What changed in this filing

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Item 1. Business

2026-06-29 compared with 2025-05-22 · 155 added, 115 removed, 564 unchanged (32% of the section changed)

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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.

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

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 the goal of establishing a major skin cancer treatment franchise.

We have been 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.

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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.

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.

As reported in the Journal of Clinical Oncology 43(33):p 3589-3599, of the 140 patients enrolled, 48.6% had stage IVM1b/c/d disease, 65.7% had primary anti–PD-1 resistance, 56.4% were PD-L1 negative, and 46.4% received prior anti–PD-1 and anti–cytotoxic T-lymphocyte antigen-4, or anti-CTLA-4, therapy.

The confirmed ORR was 32.9% (15.0% complete response) and the responses occurred with similar frequency, depth, duration, and kinetics for injected and non-injected lesions, including visceral lesions.

The median duration of response was 33.7 months and overall survival rates at 1 and 2 years were 75.3% and 63.3%, respectively.

A 3-year landmark overall survival analysis from the IGNYTE clinical trial was recently presented at the 2026 American Society of Clinical Oncology annual meeting in May 2026.

RP1 plus nivolumab achieved a median overall survival (mOS) of 32.9 months in patients with anti–PD-1–failed advanced melanoma.

At 3 years, 47.8% of all treated patients remained alive, rising to 83.5% among responders.

The survival benefit was observed across all key patient subgroups, including those with varying disease stage, PD-L1 expression status, prior anti–CTLA-4 therapy, and primary or secondary anti–PD-1 resistance.

The combination of RP1 and nivolumab continued to demonstrate a favorable and manageable safety profile over long-term follow-up, with predominantly Grade 1–2 constitutional side effects, no Grade 5 events, and no new safety signals identified.

In November 2024, we announced submission of our first Biologics License Application, or BLA, to the U.S.

Food and Drug Administration, or 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 had granted Breakthrough Therapy designation for 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 22, 2025.

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.

On July 21, 2025 the FDA issued a complete response letter, or

CRL, for the RP1 BLA for the treatment of advanced melanoma.

The FDA stated in the CRL that it was unable to approve the application in its present form and that the IGNYTE trial was not considered to be an adequate and well-controlled clinical investigation that provided substantial evidence of effectiveness, including contribution of components.

Furthermore, the FDA said the trial could not be adequately interpreted due to the heterogeneity of the patient population.

On September 2, 2025 we announced that a type A meeting with the FDA had been scheduled to discuss the CRL following our submission of a briefing book addressing the points raised in the CRL, highlighting prior agreements related to the patient population, criteria for PD-1 resistance, and use of literature to support contribution of components.

The briefing book also included an additional analysis of data from the BLA and addressed comments about the Phase 3 confirmatory trial design raised by the FDA in the CRL.

On September 18, 2025 we announced that, following the type A meeting with the FDA to discuss the CRL, which was conducted on September 16, 2025, we were evaluating feedback received during the type A meeting to determine our next steps and that, at that time, a path forward under the accelerated approval pathway had not been determined.

Following the evaluation of FDA feedback and minutes from the type A meeting, we resubmitted the BLA on October 9, 2025.

On October 20, 2025 we announced that the FDA had accepted the resubmission of the BLA for RP1 in combination with nivolumab for the treatment of advanced melanoma in patients who progress on an anti-PD-1 containing regimen.

The resubmission of the BLA included additional information, data and analyses that will be part of the BLA review.

The FDA indicated that the resubmission is considered to be a complete response to the CRL and set a target action date of April 10, 2026 based on a Class 2 resubmission timeline.

On April 10, 2026, the FDA issued a second CRL for the RP1 BLA for the treatment of advanced melanoma.

The second CRL reiterated points made in the first CRL that were presumably addressed by the FDA accepting the BLA for resubmission indicating the resubmission was a complete response to the initial CRL.

The second CRL also reverses on points the FDA made in the September 2025 Type A meeting following the initial CRL.

We announced on May 29, 2026, that following collaborative communications with the FDA, the Company and the FDA aligned on a path forward for resubmission and reconsideration of the BLA for RP1 in combination with nivolumab for the treatment of advanced melanoma.

In that announcement, we reported that the FDA indicated that it will treat the BLA resubmission as an urgent matter upon receipt and will prioritize its review in recognition of the significant unmet need for patients in the advanced melanoma community.

Without an accelerated approval of the BLA for RP1 in combination with nivolumab for the treatment of advanced melanoma from this resubmitted BLA we might not be able to continue the development of RP1 for this indication, if at all, and we may be required to implement a restructuring plan and review our priorities across the RPx portfolio and the company as a whole.

On June 26, 2026 we announced the FDA accepted the BLA resubmission as a Class 1 resubmission with an action date of August 2, 2026.

The FDA also stated that they would convene an advisory committee meeting in late July 2026.

In August 2024, we announced the dosing of the first patient in the IGNYTE-3 trial, or the I-3 trial, 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.

In the September 2025 type A meeting minutes following the initial CRL, the FDA stated a control arm of nivolumab in combination with relatlimab (Opdualag (R) ) may be an acceptable comparator for the I-3 randomized controlled trial.

However, in the second CRL we believe the FDA reverted on its position in the September 2025 type A meeting.

Following the recent collaborative communications with the FDA we plan to continue working with the FDA on a path forward for the I-3 trial.

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.

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 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 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 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 provided updated data from the NMSC cohort during our June 2025 Investor Day event and in October 2025 at the European Society for Medical Oncology, or ESMO, conference.

Responses to RP1 plus nivolumab occurred across the NMSC tumor types enrolled, with confirmed responses seen in patients with both anti–PD-1 naïve and anti-PD-1 failed disease, as well as both in locally advanced and metastatic disease.

The ORR by NMSC tumor type for anti-PD-1 naïve patients was 100.0% (n=4) in MCC, 33.3% (n=3) in BCC, 66.7% (n=6) in angiosarcoma, and 56.3% (n=16) in CSCC.

The ORR by NMSC tumor type for anti-PD-1 failed patients was 26.3% (n=19) in MCC, 30.0% (n=10) in BCC, 37.5% (n=8) in angiosarcoma, and 15.2% (n=33) in CSCC.

We closed enrollment in the NMSC tumor type cohorts in the fourth quarter of 2025.

We had been furthering development of RP1 through enrollment in a Phase 1b/2 clinical trial of single agent RP1 in solid organ transplant recipients with skin cancers, including CSCC, which we referred to as the ARTACUS trial.

The ARTACUS trial enrolled 69 patients to assess the safety and efficacy of RP1 in liver, kidney, heart, lung, and hematopoietic cell transplant patients with skin cancers.

Most recently, Dr.

Migden presented updated data from the ARTACUS trial at the

Society for Melanoma Research 22nd International Congress in October 2025.

This updated data showed anti-tumor activity in locally advanced CSCC with an ORR of 34.6% (CR rate of 23.1%) and 2-year duration of response of 61.0%.

Furthermore, the data showed that RP1 monotherapy continued to be well tolerated and the safety profile continued to be similar to that observed in non-immunocompromised patients with advanced skin cancers, and, importantly, no implant rejections were attributed to the RP1 treatment.

We have closed enrollment in the ARTACUS trial and are planning a publication of the data in 2026.

Our previous clinical trial of RP1 in patients with CSCC, which we referred to as the CERPASS trial, is fully closed and we are planning for a study report to be available in 2026.

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.

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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.

Leading the development of the RP2 product candidate is our REVEAL study.

The REVEAL study is enrolling patients in a registration-directed study of RP2 in mUM patients who are immune checkpoint inhibitor-naïve.

The REVEAL study is a randomized, Phase 2/3 open label study expected to enroll approximately 280 patients to investigate the efficacy and safety of RP2 in combination with nivolumab vs.

ipilimumab in combination with nivolumab in immune checkpoint inhibitor naïve adult patients with metastatic uveal melanoma.

The primary endpoints of the trial are overall survival and progression free survival, and key secondary endpoints are overall response rate and disease control rate.

In January 2026 we announced the Phase 2/3 transition is expected to occur in the first quarter of 2027.

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.

The protocol has been amended to include RP2 as monotherapy and we plan to release preliminary HCC data by the end of 2026.

We have also opened a cohort in our RP2 study to investigate the potential to address biliary tract cancer, or BTC, through the dosing of RP2 in combination with durvalumab.

We are currently evaluating these signal finding studies.

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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To achieve this objective, we use oncolytic immunotherapies that combine multiple mechanisms in a single product candidate.

We believe our product candidates will initiate or enhance an immune response in patients with no or minimal pre-existing cancer immunity, including to tumor neo-antigens, and thereby increase the effectiveness of immune checkpoint blockade therapies.

We believe our

product candidates will initiate or enhance an immune response in patients with no or minimal pre-existing cancer immunity, including to tumor neo-antigens, and thereby increase the effectiveness of immune checkpoint blockade therapies.

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

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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.

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.

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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.

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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.

We have also been 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.

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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.

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 nivolumab vs.

ipilimumab in combination with nivolumab 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(-).

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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.

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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All six of these PCT applications have entered the national phase and are in different stages of pending and/or issued in a range of countries.

Patent examination has started and continues in these national phase applications.

Patent examination has started and continues in these national

phase applications.

Thirteen U.S.

patents have been granted by the applicable authorities in the U.S.

Four patents have been granted by the applicable authorities in each of the European Union and Japan.

Three patents have been granted by the applicable authorities in Hong Kong, two patents have been granted by the applicable authorities in each of China and Israel and one patent has been granted by the applicable authorities in each of Singapore, India, Mexico and Australia.

Six patents have been granted by the applicable authorities in each of the European Union and Japan.

Five patents have been granted by the applicable authorities in Hong Kong, four patents have been granted by the applicable authorities in China and three patents have been granted by the applicable authorities in each of Australia and Israel.

Two patents have been granted by the applicable authorities in each of Singapore and Mexico, and one patent has been granted by the applicable authorities in each of Brazil, India and South Korea.

The granted U.S.

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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.

These third parties also compete with us in recruiting and retaining qualified scientific and management personnel, establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies and technology licenses complementary to our programs or advantageous to our business.

These third parties also compete with us in recruiting and retaining qualified scientific and

management personnel, establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies and technology licenses complementary to our programs or advantageous to our business.

Our oncolytic product candidates, if and when marketed, will compete with a number of drugs that are currently marketed or in development that also target cancer but that utilize a different mechanism of action.

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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.

Following our reduction in force after receiving the second CRL, we no longer have in-house sales, marketing or commercialization staff and will need to rebuild these capabilities to commercialize any of our product candidates, if approved.

Clinical data, the size of the opportunity for our product candidates, and the size of the commercial infrastructure required will influence our commercialization plans and decision making.

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While FDA’s guidance is not binding, it does provide FDA’s current interpretation and approach.

FDA and EU regulation

FDA and EU/UK regulation

In the United States, the FDA regulates biologics under the Federal Food, Drug, and Cosmetic Act, or FDCA, the Public Health Services Act, or PHSA, and their implementing regulations.

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• satisfactory completion of an FDA advisory committee review, if applicable;

• satisfactory completion of an FDA inspection or remote regulatory assessment of the manufacturing facility or facilities at which the products are produced to assess compliance with current good manufacturing practices, or cGMPs, and to assure that the facilities, methods, and controls are adequate to preserve the therapeutics’ identity, strength, quality, purity, and potency as well as satisfactory completion of an FDA inspection or remote regulatory assessment of selected clinical sites and selected clinical investigators to determine GCP compliance;

• satisfactory completion of an FDA inspection (remotely or in person) of the manufacturing facility or facilities at which the products are produced to assess compliance with current good manufacturing practices, or cGMPs, and to assure that the facilities, methods, and controls are adequate to preserve the therapeutics’ identity, strength, quality, purity, and potency as well as satisfactory completion of an FDA inspection (remotely or in person) of selected clinical sites and selected clinical investigators to determine GCP compliance;

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

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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.

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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A protocol for each clinical trial, and any subsequent protocol amendments, must be submitted to the FDA as part of the IND.

Sponsors will also be required to provide FDA with diversity action plans.

Sponsors will also be required to provide FDA with diversity action plans, once this requirement goes into effect.

In addition, an IRB at each study site participating in the clinical trial or a central IRB must review and approve the plan for any clinical trial, informed consent forms, and communications to study subjects before a study commences at that site.

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The IRB must continue to oversee the clinical trial while it is being conducted.

Special clinical trial ethical considerations also must be taken into account if a study involves children.

Special clinical trial ethical

considerations also must be taken into account if a study involves children.

Once an IND is in effect, each new clinical protocol and any amendments to the protocol must be added to the IND for FDA review and sent to the IRB for approval.

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• Phase 3 — These adequate and well controlled clinical trials are undertaken in expanded subject populations, generally at geographically dispersed clinical trial sites, to generate enough data to provide statistically significant evidence of clinical efficacy and safety of the product for approval, to establish the overall risk benefit profile of the product, and to provide adequate information for the labeling of the product.

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.

The FDA typically requires that an NDA or BLA include data from adequate and well-controlled clinical trials which provide substantial evidence of efficacy.

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

Real world evidence may also be used to assist in clinical trial design.

For appropriate indications sought through supplemental BLAs, data summaries may provide marketing application support.

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 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.

FDA also has different programs, such as for genetically targeted and variant protein targeted products and platform technologies which, if the relevant criteria are met, can help to streamline or expedite product development and approval.

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.

For instance, under the FDA’s expanded access program, with FDA approval and subject to certain requirements, sponsors may provide access to product candidates to patients with serious or immediately life threatening diseases or conditions for which there is no comparable or satisfactory alternative therapy, provided that the potential patient benefit justifies the risks, the risks are not unreasonable in the context of the disease or condition to be treated, and the provision of the product candidate for the requested use will not interfere with clinical investigations.

comparable or satisfactory alternative therapy, provided that the potential patient benefit justifies the risks, the risks are not unreasonable in the context of the disease or condition to be treated, and the provision of the product candidate for the requested use will not interfere with clinical investigations.

The specific expanded access criteria and requirements depend on the number of expanded access patients.

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Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.

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 relation to the clinical trial in the United Kingdom or European Union 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 in the United Kingdom, or the European Medicines Agency / European Commission or national Member States authorities in Europe, 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 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 Directive.

A new Regulation (EU) 536/2014 regarding clinical trials of medicinal products for humans, in force since January 2022, updated the clinical trials regime and included the creation of a uniform framework for the submission of applications for clinical trials by all interested EU member states.

Approval of trials and enforcement of such rules is conducted by the regulatory authority in which the trial is carried out.

With the 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 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.

In the United States, 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.

In the European Union there are specific quality requirements for drug-device combinations.

In the European Union and United Kingdom there are similar requirements and obligations.

BLA submission, review by the FDA, and marketing approval

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Fee waivers or reductions are available in certain circumstances.

One basis for a waiver of the application user fee is if the applicant employs fewer than 500 employees, including employees of affiliates, the applicant does not have an approved marketing application for a product that has been introduced or delivered for introduction into interstate commerce, and the applicant, including its affiliates, is submitting its first marketing application.

One basis for a waiver of the application user fee is if the applicant employs fewer than 500 employees, including employees of affiliates, the applicant

does not have an approved marketing application for a product that has been introduced or delivered for introduction into interstate commerce, and the applicant, including its affiliates, is submitting its first marketing application.

In addition, under the Pediatric Research Equity Act, or PREA, a BLA or supplement to a BLA for a new active ingredient, indication, dosage form, dosage regimen, or route of administration, must contain data that are adequate to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

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The FDA reviews applications to determine, among other things, whether a product is safe, pure and potent and whether the manufacturing methods and controls are adequate to assure and preserve the product’s identity, strength, quality, potency, and purity.

Before approving a BLA, the FDA typically will inspect or conduct a remote regulatory assessment of the facility or facilities where the product is manufactured, referred to as a Pre-Approval Inspection.

Before approving a BLA, the FDA typically will inspect (remotely or in person) the facility or facilities where the product is manufactured, referred to as a Pre-Approval Inspection.

The FDA will not approve an application unless it determines that the manufacturing processes and facilities, including contract manufacturers and subcontractors, are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

Additionally, before approving a BLA the FDA will inspect or conduct a remote regulatory assessment of one or more clinical trial sites to assure compliance with GCPs.

Additionally, before approving a BLA the FDA will inspect (remotely or in person) of one or more clinical trial sites to assure compliance with GCPs.

After evaluating the BLA and all related information, including the advisory committee recommendation, if any, and inspection reports regarding the manufacturing facilities and clinical trial sites, the FDA may issue an approval letter, or, in some cases, a Complete Response Letter, or CRL.

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The deficiencies identified may be minor, for example, requiring labeling changes, or major, for example, requiring additional clinical trials.

In 2025, the FDA started publicly releasing complete response letters after issuance, for both products that eventually obtained approval and products that have not yet received approval.

If a CRL is issued, the applicant may either:

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Even with submission of this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.

If and when those conditions have been met to the FDA’s satisfaction, the FDA may issue an approval letter.

If and when those conditions have been met to the FDA’s satisfaction, the FDA may issue an approval

An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications.

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Further, should new safety information arise, additional testing, product labeling, or FDA notification may be required.

While there is no direct equivalent to the separate route for biologics, broadly equivalent requirements and controls similarly apply to the submission of pediatric testing and marketing authorization applications to the European Medicines Agency in the European Union and, post-approval, to the holding of such marketing authorizations, including conditionality.

While there is no separate route for biologics, broadly equivalent requirements and controls apply to the submission of marketing authorization applications to the European Medicines Agency in the European Union or MHRA in the United Kingdom, and to the requirement to conduct pediatric testing and, post-approval obligations on, the holders of such marketing authorizations.

Additional FDA expedited review and approval programs

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FDA may also, and frequently does, require that the confirmatory Phase 4 studies be commenced prior to FDA granting a product accelerated approval.

If a Phase 4 study is not sufficiently advanced at the time of a marketing application, FDA can issue a complete response letter rather than approve the product.

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.

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.

If a confirmatory study is not sufficiently advanced at the time of a marketing application, FDA can issue a complete response letter rather than approve the product.

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

If the confirmatory 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 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.

Promotional materials for a drug or biologic approved under the accelerated approval pathway are subject to FDA prior review.

A third program that may be available is the breakthrough therapy program, which is for products that are intended, alone or in combination with one or more other products, to treat a serious or life-threatening disease or condition, and for which preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

Breakthrough therapy products may be eligible for intensive FDA guidance on development programs as early as Phase 1 clinical trials, FDA organization commitment to involve senior managers and experienced review and regulatory management staff in a proactive collaborative, proactive, and cross-disciplinary reviews, and marketing application rolling review.

Breakthrough therapy products may be eligible for intensive FDA guidance on development programs as early as Phase 1 clinical trials, FDA organization commitment to involve senior managers and

experienced review and regulatory management staff in a proactive collaborative, proactive, and cross-disciplinary reviews, and marketing application rolling review.

FDA designations may be rescinded if the applicable qualifying criteria are no longer met.

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The FDA has issued a number of guidance documents outlining its approach for review and approval of biosimilars, including guidance documents on the demonstration of interchangeability and the licensure of biosimilar and interchangeable products for fewer than all of the reference product’s licensed conditions of use.

Moreover, in 2025, the FDA took steps to facilitate the development and approval of biosimilar and interchangeable products, easing the requirements for comparative efficacy studies for biosimilar products and switching studies for interchangeable products.

A reference biologic is granted 12 years of exclusivity from the time of first licensure of the reference product, and no application for a biosimilar can be submitted for four years from the date of licensure of the reference product and not approved for another 8 years from the date of licensure of the reference product.

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This information is then published in the Purple Book.

In the European Union there is a period of 10 years (or 11 years for significant new indications) of data exclusivity so that those seeking to market biosimilars cannot apply on an abridged basis for a marketing authorization for eight years from when the product was first marketed in the European Union and cannot place it on the market for 10 or 11 years from such first marketing although the European Union has proposed legislation reducing these exclusivity periods.

In the European Union there is a period of 8 years of data protection and an additional 2 years of marketing protection.

The marketing protection can be extended by 1 year to a total of 11 years for the authorization of a new indication that demonstrates significant benefit over existing treatments.

Those seeking to market biosimilars cannot apply on an abridged basis for a marketing authorization for eight years from when the reference product was first authorized in the European Union and cannot place it on the market for 10 or 11 years from such first authorization.

Similar provisions apply in the United Kingdom.

The European Union has recently agreed (although has not yet adopted) a new regulatory regime that will reduce the baseline period of protection to 8 years of data protection and 1 year of market protection, with the possibility of extending the market protection period if certain criteria are met.

These changes will not apply in the United Kingdom.

If approved, biologics may also be eligible for periods of United States patent term restoration.

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The total patent life with the extension also cannot exceed fourteen years from the product’s approval date.

Subject to the prior limitations, the period of the extension is calculated by adding half of the time from the effective date of an IND to the initial submission of a full marketing application, and all of the time between the submission of the full marketing application and its approval.

Subject to the prior limitations, the period of the extension is calculated through an equation that takes into account half of the time from the effective date of an IND to the initial submission of a complete marketing application and all the time between the submission of the marketing application and its approval.

This period may also be reduced by any time that the applicant did not act with due diligence.

In the European Union, a supplementary protection certificate, or SPC, can similarly extend a patent term for a maximum of five years.

A further six-month additional extension is available if the SPC relates to a medicinal product for which data has been submitted according to a Pediatric Investigation Plan.

In the European Union and United Kingdom, a supplementary protection certificate, or SPC, can similarly extend a patent term for a maximum of five years if the relevant criteria are met, although this is not limited to biological products.

six-month additional extension is available if the SPC relates to a medicinal product for which data has been submitted according to a Pediatric Investigation Plan.

In an effort to increase competition in the biologic product marketplace, Congress, the executive branch, and FDA have taken certain legislative and regulatory steps.

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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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There also are continuing annual program user fee requirements for approved products.

In addition, manufacturers and other entities involved in the manufacture and distribution of approved therapeutics are required to register their establishments with the FDA and certain state agencies, list their products, and are subject to periodic announced and unannounced inspections or remote regulatory assessment by the FDA and these state agencies for compliance with cGMP and other requirements, which impose certain procedural and documentation requirements upon sponsors and third-party manufacturers.

The information that must be submitted to FDA regarding manufactured products was expanded through the Coronavirus Aid, Relief, and Economic Security, or CARES, Act to include the volume of drugs produced during the prior year.

In addition, manufacturers and other entities involved in the manufacture and distribution of approved therapeutics are required to register their establishments with the FDA and certain state agencies, list their products, and are subject to periodic announced and unannounced inspections by the FDA and these state agencies for compliance with cGMP and other requirements, which impose certain procedural and documentation requirements upon sponsors and third-party manufacturers.

The information that must be submitted to FDA regarding manufactured products further includes the volume of drugs produced during the prior year.

Manufacturers must continue to expend time, money, and effort in the areas of production and quality-control to maintain compliance with cGMPs.

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FDA regulations also require investigation and correction of any deviations from cGMP and specifications and impose reporting and documentation requirements upon the sponsor and any third-party manufacturers that the sponsor may decide to use.

Within recent years, the President and the FDA have also taken actions to encourage the use of U.S.

domestic manufacturing sites, which may impact manufacturing operations.

Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance.

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A company can make only those claims relating to safety and efficacy, purity, and potency that are consistent with the FDA approved label.

All promotional and advertising statements must further be truthful and non-misleading, adequately substantiated, and must contain a fair balance between product benefit and risk information.

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.

All promotional and advertising statements must further be truthful and non-misleading, adequately The FDA has become increasingly active in the advertising and promotional spaces, including issuing new and updated guidances and increasing its enforcement activity regarding promotion and advertising, both in the areas of promotional statements to healthcare providers and direct to consumer advertising.

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 FDA.

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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 must be transferred electronically.

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

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

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.

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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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.

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

Additional controls for biologics and oncology programs

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and long-term patient and clinical study subject follow up and regulatory reporting.

In the European Union, while there is no direct equivalent to the separate route for biologics, the EMA issues scientific guidelines on biological medicinal products and the standard Common Technical Document structure is modified for biologicals and plasma-derived products.

In the European Union and United Kingdom, while there is no direct equivalent to the separate route for biologics, the EMA and MHRA issue scientific guidelines on biological medicinal products that should be followed and incorporated into the marketing authorization application for biological products.

With respect to oncology product candidates, FDA has also established a number of different projects, intended to address different aspects of oncology development.

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Instead, the legality of the arrangement will be evaluated on a case-by-case basis based on a cumulative review of all of the facts and circumstances.

Several courts have interpreted the statute’s intent requirement to mean that if any one purpose of an arrangement involving remuneration is to induce referrals of federal healthcare covered business, including purchases of products paid by federal healthcare programs, the statute has been violated.

courts have interpreted the statute’s intent requirement to mean that if any one purpose of an arrangement involving remuneration is to induce referrals of federal healthcare covered business, including purchases of products paid by federal healthcare programs, the statute has been violated.

The ACA modified the intent requirement under the Anti-Kickback Statute to a stricter standard, such that a person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

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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, 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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If the government decides to intervene in a qui tam action and prevails in the lawsuit, the individual will share in the proceeds from any fines or settlement funds.

If the government declines to intervene, the individual may pursue the case alone.

If the government declines to intervene, the individual may, under most circumstances, pursue the case alone.

The civil False Claims Act provides for treble damages and a civil penalty for each false claim, such as an invoice or pharmacy claim for reimbursement, which can aggregate into hundreds of millions of dollars.

For these reasons, since 2004, civil False Claims Act lawsuits against biopharmaceutical companies have increased significantly in volume and breadth, leading to several substantial civil and criminal settlements, as much as $3.0 billion, regarding certain sales practices and promoting off label uses.

For these reasons, since 2004, civil False

Claims Act lawsuits against biopharmaceutical companies have increased significantly in volume and breadth, leading to several substantial civil and criminal settlements, as much as $3.0 billion, regarding certain sales practices and promoting off label uses.

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.

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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.

In addition, the civil monetary penalties statute, subject to certain exceptions, prohibits the offer or transfer of remuneration, including waivers of copayments and deductible amounts (or any part thereof), to a Medicare or state healthcare program beneficiary if the person knows or should know it is likely to influence the beneficiary’s selection of a particular provider, practitioner, or supplier of services reimbursable by Medicare or a state healthcare program.

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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For therapeutics paid under Medicare Part B, manufacturers must also calculate and report their Average Sales Price, which is used to determine the Medicare Part B payment rate.

For products approved under a BLA (including biosimilars), or an NDA, the Veterans Health Care Act, or VHCA, requires manufacturers to calculate and report to the Department Veterans Affairs, or VA, a different price called the Non-Federal Average Manufacturer Price, which is used to determine the maximum price that can be charged to certain federal agencies, referred to as the Federal Ceiling Price, or FCP.

For products approved under a BLA (including biosimilars), or an NDA, the Veterans Health Care Act, or VHCA, requires manufacturers to calculate and report to the Department of Veterans Affairs, or VA, a different price called the Non-Federal Average Manufacturer Price, which is used to determine the maximum price that can be charged to certain federal agencies, referred to as the Federal Ceiling Price, or FCP.

Like the Medicaid rebate amount, the FCP includes an inflation penalty.

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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.

licensed physicians, physician assistants, nurse practitioners, clinical nurse specialists, and certified registered nurse anesthetists and U.S.

teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family.

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

CMS makes the reported information publicly available.

There are also federal consumer protection and unfair competition laws that broadly regulate marketplace activities and activities that potentially harm consumers.

Further, we may be subject to data privacy and security regulation by both the federal government and the states in which we conduct our business.

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impose restrictions on marketing practices;

require the registration of pharmaceutical sales representatives;

or require manufacturers to track and report information related to payments, gifts, and other items of value to physicians and other healthcare providers.

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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.

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

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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.

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.

Medicaid is an insurance program for certain categories of patients whose income and assets fall below state defined levels and who are otherwise uninsured that is both federally and state funded and managed by each state.

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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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We cannot provide any assurances that we will be able to obtain and maintain third-party coverage or adequate reimbursement for our product candidates in whole or in part.

The absence in Europe of any substantive harmonization of pricing and reimbursement regimes, including health technology assessment, means that separate negotiations will need to take place with the relevant authorities in each member state and may include a variety of risk share agreements with payors.

While there are recent changes in Europe to coordinate the health technology assessment process, separate negotiations take place with the relevant pricing and reimbursement authorities in each member state and may include a variety of risk share agreements with payors.

Healthcare reform measures

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Any reduction in reimbursement from Medicare and other government programs may result in a similar reduction in payments from private payors.

This rule has now been rescinded, but similar programs have been described in recent legislative proposals.

Our results of operations could be adversely affected by current and future healthcare legislation and reforms.

This rule has now been rescinded, but other efforts to address the costs of pharmaceuticals have been adopted, including the Inflation Reduction Act of 2022, or the IRA.

The IRA requires manufacturers of selected drugs to negotiate discounted prices with the Secretary of the Department of Health and Human Services.

Failure to reach an agreement can subject manufacturers to an excise tax or withdrawal of all drug products from coverage under Medicare and Medicaid.

The legislation also requires manufacturers to pay rebates for drugs in Medicare Part D whose price increases exceed inflation and caps Medicare out-of-pocket drug costs at $2,000 a year.

Failure to participate in negotiations or to reach an agreement can result in a manufacturer being required to withdraw all drug products from coverage under Medicare and Medicaid.

Drug price negotiations and other program implementation measures could further be affected by the ongoing changes in leadership at Health and Human Services (HHS) and CMS under the current administration.

In November 2025, CMS also introduced the GENEROUS Model, which requires manufacturers to provide rebates aligned with most favored nation pricing to participating state Medicaid programs that opt into the program.

These and any additional healthcare reform measures could further constrain our business or limit the amounts that federal and state governments will pay for healthcare products and services in the U.S., which could result in additional pricing pressures.

Moreover, the ACA broadened access to health insurance, attempts to reduce or constrain the growth of healthcare spending, enhanced remedies against fraud and abuse, added new transparency requirements for healthcare and health insurance industries, imposed new taxes and fees on the health care industry, and imposed additional health policy reforms.

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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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The revisions to the AMP definition and Medicaid rebate formula can have the further effect of increasing the required 340B discounts.

Further, the ACA required manufacturers of covered therapeutics to pay mandatory Medicare Part D coverage gap rebates, and the Bipartisan Budget Act of 2018, increased the required percentage to 70% of the pharmacy charge to Medicare Part D patients while they are in the coverage gap.

Finally, the ACA imposes a significant annual fee on companies that manufacture or import branded prescription therapeutic products.

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 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.

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.

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We expect that additional state and federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could further limit the prices we are able to charge, or the amounts of reimbursement available, for our product candidates if approved and commercialized.

The Bipartisan Budget Act also extended Manufacturer responsibility for prescription costs in the Medicare Part D coverage gap to biosimilars, which had previously been exempt.

The Foreign Corrupt Practices Act

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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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Of the 465 employees, 349 are in research and development and 116 are in selling, general and administrative functions.

In April 2026, we implemented a plan for a restructuring, which included a reduction of our workforce by approximately 55%.

Without a near-term accelerated approval of our BLA for RP1 plus nivolumab for the treatment of advanced melanoma, we may be required to initiate a further reduction in our workforce.

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

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What changed 10-K

Item 1. Business