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Item 1. Business

2025-02-27 compared with 2024-02-28 · 312 added, 306 removed, 573 unchanged (52% of the section changed)

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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.

With the recent approval of our biologics license application, or BLA, 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.

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 is approved under accelerated approval based on an endpoint of overall response rate, or ORR.

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

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

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

Our multi-center trials, novel TIL products, manufacturing processes, facilities, and bioanalytical platforms have transformed TIL cell therapy into a commercially viable treatment, which many more patients with cancer can access.

We manufacture Amtagvi™ and our investigational TIL cell therapies using a centralized, scalable, and proprietary 22-day manufacturing process which rejuvenates and multiplies polyclonal T cells unique to each patient into the billions and yields a cryopreserved, individualized therapy.

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

We are investigating TIL monotherapies for patients with later stage disease who were previously treated with standard of care therapies and TIL combinations with standard of care therapies to potentially improve outcomes in patients who are earlier in their disease.

These trials include two ongoing registrational trials to support a supplementary BLA, or sBLA, of our TIL cell therapies in frontline advanced

melanoma and in advanced non-small cell lung cancer following standard of care chemo-immunotherapy.

We are also developing next generation therapies using TIL, such as genetically modified TIL cell therapy.

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.

Corporate Strategy

Be the global leader in innovating, developing and delivering TIL cell therapy

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.

Through the U.S.

launch of Amtagvi™ and the advancement of our pipeline, we are committed to continuous innovation in developing TIL cell therapy and optimizing 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

Our top priority is commercialization of Amtagvi TM in the U.S.

for the treatment of patients with post-anti-PD-1 advanced melanoma, for which we received FDA approval on February 16, 2024.

We have experienced marketing, payer access and distribution teams as well as a sales force with extensive experience in oncology and cell therapy.

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

More than half of the members of our field teams have prior cell therapy experience.

The four primary areas of our Amtagvi™ launch efforts include:

● onboarding of authorized treatment centers, or ATCs, for commercial launch, with the goal of activating 50 ATCs within 90 days of the BLA Prescription Drug User Fee Act, or PDUFA, date of February 24, 2024;

● collaboration with healthcare professionals, or HCPs, who will be administering our product;

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;

● ongoing and continuous communication with payors about the value of Amtagvi™.

Prepare for commercial manufacturing to meet forecasted 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.

To date, 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 Iovance Cell Therapy Center, or the i CTC, and by a contract manufacturing organization, or CMO.

We are building capacity to treat several thousands of cancer patients annually at the i CTC, which is the first centralized and scalable current Good Manufacturing Practice, or cGMP, manufacturing facility dedicated to producing TIL.

Located in Philadelphia, Pennsylvania, the 136,000 square feet i CTC is also among the largest cell therapy manufacturing facilities in existence.

Additional expansion at the i CTC is under way which will significantly increase this capacity.

The proximity of the i CTC to multiple airports facilitates delivery of TIL cell therapies to treatment centers, with the i CTC expected to cover logistics and delivery of TIL cell therapies in both North America and Europe.

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

We are also exploring future TIL manufacturing processes, as well as next-generation treatments and technologies, which may further streamline development timelines and costs.

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

In 2018, we began using our Gen 2 TIL manufacturing process, which reduced TIL manufacturing time to 22 days while producing a cryopreserved TIL product.

The Gen 2 process was used to manufacture Amtagvi TM for the clinical trial that supported FDA approval, and most of our ongoing clinical trials use the Gen 2 process.

Amtagvi TM is approved for commercial manufacturing at the i CTC.

In addition, our CMO is approved for additional capacity to supplement our internal manufacturing.

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.

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

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 MEK inhibitor.

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.

Amtagvi™ demonstrated deep and durable responses.

The primary efficacy analysis set included 73 patients from Cohort 4 who received the recommended Amtagvi™ dose from an approved manufacturing facility.

Among the 73 patients, 31.5% achieved an objective response by Response Evaluation Criteria in Solid Tumors, or RECIST 1.1, with a median duration of response not reached at 18.6 months follow-up;

43.5% of responses had a duration greater than 12 months.

Additionally, the supporting pooled efficacy set included a total of 153 patients from Cohort 4 and Cohort 2.

Among the 153 patients, 31.4% achieved an objective response by RECIST 1.1 with a median duration of response not reached at 21.5 months follow-up;

54.2% of responses had a duration greater than 12 months.

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

Based on the unmet need in post-anti-PD-1 advanced melanoma, as well as initial clinical data, Amtagvi™ previously received a Regenerative Medicine Advanced Therapy, or RMAT, designation from the FDA in 2018.

Amtagvi™ has a boxed warning for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment.

Warnings and precautions include treatment-related mortality, prolonged severe cytopenia, internal organ hemorrhage, severe infection, cardiac disorder, respiratory failure, acute renal failure, and hypersensitivity reactions.

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.

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

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.

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

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.

Patient-specific TIL are manufactured using our commercial Gen 2 manufacturing process.

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

Over the next 22 days, the cells are multiplied into the billions, so they can be returned to the patient to fight cancer cells.

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.

Additional details on the Gen 2 manufacturing process are provided in the Manufacturing Process section of our Annual Report on Form 10-K.

Treatment Regimen.

The patient’s cell therapy treatment begins with a preparative regimen of non-myeloablative lymphodepletion, or NMA-LD, to suppress the immunosuppressive tumor microenvironment, which we believe will enhance the efficacy of TIL cell therapy.

After NMA-LD, the patient is treated at the ATC with Amtagvi™, followed by a short course of up to six doses of Proleukin ® to promote T cell activity in the body after TIL infusion.

Until now, there were no FDA approved therapies in this treatment setting for advanced melanoma after anti-PD-1 therapy.

In May 2023, we acquired the worldwide rights to Proleukin ® (aldesleukin) 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,

allows Iovance to secure its supply chain and logistics surrounding TIL cell therapy administration, and lowers cost of goods and clinical trial expenses for Proleukin ® used with TIL cell therapies.

Proleukin ® is an IL-2 product used in the Amtagvi™ treatment regimen.

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

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

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 therapy are polyclonal or designed to target a variety of neoantigens that are unique to the patient or tumor.

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

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

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

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 frontline advanced melanoma patients who are naïve to anti-PD-1 therapy, we are investigating lifileucel in combination with pembrolizumab in the Phase 3 TILVANCE-301 clinical trial.

TILVANCE-301 is a randomized Phase 3 clinical trial intended to support registration in advanced frontline melanoma as well as to serve as a confirmatory trial for 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, by a blinded independent review committee.

● Non-Small Cell Lung Cancer:

In NSCLC, we are investigating LN-145 TIL cell therapy in two clinical trials in NSCLC patient populations with significant unmet need.

IOV-LUN-202 is a registrational clinical trial of LN-145 in advanced NSCLC patients who have progressed following chemotherapy and anti-PD-1 therapy.

The IOV-COM-202 trial in solid tumors also includes cohorts of NSCLC patients treated with LN-145 monotherapy and combination therapy.

● Gynecological Cancers:

We are planning to initiate a clinical trial for lifileucel TIL cell therapy in endometrial cancer to potentially address the unmet need for patients previously treated with anti-PD-1 therapy.

We also are exploring lifileucel in advanced cervical cancer in the C-145-04 multicenter Phase 2 clinical trial.

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, PD-1 inactivated TIL cell therapy, IOV-4001, entered a first-in-human Phase 1/2 clinical trial, IOV-GM1-201, in 2022 in patients with previously treated advanced melanoma and NSCLC.

IOV-4001 utilizes the gene-editing TALEN ® technology, licensed from Cellectis S.A., or Cellectis, to inactivate the gene coding for the programmed cell death protein-1, or PD-1.

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.

LN-145 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 patient cohorts with metastatic HNSCC.

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 and triple negative breast cancer.

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.

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.

Intellectual Property

We established leadership within the field of TIL cell therapy by building and augmenting a leading intellectual property portfolio developed internally and licensed from third parties.

We currently own more than 60 U.S.

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

Pending patent applications and granted patents cover the fields of TIL cell therapy, genetically edited TIL cell therapy, selected TIL cell therapy, small core or biopsy TIL cell therapy,

fresh or frozen tumor digest-derived TIL cell therapy, TIL and ICI combination therapy, marrow infiltrating lymphocytes, or MIL therapy, and PBL therapy.

We have established a leading intellectual property portfolio developed internally and licensed from third parties.

We currently own more than 250 granted or allowed U.S.

and international patents and patent applications pertaining to Amtagvi ® and other TIL-related technologies that are expected to provide Amtagvi ® with exclusivity into 2042.

More than 75 U.S.

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

Pending patent applications and granted patents cover the fields of TIL cell therapy, genetically edited TIL cell therapy, selected TIL cell therapy, small core or biopsy TIL cell therapy, fresh or frozen tumor digest-derived TIL cell therapy, TIL and ICI combination therapy, marrow infiltrating lymphocytes, or MIL therapy, and peripheral blood lymphocyte, or PBL, therapy.

We also license rights to a broad range of technologies related to our platforms.

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

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

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.

During the second quarter of 2023, the first patient was randomized in TILVANCE-301 in patients with unresectable or metastatic melanoma who have had no prior therapy for metastatic or unresectable disease.

TILVANCE-301 is a Phase 3 multicenter, open-label, randomized, parallel group, treatment clinical trial that will randomize approximately 670 patients to investigate lifileucel in combination with pembrolizumab in the experimental arm compared with pembrolizumab monotherapy in the control arm.

In the experimental arm, a tumor sample is procured from each patient for lifileucel manufacturing using the Gen 2 process.

Patients 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.

In 2022, 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.

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 update from April 2022 in Cohort 1A, we observed a 67% ORR in twelve patients per RECIST 1.1.

Eight patients had a confirmed objective response, including three complete responses and five partial responses.

Six responders had ongoing response, and five responders had a duration of response of more than one year at the time of the data cut.

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.

In January 2023, we disclosed that updated efficacy and safety results from nearly 20 patients treated in Cohort 1A remain consistent with previously reported Cohort 1A data and continue to support our strategy in frontline advanced melanoma.

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

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

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.

LN-145 for Advanced, or Metastatic or Unresectable NSCLC

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 our TIL cell therapy, LN-145, alone and in combination with approved therapies to treat advanced NSCLC in the IOV-LUN-202 and IOV-COM-202 clinical trials.

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.

IOV-LUN-202 Registrational Trial

IOV-LUN-202 is a single-arm, registrational trial investigating LN-145 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).

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.

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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 LN-145.

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%.

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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 of 2023.

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 LN-145 in heavily pre-treated patients with NSCLC (Cohort 3B) in 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 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.

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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.

We have paused enrollment and the LN-145 treatment regimen for new patients in IOV-LUN-202 during the clinical hold.

Patients previously treated with LN-145 in the IOV-LUN-202 trial continue to be monitored and followed according to the trial protocol.

While enrollment is currently paused due to an FDA-imposed clinical hold, enrollment is expected to be completed in 2025.

We are working closely with the FDA to safely resume enrollment in the IOV-LUN-202 trial as soon as possible in 2024.

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

We are preparing to meet with the FDA in 2024 to discuss a randomized confirmatory trial of LN-145 in frontline advanced NSCLC patients.

This confirmatory trial in frontline advanced NSCLC is expected to be well underway at the time of a potential approval of LN-145 in advanced post-anti-PD-1 NSCLC.

Our goal is to improve frontline NSCLC therapy by adding TIL cell therapy to standard of care pembrolizumab maintenance therapy, administered after completion of the initial chemo-immunotherapy.

This approach is supported by initial results from Cohort 3A in the IOV-COM-202 trial in solid tumors.

Cohort 3A is evaluating LN-145 in combination with pembrolizumab in patients who have not received prior immunotherapy, including ICIs.

In September 2023, we reported preliminary Cohort 3A data in an oral presentation at the International Association for the Study of Lung Cancer, or IASLC, 2023 World Conference on Lung Cancer.

The confirmed ORR per RECIST 1.1 was 58.3% in twelve treatment-naïve or post-chemotherapy patients with EGFR wild-type disease, regardless of PD-L1 status.

Duration of responses of 15.4+, 10.2 +, 7.1, 6.9, 6.9+, 4.6, and 3.7 months were observed in seven patients, and three of these responses remained ongoing.

Safety was consistent with other studies of Iovance TIL cell therapies in combination with pembrolizumab.

Study enrollment remains ongoing.

In addition to Cohort 3A, a separate patient cohort, Cohort 3C, in COM-202 is investigating LN-145 in combination with ipilimumab or nivolumab in patients who previously received only a prior line of approved systemic ICI monotherapy.

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

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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 plan to begin 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.

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 that included patient previously treated with chemotherapy (Cohort 1), previously treated with chemo and ICIs (Cohort 2), and patients who had not received prior systemic therapy (Cohort 3).

Cohorts 1 and 2 received lifileucel monotherapy and Cohort 3 received lifileucel in combination with pembrolizumab.

Initial results from the C-145-04 clinical trial were reported at the American Society of Clinical Oncology in June 2019 and the SITC in November 2021.

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

The C-145-04 clinical trial is expected to close during 2024.

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.

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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 ongoing.

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 LN-145 as monotherapy, using various manufacturing processes.

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 LN-145 in combination with pembrolizumab in patients with HNSCC who are naïve to anti-PD-1 therapy in IOV-COM-202 Cohort 2A.

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.

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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.

Next-Generation TIL Cell 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:

We are pursuing several targets for genetic modification that utilize the gene-editing TALEN ® platform licensed from the clinical-stage biotechnology company, 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 also ongoing with cytokine-tethered TIL products and additional TIL products and TIL-cell lines using transient and stable gene insertion and inactivation, which may expand and activate TIL to achieve better efficacy while avoiding systemic side effects of cytokines.

We are exploring potential approaches to increase potency of the final TIL product through sorting and selection of specific TIL, such CD39/69 double-negative TIL, and the use of certain inhibitors or other reagents in TIL expansion cultures.

We have also manufactured and investigated patient cohorts treated with TIL candidate, LN-145-S1, manufactured from TIL selected for PD-1 expression.

● New treatment regimens:

We are exploring potential improvements to the TIL treatment regimen.

IND-enabling studies are investigating IOV-3001, an antibody cytokine-engrafted protein, or IL-2 analog, which we licensed from Novartis Pharma AG.

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.

The NCI and other academic centers have historically manufactured TIL cell therapies for research purposes;

using site-specific processes that have not been scalable or standardized to serve sizeable patient populations.

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.

At the end of 2023, more than 700 patients had been treated with an Iovance TIL cell therapy manufactured using our proprietary processes.

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

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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 introduces manufacturing and logistical efficiencies aimed at further optimizing treatment and streamlining distribution processes.

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

For example, we have developed a proprietary process for genetic modification to manufacture IOV-4001 and other next generation TIL cell therapy candidates, as well as a 16-day Gen 3 process to manufacture TIL from core biopsy as a less invasive collection of tumor samples.

Gen 2 Manufacturing Process

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

We are manufacturing 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.

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 our MSA with WuXi as well as our Sponsored Research Agreement with the H.

Lee Moffitt Cancer Center, or Moffitt.

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.

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Manufacturing and Services Agreements

In November 2016, we entered into a three-year manufacturing services agreement, or the First WuXi MSA, with WuXi, pursuant to which WuXi agreed to provide manufacturing and other services, which has since been amended and assigned to our subsidiary Iovance Biotherapeutics Manufacturing LLC.

Under the First Wuxi MSA, we entered into two statements of work for two cGMP manufacturing suites to be operated by WuXi for us.

The terms of one of these statements of work were extended to December 2022.

In October 2022, Iovance Biotherapeutics Manufacturing LLC entered into an additional three-year MSA, or the Second WuXi MSA, with WuXi and its parent company WuXi Apptec, Co.

The Second WuXi MSA and its related statement of work superseded the statement of work under the First WuXi MSA with respect to commercial, clinical manufacturing and related testing services for the two existing manufacturing suites.

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

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

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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 was amended in 2015 and 2016, to, among other things, extend the term of the CRADA through August 2021, 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 parties have continued the development of improved methods for the generation and selection of TIL with anti-tumor reactivity in metastatic melanoma, bladder, lung, breast, and HPV-associated cancers.

In August 2021, a third amendment extended the term of the CRADA by three years to August 2024, among other things.

The research plan in this third amendment includes 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.

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

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.

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.

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.

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 have licensed exclusive, co-exclusive, and non-exclusive licenses from the National Institutes of Health, or the NIH, to certain technologies relating to autologous tumor infiltrating lymphocyte adoptive cell therapy products.

We entered into an Exclusive Patent License Agreement, or the Patent License Agreement, with the NIH, in 2011, which was amended in 2015.

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.

Effective August 1, 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.

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 also agreed 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 pursuant to the Second Amended and Restated Patent License Agreement, including payments ranging 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.

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.

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Research Collaboration and Clinical Grant Agreement

In June 2020, we entered into a Sponsored Research Agreement with Moffitt, with a term that ends either upon completion of the research thereunder or on July 1, 2022, whichever is sooner.

In August 2023, this agreement was extended until September 2023.

In December 2023, this agreement was extended until the later of November 30, 2024 or a mutually agreed determination of the completion of the Sponsored Research Agreement.

In December 2016, we entered into a clinical grant agreement with Moffitt to support an ongoing clinical trial at Moffitt that combines TIL cell therapy with nivolumab for the treatment of patients with metastatic melanoma.

In June 2017, we entered into a second clinical grant agreement with Moffitt to support a new clinical trial at Moffitt that combines TIL cell therapy with nivolumab for the treatment of patients with non-small cell lung cancer, under which we obtained a non-exclusive, royalty-free license to any new Moffitt inventions made in the performance of the agreement.

Under both clinical grant agreements with Moffit, we have non-exclusive rights to clinical data arising from the respective clinical trials, which are now concluded.

Exclusive License Agreements

We have exclusive license agreements to Moffitt’s patent-pending and patented technologies related to methods for improving TIL for adoptive cell therapy using toll-like receptor, or TLR, agonists, the use of 4-1BB agonists in conjunction with TIL manufacturing processes and therapies, and tumor digests in conjunction with TIL manufacturing processes and therapies.

We entered into a license agreement with Moffitt, or the First Moffitt License, effective as of June 28, 2014, under which we received a worldwide license to Moffitt’s rights to patent-pending technologies related to methods for improving TIL for adoptive cell therapy using TLR agonists.

Unless earlier terminated, the term of the license extends until the earlier of the expiration of the last issued patent related to the licensed technology or 20 years after the effective date of the license agreement.

Pursuant to the First Moffitt License, we paid an upfront licensing fee and a patent issuance fee upon the issuance of the first U.S.

patent covering the subject technology.

In addition, we agreed to pay milestone license fees upon completion of specified milestones, customary royalties based on a specified percentage of net sales, which percentage is in the low single digits, and sublicensing payments, as applicable, and annual minimum royalties beginning with the first sale of products based on the licensed technologies, which minimum royalties will be credited against the percentage royalty payments otherwise payable in that year.

We will also be responsible for all costs associated with the preparation, filing, maintenance and prosecution of the patent applications and patents covered by the First Moffitt License related to the treatment of any cancers in the U.S., Europe and Japan and in other countries designated by us in agreement with Moffitt.

In May 2018, we entered into a second license agreement with Moffitt, or the Second Moffitt License, under which we received an exclusive license to Moffitt’s rights to patent-pending technologies related to the use of 4-1BB agonists in conjunction with TIL manufacturing processes and therapies.

Pursuant to the Second Moffitt License, we paid an upfront licensing fee, and an annual license maintenance fee is also payable commencing on the first anniversary of the effective date.

We also agreed to pay an annual commercial use payment for each indication for which a first sale has occurred.

We subsequently exercised an option to exclusively license Moffitt’s rights to patent pending technologies related to the use of tumor digests in conjunction with TIL manufacturing processes and therapies and entered into an amended and restated Second Moffitt License in October 2021, or the Amended & Restated Second Moffit License, to include these rights.

Pursuant to the Amended & Restated Second Moffitt License, we paid an upfront licensing fee in 2021.

We also agreed to pay an annual commercial use payment for each indication for which a first sale has occurred for products relating to the use of 4-1BB agonists and for products relating to the use of tumor digests covered by the license.

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, or MDACC

Anderson Cancer Center

Strategic Alliance Agreement

In April 2017, we entered into a Strategic Alliance Agreement, or the SAA, with MDACC, under which we and MDACC agreed to conduct clinical and preclinical research studies.

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.

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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.

Cellectis S.A.

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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.

Boehringer Ingelheim Biopharmaceuticals GmbH

In May 2023, as part of the completion of the acquisition of the worldwide rights to Proleukin ® , 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.

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.

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Challenges for Cancer Immunotherapy

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

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:

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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 for patients with late-stage solid tumor cancers.

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.

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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 and governmental agencies and public and private research institutions, as well as companies developing novel targeted therapies for 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 is currently being conducted in Europe by the Netherlands Cancer Institute, the Copenhagen University Hospital at Herlev, and the University of Manchester.

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 FDA-approved therapies or that 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 exploratory trials, we anticipate substantial direct competition from other organizations developing advanced T cell therapies targeting patients who have received prior anti-PD-1/-L1 therapies.

In particular, we expect to compete with other new therapies for our lead indications developed by companies such as Agenus, BeyondSpring, Bristol-Myers Squibb, Merck, Nektar Therapeutics, Checkmate Pharmaceuticals, Daiichi Sankyo, Eisai, Exelixis, Moderna, Replimune, Regeneron Pharmaceuticals, Pfizer, and Genmab.

We also may compete with other TIL cell therapies in development by companies such as Instil Bio, Achilles Therapeutics, KSQ Therapeutics, Obsidian Therapeutics, Immatics, TILT Biotherapeutics, WindMIL Therapeutics, GRIT Biotechnology, Lyell Immunopharma, Cellular Biomedicine Group, and others.

Furthermore, we may compete with therapies based on genetically engineered T cell receptors rendered reactive against tumor-associated antigens prior to their administration to patients, as well as TIL cell therapies that are designed to be specific to neoantigens, including products developed by Adaptimmune Therapeutics, Alaunos Therapeutics, Intima Bioscience, Marker Therapeutics, Turnstone Biologics, Neogene and others.

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 BioNTech.

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

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.

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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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.

inhibitors and chemotherapy.

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

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

Early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

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

Early-stage companies may also prove to be significant competitors, including through collaborative arrangements with large and established companies.

These companies compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies that are similar to those that we have developed or that we use for, or that are complementary to, or necessary for, our programs.

Our commercial success may depend in part on our ability to obtain and maintain patent and other proprietary protection for commercially important technology, inventions, and know-how related to our business;

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We also seek to preserve the integrity and confidentiality of our data and trade secrets by maintaining physical security of our premises and physical and electronic security of our information technology systems.

While we have confidence in these individuals, organizations and systems, agreements or security measures may be breached, and we may not have adequate remedies for any breach.

While we require these individuals, organizations, and systems to take steps to abide by the terms and conditions of the confidentiality agreements, confidentiality may be breached, or our data may be improperly used or disclosed, and we may not have adequate remedies for any breach or improper use or disclosure.

In addition, our trade secrets may otherwise become known or be independently discovered by competitors.

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12,188,048 and 12,194,061.

More than 40 of these patents are related to our Gen 2 TIL manufacturing processes and have terms that we anticipate will extend to 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;

More than 40 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;

frozen tumor-based TIL technologies;

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

● approval by an independent Institutional Review Board, or IRB, or ethics committee at each clinical site or centrally, before the clinical trial is begun;

● approval by an independent Institutional Review Board, or IRB, or ethics committee at each clinical site or centrally, before the clinical trial begins;

● performance of adequate and well-controlled human clinical trials, in accordance with the FDA’s current Good Clinical Practices, or cGCP, regulation, to establish the safety, purity, and potency of the proposed biologic product candidate for its intended purpose;

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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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In such a case, the IND may be placed on clinical hold and the IND sponsor and the FDA must resolve any outstanding concerns or questions before the clinical trial can begin.

Clinical holds also

may be imposed by the FDA at any time before or during clinical trials due to safety concerns or non-compliance.

Clinical holds also may be imposed by the FDA at any time before or during clinical trials due to safety concerns or non-compliance.

Submission of an IND therefore may or may not result in FDA authorization to begin a clinical trial.

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

Furthermore, an independent IRB for each site proposing to conduct the clinical trial or centrally must review and approve the plan for any clinical trial, its informed consent documentation and processes, and any subject communications, before the clinical trial begins at that site, and upon amendment of the clinical trial protocol, and must monitor the clinical trial until completed.

Furthermore, an independent IRB for each site proposing to conduct the clinical trial centrally must review and approve the plan for any clinical trial, its informed consent documentation and processes, and any subject communications before the clinical trial begins at that site and upon amendment of the clinical trial protocol, and must monitor the clinical trial until completed.

An IRB considers, among other things, whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits and whether the planned human subject protections are adequate.

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There are also requirements governing the reporting of ongoing clinical trials and clinical trial results to public registries.

For instance, we are required to register certain clinical trials and post the results of certain completed clinical trials on a government-sponsored database, ClinicalTrials.gov, within specified timeframes, and also to certify to FDA our compliance with these requirements when we make FDA submissions.

Failure to make required ClinicalTrials.gov submissions, submitting false or misleading information to ClinicalTrials.gov, or making false certifications to FDA could result in enforcement actions, including civil money penalties and adverse publicity.

For instance, we are required to register certain clinical trials and post the results of certain completed clinical trials on a government-sponsored database, ClinicalTrials.gov, within specified timeframes, and also to certify to the FDA our compliance with these requirements when we make FDA submissions.

Failure to make required ClinicalTrials.gov submissions, submitting false or misleading information to ClinicalTrials.gov, or making false certifications to the FDA could result in enforcement actions, including civil money penalties and adverse publicity.

For purposes of BLA approval, human clinical trials are typically conducted in three sequential phases that may overlap.

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● Phase 3 - The investigational product is administered to an expanded patient population in adequate and well-controlled studies to further evaluate dosage, to provide statistically significant evidence of clinical efficacy, and to further test for safety, generally at multiple geographically dispersed clinical trial sites.

These clinical trials are intended to establish the overall

risk/benefit relationship of the investigational product and to provide an adequate basis for product approval.

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.

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Phase 1, Phase 2 and Phase 3, and Phase 4 testing, if applicable, may not be completed successfully within a specified period, if at all, and there can be no assurance that the data collected will support FDA approval or licensure of the product.

Concurrent 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.

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.

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and foreign laws and regulations may also be applicable to the handling, import, export, and transportation of biological materials, including tissue samples.

In December 2022, with the passage of Food and Drug Omnibus Reform Act, Congress required sponsors to develop and submit a diversity action plan for each Phase 3 clinical trial or any other “pivotal study” of a new drug or biological product.

These plans are meant to encourage the enrollment of more diverse patient populations in late-stage clinical trials of FDA-regulated products.

Specifically, diversity action plans must include the sponsor’s goals for enrollment, the underlying rationale for those goals, and an explanation of how the sponsor intends to meet them.

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.

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

commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms under a REMS which can materially affect the potential market and profitability of the product.

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

The FDA may also not approve label statements that are necessary for successful commercialization and marketing.

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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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The product must be intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and preliminary clinical evidence must indicate that the product has the potential to address an unmet need for such disease or condition.

Advantages of the RMAT designation include all the benefits of the Fast Track and breakthrough therapy designation programs, including early interactions

with the FDA.

Advantages of the RMAT designation include all the benefits of the Fast Track and breakthrough therapy designation programs, including early interactions with the FDA.

These early interactions may be used to discuss potential surrogate or intermediate endpoints to support accelerated approval.

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The DSCSA preempts previously enacted state laws and the pedigree requirements of the Prescription Drug Marketing Act, or PDMA.

Trading partners within the drug supply chain must now ensure certain product tracing requirements are met that they are doing business with other authorized trading partners;

Trading partners within the drug supply chain must now ensure certain product tracing requirements are met;

that they are doing business with other authorized trading partners;

and they are required to exchange transaction information, transaction history, and transaction statements.

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

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 due to the COVID-19 pandemic, although this situation may continue to evolve.

although this situation 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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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.

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.

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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.

and when there is no reasonable expectation that the cost of developing and making available the drug

or biologic in the U.S.

and when there is no reasonable expectation that the cost of developing and making available the drug or biologic in the U.S.

will be recovered from sales in the U.S.

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The FDA may also approve a product deemed to be the same as an approved orphan product for the same orphan indication, despite periods of exclusivity, if the new product is demonstrated to be clinically superior to the former product.

We plan to seek ODD for some or all of our other product candidates in specific orphan indications in which there is a medically plausible basis for the use of such products.

We plan to seek ODD for some or all of our product candidates in specific orphan indications in which there is a medically plausible basis for the use of such products.

Market and Data Exclusivity and Biosimilars

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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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There must be no difference between the reference product and a biosimilar in conditions of use, route of administration, dosage form, and strength.

switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.

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

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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 prevent in the pediatric population.

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.

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

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Other Healthcare Laws and Compliance Requirements

Our sales, promotion, medical education and other activities following product approval will be subject to regulation by numerous regulatory and law enforcement authorities in the U.S., and in addition to the FDA, these entities may include the Federal Trade Commission, the Department of Justice, the Centers for Medicare & Medicaid Services, other divisions of the Department of Health and Human Services and state and local governments.

Our promotional and scientific/educational programs must comply with the federal Anti-Kickback Statute, or AKS, the Foreign Corrupt Practices Act, or FCPA, the False Claims Act, or FCA, the Veterans Health Care Act, physician payment transparency laws, privacy laws, security laws, and additional state laws similar to the foregoing.

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;

the Department of Justice;

the Centers for Medicare & Medicaid Services, or CMS;

other divisions of the Department of Health and Human Services;

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;

the civil monetary penalties statute, or the CMP Law;

the Foreign Corrupt Practices Act, or the FCPA;

the False Claims Act, or the FCA;

the Veterans Health Care Act, or the VHCA;

physician payment transparency laws;

privacy and security laws;

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.

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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 False Claims Act.

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.

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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Failure to meet all the requirements of a particular applicable statutory exception or regulatory safe harbor does not make the conduct per se illegal under the AKS.

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

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

Our practices may not in all cases meet all the criteria for protection under a statutory exception or regulatory safe harbor.

The safe harbors are subject to change through legislative and regulatory action, and we may decide to adjust our business practices or be subject to heightened scrutiny as a result.

The civil monetary penalties statute imposes penalties 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 imposes liability on persons who, among other things, knowingly present or cause to be presented false or fraudulent claims for payment to, or approval by the federal government knowingly making or using, or causing to be made or used a false statement or record material to a claim to the federal government, or avoiding, decreasing or concealing an obligation to pay money to the federal government.

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 civil FCA has been or can 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.

FCA claims may be based on noncompliance with regulatory requirements under an implied certification theory if material to the government’s decision to buy or pay for a drug.

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.

FCA claims might be based on noncompliance with regulatory requirements under an implied certification theory if material to the government’s decision to buy or pay for a drug.

Intent to deceive is not required to establish liability under the civil FCA.

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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.

In addition, federal AKS violations (which may be alleged based on certain marketing practices, including allegations of off-label promotion) implicate the FCA.

The compliance and enforcement landscape, and related risk, is informed by government litigation and settlement precedent, Advisory Opinions, and Special Fraud Alerts.

In addition, federal AKS violations (which may be alleged based on certain marketing practices, including allegations of off-label promotion) might implicate the FCA.

The compliance and enforcement landscape, and related risk, is informed by government regulatory, enforcement, and other activities, such as litigation and settlement precedent, advisory opinions, and special fraud alerts.

Our approach to compliance may evolve over time in light of these types of developments.

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Activities that violate the FCPA, even if they occur wholly outside the U.S., can result in criminal and civil fines, imprisonment, disgorgement, oversight, and debarment from securing government contracts.

We cannot assure you that our internal control policies and procedures will protect us from reckless or negligent acts committed by our employees, future distributors,

partners, collaborators or agents.

We cannot assure you that our internal control policies and procedures will protect us from reckless or negligent acts committed by our employees, future distributors, partners, collaborators or agents.

Violations of these laws, or allegations of such violations, could result in fines, penalties or prosecution and have a negative impact on our business, results of operations and reputation.

Payment or reimbursement of prescription drugs by Medicaid or Medicare requires manufacturers of the drugs to submit pricing information to the Centers for Medicare & Medicaid Services, or CMS.

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.

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Drugs that are approved under a BLA or a New Drug Application, or NDA, including 505(b)(2) drugs, are subject to an additional inflation penalty which can substantially increase rebate payments.

In addition, for BLA and NDA drugs, the Veterans Health Care Act, or VHCA, requires manufacturers to calculate and report to the Veterans Administration, or VA, a different price called the Non Federal Average Manufacturing Price, which is used to determine the maximum price that can be charged to certain federal agencies, referred to as the Federal Ceiling Price, or FCP.

In addition, for BLA and NDA drugs, the VHCA requires manufacturers to calculate and report to the Veterans Administration, or VA, a different price called the Non-Federal Average Manufacturing Price, which is used to determine the maximum price that can be charged to certain federal agencies, referred to as the Federal Ceiling Price, or FCP.

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

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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.

HIPAA, as amended by the Health Information Technology and Clinical Health Act, or HITECH, and their respective implementing regulations, including the final omnibus rule published on January 25, 2013, imposes specific requirements relating to the privacy, security and transmission of individually identifiable health information held by covered entities and their business associates.

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.

HITECH 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 attorney’s fees and costs associated with pursuing federal civil actions.

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.

Even for entities that are not deemed “covered entities” or “business associates” under HIPAA, according to the U.S.

Federal Trade Commission, or 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).

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).

The FTC expects a company's data security measures to be reasonable and appropriate in light of the sensitivity and volume of consumer information it holds, the size and complexity of its business, and the cost of available tools to improve security and reduce vulnerabilities.

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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 2021 and beyond, as the increased cyber-attacks during the pandemic have heightened attention data privacy and security in the U.S.

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.

and other jurisdictions.

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Payments made to physicians and other healthcare providers, 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 ACA.

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.

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 was amended requiring applicable manufacturers, in 2021, to begin tracking payments and transfers of value to physician assistants, nurse practitioners, and other mid-level HCPs as well as physicians, with reporting relative to these mid-level practitioners first due in 2022.

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 PhRMA 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 recently amended and expanded by the California Privacy Rights Act, or CPRA, passed on November 3, 2020.

While the majority of the CPRA’s substantive provisions will not take effect until January 1, 2023, the CPRA’s expansion of the “Right to Know” impacts personal information collected on or after January 1, 2022.

Companies must still comply with the CCPA during the ramp up period before CPRA goes into effect.

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.

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 CPRA by the California legislature or how it will be interpreted.

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.

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.

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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 and 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.

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.

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 providers, 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.

Although we currently believe that third-party payors will provide coverage and reimbursement for our 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.

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

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.

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 product candidates such as ours, which are used in the inpatient setting, usually resulting in no separate reimbursement for pharmaceuticals.

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.

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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 Medicare Part B covers outpatient medical services.

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 patients who are otherwise uninsured and is both federally and state funded and managed by each state.

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.

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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 healthcare services and products.

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

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.

Further, some stakeholders have recently questioned whether the market price of prescription drugs may be inflated by virtue of the built-in cost imparted by the government rebate model, often negotiated indirectly in exchange for a coverage determination or formulary placement where relevant.

In the U.S., the European Union, and other potentially significant markets for our 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.

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.

Manufacturers frequently must rebate a portion of the prescription price to the third-party payors as a condition of coverage, which can greatly reduce realization on the sale.

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They may limit coverage to specific drug products on an approved list, or formulary, which might not include all the FDA-approved drug products for a particular indication, or they may control costs, particularly for new expensive therapies, by requiring prior authorization or imposing other restrictions before covering certain products, or they may condition payment based on achieving performance metrics.

Legislative proposals to reform healthcare or reduce costs under government programs may result in lower reimbursement for our product candidates or exclusion of our product candidates from coverage.

Legislative proposals to reform healthcare or reduce costs under government programs may result in lower reimbursement for our products and product candidates or exclusion of our products and product candidates from coverage.

Achieving favorable CMS coverage and reimbursement is usually a significant gating issue for successful introduction of a new product because Medicare and Medicaid can represent a sizeable share of the market and because private payors often rely on the lead of the governmental payors in rendering coverage and reimbursement determinations.

Further, the increased emphasis on managed healthcare in the U.S.

and on country and regional pricing and reimbursement controls in the European Union will likely put additional

pressure on product pricing, reimbursement, and utilization, which may adversely affect our future product sales and results of operations.

These pressures can arise from rules and practices of managed care groups, competition within therapeutic classes, availability of generic equivalents, judicial decisions and governmental laws and regulations related to Medicare, Medicaid, and healthcare reform, pharmaceutical coverage and reimbursement policies, and pricing in general.

and on country and regional pricing and reimbursement controls in Europe will likely put additional pressure on product pricing, reimbursement, and utilization, which may adversely affect our future product sales and results of operations.

These pressures can arise from rules and practices of managed care entities, competition within therapeutic classes, availability of generic equivalents, judicial decisions and governmental laws and regulations related to Medicare, Medicaid, and healthcare reform, pharmaceutical coverage and reimbursement policies, and pricing in general.

Patients who are prescribed treatments for their conditions and providers performing the prescribed services generally rely on third-party payors to reimburse all or part of the associated healthcare costs.

Sales of our product candidates will therefore depend substantially, both domestically and abroad, on the extent to which the costs of our products will be paid by health maintenance, managed care, pharmacy benefit and similar healthcare management organizations, or reimbursed by government health administration authorities, such as Medicare and Medicaid, private health insurers, and other third-party payors.

Sales of our products and product candidates will therefore depend substantially, both domestically and abroad, on the extent to which the costs of our products will be paid by health maintenance, managed care, pharmacy benefit, and similar healthcare management organizations, or reimbursed by government health administration authorities, such as Medicare and Medicaid, private health insurers, and other third-party payors.

As a result of the above, we may need to conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity and cost-effectiveness of our products, in addition to the costs required to obtain FDA approvals.

Our product candidates may not be considered medically necessary or cost-effective.

Our products and product candidates may not be considered medically necessary or cost-effective.

A payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved.

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Legislative and regulatory proposals to reform healthcare or reduce costs under government insurance programs may result in lower reimbursement for our products and product candidates or exclusion of our products and product candidates from coverage.

The cost containment measures that healthcare payors and providers are instituting and any healthcare reform could significantly reduce our revenues from the sale of any approved product candidates.

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

The cost containment measures that healthcare payors and providers are instituting and any healthcare reform could significantly reduce our revenues from the sale of products and any approved product candidates.

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 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.

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.

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In 2017, CMS promulgated a rule reducing Medicare Part B reimbursement to hospitals for drugs purchased under the 340B program by 30%.

Although hospital trade associations filed a lawsuit challenging the regulation, the final rule is now in effect.

Following an adverse U.S.

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.

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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 product candidates, if approved, and, accordingly, our financial operations.

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.

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

While we cannot predict whether any proposed cost-containment measures will be adopted or otherwise implemented in the future, the announcement or adoption of these proposals could have a material adverse effect on our ability to obtain adequate prices for our product candidates and operate profitably.

Foreign Regulation

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The requirements governing the conduct of clinical trials, product licensing, pricing, and reimbursement vary greatly from country to country.

In the EU and the United Kingdom, member states require both regulatory clearances by the national competent authority and a favorable ethics committee opinion prior to the commencement of a clinical trial.

Under the EU regulatory systems, marketing authorization applications may be submitted under either a centralized or decentralized procedure.

The centralized procedure provides for the grant of a single marketing authorization that is valid for all EU member states.

It is compulsory for medicines produced by certain biotechnological processes.

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

Under the centralized procedure, pharmaceutical companies submit a single marketing authorization application to the European Medicines Agency.

Once granted by the European Commission, a centralized marketing authorization is valid in all EU member states, as well as the European Economic Area countries.

In the EU and the UK, both regulatory clearances by the national competent authority and a favorable ethics committee opinion are required prior to the commencement of a clinical trial.

In the EU/European Economic Area, or EEA, Regulation (EU) 536/2014 on clinical trials, or CTR, requires the sponsor to submit a single clinical trial application, or CTA, through the Clinical Trials Information System, or the CTIS, an online portal to streamline the authorization process.

While under the previously applicable Directive 2001/20/EC, or CTD, sponsors had to request separate approvals in each EU/EEA member state, the CTIS is a single-entry point that allows sponsors to apply for authorization to run a clinical trial in up to 30 EU/EEA countries.

The CTIS authorization procedure is composed of two parts:

(i) member states jointly cooperate during the Part I assessment of the applicable CTA and (ii) during Part II, the applicable CTA is assessed by each member state individually.

All ongoing clinical trials in the EU/EEA were required to transition to the CTIS by January 30, 2025.

This date marked the end of a three-year transition period that began when the CTR became applicable.

Following the UK's departure from the EU, the CTR does not apply in the UK with the applicable rules currently being based largely on those set out in the CTD as have been implemented nationally via the Medicines for Human Use (Clinical Trials) Regulation 2004, as amended.

However, new UK legislation was laid before Parliament in December 2024 which will update the existing regulations, and which aims to provide a more efficient, streamlined, and adaptable regulatory framework for clinical trials.

Once made into law, the new legislation will come into force following a 12-month implementation period to ensure readiness.

Under the EU regulatory systems, in addition to using national authorization procedures (leading to a marketing authorization only valid in the relevant EU/EEA member state), an MAA may be submitted under the (i) centralized authorization procedure, (ii) mutual recognition procedure, or (iii) decentralized procedure.

The centralized procedure provides for the grant of a single marketing authorization valid across all EU/EAA member states.

This procedure is mandatory for certain medicines, optional for others, and not available for the rest.

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.

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

The application is reviewed by the Committee for Medicinal Products for Human Use, which issues a scientific opinion.

The EMA then forwards this scientific opinion to the European Commission, which is responsible for deciding whether to grant the marketing authorization.

Once granted by the European Commission, a centralized marketing authorization is valid in all EU member states, as well as the EEA countries.

By law, a company can only start to market a medicine once it has received a marketing authorization.

Employees and Human Capital Management

As of December 31, 2023, we had 557 employees, 425 of whom were engaged in research and development activities and 132 of whom were engaged in general and administrative support activities.

As of December 31, 2024, we had 838 employees, 670 of whom were engaged in research and development, and commercial manufacturing activities, and 168 of whom were engaged in general and administrative support activities.

None of our employees are subject to a collective bargaining agreement.

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What changed 10-K

Item 1. Business