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Item 1. Business

2026-02-24 compared with 2025-02-27 · 344 added, 459 removed, 426 unchanged (65% of the section changed)

We are a commercial-stage biopharmaceutical company pioneering a transformational approach to treating cancer by harnessing the human immune system’s ability to recognize and destroy diverse cancer cells using therapies personalized for each patient.

We are a commercial-stage biopharmaceutical company pioneering a transformational approach to treating cancer.

Our mission is to be the global leader in innovating, developing, and delivering tumor infiltrating lymphocyte, or TIL, cell therapies for patients with solid tumor cancers.

We are executing the U.S.

launch of Amtagvi ® (lifileucel), the first product within our autologous TIL cell therapy platform, while also marketing Proleukin ® (aldesleukin), an interleukin-2, or IL-2, product used in the Amtagvi ® treatment regimen and in other applications.

Amtagvi ® is the first and the only one-time, individualized T cell therapy to receive FDA approval for a solid tumor cancer.

Amtagvi ® is a tumor-derived autologous T cell immunotherapy indicated for the treatment of adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor.

This indication was approved in February 2024 under accelerated approval based on an endpoint of overall response rate, or ORR.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in future confirmatory trials.

Amtagvi ® and Proleukin ® are part of a treatment regimen that also includes lymphodepletion.

Beyond the U.S., we plan to launch Amtagvi ® into additional markets with a high prevalence of advanced melanoma, including the European Union, or EU, United Kingdom, or UK, Canada, Switzerland, and Australia.

In June 2024, we submitted a centralized marketing authorization application, or MAA, to the European Medicines Agency, or the EMA, for lifileucel.

In August 2024, the MAA was validated and accepted for review by the EMA.

In October 2024, an MAA was submitted to the Medicines and Healthcare products Regulatory Agency in the UK.

A new drug submission, or NDS, was deemed eligible for Notice of Compliance with Conditions, or NOC/c, by Health Canada and submitted in December 2024 and then accepted in January 2025.

The NOC/c policy includes a prioritized 200-day review process for potential NDS approval in mid-2025.

If approved, lifileucel is expected to be the first and only approved therapy in this treatment setting in these markets.

Across the U.S.

and other targeted global markets, Amtagvi ® has the potential to address more than 20,000 previously treated advanced melanoma patients annually.

Iovance was founded to build upon the promise of TIL cell therapy that was previously demonstrated in single-center clinical trials at academic research centers, including the National Cancer Institute, or the NCI.

Our multi-center trials, novel TIL cell therapy

products, manufacturing processes, facilities, and bioanalytical platforms have transformed TIL cell therapy into a commercially viable treatment which thousands of patients with cancer can access.

We manufacture Amtagvi ® and our investigational TIL cell therapies using centralized, scalable, and proprietary manufacturing processes which rejuvenate and multiply polyclonal T cells unique to each patient into the billions and yields a cryopreserved, individualized therapy.

Amtagvi ® is manufactured for commercial use at our manufacturing facility, the Iovance Cell Therapy Center, or the i CTC, and by a contract manufacturing organization, or CMO.

Our development pipeline includes multicenter trials of TIL cell therapies in additional treatment settings and indications for solid tumor cancers.

To potentially improve outcomes for patients, we are investigating TIL monotherapies for patients previously treated with standard of care therapies and TIL cell therapy in combination with standard of care therapies for patients in earlier treatment settings.

We are conducting two ongoing registrational trials to support a supplementary BLA, or sBLA, of lifileucel in frontline advanced melanoma and in advanced non-small cell lung cancer, or NSCLC, following standard of care chemo-immunotherapy.

We are also developing next generation therapies, such as genetically modified TIL cell therapy and next generation cytokines for use in the TIL cell therapy regimen.

TIL cell therapies harness the individual immune system’s ability to recognize and destroy diverse cancer cells that are unique to each patient.

These individualized therapies are manufactured using centralized, scalable, and proprietary manufacturing processes which rejuvenate and multiply each patient’s polyclonal T cells into the billions.

Iovance was founded to build upon the promise of TIL cell therapy initially developed at academic research centers, including the National Cancer Institute, or the NCI.

Our multi-center trials, scalable manufacturing, regulatory approvals and commercial infrastructure have transformed TIL cell therapy from a research product available to only a small number of patients, into a commercially viable treatment that is accessible for thousands of cancer patients.

Our two commercial products include Amtagvi ® (lifileucel) and Proleukin ® (aldesleukin), an interleukin-2, or IL-2, product used in the Amtagvi ® treatment regimen and other applications.

Amtagvi ® is the first one-time, individualized T cell therapy for a solid tumor cancer and for the treatment of adult patients with previously treated advanced, or unresectable or metastatic melanoma.

Amtagvi ® is administered as part of a treatment regimen that includes lymphodepletion and a short course of Proleukin ® .

Globally, Amtagvi ® has the potential to address more than 30,000 previously treated advanced melanoma patients annually.

Amtagvi ® is approved in the U.S.

and Canada, and we plan to launch into additional markets with a high prevalence of advanced melanoma.

Potential approvals are pending in the United Kingdom, or UK, and Australia in the first half of 2026 and Switzerland in 2027.

In the European Union, or EU, we withdrew our initial marketing authorization application, or MAA, in July 2025.

We are working with the European Medicines Agency, or EMA, to resubmit a centralized MAA in 2026.

Our development pipeline consists of TIL cell therapies and next generation approaches in additional solid tumor cancers, including one-time TIL monotherapies for previously treated patients and TIL cell therapy combined with standard of care in earlier treatment settings.

We are conducting two ongoing registrational trials in frontline advanced melanoma and previously treated advanced non-small cell lung cancer, or NSCLC.

We plan to commence a registrational trial in previously treated advanced undifferentiated pleomorphic sarcoma, or UPS, and dedifferentiated liposarcoma, or DDLPS, in the second quarter of 2026 and engage with the FDA on a path to expedited approval.

Corporate Strategy

A global leader in innovating, developing, and delivering TIL cell therapy

Our mission is to be the global leader in innovating, developing, and delivering TIL cell therapy for patients with solid tumor cancers.

We are pioneering this transformational approach to cure cancer by harnessing the human immune system’s ability to recognize and destroy diverse cancer cells in each patient.

As we continue to execute the U.S.

launch of Amtagvi ® and advance our pipeline, we are committed to continuous innovation to develop TIL cell therapies and optimize TIL treatment regimens that may extend and improve life for patients with cancer.

Successfully commercialize our lead product Amtagvi ® for the treatment of post-anti-PD-1 advanced melanoma in the U.S.

Following U.S.

FDA approval of Amtagvi ® for the treatment of patients with post-anti-PD-1 advanced melanoma on February 16, 2024, our top priority is continuing to leverage our experienced marketing, payer access, and distribution teams, as well as a sales force with extensive experience in oncology and cell therapy for our commercialization efforts.

Our medical affairs team is also educating key opinion leaders, or KOLs, about Amtagvi ® and TIL cell therapy, as well as presenting and publishing our clinical results.

We are focusing ongoing Amtagvi ® commercialization efforts on four primary areas:

● supporting operations and patient enrollment at authorized treatment centers, or ATCs, in the U.S.

and activating ATCs in the EU, UK and Canada to prepare for anticipated 2025 regulatory approvals in those markets;

● educating, training, and collaborating with healthcare professionals, or HCPs, who will be administering our product, as well as community oncologists who will be referring patients to our ATCs and larger community practices that may become ATCs;

● operational excellence in launch execution, commercial manufacturing, and delivery of therapy;

● continuous communication with payors about the value of Amtagvi ® to facilitate strong reimbursement and patient access.

Our mission is to be the global leader in innovating, developing, and delivering TIL cell therapy.

Our vision is to pioneer this transformational approach to cure solid tumor cancers.

We are committed to continuous innovation to develop TIL cell therapies and optimize TIL treatment regimens that may extend and improve life for patients with cancer.

Our top priority is to drive commercial success of Amtagvi ® for previously treated advanced melanoma across four primary areas:

● Educating, training, and collaborating with healthcare professionals, or HCPs, who will be administering our product at academic and community authorized treatment centers, or ATCs, as well as community oncologists and advocacy groups who will refer patients to our ATCs;

● Providing operational and patient support at ATCs in the U.S.

and onboarding ATCs in preparation for anticipated regulatory approvals and product launches in additional global markets;

● Collaborating with payors about the value of Amtagvi ® to continue to facilitate strong reimbursement and patient access;

● Driving operational excellence in launch execution, commercial manufacturing success, and delivery of therapy.

Commercial Launch of the First TIL Cell Therapy in Advanced Melanoma

Amtagvi ® (lifileucel) was approved by the FDA on February 16, 2024 for the treatment of adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor.

The approval is based on safety and efficacy results from the C-144-01 clinical trial, a global, multicenter trial investigating Amtagvi ® in patients with advanced melanoma previously treated with anti-PD-1 therapy and targeted therapy, where applicable.

We completed the Biologics Licensing Application, or BLA, submission in March 2023, which the FDA accepted in May 2023 for Priority Review.

Amtagvi ® is manufactured using a proprietary process to collect and multiply a patient’s unique T cells from a portion of their tumor.

Amtagvi ® returns billions of the patient’s T cells back to the body to fight cancer.

Amtagvi ® is administered to patients as part of a treatment regimen that includes lymphodepletion and a short course of high-dose Proleukin ® (aldesleukin).

There are three key steps in the Amtagvi ® treatment process.

Sample Collection.

A tumor tissue sample of at least 1.5 cm in diameter is collected during a surgical resection and shipped to an FDA-approved, centralized manufacturing facility.

Manufacturing.

Upon arrival at the manufacturing facility, TIL are separated from other cells within the patient’s tumor tissue sample.

The cells are then multiplied into the billions.

Upon completion of manufacturing, Amtagvi ® is quality tested to meet specific product release criteria.

The final product is cryopreserved and sent back to the ATC for administration to the patient.

Treatment Regimen.

The Amtagvi ® treatment regimen begins with non-myeloablative lymphodepletion, or NMA-LD, to suppress the immunosuppressive tumor microenvironment, which we believe enhances the efficacy of TIL cell therapy.

After NMA-LD, Amtagvi ® is infused and followed by a short course of up to six doses of Proleukin ® to promote T cell activity.

Prior to the FDA approval of Amtagvi ® , there were no FDA approved therapies for patients with advanced melanoma following anti-PD-1 therapy.

Proleukin ® (aldesleukin) is an IL-2 product used in the Amtagvi ® treatment regimen and manufacturing process, as well as other commercial, clinical, manufacturing, and research settings, which provides additional revenue.

In May 2023, we acquired the worldwide rights to Proleukin ® , as well as the manufacturing, supply, and commercialization income generated from such rights and associated operations from Clinigen Holdings Limited, Clinigen Healthcare Limited, and Clinigen, Inc, which we refer to collectively as Clinigen.

Ownership of Proleukin ® provides an additional revenue source, secures our Proleukin ® supply chain, lowers cost of goods, and reduces clinical trial expenses for Proleukin ® used with our TIL cell therapies.

Proleukin ® has received regulatory approvals for treatment of adults with metastatic melanoma and metastatic renal cell carcinoma in the U.S.

Proleukin ® is also licensed in multiple countries around the world for treatment of patients with metastatic renal cell carcinoma and/or metastatic melanoma.

We also sell aldesleukin for clinical trial use and for use in the manufacturing of various cell and gene therapies to numerous third-party clients.

Manufacturing capacity for forecasted commercial and clinical demand

We are the first company to obtain FDA approval for a TIL cell therapy product.

We believe that we are the only company in the U.S.

to have a centralized, scalable, and commercially viable TIL manufacturing process.

In clinical trials, more than 700 patients have been treated with Iovance TIL cell therapy products manufactured using our proprietary processes across multiple indications.

Iovance TIL cell therapies are manufactured for commercial use and clinical trials at our manufacturing facility, the i CTC, and by a CMO.

The FDA authorized i CTC for commercial manufacturing of Amtagvi ® as well as our CMO for additional capacity to supplement our internal manufacturing.

As built, the two facilities together have capacity to treat several thousands of cancer patients annually with commercial product and clinical supply.

The i CTC is the first centralized and scalable current Good Manufacturing Practice, or cGMP, manufacturing facility dedicated to producing TIL cell therapies, as well as the first FDA-approved facility for commercial TIL cell therapy.

Located in Philadelphia, Pennsylvania, the 136,000 square foot i CTC is among the largest cell therapy manufacturing facilities globally.

i CTC expansion is underway which is expected to increase capacity to supply over five thousand patients annually.

Our long-term goal is to establish a manufacturing network that can supply TIL cell therapies to over ten thousand patients per year.

The proximity of the i CTC to multiple airports facilitates delivery of TIL cell therapies to treatment centers.

The i CTC is expected to cover logistics and delivery of TIL cell therapies in North America, Europe, and Australia.

Ownership of our manufacturing facility allows us to control internal manufacturing capacity and product quality, manage supply and delivery logistics, implement process improvement and realize potential cost efficiencies for TIL cell therapies that we may develop and commercialize.

We are also exploring next generation TIL cell therapy

manufacturing processes, treatments and technologies that may further streamline development timelines and costs.

The i CTC has a flexible design that facilitates our expansion within the existing shell space and an option to build on an adjacent lot to support future growth and capacity needs.

We plan to carefully manage our cost structure and reduce the long-term cost of manufacturing our products.

Details of related agreements are provided in the Research, Development, Manufacturing and License Agreements for TIL Cell Therapy section of this Annual Report on Form 10-K.

TIL Cell Therapy Clinical Development in Advanced, Metastatic or Unresectable Solid Tumor Cancers

Our TIL cell therapy platform and manufacturing process have been initially validated through the FDA approval of Amtagvi ® .

TIL cell therapy is a T cell-based immunotherapy technology platform that leverages patient-specific cells to recognize and attack diverse cancer cells that are unique to each patient.

Unlike other cell therapies that act on a single or small number of shared antigen targets common to certain tumors, our individualized T cell therapies are polyclonal to target a variety of neoantigens that are unique to the patient and tumor.

We believe this polyclonal cell therapy may be applicable to many solid tumor cancers, where the majority of immune targets are patient specific.

We have investigated TIL cell therapy in global, multicenter clinical trials in advanced melanoma, gynecological cancers, non-small cell lung cancer, or NSCLC, and head and neck squamous cell carcinoma, or HNSCC.

Through ongoing academic collaborations, as well as government and other partners, we are investigating the next frontier for TIL cell therapy in other tumor types and treatment settings.

● Frontline Advanced Melanoma:

In patients with frontline advanced melanoma not previously treated with anti-PD-1 therapy, we are investigating lifileucel in combination with pembrolizumab in TILVANCE-301, a global randomized Phase 3 clinical trial intended to support registration in advanced frontline melanoma, as well as to serve as a confirmatory trial to support full approval in post-anti-PD-1 advanced melanoma.

TILVANCE-301 is expected to enroll approximately 670 patients and features dual primary endpoints of ORR and progression free survival, or PFS, assessed by blinded independent review committee.

We also added Cohort 1D to our IOV-COM-202 trial to investigate lifileucel in combination with relatlimab and nivolumab in frontline advanced melanoma patients.

● Advanced Non-Small Cell Lung Cancer:

In NSCLC, we are investigating lifileucel in two clinical trials in NSCLC patient populations with significant unmet need.

IOV-LUN-202 is a registrational clinical trial of lifileucel in advanced NSCLC patients who have progressed following chemotherapy and anti-PD-1 therapy.

The IOV-COM-202 trial in solid tumors includes cohorts of NSCLC patients treated with lifileucel monotherapy and combination therapy.

We added Cohorts 3D and 3E to our IOV-COM-202 trial to investigate lifileucel in combination with pembrolizumab and chemotherapy in frontline advanced NSCLC patients.

● Advanced Endometrial Cancer:

We initiated a clinical trial, IOV-END-201, in the second quarter of 2024 for lifileucel in endometrial cancer to potentially address the unmet need for patients previously treated with platinum-based chemotherapy and anti-PD-1 therapy regardless of mismatch repair.

● Next Generation TIL Cell Therapy:

Our first genetically modified, TIL cell therapy, IOV-4001, is being investigated in the multi-center Phase 2 efficacy portion of a first-in-human clinical trial, IOV-GM1-201, in previously treated patients with advanced melanoma or NSCLC.

IOV-4001 utilizes the gene-editing TALEN ® technology, licensed from the clinical-stage biotechnology company, Cellectis S.A., or Cellectis, to inactivate the gene coding for PD-1.

A second next generation TIL cell therapy, IOV-5001, is in Investigational New Drug, or IND, enabling studies.

IOV-5001 is a genetically engineered, inducible, and tethered interleukin-12 TIL cell therapy designed to enhance TIL efficacy while optimizing safety.

● Next Generation IL-2:

A Phase 1/2 clinical trial is underway to investigate IOV-3001, a second-generation, modified interleukin-2 analog, for use in the TIL therapy treatment regimen.

Preclinical studies of IOV-3001 demonstrated the potential for improved safety with strong effector T cell expansion.

● Additional Solid Tumor Cancers:

Iovance TIL cell therapy has been investigated in additional solid tumor cancers in Iovance- and investigator-sponsored clinical trials.

Lifileucel was evaluated as a monotherapy and in combination with pembrolizumab in the Phase 2 C-145-03 and IOV-COM-202 clinical trials in multiple cohorts of patients with metastatic

HNSCC, and in patients with advanced cervical cancer in the C-145-04 multicenter Phase 2 clinical trial.

Indications studied in investigator sponsored clinical trials supported by Iovance include soft tissue sarcoma, osteosarcoma, pancreatic and colorectal cancer, platinum resistant ovarian cancer, anaplastic thyroid cancer, non-melanoma skin cancer, and triple negative breast cancer.

Next-Generation TIL Therapy Product Candidates

Our next-generation technology platforms are designed to optimize outcomes with TIL cell therapy across three key initiatives:

genetic modifications, potency, and new treatment regimens.

● Genetic modifications:

In addition to IOV-4001, we are pursuing several targets for genetic modification that utilize the gene-editing TALEN ® platform licensed from Cellectis.

Single- and multiple- knockouts may further harness the immune system response to cancer and potentially increase the potency of TIL cell therapy.

Preclinical development is ongoing with additional TIL products and TIL-cell lines using transient and stable gene inactivation, which may expand and activate TIL to achieve better efficacy while avoiding systemic side effects.

● Cytokine-Tethered TIL Therapy :

Our genetically engineered, inducible, and tethered IL-12 TIL cell therapy, designated IOV-5001, is in IND-enabling studies.

In preclinical studies, IOV-5001 augmented anti-tumor activity in vitro, and a clinical trial of a prior generation IL-12 TIL therapy at the NCI showed improved efficacy.

A pre-IND meeting is planned with the FDA to discuss IOV-5001 in the first quarter of 2025 and then an IND application submission in 2026.

● New treatment regimens:

We are exploring potential improvements to the TIL treatment regimen.

We are investigating IOV-3001, a second generation, modified IL-2 analog, which we licensed from Novartis Pharma AG in 2020.

We submitted an IND application for a phase 1/2 clinical trial of IOV-3001 for use in the TIL therapy treatment regimen in the third quarter of 2024, which was accepted in the fourth quarter of 2024.

Results from non-human primate and IND-enabling studies of IOV-3001 were presented at the American Society of Clinical Oncology’s 2024 Annual Meeting and demonstrate the potential for improved safety with strong effector T cell expansion.

Additional information is included in the Iovance-Sponsored Clinical Trials section of this Annual Report on Form 10-K.

Amtagvi ® (lifileucel) is the first one-time, individualized T cell therapy approved for a solid tumor cancer and for the treatment of adult patients with previously treated advanced melanoma.

Amtagvi ® returns billions of individualized patient T cells back to the body to fight cancer and is administered as part of a treatment regimen.

Amtagvi ® is indicated for the treatment of adult patients with advanced melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor.

accelerated approval of Amtagvi ® is based on safety and efficacy results from the C-144-01 global, multicenter clinical trial.

A global, randomized Phase 3 confirmatory trial, TILVANCE-301, is investigating Amtagvi ® in combination with pembrolizumab in frontline advanced melanoma.

The Amtagvi ® treatment regimen, that includes lymphodepletion and a short course of Proleukin ® (aldesleukin), is available through a continuously growing network of ATCs.

In the final five-year analysis from the C-144-01 trial published in the Journal of Clinical Oncology and presented at ASCO in May, 2025, Amtagvi ® demonstrated unprecedented durability in previously treated advanced melanoma patients with 31.4% objective response rate, or ORR, median duration of response, or mDOR, of 36.5 months, median overall survival, or OS, of 13.9 months and five-year OS of 19.7%.

Initial data for Amtagvi in the commercial setting reinforce the published clinical data.

In February 2026, data from the first real-world, retrospective study of Amtagvi were presented at the 2026 Tandem Meetings of the American Society for Transplantation and Cellular Therapy and the Center for International Blood and Marrow Transplant Research.

Among 41 evaluable patients treated per Amtagvi ® U.S.

prescribing information, the physician-assessed ORR was 44% and the disease control rate was 73%.

Response rates with Amtagvi ® were higher in third-line or earlier patients.

The ORR was 52% following two or fewer prior lines of therapy compared to an ORR of 33% after three or more prior lines of therapy.

Amtagvi ® has multiple growth drivers, including:

● Awareness of clinical and real-world evidence data to drive adoption as well as earlier and higher volume of patient referrals for better outcomes across our ATC network.

● Higher penetration at academic ATCs through earlier tissue procurement for patients at high risk of disease progression, such as BRAF mutant patients, so they can be treated before their health status declines.

● Expansion of the ATC network with new academic and community ATCs.

● Additional approvals in new global markets.

We sell Proleukin ® (aldesleukin), an interleukin-2, or IL-2, product to three main distributors in the U.S., distributors outside the U.S., and numerous third-party clients across the three revenue channels:

1) use in the Amtagvi ® treatment regimen, or other approved oncology uses, or the primary channel, 2) use in the manufacturing process for Amtagvi ® and other cell therapies and 3) use in clinical and research settings.

Proleukin ® is approved in the U.S., and licensed in multiple international markets, for treatment of adults with metastatic renal cell carcinoma and/or metastatic melanoma.

In May 2023, we acquired the worldwide rights to Proleukin ® from Clinigen Holdings Limited, Clinigen Healthcare Limited, and Clinigen, Inc., which we refer to collectively as Clinigen.

Scalable TIL manufacturing for commercial and clinical demand

The Iovance Cell Therapy Center, or i CTC, in Philadelphia, Pennsylvania is the first FDA-approved facility to manufacture commercial TIL cell therapy.

We also believe that the i CTC is the only current Good Manufacturing Practice, or cGMP, facility with a centralized, scalable TIL manufacturing process.

To date, more than 1,500 patients have been treated with commercial and investigational TIL cell therapies manufactured using Iovance processes.

Facilitated by its proximity to multiple airports, the i CTC covers logistics and delivery of TIL cell therapies to treatment centers in North America, Europe, and Asia Pacific.

We have historically relied on our own manufacturing capabilities, together with other third parties, for the manufacturing and processing of commercial and investigational TIL cell therapy products.

The i CTC currently supplies the vast majority of commercial Amtagvi ® and clinical lifileucel with additional capacity previously supplemented by a contract manufacturer.

The i CTC has the potential capacity to supply TIL cell therapies for more than 5,000 cancer patients annually.

To utilize our internal manufacturing suites at greater scale, improve gross margin and reduce operating expenses, we are transitioning all manufacturing activities for Amtagvi ® and lifileucel to the i CTC.

Our contract manufacturer concluded production of Amtagvi ® and lifileucel and our agreement terminated in the first quarter of 2026.

This internal manufacturing strategy aligns with our ongoing initiatives to manage and reduce long-term product manufacturing costs.

We will have full control of manufacturing capacity and product quality, supply and delivery logistics, cost efficiencies and process improvements, such as automation and next generation approaches that may further streamline timelines and costs.

Certain clinical trials for our next-generation investigational TIL cell therapies will continue to be supported by contract manufacturing organizations, or CMOs.

Details of related agreements are provided in the Research, Development, Manufacturing and License Agreements in this Annual Report on Form 10-K.

TIL Cell Therapy Platforms for Advanced, or Metastatic or Unresectable, Solid Tumor Cancers

Our T cell-based immunotherapy technology platform of TIL cell therapies leverages patient-specific cells to recognize and attack diverse cancer cells that are unique to each patient.

We believe this approach is the emerging backbone for immuno-oncology approaches to treat solid tumor cancers.

We have investigated TIL cell therapy in global, multicenter Iovance-sponsored clinical trials in various treatment settings in advanced melanoma, NSCLC, cervical cancer, endometrial cancer, and head and neck squamous cell carcinoma, or HNSCC.

Through ongoing academic collaborations, as well as government and other partners, we are investigating additional solid tumor types and treatment settings.

We have provided prior or ongoing support for investigator-sponsored clinical trials in soft tissue sarcoma, osteosarcoma, pancreatic and colorectal cancer, platinum resistant ovarian cancer, anaplastic thyroid cancer, and triple negative breast cancer.

Applying our expertise in TIL cell therapy, our next-generation technology platforms are designed to optimize outcomes with TIL cell therapy across three key initiatives:

genetic modifications, potency, and new treatment regimens using an improved IL-2.

Intellectual Property

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Iovance-Sponsored Clinical Trials

Frontline Advanced Melanoma

Melanoma is a common type of skin cancer, accounting for an estimated 100,640 patients diagnosed and 8,290 deaths in 2024 in the U.S.

according to the Surveillance, Epidemiology and End Results program, or SEER, program.

Following the accelerated approval of Amtagvi ® , our confirmatory trial, TILVANCE-301, is designed to support a registrational path for lifileucel in combination with pembrolizumab in frontline advanced melanoma as well as to support full U.S.

approval for Amtagvi ® , which has received an accelerated U.S.

approval in its initial indication in post-anti-PD-1 advanced melanoma.

TILVANCE-301 is a Phase 3 multicenter, open-label, randomized, parallel group, treatment clinical trial that will randomize approximately 670 patients with unresectable or metastatic melanoma who have had no prior therapy for metastatic or unresectable disease to investigate lifileucel in combination with pembrolizumab in the experimental arm compared with pembrolizumab monotherapy in the control arm.

Patients in the experimental arm receive pembrolizumab prior to and after the lifileucel regimen until disease progression.

In the control arm, pembrolizumab monotherapy is given every six weeks until disease progression, with an optional

crossover to lifileucel monotherapy upon confirmed progressive disease verified by a blinded independent review committee, or BIRC, and if patients meet eligibility criteria.

We reached agreement with the FDA on the TILVANCE-301 clinical trial design, including dual primary endpoints of ORR to support accelerated approval and PFS to support full approval of lifileucel in frontline advanced melanoma.

The dual primary endpoints will be assessed by a BIRC using RECIST 1.1.

Our strategy in frontline melanoma is supported by clinical results from the ongoing Cohort 1A of our IOV-COM-202 clinical trial as well as prior published NCI data for TIL monotherapy in anti-PD-1 naïve melanoma patients.

As of the most recent detailed Cohort 1A clinical data update in May 2024, we observed a 65% ORR in twenty-three patients per RECIST 1.1.

Fifteen patients had a confirmed objective response, including seven complete responses and eight partial responses.

Nearly all responders had ongoing responses, and eight responders had a duration of response of more than one year at the time of the data cut.

The treatment-emergent adverse event, or TEAE, profile was consistent with the underlying advanced disease and the known adverse event profiles of pembrolizumab, lymphodepletion and IL-2 regimens.

Our strategy is also supported by several NCI trials of TIL cell therapy that were conducted prior to approval of anti-PD-1 therapies.

In these trials, ORR was over 50% in anti-PD-1 naïve melanoma patients, and approximately 22-24% of patients had a complete response per RECIST 1.1.

Most complete responses remained ongoing in three to seven years of follow up.

Combination Therapy with Lifileucel for Frontline Advanced Melanoma

We estimate a global addressable market of more than 70,000 frontline advanced melanoma patients per year.

Despite current treatment options, more than 50% of patients treated for frontline advanced melanoma experience disease progression within 12 months.

Our strategy in frontline advanced melanoma is to study the combined response rates and durability of lifileucel with pembrolizumab.

As of May 2024, lifileucel in combination with immune checkpoint inhibitor, or ICI therapy in IOV-COM-202 Cohort 1A demonstrated a 65% ORR, including a 30% complete response rate, by RECIST 1.1, and 65% progression-free survival, or PFS, at months 6 and 12.

The median PFS and mDOR were not reached at 21.7 months of median follow-up.

The treatment-emergent adverse event, or TEAE, profile was consistent with the underlying advanced disease, pembrolizumab, lymphodepletion and IL-2.

The safety profile is differentiated from ICI combination therapies, with late AEs that were consistent with pembrolizumab monotherapy.

Following the U.S.

accelerated approval of Amtagvi ® in previously treated advanced melanoma, our confirmatory trial, TILVANCE-301, is designed to support a registrational path for lifileucel in combination with pembrolizumab in frontline advanced, or unresectable or metastatic, melanoma as well as to support full U.S.

approval for Amtagvi ® in post-anti-PD-1 advanced melanoma.

We reached agreement with the FDA on the TILVANCE-301 clinical trial design.

TILVANCE-301 is a Phase 3 multicenter, open-label, clinical trial that will randomize approximately 670 patients with frontline advanced melanoma in patients who are naive to therapy for metastatic disease.

The trial was designed with the FDA and EMA input to assess contribution of components for lifileucel and pembrolizumab compared with pembrolizumab alone, with dual primary endpoints of ORR and progression free survival, or PFS, by blinded independent review committee.

Lifileucel for Previously Treated Advanced Melanoma

We continue to investigate lifileucel in previously treated advanced melanoma patients in the clinical setting, primarily outside the U.S.

in markets where we are seeking additional approvals.

IOV-MEL 202 is a single-arm, multicenter Phase 2 trial to investigate lifileucel in patients previously treated with anti-PD-1 therapy and includes second-line lifileucel therapy in BRAF positive patients without prior BRAF/MEK inhibitor therapy.

Lifileucel for Advanced, or Metastatic or Unresectable NSCLC

According to the SEER program estimates, approximately 234,580 people were diagnosed with lung and bronchus cancers, and approximately 125,070 deaths occurred related to these cancers in the U.S.

Patients previously treated with standard of care chemo-immunotherapy have a poor prognosis, limited treatment options, and a real-world overall survival of less than six months.

We are developing lifileucel alone and in combination with approved therapies to treat advanced NSCLC in the IOV-LUN-202 and IOV-COM-202 clinical trials.

We estimate an addressable market in our initial target indication of previously treated nonsquamous, or NSQ, metastatic NSCLC, or mNSCLC, without ALK, ROS or epidermal growth factor receptor, or EGFR, mutations of more than 315,000 patients per year in global target markets, including 50,000 U.S.

Following initial treatment with immune checkpoint inhibitor, or ICI, and chemotherapy, previously treated with standard of care chemo-immunotherapy have a poor prognosis, limited treatment options

with limited durability, and a real-world overall survival of less than six months.

In this treatment setting, standard-of-care docetaxel monotherapy recently showed an ORR of 12.8%, without any complete responses, an mDOR of 5.6 months and OS of 12.3 months.

We are investigating lifileucel as a monotherapy and in combination with approved therapies to treat mNSCLC in multiple patient populations and treatment settings with defined unmet need.

We believe the results from Iovance clinical trials support the potential benefit of one-time TIL cell therapy in previously treated patients with NSQ mNSCLC, as well as lifileucel in combination with ICIs in frontline advanced melanoma, including the opportunity for more durable responses.

IOV-LUN-202 Registrational Trial

IOV-LUN-202 is a single-arm, registrational trial investigating lifileucel in patients who have progressed on or after chemotherapy and anti-PD-1 therapy for advanced (unresectable or metastatic) NSCLC without epidermal growth factor receptor, or EGFR, ROS proto-oncogene receptor tyrosine kinase, or ROS, anaplastic lymphoma kinase, or ALK, genomic mutations and had received at least one line of an FDA-approved targeted therapy if indicated by other actionable tumor mutations.

IOV-LUN-202 includes two registrational patient cohorts (Cohorts 1 and 2) and two exploratory patient cohorts (Cohort 3 and 4).

The programmed death-ligand 1, or PD-L1, tumor proportion score, or TPS, in patients at the time they started frontline therapy was less than one percent or unknown in patients in Cohort 1 and greater than or equal to one percent in patients in Cohort 2.

In Cohort 3, TIL is extracted from core biopsy and manufactured using our Gen 3 process.

In Cohort 4, patients undergo surgical resection for TIL manufacturing prior to disease progression.

Based on the regulatory discussions and positive regulatory feedback received by the FDA regarding the design of the IOV-LUN-202 trial, we plan to enroll a total of approximately 120 patients into the registrational Cohorts 1 and 2 of the IOV-LUN-202 trial.

In July 2023, we announced a preliminary analysis of the IOV-LUN-202 trial from 23 NSCLC patients treated with lifileucel.

An objective response rate of 26.1% per RECIST 1.1 was observed in six patients, with one complete response and five partial responses, and a disease control rate of 82.6%.

While still early on study, the median duration of response, or DOR, was not reached.

The DOR ranged from 1.4+ months to 9.8+ months.

Treatment-emergent adverse events were consistent with the underlying disease and known adverse event profiles of non-myeloablative lymphodepletion and interleukin-2.

We also reported additional ongoing responses, and duration of response greater than six months for 71% of the confirmed responders in the trial, in an updated analysis from November 2023.

We believe the results from IOV-LUN-202 in previously treated patients with advanced NSCLC continue to support the potential benefit of one-time TIL cell therapy, including the opportunity for more durable responses than available second line chemotherapies.

The opportunity for TIL cell therapy in NSCLC is also supported by clinical results for lifileucel in heavily pre-treated patients with NSCLC in Cohort 3B of our IOV-COM-202 trial in solid tumors.

At the Society for Immunotherapy of Cancer, or SITC, in November 2021, we reported Cohort 3B results from 28 patients who had progressed on or after prior immune checkpoint inhibitor, or

ICI, therapy, including patients with oncogene-driven tumors who received prior tyrosine kinase inhibitor, or TKI, therapy.

The ORR was 21.4% per RECIST 1.1, including one complete response and five partial responses.

The complete response remained ongoing at 37 months following treatment in a subsequent data extract from November of 2022.

All Cohort 3B patients had received prior anti-PD-1/-L1 therapy, and all six responding patients had also received prior chemotherapy.

The TEAE profile was consistent with the underlying disease and known adverse event profiles of non-myeloablative lymphodepletion and IL-2.

On December 22, 2023, the FDA placed a partial clinical hold on the IOV-LUN-202 trial in response to a reported Grade 5 (fatal) serious adverse event, or SAE, potentially related to the non-myeloablative lymphodepletion pre-conditioning regimen.

In March 2024, the FDA lifted its partial clinical hold and we resumed enrollment in the IOV-LUN-202 trial.

A separate patient cohort, Cohort 3C, in IOV-COM-202 is investigating lifileucel in combination with ipilimumab or nivolumab in patients who previously received only a prior line of approved systemic ICI monotherapy.

Frontline NSCLC Development and Regulatory Strategy

In frontline NSCLC, our goal is to improve the current standard of care pembrolizumab maintenance therapy by administering TIL after completion of the initial chemo-immunotherapy.

This approach is supported by initial results from Cohort 3A in the IOV-COM-202 trial which is evaluating lifileucel in combination with pembrolizumab in patients who have not received prior immunotherapy, including ICIs, and will be further investigated in the IOV-COM-202 trial in two new cohorts, 3D and 3E.

In November 2024, we reported updated preliminary results from Cohort 3A in the IOV-COM-202 trial at the Society for Immunotherapy of Cancer Annual Meeting which continue to demonstrate robust response rates and durability for lifileucel in combination with pembrolizumab in NSCLC patients who were not previously treated with immune checkpoint inhibitor therapy.

A confirmed objective response was observed in 9 of 14 EGFR wild type patients, or 64.3%, including 6 of 11 patients, or 54.5%, who also had difficult-to-treat PD-L1 negative disease.

Median duration of response was not reached at a median study follow up of 26.5 months.

This data supports the opening of a new cohort, 3D, in the IOV-COM-202 trial to investigate lifileucel plus pembrolizumab following chemotherapy as part of frontline therapy for patients with EGFR wild type NSCLC, representing the majority of patients with an unmet medical need in this setting.

Gynecological Cancers

According to the SEER program estimates, in 2024, 67,880 women were diagnosed with uterine cancer and approximately 13,250 uterine cancer-related deaths occurred in the U.S.

Moreover, approximately 13,820 women were diagnosed with cervical cancer, and approximately 4,630 cervical cancer-related deaths occurred in the U.S.

Advanced endometrial cancer, the most common form of uterine cancer, represents a significant opportunity for TIL cell therapy.

Analogous to other tumor types, TIL cell therapy may offer benefit in the emerging treatment setting of patients who have no currently approved therapies for progression after post-anti-PD1 therapy and chemotherapy.

We began a Phase 2 trial of lifileucel in post-anti-PD-1 and post-chemotherapy advanced endometrial cancer, including mismatch repair, or MMR, deficient and MMR proficient patient populations in the first half of 2024.

Based on the TIL mechanism of action, the benefit of TIL cell therapy is likely to extend across patients with tumors that are MMR mechanism deficient and proficient.

The potential for TIL cell therapy in gynecological cancers is also supported by our clinical data for lifileucel alone and in combination with pembrolizumab in advanced cervical cancer.

C-145-04 is a Phase 2, multicenter pivotal clinical trial which evaluated lifileucel monotherapy in patients previously treated with chemotherapy or previously treated with chemotherapy and ICIs, lifileucel in combination with pembrolizumab in Cohort 3 included patients who had not received prior systemic therapy.

Following an assessment of the current treatment landscape in gynecological cancers, we are prioritizing endometrial cancer over cervical cancer.

We plan to continue to explore the use of TIL cell therapies in cervical cancer, including using genetically modified TIL products and using TIL products in combination with anti-PD-1/PD-L1 blocking antibody therapies in frontline cervical cancer, with the goal of returning to clinical development in the future.

One-time treatment with lifileucel has demonstrated a potentially best-in-class clinical profile in IOV-LUN-202 in previously treated NSQ mNSCLC.

IOV-LUN-202 is a single-arm, registrational, global phase 2 trial investigating one-time lifileucel monotherapy in mNSCLC patients previously treated with an ICI and chemotherapy and without EGFR, ROS proto-oncogene receptor tyrosine kinase 1, or ROS1, anaplastic lymphoma kinase, or ALK actionable genetic mutations.

In the two registrational patient cohorts, the programmed death-ligand 1, or PD-L1, tumor proportion score, or TPS, at the start of frontline therapy was less than one percent or unknown in Cohort 1 patients and greater than or equal to one percent in Cohort 2 patients.

We plan to enroll a total of approximately 80 NSQ NSCLC patients into registrational Cohorts 1 and 2 to support a supplemental biologics license application, or sBLA, to the U.S.

FDA for accelerated approval.

In November 2025, updated preliminary data in 39 evaluable patients demonstrated an ORR by RECIST v1.1 of 25.6%, a disease control rate of 71.8%, and mDOR was not reached after a median follow up of 25.4 months.

The safety profile was consistent with the underlying disease, non-myeloablative lymphodepletion, or “LD”, and interleukin-2, or IL-2.

FDA placed a partial clinical hold on the IOV-LUN-202 trial from the fourth quarter of 2023 into the first quarter of 2024.

All subsequent patients were enrolled to receive a reduced LD regimen that has resulted in a reduction of median post-IL-2 hospitalization days by more than half and lower incidence and shorter time to resolution of cytopenias compared with the standard LD regimen.

IOV-COM-202 Trial in Previously Treated and Frontline NSCLC

The IOV-COM-202 basket trial in solid tumors evaluated lifileucel in previously treated mNSCLC patients in Cohort 3B and lifileucel in combination with pembrolizumab in frontline mNSCLC patients in Cohort 3A.

Clinical results for Cohort 3B were published in Cancer Discovery and further support the opportunity for lifileucel in mNSCLC, with an ORR of 21.4% by RECIST v1.1 after two or more lines of therapy with ICI and chemotherapy.

As of November 2024, preliminary results from Cohort 1A demonstrated a confirmed ORR of 64.3% and mDOR was not reached at a median study follow up of 26.5 months in 14 patients with EGFR wild type NSCLC who had not received prior immunotherapy, including ICIs.

Endometrial Cancer

The Phase 2 IOV-END-201 trial is investigating lifileucel in patients with advanced endometrial cancer patients previously treated with ICI and chemotherapy, a setting with no approved therapies.

We continue to follow the currently enrolled patients and plan to provide an update following review of the initial dataset.

Soft Tissue Sarcomas

In February 2026, we announced that we plan to commence a single arm registrational trial in previously treated advanced undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma in the second quarter of 2026.

Next Generation Clinical Programs

IOV-3001 for the TIL Treatment Regimen

Dose escalation is underway in a Phase 1/2 clinical trial to investigate IOV-3001, a second-generation, modified interleukin-2 analog, for use in the TIL treatment regimen.

This recombinant fusion protein is designed to enhance TIL survival and cellular proliferation.

Preclinical studies of IOV-3001 demonstrated the potential for improved safety, convenience of less frequent dosing and strong effector T cell expansion.

IOV-4001 for Advanced Melanoma and NSCLC

We have a worldwide exclusive license from Cellectis that enables us to use certain TALEN ® technology addressing multiple gene targets in several cancer indications, to develop genetically edited and potentially more potent TIL cell therapies.

Our lead genetically modified TIL cell therapy, IOV-4001, utilizes this TALEN ® technology to inactivate the gene coding for PD-1.

We are investigating the safety and efficacy of IOV-4001 in IOV-GM1-201, a multicenter, first-in-human Phase 1/2 clinical trial in two patient cohorts.

Cohort 1 includes patients with advanced melanoma, who were previously treated with anti-PD-1/PD-L1 blocking antibody therapy and, in those patients with BRAF mutations, after BRAF/MEK inhibitor therapy.

In Cohort 2, we are investigating IOV-4001 in patients with metastatic NSCLC who have received no more than three prior lines of therapy, with or without oncogene driver mutations.

We treated the first patient with IOV-4001 in the third quarter of 2022 and the Phase 1 safety portion of the clinical trial is completed.

Additional Clinical Trials

We previously investigated the potential for TIL cell therapy in metastatic HNSCC.

The Phase 2 C-145-03 trial investigated lifileucel as monotherapy, using various manufacturing processes.

The trial began in June 2017 and closed in January 2021 after reaching its pre-specified enrollment target.

We also investigated lifileucel in combination with pembrolizumab in patients with HNSCC who are naïve to anti-PD-1 therapy in IOV-COM-202 Cohort 2A.

The results from Cohort 2A are supportive of our strategies to develop TIL cell therapy in combination with pembrolizumab in earlier treatment settings for solid tumor cancers.

We have also explored the potential for polyclonal T cell immunotherapies in blood cancers.

A first-in-human clinical trial, IOV-CLL-01, evaluated the safety and efficacy of IOV-2001, our polyclonal PBL therapy, in patients with relapsed or refractory chronic lymphocytic leukemia, or CLL, and small lymphocytic lymphoma, or SLL.

We have a worldwide exclusive license from Cellectis to certain TALEN ® technology to develop genetically edited and potentially more potent TIL cell therapies.

Our lead program, IOV-4001, utilizes TALEN ® to inactivate the gene coding for PD-1, restoring the ability of TIL cells to fight cancer.

The Phase 2 efficacy extension of a first-in-human clinical trial is investigating IOV-4001 in previously treated advanced melanoma or NSCLC.

IOV-5001 for Solid Tumors

IOV-5001 is genetically engineered to induce IL-12 expression to remodel the tumor microenvironment, or TME, into an immunosupportive state to enhance efficacy.

Tethered IL-12 is also expected to optimize safety.

An Investigational New Drug (IND) submission is planned in first half of 2026 to investigate IOV-5001 in a Phase 1/2 basket trial in solid tumors with large patient populations and significant unmet medical need.

Completed Clinical Trials

● Lifileucel in Advanced HNSCC :

Results were published in 2005 from a Phase 2 C-145-03 trial of lifileucel as a monotherapy and in combination with pembrolizumab in patients with advanced HNSCC.

● Lifileucel in Advanced Cervical Cancer :

An upcoming manuscript will publish results from the C-145-04 Phase 2 clinical trial of lifileucel as a monotherapy and in combination with pembrolizumab in patients with advanced cervical cancer.

● Peripheral Blood Lymphocytes, or PBL, Therapy :

A first-in-human clinical trial investigated a polyclonal PBL, therapy, in patients with relapsed or refractory chronic lymphocytic leukemia, or CLL, and small lymphocytic lymphoma, or SLL.

Manufacturing Processes

Iovance was founded to build upon the promise of TIL cell therapy that was previously demonstrated in single-center clinical trials at academic centers that have not been scalable or standardized to serve sizeable patient populations.

Our multicenter trials and manufacturing processes have transformed TIL cell therapy into a commercially viable treatment which many more patients with cancer can access.

Our internal research and process development team has innovated TIL manufacturing and processing.

Our initial Gen 1 manufacturing process modified the NCI’s original TIL manufacturing and processing so that it could be reproduced in a cGMP environment.

Gen 1 TIL expansion occurred over a 5-to-6-week period and produced a non-cryopreserved product.

Building upon initial success with the Gen 1 process, our proprietary Gen 2 technology introduced manufacturing and logistical efficiencies aimed at further optimizing treatment and streamlining distribution processes.

Gen 2 manufacturing takes about 22 days and produces a cryopreserved final product.

We currently use Gen 2 to manufacture our commercial product, Amtagvi ® , and in most ongoing Iovance clinical trials.

We are also committed to further improving and streamlining the processes for TIL cell therapy manufacturing and tumor sample collection.

Gen 2 Manufacturing Process

During the Gen 2 process, TILs are multiplied into the billions or 10 9 – 10 11 of TIL.

The process begins by collecting the patient’s tumor tissue by surgical biopsy for shipment to a central manufacturing facility, the i CTC or our CMO.

The tumor is fragmented to facilitate a clear path for TILs to leave the tumor tissue and placed in media that optimizes the growth of TIL rather than other cell types.

From days 0-11, cells grow slowly during the pre-rapid expansion, or pre-rep phase.

The rapid expansion phase occurs from days 11-22.

On Day 11, the cells are transferred to a larger bioreactor and feeder cells are introduced to further activate the TILs to proliferate.

On day 16, the TILs are harvested while maintaining a closed system before they are counted and placed into multiple bioreactors which are incubated one last time.

On day 22, TILs are filtered, washed, concentrated, and formulated with cryopreservation media before being placed in the final product bags and shipped back to the patient’s treatment center.

Our commercial product, Amtagvi ® , undergoes additional analytical and quality testing to meet certain criteria for commercial release prior to shipment to the ATCs.

Large-Scale Centralized Manufacturing for TIL Cell Therapies

The cell processing activities for our TIL cell therapies are conducted at centralized facilities under cGMP, using qualified equipment and materials.

We manufacture our commercial product, Amtagvi ® , at both our internal facility and a CMO to meet manufacturing capabilities and the current and expected demand for commercialization and clinical trials.

The i CTC is the first FDA-approved, centralized and scalable cGMP manufacturing facility dedicated to producing TIL cell therapies.

Through a manufacturing service agreement, or MSA, with WuXi Advanced Therapies, Inc., or WuXi, WuXi manufactures, packages, ships and handles quality assurance and quality control of our commercial product, Amtagvi ® , working closely with our employees.

Certain clinical trials for our investigational TIL cell therapies are also supported by CMOs.

These relationships are described in more detail in the Research, Development, Manufacturing, and License Agreements for TIL Cell Therapy section of this Annual Report on Form 10-K.

We expect to rely on our own manufacturing capabilities, together with other third parties, for the manufacturing and processing of commercial and investigational TIL cell therapy products to ensure sufficient capacity is available for commercial purposes and clinical trials.

As an alternative, we also believe that, given sufficient time to hire staff and increase production, we have the ability to move our production of commercial and investigational TIL cell therapy products entirely in-house.

We believe that all materials and components utilized in the production of the final TIL product are readily available from qualified suppliers.

Iovance has built upon the promise of TIL cell therapy at academic centers .

Our multicenter trials and centralized manufacturing processes have transformed TIL cell therapy into a scalable, commercially viable treatment to serve sizeable patient populations with solid tumor cancers .

Our proprietary , centralized, and scalable Gen 2 technology introduced manufacturing and logistical efficiencies aimed at optimizing treatment, streamlining distribution processes, and delivering a cryopreserved final product.

Gen 2 is the manufacturing process used for commercial Amtagvi ® and ongoing clinical trials of lifileucel.

We are committed to continuously improving and streamlining the processes for TIL cell therapy manufacturing and tumor sample collection.

Following a surgical biopsy to collect a patient’s tumor tissue, TIL cells are processed at our centralized manufacturing facility, the Iovance Cell Therapy Center, or i CTC.

The TIL cells are multiplied into the billions during two growth phases:

pre-rapid expansion, or slow growth, for the first 11 days and rapid expansion from days 11-22.

Milestones include day 11, when cells transfer to a larger bioreactor with feeder cells;

day 16, when TIL cells are harvested, counted, and incubated in multiple bioreactors;

and day 22, when TIL cells undergo cryopreservation and placement in final product bags.

The product undergoes analytical and quality testing before it is released and shipped to the patient’s authorized treatment center.

Research, Development, Manufacturing, and License Agreements for TIL Cell Therapy

WuXi Advanced Therapies, Inc.

Minaris Advanced Therapies

Manufacturing and Services Agreements

Since November 2016, we entered into various manufacturing services agreements with WuXi Advanced Therapies, Inc., and its parent company WuXi Apptec, Co.

Ltd, or collectively, WuXi, pursuant to which WuXi agreed to provide manufacturing and other services for two cGMP manufacturing suites for commercial, clinical manufacturing and related testing services.

Both suites are capable of use for the commercial manufacture of our products.

We do not utilize WuXi for the manufacture of our next generation therapies.

National Institutes of Health and the National Cancer Institute

In November 2016, we entered manufacturing services agreements, or MSAs, with WuXi Advanced Therapies, Inc., and its parent company WuXi Apptec, Co.

Ltd (collectively, “WuXi”).

Upon the acquisition of WuXi Advanced Therapies by Minaris Advanced Therapies (“Minaris”) in May 2025, we replaced WuXi with Minaris as the party of the MSAs.

Through the MSAs, Minaris

supplemented our internal capacity for Amtagvi ® and clinical lifileucel.

Following the transition of all Amtagvi /lifileucel manufacturing to our internal facility, the MSA terminated in the first quarter of 2026.

We do not utilize Minaris for the manufacture of our next-generation therapies.

National Institutes of Health, or NIH, and the National Cancer Institute, or NCI

Cooperative Research and Development Agreement

In August 2011, we signed a five-year Cooperative Research and Development Agreement, or CRADA, with the NCI to work on the development of adoptive cell immunotherapies in multiple solid tumor types, including unmodified TIL as a stand-alone therapy or in combination, improved methods for the generation and selection of TIL cell therapy with anti-tumor reactivity, and strategies for more potent TILs.

The CRADA has been amended since then to, among other things, extend the term of the CRADA, include new indications such as bladder, lung, triple-negative breast, and Human Papilloma Virus, or HPV, associated cancers and modify the focus on the development of unmodified TIL as a stand-alone therapy or in combination, the evaluation in clinical trials of strategies for development of more potent TILs, such as selection of CD39/69 double negative cells and the use of certain inhibitors or other reagents in TIL expansion cultures.

In July 2024, we and the NCI entered into a fourth amendment to the CRADA to extend its term by an additional five years to August 2029.

The fourth amendment also includes collaboration on preclinical and clinical development of enhanced tumor reactive TIL products for the treatment of a broad range of common epithelial cancers.

Pursuant to the terms of the CRADA, as amended, we were required to make quarterly payments of $0.5 million to the NCI for support of research activities through the end of 2024.

Commencing in 2025, we are required to make quarterly payments of $0.9 million to the NCI for the support of research activities through the end of the CRADA’s term.

To the extent we license patent rights relating to a TIL-based product candidate, we will be responsible for all patent-related expenses and fees, past and future, relating to the TIL-based product candidate.

We have a Cooperative Research and Development Agreement, or CRADA, with the NCI for the development of adoptive cell immunotherapies in multiple solid tumor types, including bladder, lung, and triple-negative breast cancers;

Human Papilloma Virus, or HPV, associated cancers and a broad range of epithelial cancers.

In August 2011, we signed a five-year CRADA for the development of products that included unmodified TIL as a stand-alone therapy or in combination, improved methods for the generation and selection of TIL cell therapy with anti-tumor reactivity, and strategies for more potent TILs.

Since then, the CRADA has been amended to extend the term and to include new indications and the use of certain inhibitors or other reagents in TIL expansion cultures.

In July 2024, a fourth amendment to the CRADA extended its term to August 2029 and included collaboration on development of enhanced tumor reactive TIL products in common epithelial cancers.

We are required to make quarterly payments to NCI to support research activities.

To the extent we license patent rights, we will be responsible for all patent-related expenses and fees, past and future.

In addition, we may be required to supply certain test articles, including TIL, grown and processed under cGMP conditions, suitable for use in clinical trials.

We or the NCI may unilaterally terminate the CRADA for any reason or for no reason, at any time, by providing written notice at least 60 days before the desired termination date.

Patent License Agreement Related to the Development and Manufacture of TIL Cell Therapies

We entered into an Exclusive Patent License Agreement, or the Patent License Agreement, with the National Institutes of Health, or NIH, an agency of the U.S.

Public Health Service within the Department of Health and Human Services, in 2011, as amended in 2015.

Pursuant to the Patent License Agreement, as amended, the NIH granted us licenses, including exclusive, co-exclusive, and non-exclusive licenses, to certain technologies relating to autologous tumor infiltrating lymphocyte adoptive cell therapy products for the treatment of metastatic melanoma, lung, breast, bladder, and HPV-positive cancers.

In May 2021, we entered into an Amended and Restated Patent License Agreement with NIH, which included the grant of additional exclusive, worldwide patent rights in the indications to interleukin-15 and interleukin-21 cytokine-tethered TIL technology, and expanded the non-exclusive, worldwide field of use to all cancers.

In August 2022, we entered into a Second Amended and Restated Patent License Agreement with NIH to include additional exclusive, worldwide patent rights to TIL products expressing interleukin-12, expanded rights to TIL selection technologies previously licensed under the Exclusive Patent License Agreement below, and additional non-exclusive, worldwide patent rights to certain technologies related to enhancing TIL potency.

The Second Amended and Restated Patent License Agreement requires us to pay royalties based on a percentage of net sales in jurisdictions where patent rights exist, which percentage can fall into a tier that may be less than one percent to mid-single digits depending upon certain events, including the exclusivity of the rights, and we expect lower overall royalty payments as a result.

We are also required to pay potential milestone payments on the achievement of certain clinical, regulatory, and commercial sales milestones for each of the exclusive indications and other direct costs incurred by the NIH pursuant to the Second Amended and Restated Patent License Agreement.

We have made and anticipate making additional milestone payments that could range from several hundred thousand dollars to the mid-single-digit millions of dollars in conjunction with certain development milestones, the approval of a BLA or its foreign equivalent, or the first U.S.

and foreign commercial sales of any of our product candidates covered by the Second Amended and Restated Patent License Agreement.

The term of the Second Amended and Restated Patent License Agreement continues until the expiry of the last-to-expire patent rights licensed thereunder, and the agreement contains standard termination provisions.

Exclusive Patent License Agreement Related to TIL Selection

In February 2015, we entered into an exclusive patent license agreement, or the Exclusive Patent License Agreement, with the NIH under which we received an exclusive worldwide license under the selected TIL patents.

This license was superseded and replaced by the Second Amended and Restated Patent License Agreement.

Lee Moffitt Cancer Center

Research Collaboration and Clinical Grant Agreement

In June 2020, we entered into a Sponsored Research Agreement, or the SRA, with the H.

Lee Moffitt Cancer Center, or Moffitt, with a term that ends either upon completion of the research thereunder or on July 1, 2022, whichever is sooner.

The SRA was then extended numerous times, most recently to May 31, 2025

The University of Texas M.D.

Anderson Cancer Center

Strategic Alliance Agreement

In April 2017, we entered into a Strategic Alliance Agreement, or the SAA, with the University of Texas M.D.

Anderson Cancer Center, or MDACC, under which we and MDACC agreed to conduct clinical and preclinical research studies.

We agreed in the SAA to provide total funding not to exceed approximately $14.2 million for the performance of the multi-year studies under the SAA.

In return, we acquired all rights to inventions resulting from the studies and have been granted a non-exclusive, sub-licensable, royalty-free, and perpetual license to specified background intellectual property of MDACC reasonably necessary to exploit, including the commercialization thereof.

We have also been granted certain rights to clinical data generated by MDACC outside of the clinical trials to be performed under the SAA.

The SAA’s term shall continue in effect until the later of the fourth anniversary of the SAA or the completion or termination of the research and receipt by us of all deliverables due from MDACC thereunder.

On March 28, 2024, we entered into the first amendment to the SAA, under which we and MDACC agreed to conduct additional preclinical research studies.

We or the NCI may unilaterally terminate the CRADA with prior written notice at least 60 days.

Patent License Agreements Related to TIL Cell Therapies

We entered into a patent license agreement, or the Patent License Agreement, with the NIH in 2011.

The Patent License Agreement was amended multiple times to include exclusive, co- and non-exclusive licenses to certain NIH technologies relating to autologous TIL adoptive cell therapy.

Pursuant to the Patent License Agreement, as amended, we are required to pay royalties and milestone payments.

Royalties are based on a percentage of less than one to mid-single digits of net sales, depending on certain events, in jurisdictions where patent rights exist.

Previous and anticipated potential future milestone payments range from several hundred thousand dollars to the mid-single-digit millions of dollars in conjunction with development, regulatory approvals, or the first U.S.

and foreign commercial sales of any of our product candidates covered by the Patent License Agreement, as amended.

The term of the Patent License Agreement, as amended, continues until the expiry of the last-to-expire licensed patent rights and contains standard termination provisions.

Cellectis S.A.

Research Collaboration and Exclusive Worldwide License Agreement

In December 2019, we entered into a research collaboration and exclusive worldwide license agreement whereby we will license gene-editing technology from Cellectis, a clinical-stage biopharmaceutical company, to develop TIL cell therapies that have been genetically edited, including a PD-1 inactivated product that we refer to as IOV-4001.

Financial terms of the license include annual license payments and development, regulatory and sales milestone payments from us to Cellectis, as well as royalty payments based on net sales of TALEN ® modified TIL products.

In December 2019, we entered into a research collaboration and exclusive worldwide license agreement for gene-editing technology from Cellectis, a clinical-stage biopharmaceutical company, to develop genetically edited TIL cell therapies, including a PD-1 inactivated product that we refer to as IOV-4001.

Financial terms include annual license payments;

development, regulatory and sales milestone payments;

as well as royalty payments based on net sales of TALEN ® modified TIL products, from us to Cellectis.

Novartis Pharma AG

License Agreement

In January 2020, we obtained a license from Novartis Pharma AG, or Novartis, to develop and commercialize an antibody cytokine engrafted protein, which we refer to as IOV-3001.

Under the agreement, we have paid an upfront payment to Novartis and may pay future milestones related to initiation of patient dosing in various phases of clinical development for IOV-3001 and approval of the product in the U.S., the European Union, or EU, and Japan.

Novartis is also entitled to low-to-mid single digit percentage royalties from commercial sales of the product.

In May 2023, as part of the completion of the acquisition of the worldwide rights to Proleukin®, or the Acquisition, we inherited two historical asset purchase agreements, one historical master cell bank license and working cell bank transfer agreement and one historical license agreement from Clinigen with Novartis AG, Novartis Pharma AG and Novartis Vaccines and Diagnostics, Inc.

pursuant to which, among other things, we may be required to make future milestone payments based on net sales (as defined in the relevant underlying agreements) in the U.S.

and the rest of world, which includes any and all sales outside of the U.S.

In January 2020, we obtained a license from Novartis Pharma AG, or Novartis, to develop and commercialize an antibody cytokine engrafted protein, designated as IOV-3001.

Under the agreement, we have paid an upfront payment to Novartis.

We may pay future milestones related to clinical development and approval of IOV-3001, as well as low-to-mid single digit percentage royalties from commercial sales, in the U.S., the European Union, and Japan.

In May 2023, upon our acquisition of worldwide rights to Proleukin ® , or the Acquisition, from Clinigen we inherited two historical asset purchase agreements with Novartis AG, Novartis Pharma AG and Novartis Vaccines and Diagnostics, Inc.

Pursuant to a master cell bank license and working cell bank transfer agreement and a license agreement, we may be required to make future milestone payments based on net sales, as defined in the relevant underlying agreements, in the U.S.

and the rest of world.

Boehringer Ingelheim Biopharmaceuticals GmbH

In May 2023, as part of the Acquisition, we inherited a manufacturing and supply agreement from Clinigen with Boehringer Ingelheim Biopharmaceuticals GmbH, or BI, pursuant to which BI will carry out the processing, manufacturing, and supply of Proleukin ® in unlabeled vials.

The term of this agreement is through October 2025, with automatic renewals for a period of two years unless terminated as permitted by the contract.

Under this agreement, we must purchase a minimum number of vials each calendar year at fixed prices determined by vial batch size.

In May 2023, as part of the Acquisition from Clinigen, we inherited a manufacturing and supply agreement with Boehringer Ingelheim Biopharmaceuticals GmbH, to carry out the processing, manufacturing, and supply of Proleukin ® in unlabeled vials through October 2025.

Automatic renewals are for a two-year period unless terminated.

In September 2025, the agreement was amended and extended, pursuant to which we must purchase a minimum number of vials each calendar year through December 31, 2028.

TIL Cell Therapy Landscape in Solid Tumors

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The immune system recognizes danger signals and responds to threats at a cellular level.

The most significant components of the cellular aspect of the adaptive immune response are T cells, or T lymphocytes, so called because they mature in the thymus and are distinguished from B-cells, which mature in the bone marrow.

T cells can be distinguished from other white blood cells by T cell receptors present on their cell surface.

These receptors contribute to tumor surveillance by helping T cells recognize infected as well as cancerous cells.

T cells are involved in both sensing and killing infected or cancerous cells, as well as coordinating the activation of other cells in an immune response.

T cells, or T lymphocytes, are the most significant cellular components of the adaptive immune response.

T cells are distinguished from other white blood cells by T cell receptors that contribute to tumor surveillance.

T cells are involved in sensing and killing infected or cancerous cells, as well activating other cells in an immune response.

Challenges for Cancer Immunotherapy

According to SEER, solid tumor cancers represent more than 90 percent of all cancers diagnosed in the U.S.

Despite progress over the past several decades, effective treatment of solid tumors continues to be challenging for several reasons, including:

(i) intratumoral heterogeneity, (ii) numerous mutations and tumor neoantigens, with <1% shared across patients and lack of clarity on which mutations or neoantigens are critical, and (iii) ability to adapt and evade treatments that target a single mutation.

In addition, the tumor itself and the tumor microenvironment can suppress the patient’s natural immune response.

When T cells with cancer-specific receptors are absent, present in low numbers, of poor quality, or rendered inactive by suppressive mechanisms employed by tumor tissue, the cancer can grow and spread to various organs.

In addition, certain standard of care treatments for cancer can be deleterious to T cells’ ability to kill cancer.

Advancing Immuno-Oncology with Our TIL Technology Platform

We believe that adoptive cell therapy, specifically the use of human polyclonal TIL cells to reengage the immune system, may be a significant advancement in the treatment of cancer.

Our TIL technology platform was validated by the first FDA approval of a TIL cell therapy and is potentially applicable to many solid tumor cancers.

This platform is focused on leveraging patient-specific cells to recognize and attack diverse cancer cells that are unique to each patient.

Unlike cell therapies that act on a single or small number of shared antigen targets common to certain tumors, TIL cell therapy is an individualized, polyclonal T cell therapy designed to target a variety of neoantigens that are unique to the patient or tumor .

Our initial strategy is to deliver our commercial product, Amtagvi ® , as well as investigational TIL cell therapies to patients with late-stage solid tumor cancers.

After infusion, TIL can potentially infiltrate the tumor to eliminate cancer cells, further proliferate in the body and potentially overcome several mechanisms of tumor escape to which endogenous T cells may be susceptible due to the immune-suppressive tumor microenvironment.

For earlier intervention, we are investigating our TIL cell therapy in combination with ICIs.

These ICIs seek to overcome one of the main escape mechanisms of cancer against an immune system attack.

TIL cell therapy and ICIs may work in combination to target and attack cancer cells while breaking down barriers for the immune system to mount a response.

The biotechnology and pharmaceutical industries put significant resources into developing novel and proprietary therapies for the treatment of cancer.

We compete with multiple entities who have developed and are developing immuno-oncology therapies, including large and specialty pharmaceutical and biotechnology companies, academic research institutions, other public and private research institutions, including universities and public and private research institutions in the U.S.

and Europe, as well as companies developing novel targeted therapies for cancer.

Universities and public and private research institutions in the U.S.

and Europe are also potential competitors.

For example, a Phase 3 M14TIL clinical trial comparing TIL to standard ipilimumab in patients with metastatic melanoma conducted in Europe by the Netherlands Cancer Institute, the Copenhagen University Hospital at Herlev, and the University of Manchester.

Results from the M14TIL clinical trial were presented at the European Society for Medical Oncology Congress in September 2022 and published in the New England Journal of Medicine in December 2022.

While these universities and public and private research institutions primarily have educational objectives, they may develop proprietary technologies that lead to other approved therapies or secure patent protection that we may need for the development of our technologies and products.

Due to the promising clinical therapeutic effect of competitor therapies in clinical trials, we anticipate substantial direct competition from other organizations developing therapies in our commercial and pipeline target indications.

In particular, we expect to compete with other new therapies for our lead indications developed by companies such as BioNtech, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Genmab, Immunocore, IO Biotech, Merck, Moderna, Pfizer, Regeneron Pharmaceuticals, and Replimune.

We also may compete with other T cell therapies in development, including therapies based on genetically engineered T cell receptors rendered reactive against tumor-associated antigens prior to their administration, other genetically engineered TIL products, and TIL products designed to be reactive to specific neoantigens, by companies such as AbelZeta Pharma, Achilles Therapeutics, Adaptimmune Therapeutics, Alaunos Therapeutics, Biosyngen, GRIT Biotechnology, Immatics, Immunocore, Intima Bioscience, KSQ Therapeutics, Lyell Immunopharma, Marker Therapeutics, Obsidian Therapeutics, TILT Biotherapeutics, and others.

To date, these technologies have been primarily applicable to hematologic malignancies, but their application in solid tumor indications may create competition with us.

We may also face competition from immunotherapy treatments offered by companies such as Amgen, AstraZeneca, Bristol-Myers Squibb, Merck, Pfizer, Regeneron Pharmaceuticals, Roche, and others.

We may also face competition from novel IL-2 treatments in development by Alkermes, ILToo Pharma, Merck, Nektar Therapeutics, Sanofi, Werewolf Therapeutics, and others.

Cancer can grow and spread when T cells with cancer-specific receptors are absent, low in quantity and quality, or rendered inactive by suppressive mechanisms.

Effective treatment of solid tumors is challenging for several reasons, including:

(i) intratumoral heterogeneity, (ii) <1% overlap of shared tumor neoantigens across patients;

(iii) lack of clarity on critical mutations or neoantigens, (iv) the immune system’s ability to evade treatments that target a single mutation (v) suppression of immune response by the tumor and tumor microenvironment and (vi) deleterious effect of certain treatments on T cells.

Advancing Immuno-Oncology with Our Iovance TIL Technology Platform:

Iovance TIL Technology Platform:

the Backbone of IO Therapy in Solid Tumors

We believe that Our TIL technology platform of individualized polyclonal cell therapies represents a significant advancement in the treatment of solid tumor cancers.

Unlike cell therapies that act on a single or small number of shared antigen targets common to certain tumors, TIL is an individualized, polyclonal T cell therapy designed to target a variety of patient-specific neoantigens .

This approach of polyclonal TIL cells to reengage the immune system is the basis for our first FDA-approved product and potentially applicable to many solid tumor cancers in multi-billion-dollar markets.

Infused TIL can potentially infiltrate the tumor to eliminate cancer cells, further proliferate, and overcome several mechanisms of tumor escape.

Our initial strategy is to address patients with previously treated solid tumor cancers.

For earlier intervention, we are investigating our TIL cell therapy to target and attack cancer cells in combination with immune checkpoint inhibitors, or ICIs, to break down barriers to mount an immune response.

Our portfolio includes our commercial products Amtagvi ® and Proleukin ® as well as our pipeline of investigational TIL cell therapies.

The biotechnology and pharmaceutical industries put significant resources into developing novel and proprietary cancer therapies.

Many of these companies and our other current and potential competitors have substantially greater research and development capabilities and financial, scientific, regulatory, manufacturing, marketing, sales, human resources, and experience than we do.

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and internationally.

Even with the regulatory approval for Amtagvi ® , the availability and price of our competitors’ products could limit the demand and

the price we are able to charge for our therapies.

Our competitors may obtain regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in competitors establishing a strong market position before we are able to enter the market.

Our portfolio includes our commercial products Amtagvi ® and Proleukin ® as well as our pipeline of investigational TIL cell therapies.

Currently, there are numerous companies that are developing various alternate treatments for advanced melanoma, NSCLC and other solid tumor cancers that we are seeking to address, including patients that have progressed after prior treatment with checkpoint

inhibitors and chemotherapy.

Accordingly, our TIL cell therapies face significant competition from multiple companies.

Even with the regulatory approval for Amtagvi ® , the availability and price of our competitors’ products could limit the demand and the price we are able to charge for our therapies.

We anticipate competition from several entities, as well as universities and research institutions, with current or emerging novel cancer therapies with promising clinical efficacy within immuno-oncology, novel IL-2 products and/or in our commercial and pipeline target indications.

These organizations include multiple entities within immuno-oncology, including large and specialty pharmaceutical and biotechnology companies across the following areas.

● New therapies in development for our lead indications.

Currently, there are numerous companies that are investigating various alternate treatments for advanced melanoma, NSCLC, and other solid tumor cancers that we are seeking to address, including patients that have progressed after prior treatment with checkpoint inhibitors and chemotherapy.

Accordingly, our TIL cell therapies face significant competition from multiple companies such as BioNtech, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Genmab, Immunocore, IO Biotech, Merck, Moderna, Pfizer, Regeneron Pharmaceuticals, and Replimune.

● Other genetically engineered T cell therapies and TIL products in development .

AbelZeta Pharma, Alaunos Therapeutics, Biosyngen, GRIT Biotechnology, Immatics, Immunocore, Intima Bioscience, KSQ Therapeutics, Marker Therapeutics, Obsidian Therapeutics, and others are developing T cell therapies based on genetically engineered T cell receptors rendered reactive against tumor-associated antigens, other genetically engineered TIL products, and TIL products designed to be reactive to specific neoantigens.

● Novel IL-2 treatments in development .

We may also face competition from novel IL-2 treatments in development by Alkermes, ILToo Pharma, Merck, Nektar Therapeutics, Sanofi, Werewolf Therapeutics, and others.

Universities and research institutions with proprietary technologies may secure approvals or patent protection that we may need for our technologies and products.

The Netherlands Cancer Institute, the Copenhagen University Hospital at Herlev, and the University of Manchester ran a Phase 3 M14TIL clinical trial comparing TIL to standard ipilimumab in patients with metastatic melanoma in Europe and published results in the New England Journal of Medicine in December 2022.

Mergers and acquisitions in the biotechnology and pharmaceutical industries may result in even more resources being concentrated among a smaller number of our competitors.

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patents related to TIL cell therapy, including patents directed to compositions and methods of treatment in a broad range of cancers, such as U.S.

11,141,434;11,141,438;

and 12,495,791.

More than 50 of these patents are related to our Gen 2 TIL manufacturing processes and have terms that we anticipate will extend to October 2037 or January 2038, not including any patent term extensions or adjustments that may be available.

Our owned and licensed intellectual property portfolio also includes patents and patent applications relating to TIL, marrow

infiltrating lymphocytes, or MIL, and peripheral blood lymphocyte, or PBL, therapies;

Our owned and licensed intellectual property portfolio also includes patents and patent applications relating to TIL, marrow-infiltrating lymphocytes, or MIL, and peripheral blood lymphocyte, or PBL, therapies;

frozen tumor-based TIL technologies;

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cytokine-tethered TIL cell therapies;

methods of using ICIs in combination with TIL cell therapies;

methods of using immune checkpoint inhibitor, or ICIs, in combination with TIL cell therapies;

TIL selection technologies;

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An IND is a request for authorization from the FDA to administer an investigational new drug product to humans.

The central focus of an IND submission is on the general investigational plan and the

protocol(s) for clinical trials.

The central focus of an IND submission is on the general investigational plan and the protocol(s) for clinical trials.

The IND also includes results of animal and in vitro studies assessing the toxicology, pharmacokinetics, pharmacology, and pharmacodynamic characteristics of the product;

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Informed consent must be received from each clinical trial subject prior to participation in a clinical trial.

Progress reports detailing the results of the clinical trials must also be submitted at least annually to the FDA and the IRB and more frequently if serious adverse events or other significant safety information is found.

Progress reports detailing the results of the clinical trials must

also be submitted at least annually to the FDA and the IRB and more frequently if serious adverse events or other significant safety information is found.

Regulatory authorities, the IRB, or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk, that the clinical trial is not being conducted in accordance with regulatory or IRB requirements, or that the clinical trial is unlikely to meet its stated objectives.

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These clinical trials are intended to establish the overall risk/benefit relationship of the investigational product and to provide an adequate basis for product approval.

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

Typically, one or more clinical studies are required by the FDA for product approval.

● Phase 4 - In some cases, the FDA may require, or companies may voluntarily pursue, additional clinical trials after a product is approved to gain more information about the product, known as post-approval requirements or commitments, respectively.

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Concurrently with clinical trials, companies may complete additional animal studies and develop additional information about the biological characteristics of the product candidate and must finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, must develop methods for testing the identity, strength, quality, and purity of the final product, or for biologics, the safety, purity and potency.

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

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In terms of the compliance deadline, the requirement to submit a diversity action plan applies to clinical studies for which enrollment begins 180 days after the final guidance is published, which was originally anticipated to occur in June 2025.

In January 2025, the draft guidance was removed from the FDA website, which may impact the eventual publication date of the final guidance, and as a result, may delay the compliance deadline beyond June 2025.

In January 2025, the draft guidance was removed from the FDA website, and reuploaded by court order, which has contributed to uncertainty regarding final timing and implementation.

During the development of a new therapeutic, a sponsor may be able to request a Special Protocol Assessment, or SPA, the purpose of which is to reach an agreement with the FDA on the Phase 3 clinical trial protocol design and analysis that will form the primary basis of product approval and an efficacy claim, as well as preclinical carcinogenicity trials and stability studies.

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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.

Also, under the FDA Reauthorization Act of 2017, beginning in 2020, sponsors submitting applications for product candidates intended for the treatment of adult cancer which are directed at

molecular targets that the FDA determines to be substantially relevant to the growth or progression of pediatric cancer must submit, with the application, reports from molecularly targeted pediatric cancer investigations designed to yield clinically meaningful pediatric clinical trial data, using appropriate formulations, to inform potential pediatric labeling.

Also, under the FDA Reauthorization Act of 2017, beginning in 2020, sponsors submitting applications for product candidates intended for the treatment of adult cancer which are directed at molecular targets that the FDA determines to be substantially relevant to the growth or progression of pediatric cancer must submit, with the application, reports from molecularly targeted pediatric cancer investigations designed to yield clinically meaningful pediatric clinical trial data, using appropriate formulations, to inform potential pediatric labeling.

The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.

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The FDA accepts applications for filing if it determines that the application is substantially complete to permit a substantive review.

The FDA may request additional information rather than accept a BLA for filing.

FDA may request additional information rather than accept a BLA for filing.

In this event, the application must be resubmitted with the additional information.

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The FDA may convene an advisory committee to provide clinical insight on application review questions.

Before approving a novel biologic, the FDA must either refer that biologic to an external advisory committee or provide, in an action letter, a summary of the reasons why the FDA did not refer the product candidate to an advisory committee.

Whether the FDA convenes an advisory committee depends on various factors, such as scientific and safety issued identified during review.

An advisory committee is typically a panel that includes clinicians and other experts, which review, evaluate, and make a recommendation as to whether the application should be approved and under what conditions.

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

The industry typically refers to this as the FDA approval of the manufacturing facility.

Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites to ensure compliance with cGCP.

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A Fast Track-designated product candidate may also qualify for Priority Review, under which the FDA sets the target date for FDA action on the BLA at six months after the FDA accepts the application for filing.

Priority Review is granted when there is evidence that the proposed product would be a significant improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of a serious condition.

Priority Review is granted when there is evidence that the proposed product would be a significant improvement in the safety or effectiveness of the treatment,

diagnosis, or prevention of a serious condition.

If criteria are not met for Priority Review, the application is subject to the standard FDA review period of 10 months after the FDA accepts the application for filing.

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providing timely advice to, and interactive communication with, the sponsor regarding the development of the drug to ensure that the development program to gather the nonclinical and clinical data necessary for approval is as efficient as practicable;

involving senior managers and experienced review staff, as

appropriate, in a collaborative, cross-disciplinary review;

involving senior managers and experienced review staff, as appropriate, in a collaborative, cross-disciplinary review;

assigning a cross-disciplinary project lead for the FDA review team to facilitate an efficient review of the development program and to serve as a scientific liaison between the review team and the sponsor;

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Any products for which we receive FDA approvals are subject to continuing regulation by the FDA, including, among other things, record-keeping requirements, reporting of adverse experiences with the product and deviations, annual reporting and monitoring and providing the FDA with updated safety and efficacy information, product sampling and distribution requirements, certain electronic records and signature requirements, fulfilling post-marketing clinical trial and REMS commitments, and complying with FDA promotion and advertising requirements, which include, among other things, standards for direct-to-consumer advertising, restrictions on promoting products for uses or in patient populations that are not described in the product’s approved uses or otherwise consistent with the FDA-approved product labeling (known as “off-label use”), limitations on industry-sponsored scientific and educational activities, rules regarding communication of health care economic information regarding biopharmaceutical products to payors and formularies, and requirements for promotional activities involving the internet.

Although physicians may prescribe legally available products for off-label use, if they deem such use to be appropriate in their professional medical judgment, manufacturers may not market or promote such off-label uses.

Although physicians may prescribe legally available products for off-label use, if they deem such use to be appropriate in their professional medical judgment, manufacturers

may not market or promote such off-label uses.

In the past several years, certain court decisions have impacted FDA’s enforcement activity regarding off-label promotion in light of First Amendment considerations;

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Product identifier information, an aspect of the product tracing scheme, is required.

although this situation may continue to evolve.

The DSCSA requirements, development of standards, and the system for product tracing have been and will continue to be phased in over a period of years, with the FDA indicating that it would permit certain exemptions and exclusions, and exercise enforcement discretion on certain aspects of the law including, most recently, through policies establishing an additional stabilization period to support implementation of interoperable electronic tracing at the package level, and the FDA’s enforcement approach may continue to evolve.

The distribution of product samples continues to be regulated under the PDMA, and some states also impose regulations on drug sample distribution.

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Orphan Drug Designations

During 2015, we received ODD for lifileucel in the U.S.

to treat malignant melanoma stages IIB-IV, and in 2018, we received an ODD for lifileucel for the treatment of cervical cancer with a tumor size of greater than 2 cm in diameter.

We have received ODD for lifileucel in the U.S.

to treat malignant melanoma stages IIB-IV in 2015 and to treat cervical cancer with a tumor size of greater than 2 cm in diameter in 2018.

If approved, an ODD provides seven years of market exclusivity in the U.S., which means that the FDA may not approve any other applications, including a full BLA, to market the same biologic, as sameness is defined in the FDA’s regulations, for the same indication for seven years, subject to certain limited exceptions.

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Fast Track Designations

In August 2017, we announced that the FDA had granted Fast Track designation for lifileucel for the treatment of advanced metastatic melanoma.

In February 2019, we announced that the FDA had granted Fast Track designation for lifileucel in the treatment of metastatic cervical cancer.

Additionally, in November 2021, we announced that the FDA granted Fast Track designation for lifileucel in combination with pembrolizumab for the treatment of ICI-naïve metastatic melanoma.

The FDA’s Fast Track process is designed to facilitate the development and expedite the review of drugs that treat serious conditions and fill an unmet medical need.

The FDA granted Fast Track designation, or FTD, for lifileucel for the treatment of advanced metastatic melanoma and cervical cancers in 2017 and 2019, respectively, as well as lifileucel in combination with pembrolizumab for the treatment of ICI-naïve metastatic melanoma in 2021.

The FDA also granted fast track designation for lifileucel for the treatment of adults with metastatic NSQ NSCLC that has progressed on or after chemo- and anti-PD-1 therapies and at least one line of FDA-approved targeted therapy, if indicated, for actionable tumor mutations excluding ALK, ROS1 and EGFR.

Fast Track designation allows more frequent meetings and communications with the FDA to discuss the drug’s development plans and review process.

The Fast Track designation also allows for the possibility for rolling review of a BLA by FDA, where the FDA may consider beginning review portions of a marketing application before the full submission is complete, and also potential eligibility if certain criteria are met for accelerated approval.

The Fast Track designation also allows for the possibility for rolling review of a BLA by the FDA, where the FDA may consider beginning to review portions of a marketing application before the full submission is complete, and also potential eligibility if certain criteria are met for accelerated approval.

Regenerative Medicine Advanced Therapy Designation

In October 2018, we announced that the FDA had granted RMAT designation for lifileucel for the treatment of patients with metastatic melanoma.

The RMAT designation is based on data provided to the FDA from our C-144-01 trial.

RMAT designation is granted for regenerative medicine drugs and allows for increased access to FDA during development.

Under this designation, surrogate endpoints can be used to receive approval for a product, accelerated approval may be granted, and a rolling review of a BLA may be permitted by FDA.

The FDA granted RMAT designation for lifileucel for the treatment of patients with metastatic melanoma in 2018, based on data provided to the agency from our C-144-01 trial.

Under this designation, surrogate endpoints can be used to support approval, accelerated approval may be granted, and a rolling review of a BLA may be permitted by FDA.

Breakthrough Therapy Designation

In May 2019, we announced that the FDA had granted BTD for lifileucel for the treatment of patients with metastatic cervical cancer.

The BTD was granted based on data provided to the FDA from our C-145-04 clinical trial.

Under a BTD, the FDA may take actions that help expedite the development and review of the application for a product candidate, including seeking to provide timely advice and interactive communications to the sponsor with intensive guidance during development, to help the sponsor design and

conduct a more efficient development program.

Product candidates with BTD may be suitable for alternative clinical trial designs when scientifically appropriate, which may result in smaller clinical trials or more efficient clinical trials that require less time to complete.

BTD also allows the sponsor to submit portions of the BLA on an ongoing basis for rolling review.

In addition, BTD status allows for the potential to request priority review of our BLA at the time of BLA submission if supported by clinical data.

The clinical evidence needed to support breakthrough designation is preliminary, and the FDA has authority to rescind a BTD if a product candidate no longer meets the qualifying criteria.

Under a BTD, the FDA may take actions that help expedite the development and review of a product candidate application, including seeking to provide timely advice and interactive communications to the sponsor with intensive guidance during development, to help the sponsor design and conduct a more efficient development program.

The FDA granted BTD for lifileucel for the treatment metastatic cervical cancer in 2019, based on data provided to the agency from our C-145-04 clinical trial.

Product candidates with BTD may be suitable for alternative clinical trial designs, which may result in smaller or more efficient clinical trials.

BTD also allows the sponsor to submit portions of the BLA for rolling review.

In addition, BTD status allows for the potential priority review at the time of BLA submission if supported by clinical data.

The BTD is supported by preliminary clinical evidence, and the FDA may rescind a BTD if a product candidate no longer meets the qualifying criteria.

Under the Orphan Drug Act, the FDA may grant ODD to a drug or biologic intended to treat a rare disease or condition, defined as a disease or condition with a patient population of fewer than 200,000 individuals in the U.S., or a patient population greater than 200,000 individuals in the U.S.

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The biosimilar product sponsor and reference product sponsor may, but are not required to, exchange certain patent and product information for the purpose of negotiating and determining the scope of patent litigation, including the patents to be asserted and challenged.

Based on the outcome of negotiations surrounding the exchanged information, the reference product sponsor may bring a patent infringement suit

and injunction proceedings against the biosimilar product sponsor.

Based on the outcome of negotiations surrounding the exchanged information, the reference product sponsor may bring a patent infringement suit and injunction proceedings against the biosimilar product sponsor.

The biosimilar applicant may also be able to bring an action for declaratory judgment concerning the patent under certain circumstances.

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Further, a biosimilar product may be deemed interchangeable with a prior approved product if it meets the higher hurdle of demonstrating that it can be expected to produce the same clinical results as the reference product and, for products administered multiple times, the biologic and the reference biologic may be switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.

Pediatric Exclusivity and Patent Term Extension

Pediatric exclusivity is another type of non-patent marketing exclusivity in the U.S.

and, if granted, provides for the attachment of an additional six months of marketing protection to the term of any existing regulatory exclusivity.

Under the Best Pharmaceuticals for Children Act, a six-month exclusivity may be granted if a sponsor submits pediatric data that fairly responds to a written request from the FDA for such data.

The FDA may issue such a written request on its own initiative or at the request of the sponsor.

The data do not need to show the product to be effective in the pediatric population studied;

rather, if the clinical trial is deemed to fairly respond to the FDA’s request, the additional protection is granted.

If reports of requested pediatric studies are submitted to and accepted by the FDA, whatever regulatory periods of exclusivity that already cover the product are extended by six months.

Pediatric exclusivity is thus an “add-on” exclusivity and is unique in this regard among the various regulatory exclusivities provided by FDA.

The FDA can also require pediatric studies of a drug submitted in a new drug application if the FDA determines that the product is likely to be used in a substantial number of pediatric patients, or if the product would provide a meaningful benefit in the pediatric population over existing treatments.

This requirement may be waived in certain circumstances, for example, where the indication does not occur or is not highly prevalent in the pediatric population.

Patent Term Extension

If approved, biologics may also be eligible for periods of U.S.

patent term restoration.

If granted, patent term restoration extends the patent life of a single unexpired patent that has not previously been extended, for a maximum of five years.

patent term extension.

If granted, patent term extension restores the patent life of a single unexpired patent that has not previously been extended, for a maximum of five years.

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

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

Whether any of our product candidates will be eligible for patent term restoration is currently unknown.

Whether any of our product candidates will be eligible for patent term extension is currently unknown.

Even if any of our product candidates are found to be eligible for patent term protection, the applicable authorities may subsequently determine that we are not eligible for such restoration periods.

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To help reduce the increased risk of the introduction of adventitious agents, the PHSA emphasizes the importance of manufacturing controls for products whose attributes cannot be precisely defined.

The PHSA also provides authority to the FDA to immediately suspend licenses in situations where there exists a danger to public health, to prepare or procure products in the event of shortages and critical public health needs, and to authorize the creation and enforcement of regulations to prevent the introduction or spread of communicable diseases in the U.S.

The PHSA also provides authority to the FDA to immediately suspend licenses in situations where there exists a danger to public health, to prepare or procure products in the event of

shortages and critical public health needs, and to authorize the creation and enforcement of regulations to prevent the introduction or spread of communicable diseases in the U.S.

and between states.

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Other Healthcare Laws and Compliance Requirements

Our sales, promotion, medical education, and other activities following product approval are subject to regulation by numerous federal, state, and local regulatory and law enforcement authorities in the U.S., and in addition to the FDA, these entities may include the Federal Trade Commission, or the FTC;

Our business activities, including but not limited to, research, sales, promotion, marketing, distribution, medical education, sponsorships, relationships with prescribers and other referral sources are subject to regulation by numerous federal, state, and local regulatory and law enforcement authorities in the U.S., and in addition to the FDA, these authorities may include the Federal Trade Commission, or the FTC;

the Department of Justice;

the Centers for Medicare & Medicaid Services, or CMS;

other divisions of the Department of Health and Human Services;

various divisions of the U.S.

Department of Health and Human Services, or HHS, including the Centers for Medicare & Medicaid Services, or CMS, the Office of the Inspector General, or OIG, and the Health Resources and Services Administration, or HRSA;

and state and local governments.

Our promotional and scientific/educational programs must comply with laws and regulations such as the federal Anti-Kickback Statute, or AKS;

These activities, including our promotional and scientific/educational programs, must comply with laws and regulations such as the federal Anti-Kickback Statute, or AKS;

the civil monetary penalties statute, or the CMP Law;

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and other federal, state, and local laws similar to the foregoing.

The federal AKS prohibits, among other things, any person or entity, from knowingly and willfully offering, paying, soliciting, or receiving any remuneration, directly or indirectly, overtly or covertly, in cash or in kind, to induce or in return for purchasing, leasing, ordering, or arranging for the purchase, lease, or order of any item or service reimbursable under Medicare, Medicaid, or other federal healthcare programs, in whole or in part.

The term remuneration has been interpreted broadly to include anything of value.

The federal AKS has been interpreted broadly to apply to arrangements between pharmaceutical manufacturers on the one hand and prescribers, purchasers, and formulary managers on the other.

The term “remuneration” includes kickbacks, bribes, or rebates, and also has been broadly interpreted to include anything of value, including, for example, gifts, discounts, waivers of payment, ownership interest, and providing anything at less than its fair market value.

Additionally, the intent standard under the federal AKS provides that a person or entity need not have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

In addition, a claim including items or services resulting from a violation of the federal AKS constitutes a false or fraudulent claim for purposes of the federal civil FCA.

Our business activities must comply with numerous healthcare laws, including but not limited to, anti-kickback and false claims laws and regulations as well as data privacy and security laws and regulations, which are described below.

The federal AKS prohibits, among other things, any person or entity, from knowingly and willfully offering, paying, soliciting, or receiving any remuneration, directly or indirectly, overtly or covertly, in cash or in kind, to induce or in return for purchasing, leasing, furnishing, ordering, or arranging for or recommending the purchase, lease, furnishing, or order of any item or service reimbursable under Medicare, Medicaid, or other federal healthcare programs, in whole or in part.

The AKS has been interpreted broadly to apply to arrangements between pharmaceutical manufacturers on the one hand and prescribers, purchasers, formulary managers, and beneficiaries on the other.

The term “remuneration” has been interpreted broadly to include anything of value, including kickbacks, bribes, or rebates, gifts, discounts, waivers of payment, ownership interest, and providing anything at less than its fair market value.

Additionally, the intent standard under the AKS provides that a person or entity need not have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

In addition, a claim including items or services resulting from a violation of the AKS constitutes a false or fraudulent claim for purposes of the federal civil FCA.

There are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution or other regulatory sanctions.

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The exceptions and safe harbors are subject to change through legislative and regulatory action, are also subject to changes in interpretation and application by government agencies and courts, and we may decide to adjust our business practices from time to time.

The CMP Law establishes penalties that may be assessed against any person or entity who, among other things, is determined to have presented or caused to be presented a claim for payment, or approval, 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.

The FCA prohibits any persons from, among other things, knowingly presenting or causing to be presented false or fraudulent claims for payment to, or approval by the government, knowingly making or using, or causing to be made or used a false statement or record material in a claim to the government, or avoiding, decreasing, or concealing an obligation to pay money to the government.

A claim includes “any request or demand” for money or property presented directly or indirectly to the federal government.

The CMP Law establishes substantial monetary penalties that may be assessed against any person or entity, such as a pharmaceutical manufacturer, that engages in activities including, among others:

(1) knowingly presenting, or causing to be presented, a claim for services not provided as claimed or that is otherwise false or fraudulent in any way;

(2) arranging for or contracting with an individual or entity that is excluded from participation in federal healthcare programs to provide items or services reimbursable by a federal healthcare program;

(3) violations of the AKS;

or (4) failing to report and return a known overpayment.

The FCA prohibits any person or entity from, among other things, knowingly presenting or causing to be presented false or fraudulent claims for payment to, or approval by the government, knowingly making, using, or causing to be made or used a false statement or record material to a claim to the government, or avoiding, decreasing, or concealing an obligation to pay money to the government.

A claim includes “any request or demand” for money or property presented directly or indirectly to the government.

The civil FCA has been or might be used to assert liability on the basis of kickbacks and other improper referrals, improperly reported government pricing metrics such as Best Price and Average Manufacturer Price, improper promotion of uses not expressly approved by the FDA in a drug’s label, false statements associated with government grants, and allegations of misrepresentations with respect to services rendered, as well as claims for payment that are inaccurate or fraudulent, that are for services not provided as claimed, or for services that are not medically necessary.

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Civil FCA liability may also be imposed for Medicare or Medicaid overpayments caused by understated rebate amounts that are not refunded within 60 days of discovering the overpayment, even if the overpayment was not caused by a false or fraudulent act.

Actions under the FCA may be brought by the government or as a qui tam action by a private individual in the name of the government.

If the government intervenes in a qui tam action, and prevails, the qui tam plaintiff will share in the proceeds from damages and fines or settlement funds.

If the government declines to intervene, the qui tam plaintiff may pursue the case alone.

Actions under the FCA may be brought by the government or by a private individual in the name of the government, called “qui tam” actions.

If the government intervenes in a qui tam action and prevails in the lawsuit, the qui tam plaintiff will share in the proceeds from damages and fines or settlement funds.

If the government declines to intervene, the qui tam plaintiff may pursue the case alone, subject to governmental review and certain approvals.

Qui tam complaints are filed under seal, and the cases may progress for a number of years before a complaint is unsealed and a manufacturer becomes aware of its existence.

FCA lawsuits against pharmaceutical companies have increased significantly in volume and breadth in recent years, leading to several substantial civil and criminal settlements, focusing on activities such as certain sales practices and promoting off-label drug uses.

Violations of the FCA can result in significant monetary penalties and treble damages.

The government may further prosecute conduct

under the criminal FCA, which prohibits the making or presenting of a claim to the government knowing the claim to be false, fictitious or fraudulent.

The government may further prosecute conduct under the criminal FCA, which prohibits the making or presenting of a claim to the government knowing the claim to be false, fictitious, or fraudulent.

Unlike the civil FCA, conviction requires proof of intent to submit a false claim.

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Payment or reimbursement of prescription drugs by Medicaid or Medicare requires manufacturers of the drugs to submit pricing information to CMS.

The Medicaid Drug Rebate statute requires manufacturers to calculate and report price points, which are used to determine Medicaid rebate payments shared between the states and the federal government and Medicaid payment rates for the drug.

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

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

A Department of Defense regulation requires manufacturers to provide this discount on drugs dispensed by retail pharmacies when paid by the TRICARE Program.

All these price reporting requirements create the risk of submitting false information to the government, and potential FCA liability.

The VHCA also requires manufacturers of covered drugs participating in the Medicaid program to enter into Federal Supply Schedule contracts with the VA through which their covered drugs must be sold to certain federal agencies at FCP and to report pricing information.

A Department of Defense regulation requires manufacturers to provide this discount through prescription rebates on drugs dispensed by retail pharmacies when paid by the TRICARE Program.

These price reporting requirements create a risk of submitting false information to the government and potential FCA liability.

pricing information.

This necessitates compliance with applicable federal procurement laws and regulations and subjects us to contractual remedies as well as administrative, civil, and criminal sanctions.

In addition, the VHCA requires manufacturers participating in Medicaid to agree to provide different mandatory discounts to certain Public Health Service grantees and other safety net hospitals and clinics.

The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which imposes criminal and civil penalties, prohibits, 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, any healthcare benefit program, regardless of whether the payor is public or private third-party, 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.

Manufacturers can be audited by HRSA and be subjected to civil monetary penalties for knowingly and intentionally overcharging covered entities for drugs.

The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, imposes criminal and civil penalties and prohibits, 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, any healthcare benefit program, regardless of whether the payor is public or private, 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.

A person or entity does not need to have actual knowledge of the statute, or the specific intent to violate it, to have committed a violation.

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

While we would not be a “covered entity” under HIPAA, it is possible that we may enter into a service or business arrangement that would cause us to serve as a “business associates,” defined as a person or entity that performs certain functions or activities that involve the use or disclosure of protected health information in connection with providing a service for or on behalf of, or provide services to, a covered entity.

HITECH Act also increased the civil and criminal penalties that may be imposed against covered entities, business associates, and possibly other persons and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions.

In addition, state laws govern the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the same effect.

The Department of Health and Human Services Office of Civil Rights, or the OCR, has increased its focus on compliance and continues to train state attorneys general for enforcement purposes.

HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, or the HITECH Act, and their respective implementing regulations, including as such regulations were amended by the final omnibus rule published on January 25, 2013, and subsequent rulemaking, imposes specific requirements relating to the privacy, security, and transmission of individually identifiable health information held by “covered entities” and their “business associates.” While we would not be a covered entity under HIPAA, it is possible that we may enter into a service or business arrangement that would cause us to serve as a business associates, defined as a person or entity that performs certain functions or activities that involve the use or disclosure of protected health information in connection with providing a service for or on behalf of, or provide services to, a covered entity.

The HITECH Act also increased the civil and criminal penalties that may be imposed against covered entities, business associates, and possibly other persons and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions.

In addition, other federal and state laws may govern the privacy and security of health and other information in certain circumstances and may differ from each other in significant ways and may not have the same effect.

The Department of Health and Human Services Office of Civil Rights, or the OCR, state attorneys general, and other regulators have increased their focus on compliance and enforcement.

Even for entities that are not deemed “covered entities” or “business associates” under HIPAA, according to the FTC, failing to take appropriate steps to keep consumers’ personal information secure constitutes unfair acts or practices in or affecting commerce in violation of Section 5(a) of the Federal Trade Commission Act, or the FTCA, 15 USC § 45(a).

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Medical data is considered sensitive data that merits stronger safeguards.

The FTC's guidance for appropriately securing consumers' personal information is similar to what is required by the HIPAA Security Rule.

In addition to the laws discussed above, we may see more stringent state and federal privacy legislation in 2025 and beyond, as a continued increase in cyber-attacks have heightened attention to data privacy and security in the U.S.

The FTC's guidance for appropriately securing consumers' personal information is similar to what is required by the HIPAA Security Rule under the 340B Drug Pricing Program and report the ceiling price to HRSA within HHS.

Manufacturers can be audited by HRSA and be subjected to civil monetary penalties for knowingly and intentionally overcharging covered entities for drugs.

In addition to the laws discussed above, we may see more stringent state and federal privacy legislation in coming years, as a continued increase in cyber-attacks have heightened attention to data privacy and security in the U.S.

and other jurisdictions.

We cannot predict where new legislation might arise, the scope of such legislation, or the potential impact to our business and operations.

Payments made to physicians and other healthcare providers, and other financial interests, have been the subject of a range of federal and state laws.

Payments made to physicians, other HCPs, their family members, and other financial interests, have been the subject of a range of federal and state laws.

The federal physician payment transparency requirements, sometimes referred to as the Physician Payments Sunshine Act, or the Sunshine Act, was created under the Patient Protection and Affordable Care Act, or the ACA, and implemented as the Open Payments Program.

The Sunshine Act, among other things, imposes reporting requirements on drug manufacturers for payments or other transfers of value made by them to physicians and teaching hospitals, as well as ownership and investment interests held by physicians, other healthcare providers, and their immediate family members.

The Sunshine Act, among other things, imposes reporting requirements on drug manufacturers and certain others for payments or other transfers of value made by them to physicians and teaching hospitals, as well as ownership and investment interests held by physicians, other HCPs, and their immediate family members.

Failure to submit required information may result in civil monetary penalties of up to an aggregate of $150,000 per year and up to an additional aggregate of $1 million per year for “knowing failures,” for all payments, transfers of value, or ownership or investment interests that are not timely, accurately, and completely reported in an annual submission.

The Sunshine Act requires applicable manufacturers to track payments and transfers of value to physicians, physician assistants, nurse practitioners, and other mid-level HCPs.

The Sunshine Act requires applicable manufacturers to track payments and transfers of

value to physicians, physician assistants, nurse practitioners, and other mid-level HCPs.

Additionally, certain states also mandate implementation of commercial compliance programs, impose restrictions on drug manufacturer marketing practices, and/or require the tracking and reporting of gifts, compensation, and other remuneration to physicians and other HCPs.

Analogous state laws and regulations, such as state anti-kickback and false claims laws, and other state laws addressing the pharmaceutical and healthcare industries, which may apply to items or services reimbursed by any third-party payor, including commercial insurers, and in some cases, may apply regardless of payor, i.e., even if reimbursement is not available.

Some state laws require pharmaceutical companies to comply with the pharmaceutical industry's voluntary compliance guidelines, known as the Pharmaceutical Research and Manufacturers of America Code, and the relevant compliance program guidance promulgated by the federal government in addition to requiring drug manufacturers to report pricing and marketing information, including, among other things, information related to gifts, payments, or other remuneration to physicians and other healthcare providers or marketing expenditures, state and local laws that require the registration of pharmaceutical sales representatives, and state laws governing the privacy and security of health information and the use of prescriber-identifiable data in certain circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

For example, California enacted the California Consumer Privacy Act, or CCPA, which went into effect on January 1, 2020, and was subsequently amended and expanded by the California Privacy Rights Act, or CPRA, passed on November 3, 2020.

The CPRA’s substantive provisions took full effect as of January 1, 2023, including the CPRA’s expansion of the “Right to Know” that impacts personal information collected on or after January 1, 2022.

Some state laws require pharmaceutical companies to comply with the pharmaceutical industry's voluntary compliance guidelines, known as the Pharmaceutical Research and Manufacturers of America Code, and the relevant compliance program guidance promulgated by the federal government in addition to requiring drug manufacturers to report pricing and marketing information, including, among other things, information related to gifts, payments, or other remuneration to physicians and other HCPs or marketing expenditures, state and local laws that require the registration of pharmaceutical sales representatives, and state laws governing the privacy and security of health information and the use of prescriber-identifiable data in certain circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

For example, the California Consumer Privacy Act, or CCPA, which went into effect on January 1, 2020, and was subsequently amended and expanded by the California Privacy Rights Act, or CPRA, taking full effect as of January 1, 2023, including the CPRA’s expansion of the “Right to Know” that impacts personal information collected on or after January 1, 2022.

The CCPA and CPRA, among other things, create new data privacy obligations for covered companies and provide new privacy rights to California residents, including the right to opt out of certain disclosures of their information.

The CCPA also created a private right of action with statutory damages for certain data breaches, thereby potentially increasing risks associated with a data breach.

It remains unclear what, if any, additional modifications will be made to the CCPA and CPRA by the California legislature or how they will be interpreted.

Therefore, the effects of the CCPA and CPRA are significant and will likely require us to modify our data processing practices and may cause us to incur substantial costs and expenses to comply.

Additional modifications may continue to be made to the CCPA and CPRA by the California legislature and their interpretation by regulators may continue to evolve.

Since the passage of the CCPA, certain other states have passed similar laws that may also have similar impacts on our data processing practices and incurred costs.

Some of these state laws have not taken effect, and we cannot predict if states will subsequently amend those laws, if other states will pass similar laws, or the costs and expenses that we will incur to comply with such laws.

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 HCPs.

Some of these state laws or amendments to these laws are continuing to take effect, and we cannot predict if states will subsequently amend those laws, if other states will pass similar laws, or the costs and expenses that we will incur to comply with such laws.

Therefore, the effects of these state data protection laws are significant and will likely require us to modify our data processing practices and may cause us to incur substantial costs and expenses to comply.

Because of the breadth of these laws and the narrowness of the statutory exceptions and safe harbors available under such laws, it is possible that certain business activities could be subject to challenge under one or more of such laws.

The scope and enforcement of each of these laws is uncertain and subject to rapid change in the current environment of healthcare reform, especially in light of the lack of applicable precedent and regulations.

Federal and state enforcement bodies have recently increased their scrutiny of interactions between healthcare companies and healthcare providers, which has led to a number of investigations, prosecutions, convictions, and settlements in the healthcare industry.

Ensuring that business arrangements with third parties comply with applicable healthcare laws, as well as responding to possible investigations by government authorities, can be time- and resource-consuming and can divert management's attention from the business.

If our operations are found to be in violation of any of such health regulatory laws described above or any other governmental laws and regulations that apply to us, we may be subject to penalties, including, without limitation, civil, administrative, and criminal penalties, damages, fines, disgorgement, the curtailment or restructuring of our operations, exclusion from participation in federal and state healthcare programs, individual imprisonment, injunctions, private qui tam actions brought by individual whistleblowers in the name of the government, as well as additional reporting obligations and oversight if we become subject to a corporate integrity agreement or other agreement to resolve allegations of non-compliance with these laws, any of which could adversely affect our ability to operate our business and our financial results.

Federal and state enforcement bodies have recently increased their scrutiny of interactions among pharmaceutical companies, HCPs, and patients, which has led to a number of investigations, prosecutions, convictions, and settlements in the healthcare industry.

If our operations are found to be in violation of any of such health regulatory laws or regulations described above or any other governmental laws or regulations that apply to us, we may be subject to penalties or other enforcement actions, including, without limitation, civil, administrative, and criminal penalties, damages, fines, disgorgement, the curtailment or restructuring of our operations, exclusion from participation in federal and state healthcare programs, individual imprisonment, injunctions, private qui tam actions brought by individual whistleblowers in the name of the government, as well as additional reporting obligations and oversight if we become subject to a corporate integrity agreement or other agreement to resolve allegations of non-compliance with these laws, any of which could adversely affect our ability to operate our business and our financial results.

Coverage and Reimbursement

Sales of pharmaceutical products depend significantly on the availability of third-party coverage and reimbursement.

Third-party payors include Medicare, Medicaid, and other government programs at the federal and state level, managed care entities, private health insurers, and other organizations.

Third party payors decide which drugs they will pay for on behalf of their beneficiaries and establish reimbursement levels for health care services and products.

Although we currently believe that third-party payors will provide coverage and reimbursement for our products and product candidates, if approved, these third-party payors are increasingly challenging the price and examining the cost-effectiveness of medical products and services, with a recent focus on prioritization of “equivalent,” less expensive alternatives when available.

In addition, significant uncertainty exists as to the reimbursement status of newly approved healthcare products.

We may need to conduct expensive clinical trials to demonstrate the comparative cost-effectiveness of our products.

The products and product candidates that we develop may not be considered cost-effective.

It is time-consuming and expensive for us to seek coverage and reimbursement from third-party payors.

Sales of pharmaceutical products depend significantly on the availability and adequacy of coverage and reimbursement by third-party payors such as Medicare, Medicaid, and other government programs at the federal and state level, managed care entities, private health insurers, and pharmacy benefit managers, or PBMs.

Third-party payors decide the extent to which they will cover or reimburse for drugs on behalf of their beneficiaries and members and might not provide any coverage or reimbursement for a drug.

Third-party payors are increasingly challenging the price and examining the cost-effectiveness of medical products and services.

Reimbursement for newly approved healthcare products present significant uncertainty and may require expensive clinical trials to demonstrate the comparative cost-effectiveness of our products, and our products and product candidates might not be considered cost-effective.

Seeking coverage and reimbursement from third-party payors can be time consuming and expensive.

Moreover, a payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved, especially for products and product candidates such as ours, which are used in the inpatient setting, usually resulting in no separate reimbursement for pharmaceuticals.

There are additional pressures on pricing as a result of other, peripheral policies impacting reimbursement across both government and private payors.

Additional pressures on pricing as a result of other, peripheral policies may impact reimbursement across both government and private payors.

Non-health specific policies may impart downstream impacts on private insurance reimbursement decision-making.

In consideration of these numerous factors, reimbursement may not be available or sufficient to allow us to sell our products on a competitive and profitable basis.

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

Medicare “Part A” covers inpatient hospitalization and certain other settings, and Medicare “Part B” covers outpatient medical services, including limited outpatient prescription drugs.

Medicare coverage of drugs and biological products and payment rates to providers are established by federal law and regulations.

Medicaid is an insurance program for certain categories of low-income people, families and children, pregnant people, elderly people, and people with disabilities, and is both federally and state funded and managed by each state.

The federal government sets general guidelines for Medicaid and requires rebates on outpatient drugs and biological products, including those administered by physicians if the cost is billed separately.

Each state creates specific regulations that govern its individual program, including supplemental rebate programs that prioritize coverage for drugs on the state Preferred Drug List.

Government laws and regulations also establish price controls on prescription drugs purchased by government agencies that provide health care and certain federally funded hospital outpatient departments and clinics.

In the U.S., private health insurers and other third-party payors often provide reimbursement for products and services based on the level at which the government provides reimbursement through the Medicare or Medicaid programs for such products and services.

These restrictions and limitations influence the purchase of health care services and products.

In the case of government health care programs, coverage and reimbursement may vary from program to program, including Medicare, Medicaid, and Tricare.

Medicare is a federally funded program managed by CMS through local contractors that administer coverage and reimbursement for certain healthcare items and services for people over 65 years of age or older and certain people with disabilities, even if under age 65.

Medicaid is a jointly federally and state funded insurance program managed by the applicable state for certain categories of individuals that may vary from state to state, including low-income people, families and children, pregnant people, and people with certain disabilities.

Coverage for prescription drugs under these programs is subject to and limited by strict rules and conditions, including price controls.

In the U.S., private health insurers and other third-party payors may base their reimbursement for prescription drugs based on the level at which government healthcare programs provide reimbursement for such drugs.

These restrictions and limitations influence the purchase of drugs.

In addition, government programs like Medicaid include substantial penalties for increasing commercial prices over the rate of inflation, which can affect realization and return on investment.

The Medicare Prescription Drug, Improvement, and Modernization Act of 2003, or the MMA, established the Medicare Part D program to provide a voluntary prescription drug benefit to Medicare beneficiaries.

Under Part D, Medicare beneficiaries may enroll in prescription drug plans offered by private entities that provide coverage of outpatient prescription drugs.

While all Medicare drug plans must give at least a standard level of coverage set by Medicare, Part D plan sponsors are not required to pay for all covered Part D drugs, and each Part D plan can develop its own drug formulary that identifies which drugs it will cover and at what tier or level.

Despite this flexibility, Part D prescription drug formularies must include drugs within each therapeutic category and class of covered Part D drugs, though not necessarily all the drugs in each category or class and with some exceptions for certain classes of drugs.

Any formulary used by a Part D prescription drug plan must be developed and reviewed by a pharmacy and therapeutic committee.

Government payment for some of the costs of prescription drugs may increase demand for drugs for which we obtain marketing approval.

Any negotiated prices for any of our products covered by a Part D prescription drug plan may be lower than the prices we might obtain from other payers.

A manufacturer must participate in a federal program known as the 340B drug pricing program by entering into various programs for federal funds to be available to pay for the manufacturer’s drugs under Medicaid.

The 340B program requires a participating manufacturer to charge certain federally funded clinics and safety net hospitals no more than an established discounted price for its covered outpatient drugs, per a formula defined by statute to determine the discounted price, which is based on the AMP and the unit rebate amount as calculated under the Medicaid Drug Rebate Program, discussed further below.

Manufacturers must report pricing information to CMS for HRSA on a quarterly basis.

HRSA has also issued regulations relating to the calculation of the ceiling price as well as imposition of civil monetary penalties for each instance of knowingly and intentionally overcharging a 340B covered entity

The Inflation Reduction Act of 2022, or IRA, established substantial changes to the Medicare program with certain drug pricing reforms and a Medicare Part D benefit redesign.

For example, the IRA includes measures intended to lower the cost of prescription drugs and related healthcare reforms, such as limits on price increases and subjecting an escalating number of drugs to annual price negotiations with CMS.

Specifically, the IRA authorizes and directs HHS to set drug price caps for certain high-cost Medicare Part B and Part D qualified drugs, subject to an exclusion for certain orphan drugs, with negotiated pricing for limited drugs taking effect in 2026 with a second-year list being announced for 2027.

The IRA authorizes HHS to penalize pharmaceutical manufacturers that increase the price of certain Medicare Part B and Part D drugs faster than the rate of inflation.

Effective in 2025, the IRA also created significant changes to the Medicare Part D benefit design by capping Part D beneficiaries' annual out-of-pocket spending.

The impact of the IRA on the broader pharmaceutical industry remains to be seen.

Certain legal challenges from pharmaceutical manufacturers and others in the industry continue, including challenges to the constitutionality and administrative implementation of the IRA’s drug price negotiation provisions.

We cannot predict whether the IRA, in whole or in part, will be overturned, repealed, replaced, or amended.

In the U.S., Europe, and other potentially significant markets for our products and product candidates, government authorities and private third-party payors are increasingly attempting to limit or regulate the price of medical products and services, particularly for new and innovative products and therapies, which often has resulted in average selling prices lower than they would otherwise be.

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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 products and product candidates in whole or in part.

Healthcare Reform

and some foreign jurisdictions are considering enacting or have enacted a number of legislative and regulatory proposals to change the healthcare system in ways that could affect our ability to sell our products profitably.

Among policy makers and payors in the U.S.

and elsewhere, there is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality and/or expanding access.

In the U.S., the pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by major federal and state legislative initiatives.

In addition, other legislative and regulatory changes have been proposed and adopted since the ACA was enacted.

PBMs, rebates and pricing transparency are key areas of legislative and regulatory focus and there may be changes in the regulatory landscape that could have a significant impact on the pharmaceutical supply chain and drug pricing more generally, which could affect our business operations and prospects in unknown and material ways.

In addition, other legislative and regulatory changes have been proposed and adopted since the Affordable Care Act, or ACA, was enacted.

These changes include aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, starting in 2013, which will remain in effect through 2032 unless additional Congressional action is taken.

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Supreme Court decision, however, CMS subsequently modified its policies to restore certain payments owed to hospitals and to restore the reimbursement to the full, applicable rate going forward.

In recent years, there have been and continue to be proposals by the federal government, state governments, regulators, and third-party payors to control these costs and, more generally, to reform the U.S.

health care system.

Certain of these proposals could limit the prices we are able to charge for our products or the amounts of reimbursement available for our products.

These laws and future laws may result in additional reductions in Medicare and other healthcare funding, which could have a material adverse effect on customers for our products and product candidates, if approved, and, accordingly, our financial operations.

In recent years, there federal government, state governments, regulators, and third-party payors have implemented and continue to propose changes to control costs of healthcare, including pharmaceutical drugs.

Since the ACA was enacted, there have been amendments and additional laws and regulations, such as the IRA.

Additionally, on March 11, 2021, the American Rescue Plan Act of 2021 was signed into law, which eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, effective January 1, 2024.

Current and future health care reform proposals could limit the prices we are able to charge for our products or the amounts of reimbursement available for our products.

Individual states in the United States have also become increasingly active in implementing regulations designed to control pharmaceutical product reimbursement within state healthcare programs and payers, including price or patient reimbursement constraints, rebates and other price concessions, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and other purchasing approaches.

Future laws may result in additional reductions in third-party payer reimbursement, which could have a material adverse effect on customers for our products and product candidates, if approved, and, accordingly, our financial operations.

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

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For example, the centralized authorization procedure is compulsory for medicines produced by certain biotechnological processes.

Because our products are produced in that way, we would be subject to the centralized authorization procedure.

Because our products are produced in that way, we would be subject to the centralized authorization

Under the centralized procedure, pharmaceutical companies submit a single MAA to the European Medicines Agency, or the EMA.

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We consider our relationship with our employees to be good.

Our future performance depends significantly upon the continued service of our key scientific, technical and senior management personnel and our continued ability to attract and retain highly skilled employees.

We provide our employees with competitive salaries and bonuses, opportunities for equity ownership, development programs that enable continued learning and growth, career opportunities, and a robust employment package that promotes well-being across all aspects of their lives.

We provide our employees with competitive salaries and bonuses, opportunities for equity ownership, mentoring, and development programs that enable continued learning and growth, career opportunities, and a robust employment package that promotes well-being across all aspects of their lives.

In addition to salaries, these programs include potential annual discretionary bonuses, stock awards, Employee Stock Purchase Plan, a 401(k) plan, healthcare and insurance benefits, health savings and flexible spending accounts, paid time off, family leave, and flexible work schedules, among other benefits.

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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