory Agency, or MHRA, and the European Medicines Agency, there are broadly equivalent GLP, GCP, cGMP and ethical approval requirements.

In the European Union, these rules are memorialized in the form of Regulations, which are directly enforceable in all EU member states or Directives, which may only be implemented nationally.

In the European Union, these rules are memorialized in the form of Regulations, which are directly enforceable in all European Union member states or Directives, which must be implemented nationally.

However, enforcement of such rules is conducted by the regulatory authority in which the trial is carried out, which is the MHRA in the United Kingdom.

With the full departure of the United Kingdom from the European Union in January 2021, the United Kingdom is not covered by the European Union

Clinical Trial Regulation, in force since January 2022, which inter alia introduced a portal to streamline cross-border trial applications, and is instead subject to rules equivalent to the previous 2001 EU Clinical Trials Regulation.

With the full departure of the United Kingdom from the European Union in January 2021, the United Kingdom is not covered by the European Union Clinical Trial Regulation, in force since January 2022, which inter alia introduced a portal to streamline cross-border trial applications, and is instead subject to rules equivalent to the previous 2001 EU Clinical Trials Directive.

Combination products

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for example, when the device component is intended for use with multiple therapeutics.

Sponsors of clinical studies using investigational devices are required to comply with FDA’s investigational device exemption regulations.

Sponsors of clinical studies using investigational devices are

required to comply with FDA’s investigational device exemption regulations.

Once approved or cleared, the sponsor of the device component submission (or the combination product submission, if both components are covered by one premarket submission) would need to comply with FDA’s post-market device requirements, including establishment registration, device listing, device labeling, unique device identifier, quality system regulations, medical device reporting, and reporting of corrections and removals.

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Once the submission is accepted for filing, the FDA begins an in-depth substantive review.

Under the goals and policies agreed to by the FDA under the Prescription Drug User Fee Act, or PDUFA, the FDA has set the review goal of completing its review of 90% of all applications within ten months from the 60-day filing date for its initial review of a BLA.

Under the goals and policies agreed to by the FDA under PDUFA, the FDA has set the review goal of completing its review of 90% of all applications within ten months from the 60-day filing date for its initial review of a BLA.

The FDA does not always meet its PDUFA goal dates for BLA submissions, and the review process may be extended if the FDA requests or the sponsor otherwise provides additional information or clarification regarding the submission.

The FDA may also refer certain applications to an advisory committee.

An advisory committee is typically a panel that includes clinicians and other experts, and may at times includes patients, which review, evaluate, and make a recommendation

as to whether the application should be approved and under what conditions.

An advisory committee is typically a panel that includes clinicians and other experts, and may at times includes patients, which review, evaluate, and make 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.

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Reports on the progress of the required Phase 4 confirmatory studies must be submitted to FDA every 180 days after approval.

If the confirmatory Phase 4 studies fail to verify the clinical benefit of the product, the FDA may withdraw approval of the application through a statutorily defined streamlined process.

If the confirmatory Phase 4 studies fail

to verify the clinical benefit of the product, the FDA may withdraw approval of the application through a statutorily defined streamlined process.

Failure to conduct the required Phase 4 confirmatory studies or to conduct such studies with due diligence, as well as failure to submit the required update reports can subject a sponsor to penalties.

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Failure to do so can subject the approved product sponsor to civil actions, penalties, and responsibility for attorney’s fees and costs of the civil action.

More recently, the U.S.

President issued an Executive Order to require FDA to provide administrative and legislative recommendations to accelerate approval of biosimilar products.

Post-approval requirements

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Recently, FDA has taken a few actions in the advertising and promotional spaces, including issuing a final rule and a guidance on risk and efficacy disclosures in direct to consumer advertising, and a guidance on communication of off-label scientific information about approved products.

Physicians, in their independent professional medical judgment, may prescribe legally available products for unapproved indications that are not described in the product’s labeling and that differ from those tested and approved by the

Biopharmaceutical companies, however, are required to promote their products only for the approved indications and in accordance with the provisions of the approved label.

The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability, including, but not limited to, criminal and civil penalties under the FDCA and False Claims Act, exclusion from participation in federal healthcare programs, mandatory compliance programs under corporate integrity agreements, suspension and debarment from government contracts, and refusal of orders under existing government contracts.

The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability, including, but not limited to, criminal and civil penalties under the FDCA and False Claims Act, exclusion from participation in federal healthcare programs, mandatory compliance programs under corporate integrity agreements, suspension and debarment from government procurement and non-procurement programs, and refusal of orders under existing government contracts.

Moreover, the Drug Quality and Security Act imposes obligations on manufacturers of biopharmaceutical products related to product tracking and tracing.

Among the requirements of this legislation, manufacturers are required to provide certain information regarding the products to individuals and entities to which product ownership is transferred, are required to label products with a product identifier, and are required to keep certain records regarding the product.

The transfer of information to subsequent product owners by manufacturers will also be required to be done electronically and will be required to be exchanged via an interoperable system at the package level (while this requirement was to go into effect in November 2023, FDA has stated that it does not intend to take action to enforce requirements for the interoperable, electronic, package level product tracing until November 27, 2024).

Manufacturers must also verify that purchasers of the manufacturers’ products are appropriately licensed.

Further, under this legislation, manufactures have product investigation, quarantine, disposition, and notification responsibilities related to counterfeit, diverted, stolen, and intentionally adulterated products that would result in serious adverse health consequences or death to humans, as well as products that are the subject of fraudulent transactions or which are otherwise unfit for distribution such that they would be reasonably likely to result in serious health consequences or death.

The transfer of information to subsequent product owners must be transferred electronically.

FDA is also phasing in requirements with respect to the interoperable exchange of electronic product tracing at the package level.

Manufacturers must further verify that purchasers of the manufacturers’ products are appropriately licensed.

Additionally, under this legislation, manufactures have product investigation, quarantine, disposition, and notification responsibilities related to counterfeit, diverted, stolen, and intentionally adulterated products that would result in serious adverse health consequences or death to humans, as well as products that are the subject of fraudulent transactions or which are otherwise unfit for distribution such that they would be reasonably likely to result in serious health consequences or death.

Similar requirements additionally are imposed through this legislation on other companies within the biopharmaceutical product supply chain, such as distributors and dispensers.

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Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in significant regulatory actions.

Such actions may include refusal to approve pending applications, license suspension or revocation, imposition of a clinical hold or termination of clinical trials, warning letters, untitled letters, cyber letters, modification of promotional materials or labeling, provision of corrective information, imposition of post-market requirements including the need for additional testing, imposition of distribution or other restrictions under a REMS, product recalls, product seizures or detentions, refusal to allow imports or exports, total or partial suspension of production or distribution, FDA debarment, injunctions, fines, consent decrees, corporate integrity agreements, suspension and debarment from government contracts, refusal of orders under existing government contracts, exclusion from participation in federal and state healthcare programs, restitution, disgorgement, or civil or criminal penalties, including fines and imprisonment, and result in adverse publicity, among other adverse consequences.

Such actions may include refusal to approve pending applications, license suspension or revocation, imposition of a clinical hold or termination of clinical trials, warning letters, untitled letters, cyber letters, modification of promotional materials or labeling, provision of corrective information, imposition of post-market requirements including the need for additional testing, imposition of distribution or other restrictions under a REMS, product recalls, product seizures or detentions, refusal to allow imports or exports, total or partial suspension of production or distribution, FDA debarment, injunctions, fines, consent decrees, corporate integrity agreements, suspension and debarment from government procurement and non-procurement programs, refusal of orders under existing government contracts, exclusion from participation in federal and state healthcare programs, restitution, disgorgement, civil penalties, criminal fines and imprisonment, and result in adverse publicity, among other adverse consequences.

The FDA post-approval requirements are continually evolving.

For example, in March 2020, the U.S.

Congress passed the Coronavirus Aid, Relief, and Economic Security Act, or CARES Act, which includes various provisions regarding FDA drug shortage and manufacturing volume reporting requirements, as well as provisions regarding supply chain security, such as risk management plan requirements, and the promotion of supply chain redundancy and domestic manufacturing.

Congress passed the CARES Act, which includes various provisions regarding FDA drug shortage and manufacturing volume reporting requirements, as well as provisions regarding supply chain security, such as risk management plan requirements, and the promotion of supply chain redundancy and domestic manufacturing.

As part of the CARES Act implementation, the FDA issued guidance on the reporting of the volume of drugs produced, which reporting will require additional administrative efforts by drug manufacturers.

In recent years, both the U.S.

Congress and the President have taken actions to encourage the use of domestic pharmaceutical suppliers and, there are also currently legislative proposals to limit the use of equipment and services provided by certain Chinese “biotechnology companies of concern”.

Congress and the President have taken actions to encourage the use of domestic pharmaceutical suppliers.

Broadly equivalent requirements, controls and sanctions similarly apply to supply, QA, manufacture, labelling, advertising, pharmacovigilance and tracing of medicinal products as imposed by European Union laws and enforced by European Union national regulatory authorities.

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Project Confirm is a third FDA initiative, which aims to promote transparency regarding the outcomes related to accelerated approval products.

Other regulatory agencies may also regulate our use of biological materials, which may necessitate that we, our manufacturers, or other third parties with whom we work obtain permits and otherwise comply with regulatory requirements.

Fraud and abuse, data privacy and security, and transparency laws and regulations

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There are certain statutory exceptions and regulatory safe harbors protecting some common activities from prosecution.

HHS recently promulgated a regulation that is effective in two phases.

Health and Human Services, or HHS, recently promulgated a regulation that is effective in two phases.

First, the regulation excludes from the definition of “remuneration” limited categories of (a) PBM rebates or other reductions in price to a plan sponsor under Medicare Part D or a Medicaid Managed Care Organization plan reflected in point-of sale reductions in price and (b) PBM service fees.

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A claim includes “any request or demand” for money or property presented to the U.S.

The civil False Claims Act has been used to

assert liability on the basis of kickbacks and other improper referrals, improperly reported government pricing metrics such as Best Price or Average Manufacturer Price, improper use of Medicare provider or supplier numbers when detailing a provider of services, improper promotion of off-label uses not expressly approved by the FDA in a product’s label, and allegations as to misrepresentations with respect to products, contract requirements and services rendered.

The civil False Claims Act has been used to assert liability on the basis of kickbacks and other improper referrals, improperly reported government pricing metrics such as Best Price or Average Manufacturer Price, improper use of Medicare provider or supplier numbers when detailing a provider of services, improper promotion of off-label uses not expressly approved by the FDA in a product’s label, failure to comply with cGMP requirements, and allegations as to misrepresentations with respect to products, contract requirements and services

In addition, private payers have filed follow-on lawsuits alleging fraudulent misrepresentation.

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Civil False Claims Act liability may further be imposed for known Medicare or Medicaid overpayments that are not refunded within 60 days of discovering the overpayment, even if the overpayment was not caused by a false or fraudulent act.

In addition, judgment for violating the civil False Claims Act may result in exclusion from participation in federal health care programs, suspension and debarment from government contracts, and refusal of orders under existing government contracts.

In addition, judgment for violating the civil False Claims Act may result in exclusion from participation in federal health care programs, suspension and debarment from government procurement and non-procurement programs, and refusal of orders under existing government contracts.

The government may further prosecute conduct constituting a false claim under the criminal False Claims Act.

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The civil monetary penalties statute is another potential statute under which biopharmaceutical companies may be subject to enforcement.

Among other things, the civil monetary penalties statute imposes fines against any person who is determined to have knowingly presented, or caused to be presented, claims to a federal healthcare program that the person knows, or should know, is for an item or service that was not provided as claimed or is false or fraudulent.

Among other things, the civil monetary penalties statute imposes penalties against any person who is determined to have knowingly presented, or caused to be presented, claims to a federal healthcare program that the person knows, or should know, is for an item or service that was not provided as claimed or is false or fraudulent.

Payment or reimbursement of prescription therapeutics, including, but not limited to, by Medicaid or Medicare requires manufacturers to submit certified pricing information to CMS.

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The 340B program has its own regulatory authority to impose sanctions for non-compliance and adjudicate overcharge claims against manufacturers by the purchasing entities.

The federal Health Insurance Portability and Accountability Act of 1996, as amended, or HIPAA, also created federal criminal statutes that prohibit, among other actions, knowingly and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations or promises, any of the money or property owned by, or under the custody or control of, a healthcare benefit program, regardless of whether the payor is public or private, in connection with the delivery or payment for health care benefits, knowingly and willfully embezzling or stealing from a health care benefit program, willfully obstructing a criminal investigation of a health care offense and knowingly and willfully

falsifying, concealing, or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items, or services relating to healthcare matters.

Additionally, the ACA amended the intent requirement of certain of these criminal statutes under HIPAA so that a person or entity no longer needs to have actual knowledge of the statute, or the specific intent to violate it, to have committed a violation.

Under the federal Physician Payments Sunshine Act and its implementing regulations, manufacturers of biologics for which payment is available under Medicare, Medicaid, or the Children’s Health Insurance Program (with certain exceptions) must make annual reports to CMS regarding payments and other transfers of value made to or at the request of covered recipients, such as, but not limited to, physicians, physician assistants, nurse practitioners, clinical nurse specialists, and certified registered nurse anesthetists and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family.

Certain payments for clinical trials are included within the ambit of this law.

Certain research payments, including for clinical trials, are included within the ambit of this law.

CMS makes the reported information publicly available.

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In addition, other federal and state laws, such as the California Consumer Privacy Act, may govern the privacy and security of health and other information in certain circumstances, many of which differ from each other in significant ways and may not be preempted by HIPAA, thus complicating compliance efforts.

For example, certain states, such as Washington, Nevada and Connecticut, have enacted new privacy laws with respect to health data that is not protected health information governed by HIPAA.

For example, certain states, such as Washington, Nevada and Connecticut, have enacted new privacy laws with respect to consumer health data that is not protected health information governed by HIPAA.

Many states have also adopted laws similar to each of the above federal laws, which may be broader in scope and apply to items or services reimbursed by any third-party payor, including commercial insurers.

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These laws may affect our future sales, marketing, and other promotional activities by imposing administrative and compliance burdens.

If our operations are found to be in violation of any of the laws or regulations described above or any other laws that apply to us, we may be subject penalties or other enforcement actions, including criminal and significant civil monetary penalties, damages, fines, disgorgement, imprisonment, exclusion from participation in government healthcare programs, corporate integrity agreements, suspension and debarment from government contracts, and refusal of orders under existing government contracts, reputational harm, diminished profits and future earnings, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.

If our operations are found to be in violation of any of the laws or regulations described above or any other laws that apply to us, we may be subject to penalties or other enforcement actions, including significant civil monetary penalties, damages, criminal fines, disgorgement, imprisonment, exclusion from participation in government healthcare programs, corporate integrity agreements, non- and deferred prosecution agreements, suspension and debarment from government procurement and non-procurement programs, and refusal of orders under existing government contracts, reputational harm, diminished profits and future earnings, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.

To the extent that any of our products are sold in a foreign country, we may be subject to similar foreign laws and regulations, which may include, for instance, applicable post-marketing requirements, including safety surveillance, anti-fraud and abuse laws, and implementation of corporate compliance programs and reporting of payments or transfers of value to healthcare professionals.

In the European Union, the data privacy laws are generally perceived to be stricter than those which apply in the United States and include specific requirements for the transfer of personal data outside the European Union to the United States to ensure that European Union standards of data privacy will be applied to such data.

The European Union General Data Protection Regulation, the United Kingdom General Data Protection Regulation and related data protection, cybersecurity and e-privacy laws in the European Union, European Economic Area, or the EEA, and the United Kingdom, (collectively referred to herein as the “GDPR, and equivalent Swiss laws may apply to some or all of the clinical or other personal data obtained, transmitted, stored or otherwise processed by us (or on our behalf) from those jurisdictions.

The GDPR contains potentially strict requirements with respect to lawfully processing personal data in connection with clinical trials and other business activities in Europe (including with respect to obtaining consents, securing personal data, notifying personal data breaches to supervisory authorities and affected data subjects, and transferring personal data outside

The GDPR and Swiss law allow supervisory authorities to potentially impose high regulatory fines (among other enforcement tools) in the event of violations, for example, under the GDPR up to 4% of global annual group turnover or EUR 20 million (whichever is the higher amount).

Supervisory authorities in the European Union and EEA, Switzerland and the United Kingdom may potentially levy such fines directly upon on the non-compliant entity and/or on the parent company (so-called “undertaking”) of the non-compliant entity.

Separate from regulatory enforcement actions, individuals may bring private actions (including potentially group or representative actions).

There is no statutory cap in the GDPR on the amount of compensation or the damages which individuals may recover.

Overall, the significant costs of GDPR and Swiss law compliance, risk of regulatory enforcement actions and private litigation under, and other burdens imposed by these laws as well as under other regulatory schemes throughout the world related to privacy and security of health information and other personal and private data could have an adverse impact on our business, reputation, financial condition, and results of operations.

We may also be subject to additional industry-specific privacy, cybersecurity, data protection, operational and information systems resilience, and artificial intelligence-related laws in Europe which may subject us to additional similar risks and impacts.

Coverage and reimbursement generally

The commercial success of our product candidates and our ability to commercialize any approved product candidates successfully will depend in part on the extent to which governmental payor programs at the federal and state levels, including, but not limited to, Medicare and Medicaid, private health insurers, and other third-party payors, provide coverage for and establish adequate reimbursement levels for our product candidates.

Government authorities, private health insurers, and other

organizations generally decide which therapeutics they will pay for and establish reimbursement levels for healthcare.

Government authorities, private health insurers, and other organizations generally decide which therapeutics they will pay for and establish reimbursement levels for healthcare.

Medicare is a federally funded program managed by CMS through local fiscal intermediaries and carriers that administer coverage and reimbursement for certain healthcare items and services furnished to the elderly and disabled.

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Sales of our product candidates will therefore depend substantially, both domestically and abroad, on the extent to which the costs of our products will be paid by health maintenance, managed care, pharmacy benefit and similar healthcare management organizations, or reimbursed by government health administration authorities, such as, but not limited to, Medicare and Medicaid, private health insurers, and other third-party payors.

As a result of the above, we may need to conduct expensive pharmacoeconomic and/or health technology assessment studies in order to demonstrate the medical necessity and cost-effectiveness of our products, in addition to the costs required to

obtain the FDA and EMA approvals.

Our product candidates may not be considered medically necessary or cost-effective, or the rebate percentages required to secure coverage may not yield an adequate margin over cost.

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Among policy makers and payors in the United States and elsewhere, there is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality, and expanding access.

In the United States, the biopharmaceutical industry has been a particular focus of these efforts and has been significantly affected by major legislative initiatives, such as, but not limited to, the Inflation Reduction Act and the Bayh-Dole Act march-in rights expansion.

For example, on November 27, 2020, CMS issued an interim final rule implementing a Most Favored Nation payment model under which reimbursement for certain Medicare Part B drugs and biologicals will be based on a price that reflects the lowest per capita Gross Domestic Product-adjusted (GDP-adjusted) price of any non-U.S.

member country of the Organization for Economic Co-operation and Development (OECD) with a GDP per capita that is at least sixty percent of the U.S.

For example, on November 27, 2020, CMS issued an interim final rule implementing a Most Favored Nation payment model under which reimbursement for certain Medicare Part B drugs and biologicals would have been based on a price that reflected the lowest per capita Gross Domestic Product-adjusted (GDP-adjusted) price of any non-U.S.

member country of the Organization for Economic Co-operation and Development (OECD) with a GDP per capita that was at least sixty percent of the U.S.

GDP per capita.

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The law also expanded the 340B discount program that mandates discounts to certain hospitals, community centers, and other qualifying providers, by expanding the categories of entities eligible to purchase under the program.

In addition, the ACA authorized civil monetary penalties for violating 340B pricing requirements, and regulations implementing this authority became effective on January 1, 2019.

In addition, the ACA authorized civil monetary penalties for violating 340B

pricing requirements, and regulations implementing this authority became effective on January 1, 2019.

The ACA revised the definition of “average manufacturer price”, or AMP, for reporting purposes, which generally increased the amount of Medicaid rebates to states and created a separate AMP for certain categories of administered therapeutics provided in non-retail outpatient settings.

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Substantial new provisions affecting compliance have also been enacted through the ACA and otherwise, including the reporting of therapeutic sample distribution, which may require us to modify our business practices with healthcare practitioners.

Although the ACA was recently amended to repeal the individual insurance mandate, and efforts to repeal and replace portions of the law may continue, it is likely that pressure on biopharmaceutical pricing, especially under the Medicare program, will continue, and may also increase our regulatory burdens and operating costs.

Although the ACA was later amended to repeal the individual insurance mandate, and efforts to repeal and replace portions of the law may continue, it is likely that pressure on biopharmaceutical pricing, especially under the Medicare program, will continue, and may also increase our regulatory burdens and operating costs.

Moreover, in the coming years, additional changes could be made to governmental healthcare programs that could significantly impact the success of our product candidates.

Most recently, on April 15, 2025, the U.S.

Administration released Executive Order entitled Lowering Drug Prices by Once Again Putting Americans First .

Amongst other agencies, it directs the Secretary of HHS to take wide-ranging steps aimed to lower U.S.

drug prices, including prices for biologic products.

Solely by example, the Executive Order requires the Secretary to propose and seek comment and guidance on the differential treatment of small and large molecule drug products under the IRA’s Medicare Drug Price Negotiation Program.

Depending on the ultimate outcome of these steps, the pricing and reimbursement rates for any of our approved drug products, and our ultimate revenue realization could be adversely impacted.

The cost of biopharmaceuticals continues to generate substantial governmental and third-party payor interest.

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The FCPA also obligates companies whose securities are listed in the United States to comply with books and records and accounting control provisions requiring the company to maintain books and records that accurately and fairly reflect all transactions of the corporation, including international subsidiaries, and to devise and maintain an adequate system of internal accounting controls for international operations.

Activities that violate the FCPA, even if they occur wholly outside the United States, can result in criminal and civil fines, imprisonment, disgorgement, oversight by compliance monitors, and suspension and debarment from government contracts, and refusal of orders under existing government contracts.

Activities that violate the FCPA, even if they occur wholly outside the United States, can result in

criminal and civil fines, imprisonment, disgorgement, oversight by compliance monitors, and suspension and debarment from government contracts, and refusal of orders under existing government contracts.

Other foreign anti-corruption regimes are arguably of wider application.

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Bribery Act 2010 applies to dealings with any decision maker whether in the private or public sector in a position of trust.

Background on certain of our target indications

Set forth below is a description of certain of the target indications we currently intend to pursue with our product candidates.

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin.

Metastatic melanoma is the deadliest form of the disease and occurs when cancer spreads beyond the surface of the skin to other organs.

The incidence of melanoma has been increasing steadily for the last 30 years.

In the United States, 91,270 new diagnoses of melanoma and more than 9,320 related deaths were estimated to have occurred in 2018.

Globally, the World Health Organization estimates that by 2035, melanoma incidence will reach 424,102, with 94,308 related deaths.

Melanoma is mostly curable when treated in its very early stages;

however, survival rates are roughly halved if regional lymph nodes are involved.

Solid Organ Transplant Skin Cancers

Individuals who receive an organ transplant face a significantly higher risk, greater than 50 times higher, of developing skin cancer following the transplant.

These individuals are also on chronic immuno-suppressive treatments to reduce the risk of transplant rejection by their immune system.

In the United States, transplant rates have increased by roughly 50% over the last 8 years with an estimated 1,500 solid organ transplant patients with addressable skin cancer.

Non-melanoma skin cancers

Non-melanoma skin cancer, or NMSC, are a collection of common cancer types which occurs mainly in fair-skinned populations.

About 80% of all NMSC are basal cell carcinomas, squamous cell carcinomas represent about 20%, with other diagnoses representing around 1%.

Included in that 1% are primary cutaneous lymphoma, sarcomas of the skin, Merkel cell carcinoma, and appendageal carcinoma.

NMSC is often not routinely reported to cancer registries;

hence, accurate estimates of incidence are difficult to obtain.

The World Health Organization estimates 2 to 3 million cases per year.

Cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma is the second most common form of skin cancer and is estimated to be responsible for at least 7,000 deaths each year in the United States.

It accounts for approximately 20% of all skin cancers in the U.S., with the number of newly diagnosed cases expected to rise annually.

When CSCC invades deeper layers of the skin or adjacent tissues, it is categorized as locally advanced.

Once it spreads to other distant parts of the body, it is considered metastatic.

Cemiplimab was the first approved therapy in the United States for the treatment of locally advanced or metastatic CSCC and has subsequently been approved in the European Union and Australia.

Uveal Melanoma

Uveal melanoma, or UM, represents the predominant primary intraocular malignancy among adults, comprising over 95% of cases.

Globally, the estimated annual incidence of UM is approximately 4,800 individuals, with an estimated 1,700 new diagnoses occurring in the United States each year.

Risk factors for developing UM include fair skin, light-colored eyes, congenital ocular melanocytosis, melanocytoma, and the BAP1-tumour predisposition syndrome.

Despite effective local treatments for the primary tumor, nearly 50% of UM patients develop metastatic disease with liver being the most frequent (>90%) metastatic site.

Many UMs metastasize at a very early clinical stage, suggesting micrometastases are already present by the time the tumor is first recognized and treated.

Historically, 1-year survival rate of patients with distant metastases is 15%, while reported median survival time is less than 1 year ranging from 4 to 15 months.

Human capital

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Of the 479 employees, 347 are in research and development and 132 are in selling, general and administrative functions.

We have never had a work stoppage, and none of our employees is represented by a labor organization or under any collective bargaining arrangements.

We have never had a work stoppage, and none of our employees are represented by a labor organization or under any collective bargaining arrangements.

We consider our employee relations to be good.

We believe that developing a diverse and inclusive culture is important to attracting and retaining the top talent necessary to deliver on our growth strategy.

We believe that developing an inclusive culture with talent reflecting a diverse range of backgrounds, experiences, and perspectives is important to attracting and retaining the top talent necessary to deliver on our growth strategy.

As such, we strive for, and are investing in, a work environment where our employees feel inspired and included.

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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-K

Item 1. Business