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What changed in IOVANCE BIOTHERAPEUTICS, INC.'s 10-K — 2023 vs 2024

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Paragraph-level year-over-year comparison of IOVANCE BIOTHERAPEUTICS, INC.'s 2023 and 2024 10-K annual filings, covering the Business, Risk Factors, Legal Proceedings, Cybersecurity, MD&A and Market Risk sections. Every new, removed and edited paragraph is highlighted side-by-side so you can see exactly what management changed in the 2024 report.

+837 added−701 removedSource: 10-K (2025-02-27) vs 10-K (2024-02-28)

Top changes in IOVANCE BIOTHERAPEUTICS, INC.'s 2024 10-K

837 paragraphs added · 701 removed · 586 edited across 8 sections

Item 1. Business

Business — how the company describes what it does

194 edited+55 added−46 removed215 unchanged
Biggest changeThe 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; ● operational excellence in launch execution, commercial manufacturing and delivery of therapy; and ● 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.
Biggest changeOur 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; and ● continuous communication with payors about the value of Amtagvi ® to facilitate strong reimbursement and patient access. ​ U.S.
Commercial Launch of the First TIL Cell Therapy in Advanced Melanoma Amtagvi™ 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.
Commercial Launch of the First TIL Cell Therapy in Advanced Melanoma Amtagvi ® 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.
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.
Treatment-emergent adverse events were consistent with the underlying disease and known adverse event profiles of non-myeloablative lymphodepletion and interleukin-2. We also reported additional ongoing responses, and duration of response greater than six months for 71% of the confirmed responders in the trial, in an updated analysis from November 2023.
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.
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.
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.
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. It is time-consuming and expensive for us to seek coverage and reimbursement from third-party payors.
In addition, significant uncertainty exists as to the reimbursement status of newly approved healthcare products. We may need to conduct expensive clinical trials to demonstrate the comparative cost-effectiveness of our products. The products and product candidates that we develop may not be considered cost-effective. It is time-consuming and expensive for us to seek coverage and reimbursement from third-party payors.
Sales of 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.
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 products and product candidates may not be considered medically necessary or cost-effective.
The process required by the FDA before biologic product candidates may be marketed in the U.S. generally involves the following: ● completion of preclinical laboratory tests and animal studies performed in accordance with the FDA’s current Good Laboratory Practices, or cGLP, regulation, as well as manufacturing development and formulation studies; ● 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; ● 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; ● preparation of and submission to the FDA of a BLA, after completion of pivotal clinical trial(s); ● satisfactory completion of an FDA Advisory Committee review, if applicable; ● a determination by the FDA within 60 days of its receipt of a BLA to file the application for review; ● satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities at which the proposed product is produced to assess compliance with cGMP, and to assure that the facilities, methods and controls are adequate to preserve the biological product’s continued safety, purity and potency, and of selected clinical sites to assess compliance with cGCPs; and ● FDA review and approval of the BLA to permit commercial marketing of the product for particular indications for use in the U.S., which must be updated periodically when changes are made.
The process required by the FDA before biologic product candidates may be marketed in the U.S. generally involves the following: ● completion of preclinical laboratory tests and animal studies performed in accordance with the FDA’s current Good Laboratory Practices, or cGLP, regulation, as well as manufacturing development and formulation studies; ● 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 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; ● preparation of and submission to the FDA of a BLA, after completion of pivotal clinical trial(s); ● satisfactory completion of an FDA Advisory Committee review, if applicable; ● a determination by the FDA within 60 days of its receipt of a BLA to file the application for review; ● satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities at which the proposed product is produced to assess compliance with cGMP, and to assure that the facilities, methods and controls are adequate to preserve the biological product’s continued safety, purity and potency, and of selected clinical sites to assess compliance with cGCPs; and ● FDA review and approval of the BLA to permit commercial marketing of the product for particular indications for use in the U.S., which must be updated periodically when changes are made.
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 purposes of BLA approval, human clinical trials are typically conducted in three sequential phases that may overlap.
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.
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.
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. Any reduction in reimbursement from Medicare or other government-funded programs may result in a similar reduction in payments from private payors.
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.
It remains unclear what, if any, additional modifications will be made to the CPRA by the California legislature or how it 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.
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.
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. The dual primary endpoints will be assessed by a BIRC using RECIST 1.1.
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.
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.
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.
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.
Healthcare Reform The U.S. 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.
Healthcare Reform The U.S. 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.
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.
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.
Proleukin ® 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.
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.
If the FDA designates a Breakthrough Therapy, it may take actions appropriate to expedite the development and review of the application, which may include holding meetings with the sponsor and the review team throughout the development of the therapy; 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; 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; and considering 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 and may minimize the number of patients exposed to a potentially less efficacious treatment.
If the FDA designates a Breakthrough Therapy, it may take actions appropriate to expedite the development and review of the application, which may include holding meetings with the sponsor and the review team throughout the development of the therapy; 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 21 Table of Contents 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; and considering 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 and may minimize the number of patients exposed to a potentially less efficacious treatment.
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.
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.
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 29 Table of Contents 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.
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.
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.
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.
Corporate Strategy Be the 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.
Corporate Strategy A global leader in innovating, developing, and delivering TIL cell therapy Our mission is to be the global leader in innovating, developing, and delivering TIL cell therapy for patients with solid tumor cancers.
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. annually.
Challenges for Cancer Immunotherapy According to SEER, solid tumor cancers represent more than 90 percent of all cancers diagnosed in the U.S. annually.
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 21 Table of Contents 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.
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.
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.
To date, these technologies have been primarily applicable to hematologic malignancies, but their application in solid tumor indications may create competition with us. We may also face competition from immunotherapy treatments offered by companies such as Amgen, AstraZeneca, Bristol-Myers Squibb, Merck, Pfizer, Regeneron Pharmaceuticals, Roche, and others.
In addition, other legislative and regulatory changes have been proposed and adopted since the ACA was enacted. These changes include aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, starting in 2013, which will remain in effect through 2025 unless additional Congressional action is taken.
In addition, other legislative and regulatory changes have been proposed and adopted since the ACA was enacted. These changes include aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, starting in 2013, which will remain in effect through 2032 unless additional Congressional action is taken.
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. ​ IOV-4001 for Advanced Melanoma and NSCLC We have a worldwide exclusive license from Cellectis that enables us to use certain TALEN® technology addressing multiple gene targets in several cancer indications, to develop genetically edited and potentially more potent TIL cell therapies.
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. ​ 10 Table of Contents IOV-4001 for Advanced Melanoma and NSCLC We have a worldwide exclusive license from Cellectis that enables us to use certain TALEN ® technology addressing multiple gene targets in several cancer indications, to develop genetically edited and potentially more potent TIL cell therapies.
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. approval for Amtagvi™, which has received an accelerated U.S. approval in its initial indication in post-anti-PD-1 advanced melanoma.
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.
To achieve this objective, our strategic focus has been to develop our own intellectual property, while also identifying and licensing patents from third parties that provide protection and serve as an optimal platform to enhance our intellectual property and technology base. We expect to further develop our patent portfolio as a strategic focus in 2024.
To achieve this objective, our strategic focus has been to develop our own intellectual property, while also identifying and licensing patents from third parties that provide protection and serve as an optimal platform to enhance our intellectual property and technology base. We expect to further develop our patent portfolio as a strategic focus in 2025.
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 19 Table of Contents 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.
We have established 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, such as U.S.
We have established a leading intellectual property portfolio developed internally and licensed from third parties. We currently own more than 75 U.S. patents related to TIL cell therapy, including patents directed to compositions and methods of treatment in a broad range of cancers, such as U.S.
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. The i CTC is the first FDA-approved, centralized and scalable cGMP manufacturing facility dedicated to producing TIL cell therapies.
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.
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.
Despite progress over the past several decades, effective treatment of solid tumors continues to be challenging for several reasons, including: (i) intratumoral heterogeneity, (ii) numerous mutations and tumor neoantigens, with Advancing Immuno-Oncology with Our TIL Technology Platform We believe that adoptive cell therapy, specifically the use of human polyclonal TIL cells to reengage the immune system, may be a significant advancement in the treatment of cancer.
Despite progress over the past several decades, effective treatment of solid tumors continues to be challenging for several reasons, including: (i) intratumoral heterogeneity, (ii) numerous mutations and tumor neoantigens, with 14 Table of Contents Advancing Immuno-Oncology with Our TIL Technology Platform We believe that adoptive cell therapy, specifically the use of human polyclonal TIL cells to reengage the immune system, may be a significant advancement in the treatment of cancer.
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.
In the U.S., private health insurers and other third-party payors often provide reimbursement for products and services based on the level at which the government provides reimbursement through the Medicare or Medicaid programs for such products and services. These restrictions and limitations influence the purchase of health care services and products.
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.
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.
These studies are designed to test the safety, dosage tolerance, absorption, metabolism and distribution of the investigational product in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. ● Phase 2 - The investigational product is administered to a limited patient population with a specified disease or condition to evaluate the preliminary efficacy, optimal dosages and dosing schedule and to identify possible adverse side effects and safety risks.
These studies are designed to test the safety, dosage tolerance, absorption, metabolism and distribution of the investigational product in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. 18 Table of Contents ● Phase 2 - The investigational product is administered to a limited patient population with a specified disease or condition to evaluate the preliminary efficacy, optimal dosages, and dosing schedule and to identify possible adverse side effects and safety risks.
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.
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.
Orphan Drugs 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 24 Table of Contents or biologic in the U.S. will be recovered from sales in the U.S. for that drug or biologic.
Orphan Drugs 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. will be recovered from sales in the U.S. for that drug or 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 25 Table of Contents 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.
The term "remuneration" includes kickbacks, bribes or rebates and also has been broadly interpreted to include anything of value, including, for example, gifts, discounts, waivers of payment, ownership interest and providing anything at less than its fair market value.
The term “remuneration” includes kickbacks, bribes, or rebates, and also has been broadly interpreted to include anything of value, including, for example, gifts, discounts, waivers of payment, ownership interest, and providing anything at less than its fair market value.
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. Intent to deceive is not required to establish liability under the civil FCA.
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.
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. Most complete responses remained ongoing in three to seven years of follow up.
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.
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. If approved, biologics may also be eligible for periods of U.S. patent term restoration.
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. patent term restoration.
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.
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, 22 Table of Contents although this situation may continue to evolve.
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.
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.
Coverage and Reimbursement Sales of pharmaceutical products depend significantly on the availability of third-party coverage and reimbursement. Third-party payors include Medicare, Medicaid, and other government programs at the federal and state level, managed care entities, private health insurers, and other organizations.
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. 15 Table of Contents For earlier intervention, we are investigating our TIL cell therapy in combination with ICIs.
After infusion, TIL can potentially infiltrate the tumor to eliminate cancer cells, further proliferate in the body and potentially overcome several mechanisms of tumor escape to which endogenous T cells may be susceptible due to the immune-suppressive tumor microenvironment. For earlier intervention, we are investigating our TIL cell therapy in combination with ICIs.
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.
Based on the regulatory discussions and positive regulatory feedback received by the FDA regarding the design of the IOV-LUN-202 trial, we plan to enroll a total of approximately 120 patients into the registrational Cohorts 1 and 2 of the IOV-LUN-202 trial. ​ In July 2023, we announced a preliminary analysis of the IOV-LUN-202 trial from 23 NSCLC patients treated with lifileucel.
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.
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.
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.
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 such arrangement’s facts and circumstances.
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.
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.
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.
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.
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 9 Table of Contents ICI, therapy, including patients with oncogene-driven tumors who received prior tyrosine kinase inhibitor, or TKI, therapy.
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.
The trial began in June 2017 and closed in January 2021 after reaching its pre-specified enrollment target. We also investigated lifileucel in combination with pembrolizumab in patients with HNSCC who are naïve to anti-PD-1 therapy in IOV-COM-202 Cohort 2A.
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.
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.
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 CMS.
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. ​ 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.
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 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.
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.
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 23 Table of Contents conduct a more efficient development program.
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.
Based on the outcome of negotiations surrounding the exchanged information, the reference product sponsor may bring a patent infringement suit 24 Table of Contents 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.
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. There are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution or other regulatory sanctions.
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.
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.
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 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.
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.
Boehringer Ingelheim Biopharmaceuticals GmbH In May 2023, as part of the Acquisition, we inherited a manufacturing and supply agreement from Clinigen with Boehringer Ingelheim Biopharmaceuticals GmbH, or BI, pursuant to which BI will carry out the processing, manufacturing, and supply of Proleukin ® in unlabeled vials.
The FDA may also perform certain confirmatory tests on lots of some products before releasing the lots for distribution by the manufacturer. In addition, the FDA conducts laboratory research related to the regulatory standards on the safety, purity, potency, and effectiveness of biological products.
The FDA may also perform certain confirmatory tests on lots of some products before releasing the lots for distribution by the manufacturer. 25 Table of Contents In addition, the FDA conducts laboratory research related to the regulatory standards on the safety, purity, potency, and effectiveness of biological products.
We may also face competition from novel IL-2 treatments in development by Alkermes, Werewolf, Merck, Sanofi, Neoleukin 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.
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.
Currently, there are numerous companies that are developing various alternate treatments for advanced melanoma, NSCLC and other solid tumor cancers that we are seeking to address, including patients that have progressed after prior treatment with checkpoint inhibitors and chemotherapy. Accordingly, our TIL cell therapies face significant competition from multiple companies.
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 15 Table of Contents inhibitors and chemotherapy. Accordingly, our TIL cell therapies face significant competition from multiple companies.
Advantages of the RMAT designation include all the benefits of the Fast Track and breakthrough therapy designation programs, including early interactions 22 Table of Contents with the FDA. These early interactions may be used to discuss potential surrogate or intermediate endpoints to support accelerated approval.
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.
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.
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 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. ​ 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.
We treated the first patient with IOV-4001 in the third quarter of 2022 and the Phase 1 safety portion of the clinical trial is completed. ​ Additional Clinical Trials We previously investigated the potential for TIL cell therapy in metastatic HNSCC. The Phase 2 C-145-03 trial investigated lifileucel as monotherapy, using various manufacturing processes.
Third party payors decide which drugs they will pay for on behalf of their beneficiaries and establish reimbursement levels for health care.
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.
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 18 Table of Contents may be imposed by the FDA at any time before or during clinical trials due to safety concerns or non-compliance.
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.
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.
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 17 Table of Contents protocol(s) for clinical trials.
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 approval is based on safety and efficacy results from the C-144-01 clinical trial, a global, multicenter trial investigating Amtagvi ® in patients with advanced melanoma previously treated with anti-PD-1 therapy and targeted therapy, where applicable.
We 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. and foreign commercial sales of any of our product candidates covered by 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.
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.
Other Healthcare Laws and Compliance Requirements Our sales, promotion, medical education, and other activities following product approval are subject to regulation by numerous federal, state, and local regulatory and law enforcement authorities in the U.S., and in addition to the FDA, these entities may include the Federal Trade Commission, or the FTC; 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.

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Item 1A. Risk Factors

Risk Factors — what could go wrong, per management

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Biggest changeOur business, financial condition and results of operations could be materially adversely affected by any negative impact on the global economy and capital markets resulting from the conflict in Ukraine and the Middle East, geopolitical tensions or record inflation; ● Climate change or legal, regulatory or market measures to address climate change may negatively affect our business, results of operations, cash flows and prospects; and ● Environmental, social and governance matters may impact our business and reputation. ​ Risks Related to Government Regulation: ● We are subject to extensive regulation, which can be costly, time consuming and can subject us to unanticipated delays; even after obtaining regulatory approval for some of our products and/or product candidates, those products and/or product candidates may still face regulatory difficulties; ● The FDA regulatory approval process is lengthy and time-consuming, and we may experience significant delays in the clinical development and regulatory approval of our product candidates; ● Obtaining and maintaining regulatory approval of our product candidates in one jurisdiction does not mean that we will be successful in obtaining regulatory approval of our product candidates in other jurisdictions; ● Coverage and reimbursement may be limited or unavailable in certain market segments for our product candidates, which could make it difficult for us to sell our product candidates profitably; and ● Governments outside the U.S. tend to impose strict price controls, which may adversely affect our revenues, if any. ​ The summary risk factors described above should be read together with the text of the full risk factors below in this section entitled “ Risk Factors ” and the other information set forth in this Annual Report on Form 10-K, including our consolidated financial statements and the related notes, as well as in other documents that we file with the SEC.
Biggest changeOur business, financial condition and results of operations could be materially adversely affected by any negative impact on the global economy and capital markets resulting from the conflict in Ukraine and the Middle East, geopolitical tensions, or inflation. ​ 33 Table of Contents Risks Related to Government Regulation: ● We are subject to extensive regulation, which can be costly and time consuming and can subject us to unanticipated delays in obtaining regulatory approvals for our products and/or product candidates, and even after obtaining regulatory approval for some of our products and/or product candidates, those products and/or product candidates may still face regulatory difficulties; ● The FDA and foreign regulatory approval process is lengthy and time-consuming, and we may experience significant delays in the clinical development and regulatory approval of our product candidates; ● Political uncertainty may have an adverse impact on our operating performance and results of operations, and uncertainty surrounding the potential legal, regulatory, and policy changes by a new U.S. presidential administration may directly affect us and the global economy; ● Obtaining and maintaining regulatory approval of our product candidates in one jurisdiction does not mean that we will be successful in obtaining or maintaining regulatory approval of our product candidates in other jurisdictions; and ● Coverage and reimbursement may be limited or unavailable in certain market segments for our product candidates, which could make it difficult for us to sell our product candidates profitably. ​ The summary risk factors described above should be read together with the text of the full risk factors below in this section entitled “ Risk Factors ” and the other information set forth in this Annual Report on Form 10-K, including our consolidated financial statements and the related notes, as well as in other documents that we file with the SEC.
Regardless of the merits or eventual outcome, liability claims may result in: ● decreased or interrupted demand for our products and/or product candidates; ● injury to our reputation; ● withdrawal of clinical trial participants or sites and potential termination of clinical trial sites or entire clinical programs; ● initiation of investigations by regulators (including investigation of the safety and effectiveness of our products, our manufacturing processes and facilities, or our marketing programs), refusal to approve marketing applications or supplements, warnings, and withdrawal or other limitations on product approvals; ● costs to prepare for and defend the related litigation; ● a diversion of management’s time and our resources; ● substantial monetary awards to clinical trial participants or patients; ● product recalls, withdrawals, or restrictions on labeling, marketing, or promotions; ● loss of revenue; ● significant negative media attention; ● decrease in the price of our stock and overall value of our company; ● exhaustion of our available insurance coverage and our capital resources; and/or ● the delay or inability to commercialize our product candidates or achieve adequate revenue from our products.
Regardless of the merits or eventual outcome, liability claims may result in: ● decreased or interrupted demand for our products and/or product candidates; ● injury to our reputation; ● withdrawal of clinical trial participants or sites and potential termination of clinical trial sites or entire clinical programs; ● initiation of investigations by regulators (including investigation of the safety and effectiveness of our products, our manufacturing processes and facilities, or our marketing programs), refusal to approve marketing applications or supplements, warnings, and withdrawal or other limitations on product approvals; ● costs to prepare for and defend the related litigation; ● a diversion of management’s time and our resources; ● substantial monetary awards to clinical trial participants or patients; ● product recalls, withdrawals, or restrictions on labeling, marketing, or promotions; ● loss of revenue; ● significant negative media attention; ● decrease in the price of our stock and overall value of our company; ● exhaustion of our available insurance coverage and our capital resources; and ● the delay or inability to commercialize our product candidates or achieve adequate revenue from our products.
In part because of this lack of experience, we cannot be certain that our ongoing pivotal clinical trials will be completed on time, if at all, will progress according to our plans or expectations, or that our planned clinical trials will be initiated or initiated in a timely manner, progress according to our plans or expectations, or be completed on time, if they are completed at all.
In part because of this lack of experience, we cannot be certain that our ongoing pivotal clinical trials will be completed on time, if at all, that they will progress according to our plans or expectations, or that our planned clinical trials will be initiated or initiated in a timely manner, progress according to our plans or expectations, or be completed on time, if they are completed at all.
Our product candidates may cause undesirable side effects or have other properties that could halt their clinical development, prevent their regulatory approval, limit their commercial potential, or result in significant negative consequences. Results of our clinical trials could reveal a high and unacceptable severity and prevalence of side effects or unexpected characteristics.
Our commercial product and product candidates may cause undesirable side effects or have other properties that could halt their clinical development, prevent their regulatory approval, limit their commercial potential, or result in significant negative consequences. Results of our clinical trials could reveal a high and unacceptable severity and prevalence of side effects or unexpected characteristics.
Our products, potential products, cell processing and manufacturing activities, are subject to comprehensive regulation by the FDA in the U.S. and by comparable authorities in other countries.
Our products, potential products, and cell processing and manufacturing activities are subject to comprehensive regulation by the FDA in the U.S. and by comparable authorities in other countries.
Any collaboration may pose a number of risks, including the following: ● collaborators may not perform their obligations as expected; ● collaborators may not pursue development of product candidates and/or commercialization of products that achieve regulatory approval or may elect not to continue or renew development or commercialization programs based on clinical trial results, changes in the collaborators’ strategic focus or available funding, or external factors, such as an acquisition, that divert resources or create competing priorities; ● collaborators may delay clinical trials, provide insufficient funding for a clinical trial program, stop a clinical trial or abandon a product candidate, repeat or conduct new clinical trials, or require a new formulation of a product candidate for clinical testing; ● collaborators could fail to make timely regulatory submissions for a product candidate; ● collaborators may not comply with all applicable regulatory requirements or may fail to report safety data in accordance with all applicable regulatory requirements; ● collaborators could independently develop, or develop with third parties, products that compete directly or indirectly with our products and/or product candidates if the collaborators believe that competitive products are more likely to be successfully developed or can be commercialized under terms that are more economically attractive than ours; ● products and/or product candidates discovered in collaboration with us may be viewed by our collaborators as competitive with their own products and/or product candidates, which may cause collaborators to cease to devote resources to the commercialization of our products and/or product candidates; ● a collaborator with marketing and distribution rights to one or more of our product candidates that achieve regulatory approval may not commit sufficient resources to the marketing and distribution of such product candidate or product; 61 Table of Contents ● disagreements with collaborators, including disagreements over proprietary rights, contract interpretation, or the preferred course of development, might cause delays or termination of the research, development, or commercialization of products and/or product candidates, might lead to additional responsibilities for us with respect to products and/or product candidates, or might result in litigation or arbitration, any of which would be time consuming and expensive; ● collaborators may not properly maintain or defend our intellectual property rights or may use our proprietary information in such a way as to invite litigation that could jeopardize or invalidate our intellectual property or proprietary information or expose us to potential litigation; ● collaborators may infringe the intellectual property rights of third parties, which may expose us to litigation and potential liability; ● collaborators may be involved in a business combination, resulting in the decreased emphasis or termination of development or commercialization of any product candidate subject to the collaboration agreement; and ● termination of a collaboration agreement may make it more difficult to attract new collaborators and our and our products’ or product candidates’ reputation in the medical, business, and financial communities could be adversely affected.
Any collaboration may pose a number of risks, including the following: ● collaborators may not perform their obligations as expected; ● collaborators may not pursue development of product candidates and/or commercialization of products that achieve regulatory approval or may elect not to continue or renew development or commercialization programs based on clinical trial results, changes in the collaborators’ strategic focus or available funding, or external factors, such as an acquisition, that divert resources or create competing priorities; ● collaborators may delay clinical trials, provide insufficient funding for a clinical trial program, stop a clinical trial or abandon a product candidate, repeat or conduct new clinical trials, or require a new formulation of a product candidate for clinical testing; ● collaborators could fail to make timely regulatory submissions for a product candidate; ● collaborators may not comply with all applicable regulatory requirements or may fail to report safety data in accordance with all applicable regulatory requirements; ● collaborators could independently develop, or develop with third parties, products that compete directly or indirectly with our products and/or product candidates if the collaborators believe that competitive products are more likely to be successfully developed or can be commercialized under terms that are more economically attractive than ours; ● products and/or product candidates discovered in collaboration with us may be viewed by our collaborators as competitive with their own products and/or product candidates, which may cause collaborators to cease to devote resources to the commercialization of our products and/or product candidates; ● a collaborator with marketing and distribution rights to one or more of our product candidates that achieve regulatory approval may not commit sufficient resources to the marketing and distribution of such product candidate or product; ● disagreements with collaborators, including disagreements over proprietary rights, contract interpretation, or the preferred course of development, might cause delays or termination of the research, development, or commercialization of products 62 Table of Contents and/or product candidates, might lead to additional responsibilities for us with respect to products and/or product candidates, or might result in litigation or arbitration, any of which would be time consuming and expensive; ● collaborators may not properly maintain or defend our intellectual property rights or may use our proprietary information in such a way as to invite litigation that could jeopardize or invalidate our intellectual property or proprietary information or expose us to potential litigation; ● collaborators may infringe the intellectual property rights of third parties, which may expose us to litigation and potential liability; ● collaborators may be involved in a business combination, resulting in the decreased emphasis or termination of development or commercialization of any product candidate subject to the collaboration agreement; and ● termination of a collaboration agreement may make it more difficult to attract new collaborators and our and our products’ or product candidates’ reputation in the medical, business, and financial communities could be adversely affected.
Our certificate of incorporation, as amended, provides that, subject to limited exceptions, the Court of Chancery of the State of Delaware shall, to the fullest extent permitted by law, be the sole and exclusive forum for (1) any derivative action or proceeding brought on our behalf, (2) any action asserting a claim of breach of a fiduciary duty owed by any of our directors, officers, employees or agents to us or our stockholders, creditors or other constituents, (3) any action asserting a claim against us arising pursuant to any provision of the Delaware General Corporation Law, our certificate of incorporation, as amended, or our amended bylaws, or (4) any other action asserting a claim against us that is governed by the internal affairs doctrine.
Our certificate of incorporation, as amended, provides that, subject to limited exceptions, the Court of Chancery of the State of Delaware shall, to the fullest extent permitted by law, be the sole and exclusive forum for (1) any derivative action or proceeding brought on our behalf, (2) any action asserting a claim of breach of a fiduciary duty owed by any of our directors, officers, employees or agents to us or our stockholders, creditors or other constituents, (3) any action asserting a claim against us arising pursuant to any provision of the Delaware General Corporation Law, our certificate of incorporation, as amended, or our amended and restated bylaws, or (4) any other action asserting a claim against us that is governed by the internal affairs doctrine.
Any problems or delays we or our CMOs experience in preparing for commercial scale manufacturing of a product, product candidate, or component thereof may result, in the case of product candidates, a delay in the FDA approval thereof or, in the case of products, may impair our ability to manufacture commercial quantities or such quantities at an acceptable cost, which could result in the delay, prevention, or impairment of clinical development of our product candidates and commercialization of our products and could adversely affect our business.
Any problems or delays we or our CMOs experience in preparing for commercial scale manufacturing of a product, product candidate, or component thereof may result, in the case of product candidates, a delay in the approval thereof or, in the case of products, may impair our ability to manufacture commercial quantities or such quantities at an acceptable cost, which could result in the delay, prevention, or impairment of clinical development of our product candidates and commercialization of our products and could adversely affect our business.
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.
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, BioNTech, Bristol-Myers Squibb, Merck, Pfizer, Regeneron Pharmaceuticals, Roche, and others.
Additional federal and state healthcare reform measures may be adopted in the future that may result in more rigorous coverage criteria, increased regulatory burdens and operating costs, decreased net revenue from our pharmaceutical products, decreased potential returns from our development efforts, and additional downward pressure on the price that we receive for any approved drug.
New federal and state healthcare reform measures may be adopted in the future that may result in more rigorous coverage criteria, increased regulatory burdens and operating costs, decreased net revenue from our pharmaceutical products, decreased potential returns from our development efforts, and additional downward pressure on the price that we receive for any approved drug.
Any potential acquisition or strategic partnership may entail numerous risks, including: ● increased operating expenses and cash requirements; ● the assumption of additional indebtedness or contingent liabilities; ● the issuance of our equity securities; 65 Table of Contents ● assimilation of operations, intellectual property and products of an acquired company or product, including difficulties associated with integrating new personnel; ● the diversion of our management’s attention from our existing product programs and initiatives in pursuing such a strategic merger or acquisition; ● retention of key employees, the loss of key personnel, and uncertainties in our ability to maintain key business relationships; ● risks and uncertainties associated with the other party to such a transaction, including the prospects of that party and their existing products or product candidates and regulatory approvals; and ● our inability to generate revenue from acquired technology and/or products sufficient to meet our objectives in undertaking the acquisition or even to offset the associated acquisition and maintenance costs.
Any potential acquisition or strategic partnership may entail numerous risks, including: ● increased operating expenses and cash requirements; ● the assumption of additional indebtedness or contingent liabilities; ● the issuance of our equity securities; ● assimilation of operations, intellectual property and products of an acquired company or product, including difficulties associated with integrating new personnel; ● the diversion of our management’s attention from our existing product programs and initiatives in pursuing such a strategic merger or acquisition; ● retention of key employees, the loss of key personnel, and uncertainties in our ability to maintain key business relationships; ● risks and uncertainties associated with the other party to such a transaction, including the prospects of that party and their existing products or product candidates and regulatory approvals; and 66 Table of Contents ● our inability to generate revenue from acquired technology and/or products sufficient to meet our objectives in undertaking the acquisition or even to offset the associated acquisition and maintenance costs.
Moreover, the recent and ongoing series of congressional hearings relating to drug pricing has presented heightened attention to the biopharmaceutical industry, creating the potential for political and public pressure, while the potential for resulting legislative or policy changes presents uncertainty. Assuming coverage is approved, the resulting reimbursement payment rates might not be adequate.
Moreover, recent and ongoing series of congressional hearings relating to drug pricing has presented heightened attention to the biopharmaceutical industry, creating the potential for political and public pressure. The potential for resulting legislative or policy changes presents uncertainty. Assuming coverage is approved, the resulting reimbursement payment rates might not be adequate.
Under our license or acquisition agreements with the NIH, Moffitt, Novartis, Clinigen and Cellectis for our adoptive cell therapy and immunotherapy technologies, we are currently required to pay both substantial benchmark payments and royalties to each entity based on our revenues from sales of our products utilizing the licensed or acquired technologies.
Under our license or acquisition agreements with the NIH, Novartis, Clinigen, and Cellectis for our adoptive cell therapy and immunotherapy technologies, we are currently required to pay both substantial benchmark payments and royalties to each entity based on our revenues from sales of our products utilizing the licensed or acquired technologies.
In order to maintain our license rights under the NIH, Moffitt, Novartis, and Cellectis license agreements, we will need to meet certain specified milestones, subject to certain cure provisions, in the development of our product candidates, and a milestone payment is required to Clinigen upon the approval of lifileucel in melanoma.
In order to maintain our license rights under the NIH, Novartis, and Cellectis license agreements, we will need to meet certain specified milestones, subject to certain cure provisions, in the development of our product candidates, and a milestone payment is required to Clinigen upon the approval of lifileucel in melanoma.
In order to commercialize our products, we must build our marketing, sales, and distribution capabilities or make arrangements with third parties to perform these services, which will take time and require significant financial expenditures and we may not be successful in doing so.
In order to commercialize our products, we must continue to build our marketing, sales, and distribution capabilities or make arrangements with third parties to perform these services, which will take time and require significant financial expenditures, and we may not be successful in doing so.
Even though we do not and will not control referrals of healthcare services or bill directly to Medicare, Medicaid, or other third-party payors, certain federal and state healthcare laws and regulations pertaining to fraud and abuse and patients’ rights are and will be applicable to our business.
Even though we do not and will not control referrals of healthcare services or bill directly to Medicare, Medicaid, or other third-party payors, certain federal and state healthcare laws and regulations pertaining to fraud and abuse, disclosures, and patients’ rights are and will be applicable to our business.
These combination therapies will require additional testing and clinical trials will require additional FDA regulatory approval and will increase our future cost of expenses. Any inability to successfully complete preclinical and clinical development could result in additional costs to us or impair our ability to generate revenue.
These combination therapies will require additional testing and clinical trials will require additional regulatory approval and will increase our future cost of expenses. Any inability to successfully complete preclinical and clinical development could result in additional costs to us or impair our ability to generate revenue.
Before obtaining regulatory approvals for the commercial sale of any of our product candidates, we must demonstrate through lengthy, complex and expensive preclinical testing and clinical trials that our product candidates are both safe and effective for use in each target indication.
Before obtaining additional regulatory approvals for the commercial sale of any of our product candidates, we must demonstrate through lengthy, complex and expensive preclinical testing and clinical trials that our product candidates are both safe and effective for use in each target indication.
The extent and duration of the conflicts in Ukraine and the Middle East, geopolitical tensions, record inflation, sanctions and resulting market disruptions are impossible to predict, but could be substantial. Any such disruptions may also magnify the impact of other risks described herein.
The extent and duration of the conflicts in Ukraine and the Middle East, geopolitical tensions, inflation, sanctions and resulting market disruptions are impossible to predict, but could be substantial. Any such disruptions may also magnify the impact of other risks described herein.
The degree of market acceptance of any of our products and product candidates will depend on a number of factors, including: ● the efficacy of our products and product candidates; ● the prevalence and severity of adverse events associated with such products or product candidates; ● the clinical indications for which the products are approved and the approved claims that we may make for the products; ● limitations or warnings contained in the approved product’s FDA-required labeling, including potential limitations or warnings for such products that may be more restrictive than other competitive products; ● changes in the standard of care for the targeted indications for such products and product candidates; ● the relative difficulty of administration of such products and product candidates; ● cost of treatment versus economic and clinical benefit in relation to alternative treatments or therapies; ● the availability of adequate coverage or reimbursement by third parties, such as insurance companies and other healthcare payors, and by government healthcare programs, including Medicare and Medicaid; ● the extent and strength of our marketing and distribution of such products and product candidates; ● the safety, efficacy, and other potential advantages over, and availability of, alternative treatments already used or that may later be approved for any of our intended indications; ● distribution and use restrictions imposed by the FDA with respect to such products and product candidates or to which we agree as part of a mandatory risk evaluation and mitigation strategy or voluntary risk management plan; ● the timing of market introduction of such products and product candidates, as well as competitive products; ● our ability to offer such products and product candidates for sale at competitive prices; ● the willingness of the target patient population to try new therapies and of physicians to prescribe these therapies; ● the extent and strength of our third-party manufacturer and supplier support; ● the approval of other new products for the same indications; ● adverse publicity about the product or favorable publicity about competitive products; and 46 Table of Contents ● potential product liability claims.
The degree of market acceptance of any of our products and product candidates will depend on a number of factors, including: ● the efficacy of our products and product candidates; ● the prevalence and severity of adverse events associated with such products or product candidates; ● the clinical indications for which the products are approved and the approved claims that we may make for the products; ● limitations or warnings contained in the approved product’s FDA-required labeling, including potential limitations or warnings for such products that may be more restrictive than other competitive products; ● changes in the standard of care for the targeted indications for such products and product candidates; ● the relative difficulty of administration of such products and product candidates; ● cost of treatment versus economic and clinical benefit in relation to alternative treatments or therapies; ● the availability of adequate coverage or reimbursement by third parties, such as insurance companies and other healthcare payors, and by government healthcare programs, including Medicare and Medicaid; ● the extent and strength of our marketing and distribution of such products and product candidates; ​ 46 Table of Contents ● the safety, efficacy, and other potential advantages over, and availability of, alternative treatments already used or that may later be approved for any of our intended indications; ● distribution and use restrictions imposed by the FDA with respect to such products and product candidates or to which we agree as part of a mandatory REMS or voluntary risk management plan; ● the timing of market introduction of such products and product candidates, as well as competitive products; ● our ability to offer such products and product candidates for sale at competitive prices; ● the willingness of the target patient population to try new therapies and of physicians to prescribe these therapies; ● the extent and strength of our third-party manufacturer and supplier support; ● the approval of other new products for the same indications; ● adverse publicity about the product or favorable publicity about competitive products; and ● potential product liability claims.
Our business, financial condition and results of operations could be materially adversely affected by any negative impact on the global economy and capital markets resulting from the conflicts in Ukraine and the Middle East, geopolitical tensions or record inflation.
Our business, financial condition and results of operations could be materially adversely affected by any negative impact on the global economy and capital markets resulting from the conflicts in Ukraine and the Middle East, geopolitical tensions, or inflation.
For example, in February 2024, the chair and ranking member of the House Select Committee on the Chinese Communist Party, Representatives Mike Gallagher and Raja Krishnamoorthi, respectively, along with Senators Gary Peters and Bill Haggerty sent a letter to the Biden administration requesting that both WuXi AppTec Co., Ltd., WuXi’s parent company, and the affiliated WuXi Biologics be added to the Department of Defense’s Chinese Military Companies List (1260H list), the Department of Commerce’s Bureau of Industry and Security Entity List, and the Department of Treasury’s Non-SDN Chinese Military-Industrial Complex Companies List.
For example, in February 2024, the chair and ranking member of the House Select Committee on the Chinese Communist Party, Representatives Mike Gallagher and Raja Krishnamoorthi, respectively, along with Senators Gary Peters and Bill Hagerty sent a letter to the Biden administration requesting that both WuXi AppTec Co., Ltd., WuXi’s parent company, and the affiliated WuXi Biologics be added to the Department of Defense’s Chinese Military Companies List (1260H list), the Department of Commerce’s Bureau of Industry and Security Entity List, and the Department of Treasury’s Non-SDN Chinese Military-Industrial Complex Companies List.
The FDA regulatory approval process is lengthy and time-consuming, and we may experience significant delays in the clinical development and regulatory approval of our product candidates. We completed our first submission of a rolling BLA to the FDA for lifileucel in March 2023.
The FDA and foreign regulatory approval process is lengthy and time-consuming, and we may experience significant delays in the clinical development and regulatory approval of our product candidates. We completed our first submission of a rolling BLA to the FDA for lifileucel in March 2023.
We are required to pay substantial royalties and lump sum benchmark payments under our license or acquisition agreements with the NIH, Moffitt, Novartis, Clinigen and Cellectis, and we must meet certain milestones to maintain our license rights.
We are required to pay substantial royalties and lump sum benchmark payments under our license or acquisition agreements with the NIH, Novartis, Clinigen, and Cellectis, and we must meet certain milestones to maintain our license rights.
Our management will have discretion in the application of the net proceeds from our capital raises, including our July 2023, June 2020, October 2018, and January 2018 public offerings, and the proceeds from sales pursuant to the 2023 Sale Agreement with Jefferies, which provides for the sale of up to $450.0 million of our common stock from time to time, and our stockholders will not have the opportunity as part of their investment decision to assess whether the net proceeds from our capital raises are being used appropriately.
Our management will have discretion in the application of the net proceeds from our capital raises, including our February 2024, July 2023, June 2020, October 2018, and January 2018 public offerings, and the proceeds from sales pursuant to the 2023 Sale Agreement with Jefferies, which provides for the sale of up to $450.0 million of our common stock from time to time, and our stockholders will not have the opportunity as part of their investment decision to assess whether the net proceeds from our capital raises are being used appropriately.
Even if we are able to effectively establish a sales force and develop a marketing and sales infrastructure, our sales force and marketing teams may not be successful in commercializing our current or future product candidates.
Furthermore, even if we are able to effectively establish a sales force and develop a marketing and sales infrastructure, our sales force and marketing teams may not be successful in commercializing our current or future product candidates.
We have reported preliminary results for clinical trials of our product candidates, including TIL for the treatment of metastatic melanoma, non-small cell lung cancer, cervical cancer, and head and neck cancers.
We have reported preliminary results for clinical trials of our product candidates, including TIL cell therapy for the treatment of metastatic melanoma, non-small cell lung cancer, cervical cancer, and head and neck cancers.
Large judgements have also been awarded in class action lawsuits based on therapeutics that had unanticipated side effects. If we cannot successfully defend ourselves against product liability claims, we may incur substantial liabilities or be required to limit or halt commercialization of our products and/or product candidates. Even a successful defense would require significant financial and management resources.
Large judgments have also been awarded in class action lawsuits based on therapeutics that had unanticipated side effects. If we cannot successfully defend ourselves against product liability claims, we may incur substantial liabilities or be required to limit or halt commercialization of our products and/or product candidates. Even a successful defense would require significant financial and management resources.
Additionally, our ability to use any net operating loss and credit carryforwards to offset taxable income or tax, respectively, in the future will be limited under Sections 382 and 383 of the Code, respectively, if we have a cumulative change in ownership of more than 50% within a three-year period. Prior to December 31, 2023, we experienced multiple ownership changes.
Additionally, our ability to use any net operating loss and credit carryforwards to offset taxable income or tax, respectively, in the future will be limited under Sections 382 and 383 of the Code, respectively, if we have a cumulative change in ownership of more than 50% within a three-year period. Prior to December 31, 2024, we experienced multiple ownership changes.
A failure to comply with these requirements may result in regulatory enforcement actions against our manufacturers or us, including fines and civil and criminal penalties, which could result in imprisonment, suspension or restrictions of production, 40 Table of Contents injunctions, delay or denial of product approval or supplements to approved products, clinical holds or termination of clinical trials, warning or untitled letters, regulatory authority communications warning the public about safety issues with the biologic, refusal to permit the import or export of the products, product seizure, detention, or recall, operating restrictions, suits under the civil False Claims Act, corporate integrity agreements, consent decrees, or withdrawal of product approval.
A failure to comply with these requirements may result in regulatory enforcement actions against our manufacturers or us, including fines and civil and criminal penalties, which could result in imprisonment, suspension or restrictions of production, injunctions, delay or denial of product approval or supplements to approved products, clinical holds or termination of clinical trials, warning or untitled letters, regulatory authority communications warning the public about safety issues with the biologic, refusal to permit the import or export of the products, product seizure, detention, or recall, operating restrictions, suits under the civil False Claims Act, corporate integrity agreements, consent decrees, or withdrawal of product approval.
We currently have a small commercial team focused on our commercial strategy, but we do not have a large commercial infrastructure for the marketing, sale, and distribution of biopharmaceutical products.
We currently have a commercial team focused on our commercial strategy, but we do not have a large commercial infrastructure for the marketing, sale, and distribution of biopharmaceutical products.
If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business, including the imposition of civil, criminal and administrative penalties, damages, disgorgement, monetary fines, possible exclusion from participation in Medicare, Medicaid and other federal healthcare programs, contractual damages, reputational harm, diminished profits and future earnings, compliance agreements, withdrawal of product approvals, and curtailment of our operations, among other things, any of which could 76 Table of Contents adversely affect our ability to operate our business and our results of operations.
If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business, including the imposition of civil, criminal and administrative penalties, damages, disgorgement, monetary fines, possible exclusion from participation in Medicare, Medicaid and other federal healthcare programs, contractual damages, reputational harm, diminished profits and future earnings, compliance agreements, withdrawal of product approvals, and curtailment of our operations, among other things, any of which could adversely affect our ability to operate our business and our results of operations.
We may experience difficulties or delays in patient enrollment in our clinical trials for a variety of reasons, including: ● the size and nature of the patient population; ● the severity of the disease under investigation; ● the patient eligibility criteria defined in the protocol; ● the size of the clinical trial population required for analysis of the clinical trial’s primary endpoints; ● the proximity of patients to clinical trial sites; ● the design of the clinical trial; ● our ability to recruit clinical trial investigators with the appropriate competencies and experience; ● the efforts to facilitate timely enrollment in clinical trials and the effectiveness of recruiting publicity; ● the patient referral practices of physicians; ● competing clinical trials for similar therapies or other new therapeutics not involving cell-based immunotherapy; ● clinicians’ and patients’ perceptions as to the potential advantages and side effects of the product candidate being studied in relation to other available therapies, including any new drugs or treatments that may be approved for the indications we are investigating; ● clinical investigators enrolling patients who do not meet the enrollment criteria, requiring the inclusion of additional patients in the clinical trial; 58 Table of Contents ● the ongoing COVID-19 pandemic limiting our access to patients who would otherwise be eligible for enrollment, including treatment-naïve patients who may be more likely to seek standard of care therapies available at local treatment centers rather than enroll in a clinical trial at a larger hospital; ● approval of new indications for existing therapies or approval of new therapies in general; ● our ability to obtain and maintain patient consents; and ● the risk that patients enrolled in clinical trials will not complete a clinical trial, return for post-treatment follow-up, or follow the required clinical trial procedures.
We may experience difficulties or delays in patient enrollment in our clinical trials for a variety of reasons, including: ● the size and nature of the patient population; ● the severity of the disease under investigation; ● the patient eligibility criteria defined in the protocol; ● the size of the clinical trial population required for analysis of the clinical trial’s primary endpoints; ● the proximity of patients to clinical trial sites; ● the design of the clinical trial; ● our ability to recruit clinical trial investigators with the appropriate competencies and experience; ● the efforts to facilitate timely enrollment in clinical trials and the effectiveness of recruiting publicity; ● the patient referral practices of physicians; ● competing clinical trials for similar therapies or other new therapeutics not involving cell-based immunotherapy; ● clinicians’ and patients’ perceptions as to the potential advantages and side effects of the product candidate being studied in relation to other available therapies, including any new drugs or treatments that may be approved for the indications we are investigating; ● clinical investigators enrolling patients who do not meet the enrollment criteria, requiring the inclusion of additional patients in the clinical trial; ● health epidemics, such as the COVID-19 pandemic, limiting our access to patients who would otherwise be eligible for enrollment, including treatment-naïve patients who may be more likely to seek standard of care therapies available at local treatment centers rather than enroll in a clinical trial at a larger hospital; ● approval of new indications for existing therapies or approval of new therapies in general; 59 Table of Contents ● our ability to obtain and maintain patient consents; and ● the risk that patients enrolled in clinical trials will not complete a clinical trial, return for post-treatment follow-up, or follow the required clinical trial procedures.
If we are unable to contract for a sufficient supply of needed materials on acceptable terms, or if we should encounter delays or difficulties in our relationships with manufacturers, our clinical testing and/or commercialization efforts may be delayed, thereby delaying the submission of products for regulatory approval or the market introduction and subsequent sales of our products.
If we are unable to contract for a sufficient supply of needed materials on acceptable terms, or if we should encounter delays or difficulties in our relationships with manufacturers, our clinical testing and/or commercialization efforts may be delayed, thereby delaying the submission of products for regulatory approval or the market introduction and subsequent sales of our products and product candidates.
Obtaining and maintaining regulatory approval of our product candidates in one jurisdiction does not mean that we will be successful in obtaining regulatory approval of our product candidates in other jurisdictions.
Obtaining and maintaining regulatory approval of our product candidates in one jurisdiction does not mean that we will be successful in obtaining or maintaining regulatory approval of our product candidates in other jurisdictions.
For instance, states such as California have begun enacting transparency laws aimed at curbing drug price increases and with the change in administration it is possible that President Biden may issue executive orders with the potential to change a number of prior executive branch actions on drug pricing.
For instance, states such as California have begun enacting transparency laws aimed at curbing drug price increases and with the change in administration it is possible that President Trump may issue executive orders with the potential to change a number of prior executive branch actions on drug pricing.
In addition, regulatory agencies may lack experience with our technologies and products, which may lengthen the regulatory review process, increase our development costs and delay or prevent their commercialization. Prior to Amtagvi™, no adoptive cell therapy using TIL had been approved for marketing by the FDA.
In addition, regulatory agencies may lack experience with our technologies and products, which may lengthen the regulatory review process, increase our development costs and delay or prevent their commercialization. Prior to Amtagvi ® , no adoptive cell therapy using a TIL product had been approved for marketing by the FDA.
For each of these, we rely or may rely on treatment sites, limited manufacturers, sole source vendors, or a limited number of vendors, which could impair our ability to manufacture and supply our products; ● Because our current products represent, and our other potential product candidates will represent novel approaches to the treatment of disease, there are many uncertainties regarding the development, the market acceptance, third-party reimbursement coverage and the commercial potential of our product candidates; ● No assurance can be given that the Gen 2 manufacturing process or other processes we have selected will be FDA-compliant or more efficient and will lower the cost to manufacture TIL products; ● We face significant competition from other biotechnology and pharmaceutical companies and from non-profit institutions; ● Our projections regarding the market opportunities for our products and product candidates may not be accurate, and the actual market for our products and product candidates may be smaller than we estimate; ● We may be unable to establish effective marketing and sales capabilities or enter into agreements with third parties to market and sell our products and product candidates, if they are approved, and as a result, we may be unable to generate significant product revenues; ● If our products or product candidates do not achieve broad market acceptance, the revenues that we generate from their sales will be limited; ● Our products and product candidates may face competition sooner than anticipated; ● As a condition of approval, the FDA may require that we implement various post-marketing requirements and conduct post-marketing studies, any of which would require a substantial investment of time, effort, and money, and which may limit our commercial prospects; ● We will need to grow the size and capabilities of our organization, and we may experience difficulties in managing this growth; ● We may rely on third parties to perform many essential services for any products that we commercialize, including services related to distribution, government price reporting, customer service, accounts receivable management, cash collection, and adverse event reporting.
For each of these, we rely or may rely on treatment sites, limited manufacturers, sole source vendors, or a limited number of vendors, which could impair our ability to manufacture and supply our products; ● Because our current products represent, and our other potential product candidates will represent novel approaches to the treatment of disease, there are many uncertainties regarding the development, the market acceptance, third-party reimbursement coverage, and the commercial potential of our product candidates; 32 Table of Contents ● No assurance can be given that the Gen 2 manufacturing process or other processes we have selected will be FDA-compliant or more efficient and will lower the cost to manufacture TIL products; ● We face significant competition from other biotechnology and pharmaceutical companies and from non-profit institutions; ● Our projections regarding the market opportunities for our products and product candidates may not be accurate, and the actual market for our products and product candidates may be smaller than we estimate; ● We have limited commercial experience and may be unable to establish effective marketing and sales capabilities or enter into agreements with third parties to market and sell our products and product candidates, if they are approved, and as a result, we may be unable to generate significant product awareness, and the lack of awareness may limit the revenues that we generate; ● If our products or product candidates do not achieve broad market acceptance, the revenues that we generate from their sales will be limited; ● Our products and product candidates may face competition sooner than anticipated; ● As a condition of approval, the FDA and foreign regulatory authorities may require that we implement various post-marketing requirements and conduct post-marketing studies, any of which would require a substantial investment of time, effort, and money, and which may limit our commercial prospects; ● We will need to grow the size and capabilities of our organization, and we may experience difficulties in managing this growth; ● We may rely on third parties to perform many essential services for any products that we commercialize, including services related to distribution, government price reporting, customer service, accounts receivable management, cash collection, and adverse event reporting.
You are encouraged to carefully review our full discussion of the material risk factors relevant to an investment in our business, which follows the brief bulleted list of our principal risk factors set forth below: ​ 32 Table of Contents Risks Related to Our Business: ● We have a history of operating losses; we expect to continue to incur losses and we may never be profitable; ● We may need additional financing to fund our operations and complete the development of our various product candidates and commercialization of our products, and if we are unable to obtain such financing, we may be unable to complete the development of our product candidates and commercialization of our products.
You are encouraged to carefully review our full discussion of the material risk factors relevant to an investment in our business, which follows the brief bulleted list of our principal risk factors set forth below. ​ Risks Related to Our Business: ● We have a history of operating losses; we expect to continue to incur losses, and we may never be profitable; ● We may need additional financing to fund our operations and complete the development of our various product candidates and commercialization of our products, and if we are unable to obtain such financing, we may be unable to complete the development of our product candidates and commercialization of our products.
We may not be successful in defending future claims and cannot provide assurance that insurance proceeds will be sufficient to cover any costs or liability under such claims. ​ For example, on December 11, 2020, a purported stockholder derivative complaint was filed by plaintiff Leo Shumacher against us, as nominal defendant, and then current directors, as defendants, in the Court of Chancery in the State of Delaware, or the Court.
We may not be successful in defending future claims and cannot provide assurance that insurance proceeds will be sufficient to cover any costs or liability under such claims. ​ 84 Table of Contents For example, on December 11, 2020, a purported stockholder derivative complaint was filed by plaintiff Leo Shumacher against us, as nominal defendant, and then current directors, as defendants, in the Court of Chancery in the State of Delaware, or the Court.
In addition, as previously disclosed, Iovance began startup activities for a confirmatory Phase 3 clinical trial, TILVANCE-301, of lifileucel in combination with pembrolizumab in frontline metastatic melanoma in late 2022. The FDA previously granted Fast Track Designation for lifileucel in combination with pembrolizumab for the treatment of immune checkpoint inhibitor naïve metastatic melanoma.
In addition, as previously disclosed, Iovance began a confirmatory Phase 3 clinical trial, TILVANCE-301, of lifileucel in combination with pembrolizumab in frontline metastatic melanoma in late 2022. The FDA previously granted Fast Track Designation for lifileucel in combination with pembrolizumab for the treatment of immune checkpoint inhibitor naïve metastatic melanoma.
These false claims statutes include the federal civil False Claims Act, which allows any individual to bring a lawsuit against a biopharmaceutical company on behalf of the federal government alleging submission of false or fraudulent claims or causing others to present such false or fraudulent claims, for payment by a federal program such as Medicare or Medicaid.
These false claims statutes include the federal civil FCA, which allows any individual to bring a lawsuit against a biopharmaceutical company on behalf of the federal government alleging submission of false or fraudulent claims or causing others to present such false or fraudulent claims, for payment by a federal program such as Medicare or Medicaid.
Accordingly, we may only be able to launch our products with a limited number of treatment centers, which could ultimately reduce the uptake of our products. Although we have a team allocated to authorize and monitor our treatment centers, substantial resources and investment from us and each treatment center may be required.
Accordingly, we may only be able to launch our products with a limited number of ATCs, which could ultimately reduce the uptake of our products. Although we have a team allocated to authorize and monitor our ATCs, substantial resources and investment from us and each treatment center may be required.
Even if we were to receive product approval, such approval could be contingent on inclusion of unfavorable information in our product labeling, such as limitations on the indications for use for which the products may be marketed or distributed, a label with significant safety warnings, including boxed warnings, contraindications, and precautions, a label without statements necessary or desirable for successful commercialization, or requirements for costly post marketing testing and surveillance, or other requirements, including a Risk Evaluation and Mitigations Strategy or REMS, to monitor the safety or efficacy of the products, and in turn prevent us from commercializing and generating revenues from the sale of our current or future product candidates.
Even if we were to receive product approval, such approval could be contingent on inclusion of unfavorable information in our product labeling, such as limitations on the indications for use for which the products may be marketed or distributed, a label with significant safety warnings, including boxed warnings, contraindications, and precautions, a label without statements necessary or desirable for successful commercialization, or requirements for costly post marketing testing and surveillance, or other requirements, including a REMS, to monitor the safety or efficacy of the products, and in turn prevent us from commercializing and generating revenues from the sale of our current or future product candidates.
Prior to our completion of a rolling BLA submission for lifileucel in March 2023 and its acceptance by the FDA in May 2023, we had not previously submitted a BLA to the FDA, or a similar marketing application to comparable foreign authorities, for any product candidate, and we cannot be certain that our current or any future product candidates will be successful in clinical trials or receive regulatory approval.
Prior to our completion of a rolling BLA submission for lifileucel in March 2023 and its acceptance by the FDA in May 2023 and accelerated approval in February 2024, we had not previously submitted a BLA to the FDA, or a similar marketing application to comparable foreign authorities, for any product candidate, and we cannot be certain that our current or any future product candidates will be successful in clinical trials or receive regulatory approval.
U.S. and global markets are experiencing volatility and disruption following the escalation of geopolitical tensions and the start of the military conflict between Russia and Ukraine. On February 24, 2022, a full-scale military invasion of Ukraine by Russian troops was reported.
U.S. and global markets are experiencing volatility and disruption following the escalation of geopolitical tensions and the continuation of the military conflict between Russia and Ukraine. On February 24, 2022, a full-scale military invasion of Ukraine by Russian troops was reported.
The COVID-19 pandemic could materially affect our operations, including at our headquarters in San Carlos, California, at our manufacturing facility in Philadelphia, Pennsylvania, which have previously been subject to state executive orders and shelter-in-place orders, and at our clinical trial sites, as well as the business or operations of our other manufacturers, contract research organizations, or CROs, or other third parties with whom we conduct business.
The COVID-19 pandemic could materially affect our operations, including at our headquarters in San Carlos, California, at our manufacturing facility in Philadelphia, Pennsylvania, which have previously been subject to state executive orders and shelter-in-place orders, and at our clinical trial sites, as well as the business or operations of our other manufacturers, CROs, or other third parties with whom we conduct business.
Finally, in February 2024, the chair and ranking member of the House Select Committee on the Chinese Communist Party, Representatives Mike Gallagher and Raja Krishnamoorthi, respectively, along with Senators Gary Peters and Bill Haggerty sent a letter to the Biden administration requesting that both WuXi AppTec Co., Ltd., WuXi’s parent company, and the affiliated WuXi Biologics be added to the Department of Defense’s Chinese Military Companies List (1260H list), the Department of Commerce’s Bureau of Industry and Security Entity List, and the Department of Treasury’s Non-SDN Chinese Military-Industrial Complex Companies List.
Additionally, in February 2024, the chair and ranking member of the House Select Committee on the Chinese Communist Party, Representatives Mike Gallagher and Raja Krishnamoorthi, respectively, along with Senators Gary Peters and Bill Hagerty, sent a letter to the Biden administration requesting that both WuXi AppTec Co., Ltd., WuXi’s parent company, and the affiliated WuXi Biologics be added to the Department of Defense’s Chinese Military Companies List (1260H list), the Department of Commerce’s Bureau of Industry and Security Entity List, and the Department of Treasury’s Non-SDN Chinese Military-Industrial Complex Companies List.
While lifileucel has received ODD for melanoma stages IIB-IV and for cervical cancer patients with tumors greater than 2 cm, there is no guarantee that we will be able to maintain this designation, receive these designations for any of our other product candidates, or receive or maintain any corresponding benefits, including periods of exclusivity.
While lifileucel has received orphan drug designation for melanoma stages IIB-IV and for cervical cancer patients with tumors greater than 2 cm, there is no guarantee that we will be able to maintain this designation, receive these designations for any of our other product candidates, or receive or maintain any corresponding benefits, including periods of exclusivity.
However, we may not be successful in finalizing the development of our own manufacturing facility or capability. We may establish multiple manufacturing facilities as we expand our commercial footprint to multiple geographies, which may lead to regulatory delays or prove costly.
However, we may not be successful in finalizing the expansion of our own manufacturing facility or capability. We may establish multiple manufacturing facilities as we expand our commercial footprint to multiple geographies, which may lead to regulatory delays or prove costly.
Additionally, the treatment center onboarding process can be complicated and requires extensive training, technical equipment, and coordination of processes. Once authorized, treatment centers will be required to ensure that their training, facilities, and treatment capabilities are adequately maintained.
Additionally, the treatment center onboarding process can be complicated and requires extensive training, technical equipment, and coordination of processes. Once authorized, ATCs will be required to ensure that their training, facilities, and treatment capabilities are adequately maintained.
Events that may prevent successful or timely initiation or completion of clinical development, or product approval include: ● regulators or IRBs may not authorize us or our investigators to commence a clinical trial, conduct a clinical trial at a prospective clinical trial site, or amend clinical trial protocols, or regulators or IRBs may require that we modify or amend our clinical trial protocols; ● delays in reaching a consensus or inability to obtain agreement with regulatory agencies on clinical trial design; ● the FDA or comparable foreign regulatory authorities may disagree with our intended indications, clinical trial design or our interpretation of data from preclinical studies and clinical trials or find that a product candidate’s benefits do not outweigh its safety risks; ● the FDA or comparable foreign regulatory authorities may not accept data from studies with clinical trial sites in foreign countries; ● the FDA may not allow us to use the clinical trial data from a research institution to support an IND if we cannot demonstrate the comparability of our product candidates with the product candidate used by the relevant research institution in its clinical trials; ● delays in or failure to reach an agreement on acceptable terms with prospective CROs and clinical trial sites, the terms of which can be subject to extensive negotiation and may vary significantly among different CROs and clinical trial sites; ● delays in obtaining required IRB approval at each clinical trial site; ● imposition of a temporary or permanent clinical hold, suspensions or terminations by regulatory agencies, IRBs, or us for various reasons, including noncompliance with regulatory requirements or a finding that the participants are being exposed to unacceptable health risks, undesirable side effects, or other unexpected characteristics of the product candidate, or due to findings of undesirable effects caused by a biologically or mechanistically similar therapeutic or therapeutic candidate; ● delays in recruiting suitable patients to participate in our clinical trials; ● delay in adding new investigators or clinical trial sites, or withdrawal of clinical trial sites from a clinical trial; ● delay or change in strategic direction for an indication resulting from differences in results between cohorts in a clinical trial, such as the previously disclosed preliminary results for the C-145-04 clinical trial and the final patient population and results, including differences in patient population, such as differences that might arise due to the impact of the existing immunotherapy treatment landscape, or from different interpretations of investigator results by IRC; ● failure by our CROs, clinical trial sites, patients, or other third parties, or us to adhere to clinical trial requirements, including regulatory, contractual or protocol requirements; ● failure to perform in accordance with the FDA’s cGCP requirements or applicable regulatory guidelines in other countries; ● the number of patients required for clinical trials of our product candidates may be larger than we anticipate or enrollment in these clinical trials may be slower than we anticipate, potentially affecting our timelines for approval of our product candidates; 54 Table of Contents ● patients that enroll in our studies may misrepresent their eligibility or may otherwise not comply with the clinical trial protocol, resulting in the need to drop such patients from the clinical trial, increase the needed enrollment size for the clinical trial or extend the clinical trial’s duration; ● patients dropping out of a clinical trial; ● occurrence of adverse events associated with the product candidate that are viewed to outweigh its potential benefits; ● changes in regulatory requirements and guidance that require amending or submitting new clinical protocols to regulatory authorities and IRBs, and which may cause delays in our development programs, or changes to regulatory review times; ● there may be regulatory questions or disagreements regarding interpretations of data and results, or new information may emerge regarding our product candidates; ● changes in the standard of care on which a clinical development plan was based, which may require new or additional clinical trials; ● the cost of clinical trials of our product candidates being greater than we anticipate, or we may have insufficient funds for a clinical trial or to pay the substantial user fees required by the FDA upon the filing of a BLA; ● clinical trials of our product candidates producing negative or inconclusive results may fail to provide sufficient data and information to support product approval, or our studies may fail to reach the necessary level of statistical or clinical significance, which may result in our deciding, or regulators requiring us, to conduct additional clinical trials studies, or preclinical studies, or abandon product development programs; ● early results from our clinical trials of our product candidates may be negatively affected by changes in efficacy measures such as overall response rate and duration of response as more patients are enrolled in our clinical trials or as new cohorts of our clinical trials are tested, and overall response rate and duration of response may be negatively affected by the inclusion of unconfirmed responses in preliminary results that we report if such responses are not later confirmed; ● we may not be able to demonstrate that a product candidate provides an advantage over current standards of care or current or future competitive therapies in development; ● there may be changes to the therapeutics or their regulatory status which we are administering in combination with our product candidates; ● delays in patient enrollment due to the ongoing COVID-19 pandemic; ● the FDA or comparable foreign regulatory authorities may fail to approve or subsequently find fault with the manufacturing processes or our manufacturing facilities for clinical and future commercial supplies; ● the FDA or comparable regulatory authorities may take longer than we anticipate making a decision on our product candidates; ● transfer of our manufacturing processes to our CMOs or other larger-scale facilities operated by a CMO or by us and delays or failures by our CMOs or us to make any necessary changes to such manufacturing process; ● our use of different manufacturing processes within our clinical trials, including our Gen 1 and Gen 2 manufacturing processes, and any effects that may result from the use of different processes on the clinical data that we have reported and will report in the future; and ● delays in manufacturing, testing, releasing, validating, or importing/exporting sufficient stable quantities of our product candidates for use in clinical trials or the inability to do any of the foregoing, including as a result of any quality issues associated with the contract manufacturer.
Events that may prevent successful or timely initiation or completion of clinical development, or product approval include: ● regulators or IRBs may not authorize us or our investigators to commence a clinical trial, conduct a clinical trial at a prospective clinical trial site, or amend clinical trial protocols, or regulators or IRBs may require that we modify or amend our clinical trial protocols; ● delays in reaching a consensus or inability to obtain agreement with regulatory agencies on clinical trial design; ● the FDA or comparable foreign regulatory authorities may disagree with our intended indications, clinical trial design or our interpretation of data from preclinical studies and clinical trials or find that a product candidate’s benefits do not outweigh its safety risks; ● the FDA or comparable foreign regulatory authorities may not accept data from studies with clinical trial sites in foreign countries; ● the FDA may not allow us to use the clinical trial data from a research institution to support an IND if we cannot demonstrate the comparability of our product candidates with the product candidate used by the relevant research institution in its clinical trials; ● delays in or failure to reach an agreement on acceptable terms with prospective CROs and clinical trial sites, the terms of which can be subject to extensive negotiation and may vary significantly among different CROs and clinical trial sites; ● delays in obtaining required IRB approval at each clinical trial site; ● imposition of a temporary or permanent clinical hold, suspensions or terminations by regulatory agencies, IRBs, or us for various reasons, including noncompliance with regulatory requirements or a finding that the participants are being exposed to unacceptable health risks, undesirable side effects, or other unexpected characteristics of the product candidate, or due to findings of undesirable effects caused by a biologically or mechanistically similar therapeutic or therapeutic candidate; ● delays in recruiting suitable patients to participate in our clinical trials; ● delay in adding new investigators or clinical trial sites, or withdrawal of clinical trial sites from a clinical trial; ● delay or change in strategic direction for an indication resulting from differences in results between cohorts in a clinical trial, such as the previously disclosed preliminary results for the C-145-04 clinical trial and the final patient population and results, including differences in patient population, such as differences that might arise due to the impact of the existing immunotherapy treatment landscape, or from different interpretations of investigator results by IRC; ● failure by our CROs, clinical trial sites, patients, or other third parties, or us to adhere to clinical trial requirements, including regulatory, contractual or protocol requirements; ● failure to perform in accordance with the FDA’s cGCP requirements or applicable regulatory guidelines in other countries; ● the number of patients required for clinical trials of our product candidates may be larger than we anticipate or enrollment in these clinical trials may be slower than we anticipate, potentially affecting our timelines for approval of our product candidates; ● patients that enroll in our studies may misrepresent their eligibility or may otherwise not comply with the clinical trial protocol, resulting in the need to drop such patients from the clinical trial, increase the needed enrollment size for the clinical trial or extend the clinical trial’s duration; ● patients dropping out of a clinical trial; ● occurrence of adverse events associated with the product candidate that are viewed to outweigh its potential benefits; ● changes in regulatory requirements and guidance that require amending or submitting new clinical protocols to regulatory authorities and IRBs, and which may cause delays in our development programs, or changes to regulatory review times; ● there may be regulatory questions or disagreements regarding interpretations of data and results, or new information may emerge regarding our product candidates; ● changes in the standard of care on which a clinical development plan was based, which may require new or additional clinical trials; ● the cost of clinical trials of our product candidates being greater than we anticipate, or we may have insufficient funds for a clinical trial or to pay the substantial user fees required by the FDA upon the filing of a BLA; ● clinical trials of our product candidates producing negative or inconclusive results may fail to provide sufficient data and information to support product approval, or our studies may fail to reach the necessary level of statistical or clinical significance, which may result in our deciding, or regulators requiring us, to conduct additional clinical trials studies, or preclinical studies, or abandon product development programs; ● early results from our clinical trials of our product candidates may be negatively affected by changes in efficacy measures such as overall response rate and duration of response as more patients are enrolled in our clinical trials or as new cohorts of 55 Table of Contents our clinical trials are tested, and overall response rate and duration of response may be negatively affected by the inclusion of unconfirmed responses in preliminary results that we report if such responses are not later confirmed; ● we may not be able to demonstrate that a product candidate provides an advantage over current standards of care or current or future competitive therapies in development; ● there may be changes to the therapeutics or their regulatory status which we are administering in combination with our product candidates; ● delays in patient enrollment due to potential health epidemics, such as the COVID-19 pandemic; ● the FDA or comparable foreign regulatory authorities may fail to approve or subsequently find fault with the manufacturing processes or our manufacturing facilities for clinical and future commercial supplies; ● the FDA or comparable regulatory authorities may take longer than we anticipate when making a decision on our product candidates and prolonged government shutdowns, inadequate funding, loss of employees, changes in regulations or policies by the new U.S. administration or other disruptions may occur at the FDA, and thus, final FDA approval of our product candidates may be further delayed; ● transfer of our manufacturing processes to our CMOs or other larger-scale facilities operated by a CMO or by us and delays or failures by our CMOs or us to make any necessary changes to such manufacturing process; ● our use of different manufacturing processes within our clinical trials, including our Gen 1 and Gen 2 manufacturing processes, and any effects that may result from the use of different processes on the clinical data that we have reported and will report in the future; and ● delays in manufacturing, testing, releasing, validating, or importing/exporting sufficient stable quantities of our product candidates for use in clinical trials or the inability to do any of the foregoing, including as a result of any quality issues associated with the contract manufacturer.
Although we believe Gen 2 is a commercially viable process, there are risks associated with scaling to the level required for advanced clinical trials or commercialization, including, among others, cost overruns, potential problems with process scale-up, process reproducibility, stability issues, lot consistency, and timely availability of raw materials.
Although we believe Gen 2 is a commercially viable process, there are risks associated with scaling to the level required for advanced clinical trials or commercialization, including, among others, cost 38 Table of Contents overruns, potential problems with process scale-up, process reproducibility, stability issues, lot consistency, and timely availability of raw materials.
We may also face competition from novel IL-2 treatments in development by Alkermes, Werewolf, Nektar Therapeutics, Merck, Sanofi, Neoleukin 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.
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.
If the quality or accuracy of the data maintained by these service providers is insufficient, or these third parties otherwise fail to comply with regulatory requirements related to adverse event reporting, we could be subject to regulatory sanctions. 48 Table of Contents Additionally, we may contract with a third-party to calculate and report pricing information mandated by various government programs.
If the quality or accuracy of the data maintained by these service providers is insufficient, or these third parties otherwise fail to comply with regulatory requirements related to adverse event reporting, we could be subject to regulatory sanctions. Additionally, we may contract with a third-party to calculate and report pricing information mandated by various government programs.
These False Claims Act lawsuits against manufacturers of drugs and biologics have increased significantly in volume and breadth, leading to several substantial civil and criminal settlements, up to $3.0 billion, pertaining to certain sales practices and promoting off-label uses. In addition, False Claims Act lawsuits may expose manufacturers to follow-on claims by private payors based on fraudulent marketing practices.
These FCA lawsuits against manufacturers of drugs and biologics have increased significantly in volume and breadth, leading to several substantial civil and criminal settlements, up to $3.0 billion, pertaining to certain sales practices and promoting off-label uses. In addition, FCA lawsuits may expose manufacturers to follow-on claims by private payors based on fraudulent marketing practices.
We continue to monitor the impact, if any, of the COVID-19 pandemic on our current and future operations, including our regulatory filing timelines and strategy as well as our preparation for commercial launch.
We continue to monitor the impact, if any, of health epidemics, including the COVID-19 pandemic, on our current and future operations, including our regulatory filing timelines and strategy, as well as our preparation for commercial launch.
Moreover, our fixed expenses such as rent, minimum payments to our contract manufacturers, and other contractual commitments, including those for our research collaborations, are substantial and are expected to increase in the future. 35 Table of Contents We will need to obtain additional financing to fund our future operations, including completing the development of our product candidates and commercialization of our products.
Moreover, our fixed expenses such as rent, minimum payments to our contract manufacturers, and other contractual commitments, including those for our research collaborations, are substantial and are expected to increase in the future. We will need to obtain additional financing to fund our future operations, including completing the development of our product candidates and commercialization of our products.
In addition, third-party payors are requiring higher levels of evidence of the benefits and clinical outcomes of new technologies and are challenging the prices charged. We, and our collaborators, cannot be sure that coverage will be available for any product candidate that we, or they, commercialize and, if available, that the reimbursement rates will be adequate.
In addition, third-party payors are requiring higher levels of evidence of the benefits and clinical outcomes of new technologies and are challenging the prices charged. We, and our collaborators, cannot be sure that coverage will be 76 Table of Contents available for any product candidate that we, or they, commercialize and, if available, that the reimbursement rates will be adequate.
These measures include: (i) comprehensive financial sanctions against major Russian banks; (ii) additional designations of Russian individuals with significant business interests and government connections; (iii) designations of individuals and entities involved in Russian military activities; and (iv) enhanced export controls and trade sanctions limiting Russia’s ability to import various goods.
These measures include: (i) comprehensive financial sanctions against major Russian banks; (ii) additional designations of Russian individuals with significant business interests and government connections; (iii) designations of individuals and entities involved in Russian military activities; and (iv) enhanced export controls and trade sanctions limiting Russia’s ability to import various 67 Table of Contents goods.
Moreover, the factors noted above have continued to be the focus of policy and regulatory debate that has, thus far, shown the potential for movement towards permanent policy changes; this trend is apt to continue, and may result in more or less favorable impacts on pricing.
Moreover, the factors noted above have continued to be the focus of policy and regulatory debate that has, thus far, shown the potential for movement towards permanent policy changes; 75 Table of Contents this trend is apt to continue, and may result in more or less favorable impacts on pricing.
The U.S. government, state legislatures and foreign governmental entities have shown significant interest in implementing cost containment programs to limit the growth of government-paid healthcare costs, including price controls, restrictions on reimbursement 75 Table of Contents and coverage and requirements for substitution of generic products for branded prescription drugs.
The U.S. government, state legislatures and foreign governmental entities have shown significant interest in implementing cost containment programs to limit the growth of government-paid healthcare costs, including price controls, restrictions on reimbursement and coverage and requirements for substitution of generic products for branded prescription drugs.
While additional technologies that may be developed under our CRADA may be licensed to us on an exclusive basis, no assurance can be given that our existing exclusive rights and will be sufficient to prevent others from competing with us and developing substantially similar products. 78 Table of Contents The use of our technologies could potentially conflict with the rights of others.
While additional technologies that may be developed under our CRADA may be licensed to us on an exclusive basis, no assurance can be given that our existing exclusive rights will be sufficient to prevent others from competing with us and developing substantially similar products. The use of our technologies could potentially conflict with the rights of others.
Proceedings to enforce our patent rights in foreign jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business, could put our patents at risk of being invalidated or interpreted narrowly and our patent applications at risk of not issuing and could provoke third parties to assert claims against us.
Proceedings to enforce our patent rights in foreign jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business, could put our patents at risk of being invalidated or interpreted narrowly and our patent applications at 82 Table of Contents risk of not issuing and could provoke third parties to assert claims against us.
Depending on the outcome of our open-label studies, we may need to conduct one or more follow-up or supporting studies in order to successfully develop our products for FDA approval.
Depending on the outcome of our open-label studies, we may need to conduct one or more follow-up or supporting studies in order to successfully develop our products for regulatory approval.
As recently as April 2022, ports and airports in Shanghai, China have been closed due to another outbreak of COVID-19, resulting in a lockdown of the city and disruption to export and import activities.
As recently as April 2022, ports and airports in Shanghai, China closed due to another outbreak of COVID-19, resulting in a lockdown of the city and disruption to export and import activities.
The cGMP requirements include quality control, quality assurance, and the maintenance of records and documentation. The FDA and other regulatory authorities enforce these requirements through facility inspections. Manufacturing facilities must submit to pre-approval inspections by the FDA that will be conducted after we submit our marketing applications, including our BLAs, to the FDA.
The cGMP requirements include quality control, quality assurance, and the maintenance of records and documentation. The FDA and other regulatory authorities enforce these requirements through facility inspections. Manufacturing facilities must submit to pre-approval inspections by the FDA that will be conducted after we submit our marketing applications for our product candidates, including our BLAs, to the FDA.
There can be no assurance as to the length of the clinical trial period, the number of patients the FDA will require to be enrolled in the clinical trials in order to establish the safety, efficacy, purity and potency of immunotherapy products, or that the data generated in these clinical trials will be acceptable to the FDA to support marketing approval.
There can be no assurance as to the length of the clinical trial period, the number of patients the FDA and foreign regulatory authorities will require to be enrolled in the clinical trials in order to establish the safety, efficacy, purity and potency of immunotherapy products, or that the data generated in these clinical trials will be acceptable to the FDA and foreign regulatory authorities to support marketing approval.
We expect to rely on medical institutions, academic institutions, or CROs to conduct, supervise or monitor some or all aspects of clinical trials involving our products. We will have less control over the timing and other aspects of these clinical trials than if we conducted them entirely on our own.
We expect to rely on medical institutions, academic institutions, or CROs to conduct, supervise or monitor some or all aspects of clinical trials involving our products. We will have less control over the timing and other aspects of these clinical trials than if we 57 Table of Contents conducted them entirely on our own.
Shortly following the attack, Israel’s security cabinet declared war against Hamas and launched an aerial bombardment of various targets within the Gaza Strip. The Israeli government subsequently called for the evacuation of over one million residents of the northern part of the Gaza Strip and began a ground invasion of the Gaza Strip.
Shortly following the attack, Israel’s security cabinet declared war against Hamas and launched an aerial bombardment of various targets within the Gaza Strip. The Israeli government subsequently called for the evacuation of over one million residents of the northern part of the Gaza Strip and began a ground invasion of the Gaza Strip that remains ongoing.
If a defendant or third 77 Table of Contents party were to prevail on a legal assertion of invalidity and/or unenforceability, we would lose at least part, and perhaps all, of the patent protection on our product candidates. Such a loss of patent protection could have a material adverse impact on our business.
If a defendant or third party were to prevail on a legal assertion of invalidity and/or unenforceability, we would lose at least part, and perhaps all, of the patent protection on our product candidates. Such a loss of patent protection could have a material adverse impact on our business.
If approved for marketing by applicable regulatory authorities, our ability to generate revenues from our product candidates will depend on our ability to: ● price our product candidates competitively such that third-party and government reimbursement leads to broad product adoption; ● prepare a broad network of clinical sites for administration of our product; ● train and monitor sites for product delivery and consistent flow of appropriate patients; ● create market demand for our product candidates through our own marketing and sales activities, and any other arrangements to promote these product candidates that we may otherwise establish; ● receive regulatory approval for the targeted patient population(s) and claims that are necessary or desirable for successful marketing; ● obtain the necessary regulatory approvals to deliver the therapies to a sufficiently sized patient population; ● effectively commercialize our products; ● manufacture product candidates through CMOs or in our own manufacturing facility in sufficient quantities and at acceptable quality and manufacturing cost to meet commercial demand at launch and thereafter; ● establish and maintain agreements with wholesalers, distributors, pharmacies, and group purchasing organizations on commercially reasonable terms; ● maintain patent and trade secret protection and regulatory exclusivity for our product candidates; ● launch commercial sales of our product candidates; 50 Table of Contents ● maintain compliance with applicable laws, regulations, and guidance specific to commercialization, including interactions with health care professionals, patient advocacy groups, and communication of health care economic information to payors and formularies; ● achieve market acceptance of our product candidates by patients, the medical community, and third-party payors; ● achieve appropriate reimbursement for our product candidates; ● obtain payor coverage at rates that will enable the market to adopt our product and enable sites to deliver the entire therapy to patients; ● partner with third party logistics providers that will successfully distribute our products; ● maintain a distribution and logistics network capable of product storage within our specifications and regulatory guidelines, and further capable of timely product delivery to commercial clinical sites; ● effectively compete with other therapies or competitors; and ● following launch, ensure that our product will be used as directed and that additional unexpected safety risks will not arise. ​ Development of a product candidate intended for use in combination with an already approved product may present more or different challenges than development of a product candidate for use as a single agent.
If approved for marketing by applicable regulatory authorities, our ability to generate revenues from our product candidates will depend on our ability to: ● price our product candidates competitively such that third-party and government reimbursement leads to broad product adoption; ● prepare a broad network of clinical sites ( e.g. , ATCs) for administration of our product; ● train and monitor sites for product delivery and consistent flow of appropriate patients; ● create market demand for our product candidates through our own marketing and sales activities, as well as through other arrangements with third parties marketing or selling on our behalf; ● receive regulatory approval for the targeted patient population(s) and claims that are necessary or desirable for successful marketing; ● obtain the necessary regulatory approvals to deliver the therapies to a sufficiently sized patient population; ● effectively commercialize our products; ● manufacture product candidates through CMOs or in our own manufacturing facility in sufficient quantities and at acceptable quality and manufacturing cost to meet commercial demand at launch and thereafter; ● establish and maintain agreements with wholesalers, distributors, pharmacies, and group purchasing organizations on commercially reasonable terms; ● maintain patent and trade secret protection and regulatory exclusivity for our product candidates; ● launch commercial sales of our product candidates; ● maintain compliance with applicable laws, regulations, and guidance specific to commercialization, including interactions with health care professionals, patient advocacy groups, and communication of health care economic information to payors and formularies; ● achieve market acceptance of our product candidates by patients, the medical community, and third-party payors; ● obtain appropriate coverage and reimbursement for our product candidates, including at rates that will enable the market to adopt our products and enable sites to deliver the entire therapy to patients; ● partner with third party logistics providers that will successfully distribute our products; ● maintain a distribution and logistics network capable of product storage within our specifications and regulatory guidelines, and further capable of timely product delivery to commercial clinical sites; ● effectively compete with other therapies or competitors; and ● following launch, ensure that our product will be used as directed and that additional unexpected safety risks will not arise. ​ 51 Table of Contents Development of a product candidate intended for use in combination with an already approved product may present more or different challenges than development of a product candidate for use as a single agent.
To the extent that we are required to establish and implement any post-approval 47 Table of Contents requirements, we will likely need to invest a significant amount of time, effort, and money. Such post-approval requirements may also limit the commercial prospects of our products and product candidates.
To the extent that we are required to establish and implement any post-approval requirements, we will likely need to invest a significant amount of time, effort, and money. Such post-approval requirements may also limit the commercial prospects of our products and product candidates.
For example, we will remain responsible for ensuring that each of our clinical trials is conducted in accordance with the general 52 Table of Contents investigational plan and protocols for the clinical trial and for ensuring that our preclinical studies are conducted in accordance with Good Laboratory Practices, or GLPs, as appropriate.
For example, we will remain responsible for ensuring that each of our clinical trials is conducted in accordance with the general investigational plan and protocols for the clinical trial and for ensuring that our preclinical studies are conducted in accordance with Good Laboratory Practices, or GLPs, as appropriate.
We cannot assure you that upon inspection by a given regulatory authority, such regulatory authority will determine that any of our clinical trials comply with GCP regulations. In addition, our clinical trials must be conducted with product candidates that were produced under cGMP.
We cannot assure you that upon inspection by a given regulatory authority, such regulatory authority will determine that any of our clinical trials comply with GCP regulations. 53 Table of Contents In addition, our clinical trials must be conducted with product candidates that were produced under cGMP.
Although our business has not been materially impacted by the ongoing military conflicts between Russia and Ukraine or Israel and Hamas, geopolitical tensions, or record inflation to date, it is impossible to predict the extent to which our operations, or those of our suppliers and manufacturers, will be impacted in the short and long term, or the ways in which the conflict may impact our business.
Although our business has not been materially impacted by the ongoing military conflicts between Russia and Ukraine or Israel and Hamas, Hezbollah, and the Houthis, geopolitical tensions, tariffs, or inflation to date, it is impossible to predict the extent to which our operations, or those of our suppliers and manufacturers, will be impacted in the short and long term, or the ways in which the conflict may impact our business.
These changes may require FDA approval or notification, may not have their desired effect, or the FDA may not accept data from prior versions of the product to support an application, delaying our clinical trials or programs or necessitating additional clinical trials or preclinical studies.
These changes may require regulatory approval or notification, may not have their desired effect, or the FDA or foreign regulatory authorities may not accept data from prior versions of the product to support an application, delaying our clinical trials or programs or necessitating additional clinical trials or preclinical studies.
The GDPR, which is wide-ranging in scope, imposes several requirements relating to the consent of the individuals to whom the personal data relates, the information provided to the individuals, the security and confidentiality of the personal data, data breach notification and the use of third-party processors in connection with the processing of personal data.
The GDPR, which is wide-ranging in scope, imposes several requirements relating to the consent of the individuals to whom the personal data relates, the information provided to the individuals, the security and 65 Table of Contents confidentiality of the personal data, data breach notification and the use of third-party processors in connection with the processing of personal data.
It could take as much as 12 months or more before we learn the results from any clinical trial using our adoptive cell therapy with TIL. The data collected from our clinical trials may not be sufficient to support approval by the FDA of our TIL-based product candidates for the treatment of solid tumors.
It could take as much as 12 months or more before we learn the results from any clinical trial using our adoptive cell therapy with TIL. The data collected from our clinical trials may not be sufficient to support approval by the FDA and foreign regulatory authorities of our TIL-based product candidates for the treatment of solid tumors.
The cost of compliance with post-approval regulations may have a negative effect on our operating results and financial condition. 70 Table of Contents Later discovery of previously unknown problems with our product candidates, including adverse events of unanticipated severity or frequency, that the product is less effective than previously thought, problems with our third-party manufacturers or manufacturing processes, or failure to comply with regulatory requirements, may result in, among other things: ● restrictions on the marketing, distribution, or manufacturing of our product candidates, withdrawal of the product from the market, or voluntary or mandatory product recalls; ● restrictions on the labeling of our product candidates, including required additional warnings, such as black box warnings, contraindications, precautions, and restrictions on the approved indication or use; ● modifications to promotional pieces; ● changes to product labeling or the way the product is administered; ● liability for harm caused to patients or subjects; ● fines, restitution, disgorgement, warning letters, untitled letters, or holds on or termination of clinical trials; ● refusal by the FDA to approve pending applications or supplements to approved applications filed by us or suspension or revocation of license approvals; ● product seizure or detention, or refusal to permit the import or export of our product candidates; ● injunctions or the imposition of civil or criminal penalties, including imprisonment; ● FDA debarment, debarment from government contracts, and refusal of future orders under existing contracts, exclusion from federal healthcare programs, consent decrees, or corporate integrity agreements; ● regulatory authority issuance of safety alerts, Dear Healthcare Provider letters, press releases, or other communications containing warnings or other safety information about the biologic; ● FDA restrictions on manufacturing or distribution if there is an inability to trace the source of a problem due to the nature of cell therapy; ● withdrawal of regulatory approvals for the Proleukin ® product; ● reputational harm; or ● the product becoming less competitive.
Later discovery of previously unknown problems with our product candidates, including adverse events of unanticipated severity or frequency, that the product is less effective than previously thought, problems with our third-party manufacturers or manufacturing processes, or failure to comply with regulatory requirements, may result in, among other things: ● restrictions on the marketing, distribution, or manufacturing of our product candidates, withdrawal of the product from the market, or voluntary or mandatory product recalls; ● restrictions on the labeling of our product candidates, including required additional warnings, such as black box warnings, contraindications, precautions, and restrictions on the approved indication or use; ● modifications to promotional pieces; ● changes to product labeling or the way the product is administered; ● liability for harm caused to patients or subjects; ● fines, restitution, disgorgement, warning letters, untitled letters, or holds on or termination of clinical trials; ● refusal by the FDA to approve pending applications or supplements to approved applications filed by us or suspension or revocation of license approvals; ● product seizure or detention, or refusal to permit the import or export of our product candidates; ● injunctions or the imposition of civil or criminal penalties, including imprisonment; 72 Table of Contents ● FDA debarment, debarment from government contracts, and refusal of future orders under existing contracts, exclusion from federal healthcare programs, consent decrees, or corporate integrity agreements; ● regulatory authority issuance of safety alerts, Dear Healthcare Provider letters, press releases, or other communications containing warnings or other safety information about the biologic; ● FDA restrictions on manufacturing or distribution if there is an inability to trace the source of a problem due to the nature of cell therapy; ● withdrawal of regulatory approvals for the Proleukin ® product; ● reputational harm; or ● the product becoming less competitive.

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Item 1C. Cybersecurity

Cybersecurity — threats and controls disclosure

2 edited+1 added−8 removed5 unchanged
Biggest changeOur employees are also required to certify their understanding and completion of training for our cybersecurity policies. ​ As of the date of this report, we are not aware of any material risks from cybersecurity threats, including as a result of any previous cybersecurity incidents, that have materially affected our business strategy, results of operations, or financial condition.
Biggest changeAs of the date of this report, we are not aware of any material risks from cybersecurity threats, including as a result of any previous cybersecurity incidents, that have materially affected our business strategy, results of operations, or financial condition.
Refer to Item 1A – “ Our internal computer systems, or those used by our contract research organizations or other contractors or consultants, may fail or suffer security breaches ” and “ We are dependent on information technology, systems, infrastructure and data ,” which are incorporated by reference into this Item 1C.
Refer to Item 1A – “ Our internal computer systems, or those used by our CROs or other contractors or consultants, may fail or suffer security breaches ” and “ We are dependent on information technology, systems, infrastructure and data ,” which are incorporated by reference into this Item 1C.
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Cybersecurity We operate in the biopharmaceutical sector, which is subject to various cybersecurity risks that could adversely affect our business, financial condition, and the results of operations, including intellectual property theft, fraud, extortion, harm to employees, third party vendors or customers, violation of privacy laws and other litigation and legal risk, and reputational risk. ​ Risk Management and Strategy ​ We have processes in place for assessing, identifying, and managing material risks from cybersecurity threats, which are integrated into our overall risk management processes.
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Cybersecurity We operate in the biopharmaceutical sector, which is subject to various cybersecurity risks that could adversely affect our business, financial condition, and the results of operations, including intellectual property theft, fraud, extortion, harm to employees, third party vendors or customers, violation of privacy laws and other litigation and legal risk, and reputational risk. ​ Risk Management and Strategy ​ We have designed and implemented a cybersecurity program which includes administrative, technical, and physical controls and processes to manage and mitigate material risks from internal and external cybersecurity threats, including but not limited to the following: ​ ● A team responsible for designing, implementing, and continually improving our policies, procedures, and technology. ● A risk management process to identify, assess, and treat internal and external ( third-party ) cybersecurity risks. 86 Table of Contents ● An incident management program to effectively and efficiently identify, review, and escalate incidents with the appropriate stakeholders (e.g., CEO, CFO, Legal, Finance, and others, as required). ● A vulnerability management program to scan and penetration test, on an ongoing basis, our systems and networks to identify and treat identified vulnerabilities. ● A security awareness program that educates our team members on an ongoing basis on internal security policies and secure behaviors. ● Engage with key vendors, industry participants and intelligence and law enforcement communities as part of continuing efforts to evaluate and enhance the effectiveness of our information security program. ● Periodically reporting risks , previous and current incidents, and ways to mitigate risks to the Chief Executive Officer, the Audit Committee of the Board of Directors, and other members of senior management .
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These processes include identifying and assessing risks from cybersecurity threats associated with the use of third-party service providers, if any. The response to any cybersecurity incident detected or reported is led by our Computer Security Incident Response Team, or the CSIRT, to assess the nature and magnitude of event and classify severity in accordance with our internal policies and procedures.
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Depending on the severity of the incident, appropriate level of management members, including our Chief Executive Officer, Chief Financial Officer, external legal counsel, and certain members of the finance and investor relations organizations, will be notified and take appropriate actions.
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In addition, the Information Technology, or IT, team provides periodic reports to the Chief Executive Officer and other members of our senior management, as appropriate, and provides periodic reports to the Audit Committee of the Board of Directors as needed.
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These reports include updates on our cyber risks and threats as well as the status of previously identified and/or reported cybersecurity incidents, if any.
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We also actively engage with key vendors, 83 Table of Contents industry participants and intelligence and law enforcement communities as part of continuing efforts to evaluate and enhance the effectiveness of our information security policies and procedures. ​ We use various tools and methodologies to assess, identify, and manage material risks from cybersecurity threats that are tested on a regular cadence.
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We also monitor and evaluate our cybersecurity posture and performance on an ongoing basis through regular vulnerability scans, penetration tests and use of threat intelligence feeds.
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The results of these activities and any key actions are reported at least once per quarter and more frequently as needed to the Audit Committee of the Board of Directors, our Chief Executive Officer, and key members of senior management.

Item 2. Properties

Properties — owned and leased real estate

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Biggest changeOn August 1, 2020, we entered into an agreement to lease approximately 2,965 square feet of a training facility space in Plymouth Meeting, Pennsylvania for a twelve-month term at a rate of approximately $6,500 per month.
Biggest changeAmerican National Red Cross Lease On February 1, 2022, we entered into an agreement to lease approximately 4,500 square feet of rentable area located in Pennsylvania, consisting of laboratories, clean room and office space, for a three-year term at a rate of approximately $17,000 a month subject to an annual increase of 2.5%.
On December 22, 2021, we entered into a second amendment to lease an additional 2,731 square feet of space through June 5, 2025, co-terminus with the existing leased space. Upon completion of tenant improvements of the premise, lease payments will be approximately $45,000 per month.
On December 22, 2021, we entered into a second 88 Table of Contents amendment to lease an additional 2,731 square feet of space through June 5, 2025, co-terminus with the existing leased space. Upon completion of tenant improvements of the premises, lease payments will be approximately $45,000 per month.
Netherlands Office Lease On July 28, 2023, we entered into an agreement to lease a satellite office space in Amsterdam, Netherlands for a twelve-month term at a rate of approximately 5,400 € per month.
Netherlands Office Lease On July 28, 2023, we entered into an agreement to lease satellite office space in Amsterdam, Netherlands for a twelve-month term at a rate of approximately €5,400 per month, which was renewed in 2024 to extend the lease term through July 28, 2025.
The New Headquarters Lease includes an option to extend the term of the lease for 60 months, exercisable under certain conditions and at a market rate as described in the New Headquarters Lease.
The Headquarters Lease, which commenced in January 2022, had an initial term of 120 months and included an option to extend the term of the lease for 60 months, exercisable under certain conditions and at a market rate as described in the Headquarters Lease.
Commencing 210 days after the Rent Commencement Date as the result of a rent abatement, our monthly base rent under the New Headquarters Lease is approximately $0.3 million, subject to an annual increase of 3%.
Commencing 210 days after the rent commencement date as the result of a rent abatement, our monthly base rent under the Headquarters Lease was approximately $0.3 million, subject to an annual increase of 3%. We were also responsible for paying operating expenses such as common area maintenance.
We are also responsible for paying operating expenses such as common area maintenance. 84 Table of Contents Minimum rental payments under the New Headquarters Lease total $36.7 million for the entire term of the lease, which does not include rental payments related to our one-time option to extend for an additional five years.
Minimum rental payments under the Headquarters Lease totaled $36.7 million for the entire term of the lease, which does not include rental payments related to our one-time option to extend for an additional five years.
Item 2. Properties San Carlos Headquarters Lease On February 8, 2021, we entered into a lease agreement, or the New Headquarters Lease, for laboratories and offices to be constructed in Suite 400 of an existing building located at 825 Industrial Road, San Carlos, California, or the Building.
Item 2. Properties New San Carlos Headquarters Lease On November 15, 2024, we entered into a sublease agreement, or the New Headquarters Lease, with a third party for Suite 100 in an existing building located at 825 Industrial Road, San Carlos, California, or the Building.
Under the New Headquarters Lease, we lease approximately 49,918 rentable square feet of space in the Building that currently serves as the premises for our headquarters. The New Headquarters Lease, which commenced in January 2022, has an initial term of 120 months.
Under the Headquarters Lease, we leased approximately 49,918 rentable square feet of space in the Building that served as the premises for our headquarters.
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Under the New Headquarters Lease, we will lease approximately 16,731 rentable square feet of space in the Building. The New Headquarters Lease is for a term of 24 months and commenced on December 12, 2024.
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The New Headquarters Lease includes two options to extend the term of the lease for 12 months each, exercisable under certain conditions and at a rate increased by 3% from the applicable monthly base rent as described in the New Headquarters Lease.
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Beginning on the commencement date, our monthly base rent under the New Headquarters Lease will be $0.1 million during the term.
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We are also responsible for paying operating expenses such as common area maintenance. 87 Table of Contents San Carlos Headquarters Lease On February 8, 2021, we entered into a lease agreement, or the Headquarters Lease, for laboratories and offices to be constructed in Suite 400 of the Building.
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On November 15, 2024, the Company entered into an Agreement for Termination of Lease and Voluntary Surrender of Premises with the Landlord, or the Termination Agreement, in connection with the termination of that certain Lease Agreement, dated as of February 8, 2021, with the Landlord, or the Prior Headquarters Lease, of Suite 400 of the Building, or the Prior Premises.
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Pursuant to the Termination Agreement, the Company and the Landlord agreed to terminate the Prior Headquarters Lease effective as of the earlier of (i) the date the Company vacates and surrenders the Prior Premises in accordance with all the conditions and requirements set forth in the Prior Headquarters Lease; or (ii) 11:59 p.m. Pacific Time on December 31, 2024.
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In connection with the termination of the Prior Headquarters Lease, the Company agreed to surrender the Prior Premises and pay a lease modification payment to the Landlord upon mutual execution of the Termination Agreement. The Prior Headquarters Lease termination is related to continued efforts by the Company to identify cost reduction opportunities.
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Concurrently with the termination of the Prior Headquarters Lease and the effectiveness of the Termination Agreement, the Company intends to relocate its offices to the Premises, with significantly reduced square footage and ongoing operating costs.

Item 3. Legal Proceedings

Legal Proceedings — active lawsuits and investigations

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Biggest changeThere are no matters which constitute material pending legal proceedings to which we are a 85 Table of Contents party other than those incorporated into this item by reference from Note 11 to our consolidated financial statements for the year ended December 31, 2023, contained in this Annual Report on Form 10-K. ​ Item 4.
Biggest changeThere are no matters which constitute material pending legal proceedings to which we are a party other than those incorporated into this item by reference from Note 11 to our consolidated financial statements for the year ended December 31, 2024, contained in this Annual Report on Form 10-K. ​ Item 4. Mine Safety Disclosures Not applicable. PART II
Item 3. Legal Proceedings The information in Note 15 to the consolidated financial statements contained in Part III, Item 15 of this Annual Report on Form 10-K is incorporated herein by reference.
Item 3. Legal Proceedings The information in Note 16 to the consolidated financial statements contained in Part III, Item 15 of this Annual Report on Form 10-K is incorporated herein by reference.
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Mine Safety Disclosures Not applicable. ​ ​ PART II

Item 5. Market for Registrant's Common Equity

Market for Common Equity — stock, dividends, buybacks

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Biggest changeUnder the terms of our Series A Convertible Preferred Stock, we may not declare, pay or set aside any dividends on shares of any class or series of capital stock (other than dividends on shares of common stock payable in shares of common stock) unless the holders of our Series A Convertible Preferred Stock first receive, or simultaneously receive, an equal dividend on each outstanding share of Series A Convertible Preferred Stock.
Biggest changePayment of future cash dividends, if any, will be at the discretion of the Board of Directors after considering various factors, including our financial condition, operating results, current and anticipated cash needs. 89 Table of Contents Under the terms of our Series A Convertible Preferred Stock, we may not declare, pay or set aside any dividends on shares of any class or series of capital stock (other than dividends on shares of common stock payable in shares of common stock) unless the holders of our Series A Convertible Preferred Stock first receive, or simultaneously receive, an equal dividend on each outstanding share of Series A Convertible Preferred Stock.
The stockholder return shown in the graph below is not necessarily indicative of future performance, and we do not make or endorse any predictions as to future stockholder returns. ​ ​ Equity Compensation Plan Information Information regarding our equity compensation plans is incorporated by reference from the information in our Proxy Statement for our 2024 Annual Meeting of Stockholders, which we will file with the SEC within 120 days after the end of the fiscal year to which this Annual Report on Form 10-K relates. ​ Item 6. [Reserved] ​
The stockholder return shown in the graph below is not necessarily indicative of future performance, and we do not make or endorse any predictions as to future stockholder returns. ​ ​ Equity Compensation Plan Information Information regarding our equity compensation plans is incorporated by reference from the information in our Proxy Statement for our 2025 Annual Meeting of Stockholders, which we will file with the SEC within 120 days after the end of the fiscal year to which this Annual Report on Form 10-K relates. 90 Table of Contents Item 6. [Reserved] ​
Item 5. Market for Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities Market Information Our common stock is traded on The Nasdaq Global Market under the symbol “IOVA.” Stockholders As of December 31, 2023, there were approximately 17 holders of record of our common stock.
Item 5. Market for Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities Market Information Our common stock is traded on The Nasdaq Global Market under the symbol “IOVA.” Stockholders As of December 31, 2024, there were approximately 18 holders of record of our common stock.
Repurchases of Common Stock There were no share repurchases during the year ended December 31, 2023. 86 Table of Contents Stock Performance Graph ​ The following graph illustrates a comparison of the total cumulative stockholder return on our common stock since December 31, 2018, to two indices: the Russell 3000 and the NASDAQ Biotechnology Index.
Repurchases of Common Stock There were no share repurchases during the year ended December 31, 2024. Stock Performance Graph ​ The following graph illustrates a comparison of the total cumulative stockholder return on our common stock since December 31, 2019, to two indices: the Russell 3000 and the NASDAQ Biotechnology Index.
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Payment of future cash dividends, if any, will be at the discretion of the Board of Directors after considering various factors, including our financial condition, operating results, current and anticipated cash needs.

Item 7. Management's Discussion & Analysis

Management's Discussion & Analysis (MD&A) — revenue / margin commentary

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Biggest changeThe 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 date of February 24, 2024; ● collaboration with healthcare professionals, or HCPs, who will be administering our product; ● operational excellence in launch execution, commercial manufacturing and delivery of therapy; and ● ongoing and continuous communication with payors about the value of Amtagvi™. 88 Table of Contents ​ Prepare for commercial manufacturing to meet forecasted demand We are the first company to obtain FDA approval for a TIL cell therapy product.
Biggest changeOur 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; and ● continuous communication with payors about the value of Amtagvi ® to facilitate strong reimbursement and patient access. ​ U.S.
Commercial Launch of the First TIL Cell Therapy in Advanced Melanoma Amtagvi™ 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.
Commercial Launch of the First TIL Cell Therapy in Advanced Melanoma Amtagvi ® 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 increase was primarily attributable to (i) a $40.0 million increase in payroll and related expenses, driven by increased hiring of research and development employees to support our manufacturing at i CTC and clinical development activities, (ii) a $10.3 million increase in manufacturing costs to support the increased production and qualifying i CTC suites for commercial manufacturing readiness, (iii) a $7.0 million increase in clinical trial costs driven primarily by the initiation of our Phase 3 TILVANCE-301 clinical trial, (iv) a $5.9 million increase in facility and related costs, including depreciation, maintenance, environmental monitoring and other costs primarily related to the i CTC build-out intended to expand manufacturing capacity, and (v) a $2.4 million increase in other costs, including license costs related to the expansion of our information technology infrastructure to support our clinical activities and research alliance costs.
The increase was primarily attributable to (i) a $40.0 million increase in payroll and related expenses, driven by increased hiring of research and development employees to support our manufacturing at the i CTC and clinical development activities, (ii) a $10.3 million increase in manufacturing costs to support the increased production and qualifying i CTC suites for commercial manufacturing readiness, (iii) a $7.0 million increase in clinical trial costs driven primarily by the initiation of our Phase 3 TILVANCE-301 clinical trial, (iv) a $5.9 million increase in facility and related costs, including depreciation, maintenance, environmental monitoring, and other costs primarily related to the i CTC build-out intended to expand manufacturing capacity, and (v) a $2.4 million increase in other costs, including license costs related to the expansion of our information technology infrastructure to support our clinical activities and research alliance costs.
Product candidates in later stage of clinical development generally have higher development costs than those in earlier stages of clinical development, primarily due to the increased size and duration of later-stage clinical trials. We separate our research and development expenses into two broad categories: direct and indirect.
Product candidates in later stages of clinical development generally have higher development costs than those in earlier stages of clinical development, primarily due to the increased size and duration of later-stage clinical trials. We separate our research and development expenses into two broad categories: direct and indirect.
These increases were partially offset by (i) a $6.1 million decrease in stock-based compensation expenses, primarily driven by a lower average stock price, (ii) a $4.3 million decrease in legal costs related to intellectual property related matters, and (iii) a $4.4 million decrease in other costs, including marketing, advertising and software license costs. ​ Interest income, net ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Years Ended December 31, Increase (Decrease) ​ (in thousands) 2023 2022 $ % Interest income, net ​ $ 13,043 $ 2,985 $ 10,058 ​ 337 % ​ Interest income results from our interest-bearing cash and investment balances.
These increases were partially offset by (i) a $6.1 million decrease in stock-based compensation expenses, primarily driven by a lower average stock price, (ii) a $4.3 million decrease in legal costs related to intellectual property related matters, and (iii) a $4.4 million decrease in other costs, including marketing, advertising and software license costs. ​ Interest and other income, net ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Years Ended December 31, Increase (Decrease) (in thousands) 2023 2022 $ % Interest and other income, net ​ $ 13,043 $ 2,985 ​ 10,058 337 ​ Interest and other income, net results from our interest-bearing cash and investment balances.
Such direct research and development expenses include third-party contract costs relating to the manufacturing of TILs as well as preclinical and clinical trial activities. All remaining research and development expenses are categorized as indirect research and development expenses.
Such direct research and development expenses include third-party contract costs relating to the manufacturing of TILs as well as preclinical and clinical trial activities. ​ All remaining research and development expenses are categorized as indirect research and development expenses.
Such indirect research and development expenses include employee salaries and benefits, stock-based compensation, consulting and contracted services to supplement our in-house activities, and costs associated with our facilities. These expenses are not directly tied to any individual project and are generally deployed across multiple projects.
Such indirect research and development expenses include employee salaries and benefits, stock-based compensation, consulting and contracted services to supplement our in-house activities, and costs associated with our facilities. These expenses are not directly tied to any individual project and are generally deployed across multiple projects.
Financing Activities Net cash provided by financing activities for the year ended December 31, 2023 was $463.0 million compared to net cash provided of $190.2 million for the same period in 2022.
Net cash provided by financing activities for the year ended December 31, 2023 was $463.0 million compared to net cash provided of $190.2 million for the same period in 2022.
Costs and expenses The following table summarizes the period-over-period changes in our costs and expenses: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Increase ​ ​ ​ Years Ended December 31, ​ (Decrease) ​ (in thousands) 2023 2022 ​ $ % ​ Cost of sales ​ $ 10,755 ​ $ — ​ ​ 10,755 ​ 100 % Research and development expense ​ ​ 344,077 ​ ​ 294,781 ​ ​ 49,296 ​ 17 % Selling, general and administrative expense ​ 106,916 ​ 104,097 ​ ​ 2,819 ​ 3 % ​ Cost of sales Cost of sales for the year ended December 30, 2023 was $10.7 million, which consists of $1.0 million cost of inventory and related inventoriable costs associated with sales of Proleukin ® and $9.7 million of amortization expense for the developed technology intangible asset recorded as part of the Acquisition.
Costs and expenses ​ The following table summarizes the period-over-period changes in our costs and expenses: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Years Ended December 31, ​ Increase (Decrease) (in thousands) ​ 2023 2022 ​ $ % Cost of sales ​ $ 10,755 ​ $ — ​ $ 10,755 ​ 100 Research and development expense ​ ​ 344,077 ​ ​ 294,781 ​ ​ 49,296 ​ 17 Selling, general, and administrative expense ​ ​ 106,916 ​ ​ 104,097 ​ ​ 2,819 ​ 3 ​ Cost of sales Cost of sales for the year ended December 31, 2023 was $10.7 million, which consists of $1.0 million cost of inventory and related inventoriable costs associated with sales of Proleukin ® and $9.7 million of amortization expense for the developed technology intangible asset recorded as part of the Acquisition.
As such, we do not maintain information regarding those costs incurred on a project specific basis. ​ The table below summarizes our research and development expenses by therapeutic area (in thousands): ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Increase ​ ​ Years Ended December 31, ​ (Decrease) ​ ​ 2023 2022 ​ $ % Direct research and development expense by product candidate ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ TIL, including combination therapy ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Lifileucel ​ $ 35,487 ​ $ 18,489 ​ ​ 16,998 ​ 92% LN-145 ​ ​ 41,386 ​ ​ 34,129 ​ ​ 7,257 ​ 21% Combination Therapy ​ ​ 17,809 ​ ​ 26,873 ​ ​ (9,064) ​ -34% Next Generation ​ ​ 9,987 ​ ​ 3,895 ​ ​ 6,092 ​ 156% Others clinical, preclinical and research programs under development ​ ​ 16,983 ​ ​ 17,136 ​ ​ (153) ​ -1% Indirect research and development expenses ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Personnel related (excluding stock-based compensation) ​ ​ 116,628 ​ ​ 84,100 ​ ​ 32,528 ​ 39% Stock-based compensation expenses ​ ​ 34,926 ​ ​ 50,242 ​ ​ (15,316) ​ -30% Contractors and outside services ​ ​ 20,636 ​ ​ 14,457 ​ ​ 6,179 ​ 43% Office and facilities ​ ​ 50,235 ​ ​ 45,460 ​ ​ 4,775 ​ 11% Total Research and Development ​ $ 344,077 ​ $ 294,781 ​ ​ 49,296 ​ 17% ​ Selling, general and administrative expense ​ Selling, general and administrative expense for the year ended December 31, 2023, increased by $2.8 million, or 3%, compared to the year ended December 31, 2022.
As such, we do not maintain information regarding those costs incurred on a project specific basis. ​ The table below summarizes our research and development expenses by therapeutic area (in thousands): ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Years Ended December 31, ​ Increase (Decrease) ​ ​ 2023 2022 ​ $ % Direct research and development expense by product candidate ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ TIL, including combination therapy ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Lifileucel monotherapy ​ $ 35,487 ​ $ 18,489 ​ ​ 16,998 ​ 92% Lifileucel ​ ​ 41,386 ​ ​ 34,129 ​ ​ 7,257 ​ 21% Combination Therapy ​ ​ 17,809 ​ ​ 26,873 ​ ​ (9,064) ​ -34% Next Generation ​ ​ 9,987 ​ ​ 3,895 ​ ​ 6,092 ​ 156% Others clinical, preclinical, and research programs under development ​ ​ 16,983 ​ ​ 17,136 ​ ​ (153) ​ -1% Indirect research and development expenses ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Personnel related (excluding stock-based compensation) ​ ​ 116,628 ​ ​ 84,100 ​ ​ 32,528 ​ 39% Stock-based compensation expenses ​ ​ 34,926 ​ ​ 50,242 ​ ​ (15,316) ​ -30% Contractors and outside services ​ ​ 20,636 ​ ​ 14,457 ​ ​ 6,179 ​ 43% Office and facilities ​ ​ 50,235 ​ ​ 45,460 ​ ​ 4,775 ​ 11% Total Research and Development ​ $ 344,077 ​ $ 294,781 ​ ​ 49,296 ​ 17% ​ Selling, general, and administrative expense ​ Selling, general, and administrative expense for the year ended December 31, 2023, increased by $2.8 million, or 3%, compared to the year ended December 31, 2022.
We have a history of contracting with third parties that perform various clinical trial activities on our behalf in connection with the ongoing development of our product candidates. The financial terms of these contracts are subject to negotiations and may vary from contract to contract and may result in uneven payment flow.
We have a history of contracting with third parties that perform various clinical trial activities on our behalf in connection with the ongoing development of our product candidates. The financial terms of these contracts are subject to negotiations and may vary from contract to contract and may result in an uneven payment flow.
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; remnant TIL and digest TIL compositions, methods and processes; methods of manufacturing TIL, MIL, and PBL therapies; the use of costimulatory and T cell modulating molecules in TIL cell therapy and manufacturing; stable and transient genetically-modified TIL cell therapies, including genetic knockouts of immune checkpoints; cytokine-tethered TIL cell therapies; methods of using ICIs in combination with TIL cell therapies; TIL selection technologies; and methods of treating patient subpopulations.
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; remnant TIL and digest TIL compositions, methods, and processes; methods of manufacturing TIL, MIL, and PBL therapies; the use of costimulatory and T cell modulating molecules in TIL cell therapy and manufacturing; stable and transient genetically-modified TIL cell therapies, including genetic knockouts of immune checkpoints; cytokine-tethered TIL cell therapies; methods of using immune checkpoint inhibitor, or ICIs, in combination with TIL cell therapies; TIL selection technologies; and methods of treating patient subpopulations.
Proleukin ® 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.
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.
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.
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.
Corporate Strategy Be the 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.
Corporate Strategy A global leader in innovating, developing, and delivering TIL cell therapy Our mission is to be the global leader in innovating, developing, and delivering TIL cell therapy for patients with solid tumor cancers.
These expenses were partially offset by (i) a $15.3 million decrease in stock-based compensation expenses, primarily driven by a lower average stock price, and (ii) a $1.0 million decrease in costs associated with travel and medical affairs activities such as publications and medical conferences. 93 Table of Contents Research and development activities are central to our business model.
These expenses were partially offset by (i) a $15.3 million decrease in stock- 100 Table of Contents based compensation expenses, primarily driven by a lower average stock price, and (ii) a $1.0 million decrease in costs associated with travel and medical affairs activities such as publications and medical conferences. Research and development activities are central to our business model.
We expect to continue to incur significant expenses to support our execution of the commercial launch of Amtagvi™, fund ongoing clinical programs, including our NSCLC registration study, IOV-LUN-202, and our frontline advanced melanoma Phase 3 confirmatory trial, TILVANCE-301, continue the development of our pipeline candidates, and for other general corporate purposes.
We expect to continue to incur significant expenses to support our execution of the commercial launch of Amtagvi ® , fund ongoing clinical programs, including our NSCLC registrational study, IOV-LUN-202, and our frontline advanced melanoma Phase 3 confirmatory trial, TILVANCE-301, continue the development of our pipeline candidates, and for other general corporate purposes.
Additionally, with respect to direct research and development expenses, we further divide expenses into the following sub-categories: “TIL, including combination therapy,” “Next Generation,” and “Other clinical, preclinical and research programs under development.” For direct research and development expenses, we track specific project research and development expenses that are directly attributable to our preclinical and clinical development candidates that have been selected for further development.
Additionally, with respect to direct research and development expenses, we further divide expenses into the following sub-categories: “TIL, including combination therapy,” “Next Generation,” and “Others clinical, preclinical and research programs under development.” For direct research and development expenses, we track specific project research and development expenses that are directly attributable to our preclinical and clinical development candidates that have been selected for further development.
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.
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.
No benefit or expense was recorded for the year ended December 31, 2022. ​ Net loss ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Years Ended December 31, (Increase) Decrease ​ (in thousands) 2023 2022 $ % Net loss ​ $ (444,037) $ (395,893) $ (48,144) ​ 12 % ​ Net loss for the year ended December 31, 2023, increased by $48.1 million or 12.0%, compared to the year ended December 31, 2022.
No benefit or expense was recorded for the year ended December 31, 2022 ​ Net loss ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Years Ended December 31, (Increase) Decrease ​ 2023 2022 $ % Net loss ​ $ (444,037) ​ $ (395,893) ​ (48,144) (12) ​ Net loss for the year ended December 31, 2023, increased by $48.1 million, or 12.0%, compared to the year ended December 31, 2022.
These arrangements may be material individually, and in the event that milestones for multiple products covered by these arrangements were reached in the same period, the aggregate charge to expense could be material to the results of operations in any one period.
These arrangements may be material individually, and in the event that milestones for multiple products covered by these arrangements are reached in the same period, the aggregate charge to expense could be material to the results of operations in any one period.
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.
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.
We expect our research and development expenses to decrease in conjunction with an expected increase in commercial activities and selling, general and administrative expense due to the approval of Amtagvi TM (lifileucel).
We expect our research and development expenses to decrease in conjunction with an expected increase in commercial activities and selling, general, and administrative expense due to the approval of Amtagvi ® .
In addition, it reflects a $31.4 million increase in cash used by assets and liabilities driven primarily by changes in accruals and accounts payable as well as prepaid assets, resulting from the increased workforce, overall growth in the business and operations, and the timing of vendor invoicing and related payments.
In addition, it reflects a $31.4 million increase in cash used by assets and liabilities driven primarily by changes in 104 Table of Contents accruals and accounts payable as well as prepaid assets, resulting from the increased workforce, overall growth in the business and operations, and the timing of vendor invoicing and related payments.
Other significant costs include facility costs not otherwise included in research and development expenses, legal fees relating to corporate matters and intellectual property, insurance, public company expenses relating to maintaining compliance with Nasdaq listing rules and SEC requirements, investor relations costs, and fees for accounting and consulting services.
Other significant costs include facility costs not otherwise capitalized in inventory or included in research and development expenses, legal fees relating to corporate matters and intellectual property, insurance, public company expenses relating to maintaining compliance with Nasdaq listing rules and SEC requirements, investor relations costs, and fees for accounting and consulting services.
The net cash provided by financing activities during the year ended December 30, 2022, related to $189.5 million net cash proceeds from our “at the market” offering, $1.7 million of cash receipts from the issuance of common stock under the 2020 ESPP, and $1.6 million of cash receipts from the issuance of common stock upon the exercise of stock options.
The net cash provided by financing activities during the year ended December 31, 2022 related to $189.5 million net cash proceeds from our “at the market” offering program, $1.7 million of cash receipts from the issuance of common stock under the 2020 ESPP, and $1.6 million of cash receipts from the issuance of common stock upon the exercise of stock options.
Net interest income increased by $10.1 million, or 337%, primarily due to increases in interest rates as well as a shift in our portfolio to interest bearing investments such as U.S. treasury securities and money market funds. 94 Table of Contents Income tax benefit ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Years Ended December 31, Increase (Decrease) ​ (in thousands) 2023 2022 $ % Income tax benefit ​ $ 3,479 $ — $ 3,479 ​ 100 % ​ Income tax benefit for the year ended December 31, 2023 was $3.5 million as a result of the tax benefit from the realization of the related deferred taxes for operations in the United Kingdom.
Net interest income increased by $10.1 million, or 337%, primarily due to increases in interest rates as well as a shift in our portfolio to interest bearing investments such as U.S. treasury securities and money market funds. 101 Table of Contents Income tax benefit ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Years Ended December 31, Increase (Decrease) (in thousands) ​ 2023 2022 $ % Income tax benefit ​ $ 3,479 $ — 3,479 ​ 100 ​ Income tax benefit for the year ended December 31, 2023 was $3.5 million as a result of the tax benefit from the realization of the related deferred taxes for operations in the UK.
If the screen test is met, the transaction is accounted for as an asset acquisition. If the screen test is not met, further assessment is required to determine whether we have acquired inputs and processes that have the ability to create outputs, which would meet the requirements of a business.
If the screen test is met, the transaction is accounted for as an asset acquisition. If the screen test is not met, further assessment 106 Table of Contents is required to determine whether we have acquired inputs and processes that have the ability to create outputs, which would meet the requirements of a business.
The total estimated net proceeds to us from the offering, including the exercise of the option 97 Table of Contents by the underwriters, were $161.5 million after deducting underwriting discounts and commissions and estimated offering expenses payable by us.
The total estimated net proceeds to us from the offering, including the exercise of the option by the underwriters, were $161.5 million after deducting underwriting discounts and commissions and estimated offering expenses payable by us.
If the assets are found to not be recoverable, we measure the amount of impairment by comparing the carrying value of the assets to their fair values. We determined that no indicators of impairment existed as of December 31, 2023. No intangible assets existed as of December 31, 2022.
If the assets are found to not be recoverable, we measure the amount of impairment by comparing the carrying value of the assets to their fair values. We determined that no indicators of impairment existed as of December 31, 2024 or December 31, 2023.
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.
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.
Operating cash flow is derived by adjusting our net loss for non-cash items and changes in operating assets and liabilities. Net cash used in operating activities for the year ended December 31, 2023 was $361.8 million compared to $292.8 million for the same period in 2022.
Operating cash flow is derived by adjusting our net loss for non-cash items and changes in operating assets and liabilities. Net cash used in operating activities for the year ended December 31, 2024, was $353.0 million compared to $361.8 million for the same period in 2023.
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: We are pursuing several targets for genetic modification that utilize the gene-editing TALEN® platform licensed from the clinical-stage biotechnology company, Cellectis.
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.
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.
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 TILVANCE-301, a 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.
Actual results may differ from these estimates under different assumptions or conditions. 100 Table of Contents We believe the following critical accounting policies reflect the more significant judgments and estimates used in the preparation of our consolidated financial statements: Asset Acquisitions ​ We make certain judgments to determine whether transactions should be accounted for acquisitions of assets or business combinations using the guidance in Accounting Standard Codification, or ASC, Topic 805, Business Combinations by first applying a screen test to assess if substantially all of the fair value of the gross assets acquired is concentrated in a single identifiable asset or group of assets.
We believe the following critical accounting policies reflect the more significant judgments and estimates used in the preparation of our consolidated financial statements: Asset Acquisitions We make certain judgments to determine whether transactions should be accounted for as acquisitions of assets or business combinations using the guidance in Accounting Standard Codification, or ASC, Topic 805, Business Combinations by first applying a screen test to assess if substantially all of the fair value of the gross assets acquired is concentrated in a single identifiable asset or group of assets.
However, such revenues for Amtagvi™ and Proleukin ® may not be material during the 12 months from the date the consolidated financial statements are issued and this Annual Report on Form 10-K is filed.
However, such revenues for Amtagvi ® and Proleukin ® may not be material enough to generate positive operational cash flows during the 12 months from the date the consolidated financial statements are issued and this Annual Report on Form 10-K is filed.
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.
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.
Patent Nos. 10,130,659; 10,166,257; 10,272,113; 10,363,273; 10,398,734; 10,420,799; 10,463,697; 10,517,894; 10,537,595; 10,639,330; 10,646,517; 10,653,723; 10,695,372; 10,894,063; 10,905,718; 10,918,666; 10,925,900; 10,933,094; 10,946,044; 10,946,045; 10,953,046; 10,953,047; 11,007,225; 11,007,226; 11,013,770; 11,026,974; 11,040,070; 11,052,115; 11,052,116; 11,058,728; 11,083,752; 11,123,371; 11,141,438; 11,168,303; 11,168,304; 11,179,419; 11,202,803; 11,202,804; 11,220,670; 11,241,456; 11,254,913; 11,266,694; 11,273,180; 11,273,181; 11,291,687; 11,304,979; 11,304,980; 11,311,578; 11,337,998; 11,344,579; 11,344,580; 11,344,581; 11,351,197; 11,351,198; 11,351,199; 11,364,266; 11,369,637; 11,384,337; 11,433,097; 11,517,592; 11,529,372 ; 11,541,077; 11,713,446; 11,819,517; and 11,866,688.
Patent Nos. 10,130,659; 10,166,257; 10,272,113; 10,363,273; 10,398,734; 10,420,799; 10,463,697; 10,517,894; 10,537,595; 10,639,330; 10,646,517; 10,653,723; 10,695,372; 10,894,063; 10,905,718; 10,918,666; 10,925,900; 10,933,094; 10,946,044; 10,946,045; 10,953,046; 10,953,047; 11,007,225; 11,007,226; 11,013,770; 11,026,974; 11,040,070; 11,052,115; 11,052,116; 11,058,728; 11,083,752; 11,123,371; 11,141,438; 11,168,303; 11,168,304; 11,179,419; 11,202,803; 11,202,804; 11,220,670; 11,241,456; 11,254,913; 11,266,694; 11,273,180; 11,273,181; 11,291,687; 11,304,979; 11,304,980; 11,311,578; 11,337,998; 11,344,579; 11,344,580; 11,344,581; 11,351,197; 11,351,198; 11,351,199; 11,364,266; 11,369,637; 11,384,337; 11,433,097; 11,517,592; 11,529,372; 11,541,077; 11,713,446; 11,819,517; 11,857,573; 11,865,140; 11,866,688; 11,939,596; 11,969,444; 11,975,028; 11,981,921; 12,023,355; 12,024,718; 12,031,157; 12,104,172; 12,121,541; 12,159,700; 12,170,134; 12,188,048 and 12,194,061.
To the extent the transaction price includes variable consideration, we estimate the amount of variable consideration that should be included in the transaction price using the most likely method based on historical experience as well as applicable information currently available. ​ Accrued Research and Development Costs ​ Research and development costs are expensed as incurred.
To the extent the transaction price includes variable consideration, we estimate the amount of variable consideration that should be included in the transaction price using the most likely method based on historical experience, as well as applicable information currently available.
Revenue Recognition We recognize revenue from product sales in accordance with ASC 606, Revenue from Contracts with Customers . Under ASC 606, revenue is recognized when a customer obtains control of promised goods or services in an amount that reflects the consideration which the entity expects to receive in exchange for those goods or services.
Under ASC 606, revenue is recognized when a customer obtains control of promised goods or services in an amount that reflects the consideration which the entity expects to receive in exchange for those goods or services.
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). There are three key steps in the Amtagvi™ treatment process. ● Step 1: Sample Collection.
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. ● Step 1: Sample Collection.
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 90 Table of Contents HNSCC.
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 patient cohorts with metastatic HNSCC, and in patients with advanced cervical cancer in the C-145-04 multicenter Phase 2 clinical trial.
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.
Food and Drug Administration, or the 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.
In addition, these arrangements often give us the discretion to unilaterally terminate development of the product, which would allow us to avoid making contingent payments. ​ ​ Off-Balance Sheet Arrangements As of December 31, 2023 we did not have, and currently do not have, any off-balance sheet arrangements.
In addition, these arrangements often give us the discretion to unilaterally terminate development of the product, which would allow us to avoid making contingent payments. ​ Off-Balance Sheet Arrangements As of December 31, 2024, we had no obligations that would require disclosure as off-balance sheet arrangements.
Intellectual Property We have established 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, such as U.S.
We currently own more than 75 U.S. patents related to TIL cell therapy, including patents directed to compositions and methods of treatment in a broad range of cancers, such as U.S.
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.
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.
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 U.S.
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.
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 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.
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.
Net cash provided by investing activities for the year ended December 31, 2021 was $0.1 million compared to net cash used in investing activities of $317.9 million for the same period in 2020.
Net cash used in investing activities for the year ended December 31, 2024, was $96.4 million compared to net cash provided by investing activities of $155.2 million for the same period in 2023.
General and administrative costs are expensed as incurred, and we accrue for services provided by third parties related to the above expenses by monitoring the status of services provided and receiving estimates from its service providers and adjusting its accruals as actual costs become known. ​ We anticipate selling, general and administrative expenses will increase as we execute the launch of Amtagvi™ and market Proleukin ® , as well as execute an expected expansion of the internal general and administrative team to support the overall growth in our business. ​ ​ ​ 92 Table of Contents Interest income, net ​ Interest income, net results from our interest-bearing cash and investment balances. ​ Income tax benefit ​ Income tax benefit pertains to the operations in the United Kingdom and realization of related deferred taxes. ​ ​ Results of Operations for the Years Ended December 31, 2023 and 2022 ​ ​ Revenue ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Years Ended December 31, ​ Increase (Decrease) ​ (in thousands) 2023 2022 $ % Revenue - product sales ​ $ 1,189 ​ $ — ​ $ 1,189 ​ 100 % ​ Revenue for the year ended December 31, 2023 was $1.2 million and related entirely to product sales of Proleukin ® in licensed markets outside of the U.S following the completion of the acquisition of worldwide rights to Proleukin ® in May 2023.
Selling, general, and administrative costs are expensed as incurred, and we accrue for services provided by third parties related to the above expenses by monitoring the status of services provided and receiving estimates from its service providers and adjusting its accruals as actual costs become known. ​ We anticipate selling, general, and administrative expenses will increase as we execute the launch of Amtagvi ® and market Proleukin ® , as well as execute an expected expansion in the U.S. market and outside of the U.S. of the internal general and administrative team to support the overall growth in our business. ​ 96 Table of Contents Interest and other income, net ​ Interest and other income, net is derived from our interest-bearing cash, cash equivalents and investment balances as well as other income associated with non-recurring activities such as lease terminations. ​ Income tax benefit ​ Income tax benefit pertains to the operations in the UK and realization of related deferred taxes. ​ Results of Operations for the Years Ended December 31, 2024 and 2023 ​ Revenue ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Years Ended December 31, ​ Increase (Decrease) (in thousands) 2024 2023 $ % Amtagvi ® ​ $ 103,567 ​ $ — ​ 103,567 ​ 100 Proleukin ® ​ ​ 60,503 ​ ​ 1,189 ​ 59,314 ​ 4,988 Total product revenue ​ $ 164,070 ​ $ 1,189 ​ 162,881 ​ 13,698 ​ Revenue for the year ended December 31, 2024, increased by $162.9 million, or 13,698% compared to the same period in 2023.
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.
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.
Inputs used in our determination of estimates discussed above may vary from actual, which will result in adjustments to research and development expense in future periods. ​ Recent Accounting Standards In December 2023, the FASB issued ASU 2023-09, Income Taxes (Topic 740): Improvements to Income Tax Disclosures, which enhances the disclosures of income taxes.
Inputs used in our determination of estimates discussed above may vary from actual, which will result in adjustments to research and development expense in future periods. ​ Recent Accounting Standards In November 2023, the FASB issued ASU 2023-07, Segment Reporting (Topic 280): Improvements to Reportable Segment Disclosures, which enhances the disclosures required for operating segments in annual and interim consolidated financial statements.
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.
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.
Clinical development costs compose a significant component of research and development costs. We have a history of contracting with third parties, including CROs, independent clinical investigators, and CMOs, that perform various clinical trial activities on our behalf in connection with the ongoing development of our product candidates.
We have a history of contracting with third parties, including CROs, independent clinical investigators, and CMOs, that perform various clinical trial activities on our behalf in connection with the ongoing development of our product candidates. The financial terms of these contracts are subject to negotiations and may vary from contract to contract and may result in uneven payment flow.
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.
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.
These obligations met the conditions of embedded leases under Topic ASC 842 and were included in the Operating lease liabilities in the consolidated balance sheets.
These obligations met the conditions of embedded leases under Accounting Standard Codification (ASC) Topic 842 and were included in the Operating lease liabilities in the consolidated balance sheets. However, these contracts are cancellable upon prior notice and as a result, are not included in the above table.
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 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.
However, these contracts are cancellable upon prior notice and as a result, are not included in the above table. ​ (2) We have purchase obligations of $34.3 million related to manufacturing and supply agreements for Proleukin ® under a contract we inherited as part of the Acquisition.
(2) We have purchase obligations of $27.2 million related to manufacturing and supply agreements for Proleukin ® under a contract we inherited as part of the Acquisition.
The total estimated net proceeds to us from the offering are expected to be approximately $197.1 million after deducting underwriting discounts and commissions and estimated offering expenses payable by us. In the future, we may periodically offer one or more of these securities in amounts, prices and terms to be announced when and if the securities are offered.
The total estimated net proceeds to us from the offering are expected to be approximately $197.1 million after deducting underwriting discounts and commissions and estimated offering expenses payable by us.
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.
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.
Investing Activities Net cash (used in)/provided by investing activities primarily relates to the cash utilized to fund the Acquisition and the purchases and maturities of our investments and capital expenditures.
These increases were offset by a net increase in our operating lease liabilities primarily driven by receipts of tenant improvement allowances for our new corporate headquarters office. Investing Activities Net cash (used in) / provided by investing activities primarily relates to the cash utilized to fund the Acquisition and the purchases and maturities of our investments and capital expenditures.
Early adoption is permitted. We are currently evaluating the impact of ASC 2023-07 on our consolidated financial statements
We are currently evaluating the impact of ASU 2024-03 on our consolidated financial statements.
Based on the funds we have available as of the date our consolidated financial statements for the year ended December 31, 2023 are issued, which include estimated net proceeds (after deducting underwriting and other offering expenses) of approximately $197.1 million from the public offering of our common stock completed on February 22, 2024, we believe that we have sufficient capital to fund our anticipated operating expenses and capital expenditures as planned for at least the next twelve months following the issuance of our consolidated financial statements included in this Annual Report on Form 10-K.
Based on the funds we have available as of the date our consolidated financial statements for the year ended December 31, 2024 are issued, which includes net proceeds of approximately $122.3 million raised through the open market sales agreement through February 14, 2025, we believe that we have sufficient capital to fund our anticipated operating expenses and capital expenditures as planned for at least the next twelve months following the issuance of our consolidated financial statements included in this Annual Report on Form 10-K. 102 Table of Contents Corporate Capitalization As of December 31, 2024, we had outstanding 305,252,194 shares of our $0.000041666 par value common stock, 194 shares of our $0.001 par value Series A Convertible Preferred Stock, and 2,842,158 shares of our $0.001 par value Series B Convertible Preferred Stock.
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.
We believe this polyclonal cell therapy may be applicable to many solid tumor cancers, where the majority of immune targets are patient-specific. 93 Table of Contents 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.
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. ● Step 2: Manufacturing. Patient-specific TIL are manufactured using our commercial Gen 2 manufacturing process.
A tumor tissue sample of at least 1.5 cm in diameter is collected during a surgical resection and shipped to an approved, centralized manufacturing facility. ● Step 2: Manufacturing. Upon arrival at the manufacturing 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.
All forward-looking statements included in this report are based on information available to us on the date hereof and, except as required by law, we assume no obligation to update any such forward-looking statements. 87 Table of Contents Overview ​ We are a commercial-stage biopharmaceutical company pioneering a transformational approach to treating cancer by harnessing the human immune system’s ability to recognize and destroy diverse cancer cells using therapies personalized for each patient.
Overview ​ We are a commercial-stage biopharmaceutical company pioneering a transformational approach to treating cancer by harnessing the human immune system’s ability to recognize and destroy diverse cancer cells using therapies personalized for each patient.
TILVANCE-301 is expected to enroll approximately 670 patients and features dual primary endpoints of ORR and progression free survival, or PFS, by 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.
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.
Additionally, with respect to direct research and development expenses, we further divide expenses into the following sub-categories: “TIL, including combination 95 Table of Contents therapy,” “Next Generation,” and “Other clinical, preclinical and research programs under development.” For direct research and development expenses, we track specific project research and development expenses that are directly attributable to our preclinical and clinical development candidates that have been selected for further development.
Additionally, with respect to direct research and development expenses, we further divide expenses into the following sub-categories: “TIL, including combination therapy,” “Next Generation,” and “Others clinical, preclinical, and research programs under development.” Lifileucel monotherapy includes our TIL monotherapy clinical trials, including clinical trials previously reported as LN-145.
Cash Flows Cash flows from operating, investing and financing activities (in thousands): ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Years Ended December 31, ​ ​ 2023 2022 2021 Net cash (used in) provided by: ​ ​ ​ ​ Operating activities ​ $ (361,820) ​ $ (292,757) ​ $ (227,941) Investing activities ​ (155,242) ​ 256,455 ​ 132 Financing activities ​ 462,959 ​ 190,150 ​ 239,268 Net increase in cash, cash equivalents and restricted cash ​ $ (54,103) ​ $ 153,848 ​ $ 11,459 * Excludes effect of exchange rate changes ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Operating Activities Net cash used in operating activities represents cash disbursements related to all of our activities other than investing and financing activities.
If any of the securities covered by the 2020 Shelf Registration Statement are offered for sale, a prospectus supplement will be prepared and filed with the SEC containing specific information about the terms of such offering at that time. 103 Table of Contents Cash Flows Cash flows from operating, investing and financing activities (in thousands): ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Years Ended December 31, ​ ​ 2024 2023 2022 Net cash (used in) provided by: ​ ​ ​ ​ Operating activities ​ $ (352,977) ​ $ (361,820) ​ $ (292,757) Investing activities ​ (96,411) ​ (155,242) ​ 256,455 Financing activities ​ 390,664 ​ 462,959 ​ 190,150 Net (decrease) increase in cash, cash equivalents and restricted cash* ​ $ (58,724) ​ $ (54,103) ​ $ 153,848 * Excludes effect of exchange rate changes ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Operating Activities Net cash used in operating activities represents cash disbursements related to all of our activities other than investing and financing activities.
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 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.
Estimates are assessed each period and updated to reflect current information.
Estimates are assessed each period and updated to reflect current information. Actual results may differ from these estimates under different assumptions or conditions.
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.
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.
Proleukin ® has also received regulatory approvals for treatment of adults with metastatic melanoma and metastatic renal cell carcinoma in the United States.
Proleukin ® is also licensed in multiple countries around the world for treatment of patients with metastatic renal cell carcinoma and/or metastatic melanoma.
This was offset by cash used of $2.6 million for tax payments related to vested RSUs. Net cash provided by financing activities for the year ended December 31, 2021 was $239.3 million compared to net cash provided of $576.4 million for the same period in 2020.
Financing Activities Net cash provided by financing activities for the year ended December 31, 2024 was $390.7 million compared to net cash provided of $463.0 million for the same period in 2023.
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.
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. ​ TIL Cell T herapy 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.
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.
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 U.S. Food and Drug Administration, or FDA, approval for a solid tumor cancer. Amtagvi™ and Proleukin ® are part of a treatment regimen that also includes lymphodepletion.
This indication was approved in February 2024 under accelerated approval based on an endpoint of overall response rate, or ORR. Continued approval for this indication may be contingent upon verification and description of clinical benefit in future confirmatory trials. Amtagvi ® and Proleukin ® are part of a treatment regimen that also includes lymphodepletion.
Net loss ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Years Ended December 31, (Increase) Decrease (in thousands) 2022 2021 $ % Net loss ​ $ (395,893) ​ $ (342,252) ​ $ (53,641) 16 % ​ 96 Table of Contents Net loss for the year ended December 31, 2022, increased by $53.6 million or 16%, compared to the year ended December 31, 2021.
This decrease was the result of increased operations in the UK. 99 Table of Contents Net loss ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Years Ended December 31, (Increase) Decrease (in thousands) 2024 2023 $ % Net loss ​ $ (372,177) $ (444,037) $ 71,860 ​ 16 ​ Net loss for the year ended December 31, 2024 decreased by $71.9 million, or 16%, compared to the year ended December 31, 2023.
With the recent approval of our BLA, we expect to generate revenue from the sale of our product, Amtagvi™ (lifileucel). Furthermore, upon the completion of the closing of the acquisition of the worldwide rights to Proleukin ® in the second quarter of 2023, we began to generate revenue from the sales of Proleukin ® .
With the approval of our BLA, we expect to continue to generate revenue from the sale of our product, Amtagvi ® .

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Item 7A. Quantitative and Qualitative Disclosures About Market Risk

Market Risk — interest-rate, FX, commodity exposure

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Biggest changeIf interest rates had varied by 1% in the year ended December 31, 2023, the fair value of our investment portfolio would increase or decrease by approximately $0.4 million. 102 Table of Contents Inflation Risk Inflation has not had a material effect on our business, financial condition or results of operations during the years ended December 31, 2023, 2022, or 2021. ​ Foreign currency exchange risk ​ In addition to our existing foreign operations, we acquired and established newly formed foreign subsidiaries to consummate our acquisition of worldwide rights in Proleukin ® in the second quarter of 2023.
Biggest changeInflation Risk Inflation has not had a material effect on our business, financial condition or results of operations during the years ended December 31, 2024, 2023, or 2022. ​ Foreign currency exchange risk ​ In addition to our existing foreign operations, we acquired and established newly formed foreign subsidiaries to consummate our acquisition of worldwide rights in Proleukin ® in the second quarter of 2023.
As of December 31, 2023, we had $199.0 million invested in marketable securities with a maturity date of less than one year. As such we believe that we are not exposed to any material market risk.
As of December 31, 2024, we had $269.5 million invested in marketable securities with a maturity date of less than one year. As such we believe that we are not exposed to any material market risk.
Conversely, when the U.S. dollar weakens against these currencies, the relative value of such sales increase. ​ All of our product sales during the year ended December 31, 2023 were denominated in foreign currencies; however, foreign currency transaction gain was immaterial for the year ended December 31, 2023.
Conversely, when the U.S. dollar weakens against these currencies, the relative value of such sales increase. ​ The majority of our product sales during the year ended December 31, 2024 were denominated in the U.S. dollar.
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No foreign currency exchange risk existed for the year ended December 31, 2022 or 2021. ​
Added
If interest rates had varied by 1% in the year ended December 31, 2024, the fair value of our investment portfolio would increase or decrease by approximately $0.5 million.
Added
However, we do have some sales denominated in foreign currencies during the year ended December 31, 2024 and all our sales during the year ended December 31, 2023 were denominated in foreign currencies. Nevertheless, foreign currency transaction gains and losses were immaterial for the years ended December 31, 2024 and 2023. ​

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