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What changed in IOVANCE BIOTHERAPEUTICS, INC.'s 10-K — 2024 vs 2025

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Paragraph-level year-over-year comparison of IOVANCE BIOTHERAPEUTICS, INC.'s 2024 and 2025 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 2025 report.

+670 added−753 removedSource: 10-K (2026-02-24) vs 10-K (2025-02-27)

Top changes in IOVANCE BIOTHERAPEUTICS, INC.'s 2025 10-K

670 paragraphs added · 753 removed · 471 edited across 8 sections

Item 1. Business

Business — how the company describes what it does

152 edited+74 added−137 removed175 unchanged
Biggest changeThe 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.
Biggest changeSuch actions may include refusal to approve pending applications, license suspension or revocation, withdrawal of an approval, imposition of a clinical hold or termination of clinical trials, warning letters, untitled letters, modification of promotional materials or labeling, provision of corrective information, imposition of post-market requirements, including the need for additional testing, imposition of distribution or other restrictions under a Risk Evaluation and Mitigation Strategy, or REMS, product recalls, product seizures or detentions, refusal to allow imports or exports, total or partial suspension of production or distribution, FDA debarment, injunctions, fines, consent decrees, corporate integrity agreements, debarment from receiving government contracts and new orders under existing contracts, exclusion from participation in federal and state healthcare programs, restitution, disgorgement, or civil or criminal penalties, including fines and imprisonment, and adverse publicity, among other adverse consequences. 13 Table of Contents 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.
The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, must develop methods for testing the identity, strength, quality, and purity of the final product, or for biologics, the safety, purity and potency.
The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, must develop methods for testing the identity, strength, quality, and purity of the final product, or for biologics, safety, purity, and potency.
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.
In addition, a claim including items or services resulting from a violation of the AKS constitutes a false or fraudulent claim for purposes of the federal civil FCA. There are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution or other regulatory sanctions.
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.
If our operations are found to be in violation of any of such health regulatory laws or regulations described above or any other governmental laws or regulations that apply to us, we may be subject to penalties or other enforcement actions, including, without limitation, civil, administrative, and criminal penalties, damages, fines, disgorgement, the curtailment or restructuring of our operations, exclusion from participation in federal and state healthcare programs, individual imprisonment, injunctions, private qui tam actions brought by individual whistleblowers in the name of the government, as well as additional reporting obligations and oversight if we become subject to a corporate integrity agreement or other agreement to resolve allegations of non-compliance with these laws, any of which could adversely affect our ability to operate our business and our financial results.
The Fast Track designation also allows for the possibility for rolling review of a BLA by FDA, where the FDA may consider beginning review portions of a marketing application before the full submission is complete, and also potential eligibility if certain criteria are met for accelerated approval.
The Fast Track designation also allows for the possibility for rolling review of a BLA by the FDA, where the FDA may consider beginning to review portions of a marketing application before the full submission is complete, and also potential eligibility if certain criteria are met for accelerated approval.
We provide our employees with competitive salaries and bonuses, opportunities for equity ownership, development programs that enable continued learning and growth, career opportunities, and a robust employment package that promotes well-being across all aspects of their lives.
We provide our employees with competitive salaries and bonuses, opportunities for equity ownership, mentoring, and development programs that enable continued learning and growth, career opportunities, and a robust employment package that promotes well-being across all aspects of their lives.
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.
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.
The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which imposes criminal and civil penalties, prohibits, among other actions, knowingly and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations, or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of whether the payor is public or private third-party, knowingly and willfully embezzling or stealing from a health care benefit program, willfully obstructing a criminal investigation of a health care offense, and knowingly and willfully falsifying, concealing, or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items, or services relating to healthcare matters.
The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, imposes criminal and civil penalties and prohibits, among other actions, knowingly and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations, or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of whether the payor is public or private, knowingly and willfully embezzling or stealing from a health care benefit program, willfully obstructing a criminal investigation of a health care offense, and knowingly and willfully falsifying, concealing, or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items, or services relating to healthcare matters.
Additionally, the intent standard under the federal AKS provides that a person or entity need not have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.
Additionally, the intent standard under the AKS provides that a person or entity need not have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.
Financial terms of the license include annual license payments and development, regulatory and sales milestone payments from us to Cellectis, as well as royalty payments based on net sales of TALEN ® modified TIL products.
Financial terms include annual license payments; development, regulatory and sales milestone payments; as well as royalty payments based on net sales of TALEN ® modified TIL products, from us to Cellectis.
The Medicaid Drug Rebate statute requires manufacturers to calculate and report price points, which are used to determine Medicaid rebate payments shared between the states and the federal government and Medicaid payment rates for the drug.
The Medicaid Drug Rebate statute requires manufacturers to calculate and report price points, which are used to determine Medicaid rebate payments shared between the states and the federal government and Medicaid payment rates for drugs.
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.
Some state laws require pharmaceutical companies to comply with the pharmaceutical industry's voluntary compliance guidelines, known as the Pharmaceutical Research and Manufacturers of America Code, and the relevant compliance program guidance promulgated by the federal government in addition to requiring drug manufacturers to report pricing and marketing information, including, among other things, information related to gifts, payments, or other remuneration to physicians and other HCPs or marketing expenditures, state and local laws that require the registration of pharmaceutical sales representatives, and state laws governing the privacy and security of health information and the use of prescriber-identifiable data in certain circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.
The federal AKS prohibits, among other things, any person or entity, from knowingly and willfully offering, paying, soliciting, or receiving any remuneration, directly or indirectly, overtly or covertly, in cash or in kind, to induce or in return for purchasing, leasing, ordering, or arranging for the purchase, lease, or order of any item or service reimbursable under Medicare, Medicaid, or other federal healthcare programs, in whole or in part.
The federal AKS prohibits, among other things, any person or entity, from knowingly and willfully offering, paying, soliciting, or receiving any remuneration, directly or indirectly, overtly or covertly, in cash or in kind, to induce or in return for purchasing, leasing, furnishing, ordering, or arranging for or recommending the purchase, lease, furnishing, or order of any item or service reimbursable under Medicare, Medicaid, or other federal healthcare programs, in whole or in part.
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.
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.
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 have established a leading intellectual property portfolio developed internally and licensed from third parties. We currently own more than 90 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.
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.
More than 50 of these patents are related to our Gen 2 TIL manufacturing processes and have terms that we anticipate will extend to October 2037 or January 2038, not including any patent term extensions or adjustments that may be available.
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 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.
Our promotional and scientific/educational programs must comply with laws and regulations such as the federal Anti-Kickback Statute, or AKS; the civil monetary penalties statute, or the CMP Law; the Foreign Corrupt Practices Act, or the FCPA; the False Claims Act, or the FCA; the Veterans Health Care Act, or the VHCA; physician payment transparency laws; privacy and security laws; and other federal, state, and local laws similar to the foregoing.
These activities, including our promotional and scientific/educational programs, must comply with laws and regulations such as the federal Anti-Kickback Statute, or AKS; the civil monetary penalties statute, or the CMP Law; the Foreign Corrupt Practices Act, or the FCPA; the False Claims Act, or the FCA; the Veterans Health Care Act, or the VHCA; physician payment transparency laws; privacy and security laws; and other federal, state, and local laws similar to the foregoing.
A claim includes “any request or demand” for money or property presented directly or indirectly to the federal government.
A claim includes “any request or demand” for money or property presented directly or indirectly to the government.
This period may also be reduced by any time that the applicant did not act with due diligence. Whether any of our product candidates will be eligible for patent term restoration is currently unknown.
This period may also be reduced by any time that the applicant did not act with due diligence. Whether any of our product candidates will be eligible for patent term extension is currently unknown.
The PHSA also provides authority to the FDA to immediately suspend licenses in situations where there exists a danger to public health, to prepare or procure products in the event of shortages and critical public health needs, and to authorize the creation and enforcement of regulations to prevent the introduction or spread of communicable diseases in the U.S. and between states.
The PHSA also provides authority to the FDA to immediately suspend licenses in situations where there exists a danger to public health, to prepare or procure products in the event of 21 Table of Contents shortages and critical public health needs, and to authorize the creation and enforcement of regulations to prevent the introduction or spread of communicable diseases in the U.S. and between states.
Typically, two Phase 3 studies are required by the FDA for product approval. ● Phase 4 - In some cases, the FDA may require, or companies may voluntarily pursue, additional clinical trials after a product is approved to gain more information about the product, known as post-approval requirements or commitments, respectively.
Typically, one or more clinical studies are required by the FDA for product approval. ● Phase 4 - In some cases, the FDA may require, or companies may voluntarily pursue, additional clinical trials after a product is approved to gain more information about the product, known as post-approval requirements or commitments, respectively.
Our owned and licensed intellectual property portfolio also includes patents and patent applications relating to TIL, marrow 16 Table of Contents 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.
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.
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.
The 27 Table of Contents HITECH Act also increased the civil and criminal penalties that may be imposed against covered entities, business associates, and possibly other persons and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions.
The HITECH Act also increased the civil and criminal penalties that may be imposed against covered entities, business associates, and possibly other persons and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions.
There are additional pressures on pricing as a result of other, peripheral policies impacting reimbursement across both government and private payors. Non-health specific policies may impart downstream impacts on private insurance reimbursement decision-making. In consideration of these numerous factors, reimbursement may not be available or sufficient to allow us to sell our products on a competitive and profitable basis.
Additional pressures on pricing as a result of other, peripheral policies may impact reimbursement across both government and private payors. Non-health specific policies may impart downstream impacts on private insurance reimbursement decision-making. In consideration of these numerous factors, reimbursement may not be available or sufficient to allow us to sell our products on a competitive and profitable basis.
The VHCA also requires manufacturers of covered drugs participating in the Medicaid program to enter into Federal Supply Schedule contracts with the VA through which their covered drugs must be sold to certain federal agencies at FCP and to report pricing information.
The VHCA also requires manufacturers of covered drugs participating in the Medicaid program to enter into Federal Supply Schedule contracts with the VA through which their covered drugs must be sold to certain federal agencies at FCP and to report 23 Table of Contents pricing information.
More than 75 U.S. patents are related to TIL cell therapy, including patents directed to compositions and methods of treatment in a broad range of cancers.
More than 90 U.S. patents are related to TIL cell therapy, including patents directed to compositions and methods of treatment in a broad range of cancers.
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.
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.
Like the Medicaid rebate amount, the FCP includes an inflation penalty. A Department of Defense regulation requires manufacturers to provide this discount on drugs dispensed by retail pharmacies when paid by the TRICARE Program. All these price reporting requirements create the risk of submitting false information to the government, and potential FCA liability.
Like the Medicaid rebate amount, the FCP includes an inflation penalty. A Department of Defense regulation requires manufacturers to provide this discount through prescription rebates on drugs dispensed by retail pharmacies when paid by the TRICARE Program. These price reporting requirements create a risk of submitting false information to the government and potential FCA liability.
Progress reports detailing the results of the clinical trials must also be submitted at least annually to the FDA and the IRB and more frequently if serious adverse events or other significant safety information is found.
Progress reports detailing the results of the clinical trials must 14 Table of Contents also be submitted at least annually to the FDA and the IRB and more frequently if serious adverse events or other significant safety information is found.
Because our products are produced in that way, we would be subject to the centralized authorization procedure. Under the centralized procedure, pharmaceutical companies submit a single MAA to the European Medicines Agency, or the EMA. The application is reviewed by the Committee for Medicinal Products for Human Use, which issues a scientific opinion.
Because our products are produced in that way, we would be subject to the centralized authorization 28 Table of Contents procedure. Under the centralized procedure, pharmaceutical companies submit a single MAA to the European Medicines Agency, or the EMA. The application is reviewed by the Committee for Medicinal Products for Human Use, which issues a scientific opinion.
The government may further prosecute conduct 26 Table of Contents under the criminal FCA, which prohibits the making or presenting of a claim to the government knowing the claim to be false, fictitious or fraudulent. Unlike the civil FCA, conviction requires proof of intent to submit a false claim.
The government may further prosecute conduct under the criminal FCA, which prohibits the making or presenting of a claim to the government knowing the claim to be false, fictitious, or fraudulent. Unlike the civil FCA, conviction requires proof of intent to submit a false claim.
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.
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.
Once a BLA has been submitted, the FDA has sixty days to determine whether it will accept the application for filing. The FDA accepts applications for filing if it determines that the application is substantially complete to permit a substantive review. The FDA may request additional information rather than accept a BLA for filing.
Once a BLA has been submitted, the FDA has sixty days to determine whether it will accept the application for filing. The FDA accepts applications for filing if it determines that the application is substantially complete to permit a substantive review. The 16 Table of Contents FDA may request additional information rather than accept a BLA for filing.
Priority Review is granted when there is evidence that the proposed product would be a significant improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of a serious condition.
Priority Review is granted when there is evidence that the proposed product would be a significant improvement in the safety or effectiveness of the treatment, 17 Table of Contents diagnosis, or prevention of a serious condition.
Orphan Drug Designations During 2015, we received ODD for lifileucel in the U.S. to treat malignant melanoma stages IIB-IV, and in 2018, we received an ODD for lifileucel for the treatment of cervical cancer with a tumor size of greater than 2 cm in diameter.
Orphan Drug Designations We have received ODD for lifileucel in the U.S. to treat malignant melanoma stages IIB-IV in 2015 and to treat cervical cancer with a tumor size of greater than 2 cm in diameter in 2018.
In addition, state laws govern the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the same effect.
In addition, other federal and state laws may govern the privacy and security of health and other information in certain circumstances and may differ from each other in significant ways and may not have the same effect.
Research Collaboration and Exclusive Worldwide License Agreement In December 2019, we entered into a research collaboration and exclusive worldwide license agreement whereby we will license gene-editing technology from Cellectis, a clinical-stage biopharmaceutical company, to develop TIL cell therapies that have been genetically edited, including a PD-1 inactivated product that we refer to as IOV-4001.
Research Collaboration and Exclusive Worldwide License Agreement In December 2019, we entered into a research collaboration and exclusive worldwide license agreement for gene-editing technology from Cellectis, a clinical-stage biopharmaceutical company, to develop genetically edited TIL cell therapies, including a PD-1 inactivated product that we refer to as IOV-4001.
In addition to the laws discussed above, we may see more stringent state and federal privacy legislation in 2025 and beyond, as a continued increase in cyber-attacks have heightened attention to data privacy and security in the U.S. and other jurisdictions.
In addition to the laws discussed above, we may see more stringent state and federal privacy legislation in coming years, as a continued increase in cyber-attacks have heightened attention to data privacy and security in the U.S. and other jurisdictions.
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” has been interpreted broadly to include anything of value, including kickbacks, bribes, or rebates, gifts, discounts, waivers of payment, ownership interest, and providing anything at less than its fair market value.
Although physicians may prescribe legally available products for off-label use, if they deem such use to be appropriate in their professional medical judgment, manufacturers may not market or promote such off-label uses.
Although physicians may prescribe legally available products for off-label use, if they deem such use to be appropriate in their professional medical judgment, manufacturers 18 Table of Contents may not market or promote such off-label uses.
The Sunshine Act, among other things, imposes reporting requirements on drug manufacturers for payments or other transfers of value made by them to physicians and teaching hospitals, as well as ownership and investment interests held by physicians, other healthcare providers, and their immediate family members.
The Sunshine Act, among other things, imposes reporting requirements on drug manufacturers and certain others for payments or other transfers of value made by them to physicians and teaching hospitals, as well as ownership and investment interests held by physicians, other HCPs, and their immediate family members.
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.
Future laws may result in additional reductions in third-party payer reimbursement, which could have a material adverse effect on customers for our products and product candidates, if approved, and, accordingly, our financial operations. Any reduction in reimbursement from Medicare or other government-funded programs may result in a similar reduction in payments from private payors.
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.
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; 11,141,434;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; 11,293,009; 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; 11,401,507; 11,433,097; 11,517,592; 11,529,372; 11,541,077; 11,631,483; 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; 11,998,568; 12,023,355; 12,024,718; 12,031,157; 12,104,172; 12,121,541; 12,159,700; 12,170,134; 12,188,048; 12,194,061; 12,226,434; 12,226,522; 12,230,378; 12,230,379; 12,233,075; 12,280,140; 12,343,380 ; 12,485,145; and 12,495,791.
Actions under the FCA may be brought by the government or as a qui tam action by a private individual in the name of the government. If the government intervenes in a qui tam action, and prevails, the qui tam plaintiff will share in the proceeds from damages and fines or settlement funds.
Actions under the FCA may be brought by the government or by a private individual in the name of the government, called “qui tam” actions. If the government intervenes in a qui tam action and prevails in the lawsuit, the qui tam plaintiff will share in the proceeds from damages and fines or settlement funds.
Regenerative Medicine Advanced Therapy Designation In October 2018, we announced that the FDA had granted RMAT designation for lifileucel for the treatment of patients with metastatic melanoma. The RMAT designation is based on data provided to the FDA from our C-144-01 trial. RMAT designation is granted for regenerative medicine drugs and allows for increased access to FDA during development.
Regenerative Medicine Advanced Therapy Designation RMAT designation is granted for regenerative medicine drugs and allows for increased access to FDA during development. The FDA granted RMAT designation for lifileucel for the treatment of patients with metastatic melanoma in 2018, based on data provided to the agency from our C-144-01 trial.
Unlike cell therapies that act on a single or small number of shared antigen targets common to certain tumors, TIL cell therapy is an individualized, polyclonal T cell therapy designed to target a variety of neoantigens that are unique to the patient or tumor .
Unlike cell therapies that act on a single or small number of shared antigen targets common to certain tumors, TIL is an individualized, polyclonal T cell therapy designed to target a variety of patient-specific neoantigens .
We cannot predict where new legislation might arise, the scope of such legislation, or the potential impact to our business and operations. Payments made to physicians and other healthcare providers, and other financial interests, have been the subject of a range of federal and state laws.
We cannot predict where new legislation might arise, the scope of such legislation, or the potential impact to our business and operations. Payments made to physicians, other HCPs, their family members, and other financial interests, have been the subject of a range of federal and state laws.
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.
Breakthrough Therapy Designation Under a BTD, the FDA may take actions that help expedite the development and review of a product candidate application, including seeking to provide timely advice and interactive communications to the sponsor with intensive guidance during development, to help the sponsor design and conduct a more efficient development program.
Federal and state enforcement bodies have recently increased their scrutiny of interactions between healthcare companies and healthcare providers, which has led to a number of investigations, prosecutions, convictions, and settlements in the healthcare industry.
Federal and state enforcement bodies have recently increased their scrutiny of interactions among pharmaceutical companies, HCPs, and patients, which has led to a number of investigations, prosecutions, convictions, and settlements in the healthcare industry.
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.
Seeking coverage and reimbursement from third-party payors can be time consuming and expensive. Moreover, a payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved, especially for products and product candidates such as ours, which are used in the inpatient setting, usually resulting in no separate reimbursement for pharmaceuticals.
By law, a company can only start to market a medicine once it has received a marketing authorization. 31 Table of Contents Employees and Human Capital Management As of December 31, 2024, we had 838 employees, 670 of whom were engaged in research and development, and commercial manufacturing activities, and 168 of whom were engaged in general and administrative support activities.
By law, a company can only start to market a medicine once it has received a marketing authorization. Employees and Human Capital Management As of December 31, 2025, we had 975 employees, 775 of whom were engaged in research and development, and commercial manufacturing activities, and 200 of whom were engaged in general and administrative support activities.
Ensuring that business arrangements with third parties comply with applicable healthcare laws, as well as responding to possible investigations by government authorities, can be time- and resource-consuming and can divert management's attention from the business.
Ensuring that business arrangements with third parties comply with applicable healthcare laws, as well as responding to possible investigations by government authorities, can be time- and resource-consuming and can divert management's attention from the business, even if investigators ultimately find that no violation has occurred.
The programmed death-ligand 1, or PD-L1, tumor proportion score, or TPS, in patients at the time they started frontline therapy was less than one percent or unknown in patients in Cohort 1 and greater than or equal to one percent in patients in Cohort 2.
In the two registrational patient cohorts, the programmed death-ligand 1, or PD-L1, tumor proportion score, or TPS, at the start of frontline therapy was less than one percent or unknown in Cohort 1 patients and greater than or equal to one percent in Cohort 2 patients.
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.
Following the U.S. accelerated approval of Amtagvi ® in previously treated advanced melanoma, our confirmatory trial, TILVANCE-301, is designed to support a registrational path for lifileucel in combination with pembrolizumab in frontline advanced, or unresectable or metastatic, melanoma as well as to support full U.S. approval for Amtagvi ® in post-anti-PD-1 advanced melanoma.
The term of the Second Amended and Restated Patent License Agreement continues until the expiry of the last-to-expire patent rights licensed thereunder, and the agreement contains standard termination provisions.
The term of the Patent License Agreement, as amended, continues until the expiry of the last-to-expire licensed patent rights and contains standard termination provisions. Cellectis S.A.
To the extent we license patent rights relating to a TIL-based product candidate, we will be responsible for all patent-related expenses and fees, past and future, relating to the TIL-based product candidate. In addition, we may be required to supply certain test articles, including TIL, grown and processed under cGMP conditions, suitable for use in clinical trials.
We are required to make quarterly payments to NCI to support research activities. To the extent we license patent rights, we will be responsible for all patent-related expenses and fees, past and future. In addition, we may be required to supply certain test articles, including TIL, grown and processed under cGMP conditions, suitable for use in clinical trials.
Novartis Pharma AG License Agreement In January 2020, we obtained a license from Novartis Pharma AG, or Novartis, to develop and commercialize an antibody cytokine engrafted protein, which we refer to as IOV-3001.
Novartis Pharma AG License Agreement In January 2020, we obtained a license from Novartis Pharma AG, or Novartis, to develop and commercialize an antibody cytokine engrafted protein, designated as IOV-3001. Under the agreement, we have paid an upfront payment to Novartis.
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.
Coverage and Reimbursement Sales of pharmaceutical products depend significantly on the availability and adequacy of coverage and reimbursement by third-party payors such as Medicare, Medicaid, and other government programs at the federal and state level, managed care entities, private health insurers, and pharmacy benefit managers, or PBMs.
The term remuneration has been interpreted broadly to include anything of value. The federal AKS has been interpreted broadly to apply to arrangements between pharmaceutical manufacturers on the one hand and prescribers, purchasers, and formulary managers on the other.
The AKS has been interpreted broadly to apply to arrangements between pharmaceutical manufacturers on the one hand and prescribers, purchasers, formulary managers, and beneficiaries on the other.
Research, Development, Manufacturing, and License Agreements for TIL Cell Therapy WuXi Advanced Therapies, Inc. Manufacturing and Services Agreements Since November 2016, we entered into various manufacturing services agreements with WuXi Advanced Therapies, Inc., and its parent company WuXi Apptec, Co.
Research, Development, Manufacturing, and License Agreements for TIL Cell Therapy Minaris Advanced Therapies Manufacturing and Services Agreements In November 2016, we entered manufacturing services agreements, or MSAs, with WuXi Advanced Therapies, Inc., and its parent company WuXi Apptec, Co. Ltd (collectively, “WuXi”).
In addition, BTD status allows for the potential to request priority review of our BLA at the time of BLA submission if supported by clinical data. The clinical evidence needed to support breakthrough designation is preliminary, and the FDA has authority to rescind a BTD if a product candidate no longer meets the qualifying criteria.
BTD also allows the sponsor to submit portions of the BLA for rolling review. In addition, BTD status allows for the potential priority review at the time of BLA submission if supported by clinical data. The BTD is supported by preliminary clinical evidence, and the FDA may rescind a BTD if a product candidate no longer meets the qualifying criteria.
Certain of these proposals could limit the prices we are able to charge for our products or the amounts of reimbursement available for our products.
Current and future health care reform proposals could limit the prices we are able to charge for our products or the amounts of reimbursement available for our products.
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.
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.
Our competitors may obtain regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in competitors establishing a strong market position before we are able to enter the market. Our portfolio includes our commercial products Amtagvi ® and Proleukin ® as well as our pipeline of investigational TIL cell therapies.
Our competitors may obtain regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in competitors establishing a strong market position before we are able to enter the market.
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.
Currently, there are numerous companies that are investigating various alternate treatments for advanced melanoma, NSCLC, and other solid tumor cancers that we are seeking to address, including patients that have progressed after prior treatment with checkpoint inhibitors and chemotherapy.
We currently own more than 250 granted or allowed U.S. and international patents and patent applications pertaining to Amtagvi ® and other TIL-related technologies that are expected to provide Amtagvi ® with exclusivity into 2042.
Intellectual Property ​ We have established a leading intellectual property portfolio developed internally and licensed from third parties. We currently own more than 330 granted or allowed U.S. and international patents and patent applications pertaining to Amtagvi ® and other TIL-related technologies that are expected to provide Amtagvi ® with exclusivity into 2042.
The Sunshine Act requires applicable manufacturers to track payments and transfers of value to physicians, physician assistants, nurse practitioners, and other mid-level HCPs. Additionally, certain states also mandate implementation of commercial compliance programs, impose restrictions on drug manufacturer marketing practices and/or require the tracking and reporting of gifts, compensation, and other remuneration to physicians and other HCPs.
Additionally, certain states also mandate implementation of commercial compliance programs, impose restrictions on drug manufacturer marketing practices, and/or require the tracking and reporting of gifts, compensation, and other remuneration to physicians and other HCPs.
In the U.S., private health insurers and other third-party payors often provide reimbursement for products and services based on the level at which the government provides reimbursement through the Medicare or Medicaid programs for such products and services. These restrictions and limitations influence the purchase of health care services and products.
In the U.S., private health insurers and other third-party payors may base their reimbursement for prescription drugs based on the level at which government healthcare programs provide reimbursement for such drugs. These restrictions and limitations influence the purchase of drugs.
Patients previously treated with standard of care chemo-immunotherapy have a poor prognosis, limited treatment options, and a real-world overall survival of less than six months.
Following initial treatment with immune checkpoint inhibitor, or ICI, and chemotherapy, previously treated with standard of care chemo-immunotherapy have a poor prognosis, limited treatment options 7 Table of Contents with limited durability, and a real-world overall survival of less than six months.
Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites to ensure compliance with cGCP. 20 Table of Contents If the FDA determines that the application, manufacturing process or manufacturing facilities are not acceptable, it will outline the deficiencies in the submission and often will request additional testing, clinical trials, application modifications, or information in a complete response letter, or CRL.
If the FDA determines that the application, manufacturing process, or manufacturing facilities are not acceptable, it will outline the deficiencies in the submission and often will request additional testing, clinical trials, application modifications, or information in a complete response letter, or CRL.
The Department of Health and Human Services Office of Civil Rights, or the OCR, has increased its focus on compliance and continues to train state attorneys general for enforcement purposes.
The Department of Health and Human Services Office of Civil Rights, or the OCR, state attorneys general, and other regulators have increased their focus on compliance and enforcement.
Some of these state laws have not taken effect, and we cannot predict if states will subsequently amend those laws, if other states will pass similar laws, or the costs and expenses that we will incur to comply with such laws. 28 Table of Contents To the extent that any of our products are sold in a foreign country, we may be subject to similar foreign laws and regulations, which may include, for instance, applicable post-marketing requirements, including safety surveillance, anti-fraud and abuse laws, and implementation of corporate compliance programs and reporting of payments or transfers of value to HCPs.
To the extent that any of our products are sold in a foreign country, we may be subject to similar foreign laws and regulations, which may include, for instance, applicable post-marketing requirements, including safety surveillance, anti-fraud and abuse laws, and implementation of corporate compliance programs and reporting of payments or transfers of value to HCPs.
In December 2022, with the passage of Food and Drug Omnibus Reform Act, Congress required sponsors to develop and submit a diversity action plan for each Phase 3 clinical trial or any other “pivotal study” of a new drug or biological product.
Additional U.S. and foreign laws and regulations may also be applicable to the handling, import, export, and transportation of biological materials, including tissue samples. 15 Table of Contents In December 2022, with the passage of Food and Drug Omnibus Reform Act, Congress required sponsors to develop and submit a diversity action plan for each Phase 3 clinical trial or any other “pivotal study” of a new drug or biological product.
Since the passage of the CCPA, certain other states have passed similar laws that may also have similar impacts on our data processing practices and incurred costs.
Additional modifications may continue to be made to the CCPA and CPRA by the California legislature and their interpretation by regulators may continue to evolve. Since the passage of the CCPA, certain other states have passed similar laws that may also have similar impacts on our data processing practices and incurred costs.
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.
Boehringer Ingelheim Biopharmaceuticals GmbH In May 2023, as part of the Acquisition from Clinigen, we inherited a manufacturing and supply agreement with Boehringer Ingelheim Biopharmaceuticals GmbH, to carry out the processing, manufacturing, and supply of Proleukin ® in unlabeled vials through October 2025. Automatic renewals are for a two-year period unless terminated.
National Institutes of Health and the National Cancer Institute Cooperative Research and Development Agreement In August 2011, we signed a five-year Cooperative Research and Development Agreement, or CRADA, with the NCI to work on the development of adoptive cell immunotherapies in multiple solid tumor types, including unmodified TIL as a stand-alone therapy or in combination, improved methods for the generation and selection of TIL cell therapy with anti-tumor reactivity, and strategies for more potent TILs.
In August 2011, we signed a five-year CRADA for the development of products that included unmodified TIL as a stand-alone therapy or in combination, improved methods for the generation and selection of TIL cell therapy with anti-tumor reactivity, and strategies for more potent TILs.
We also may compete with other T cell therapies in development, including therapies based on genetically engineered T cell receptors rendered reactive against tumor-associated antigens prior to their administration, other genetically engineered TIL products, and TIL products designed to be reactive to specific neoantigens, by companies such as AbelZeta Pharma, Achilles Therapeutics, Adaptimmune Therapeutics, Alaunos Therapeutics, Biosyngen, GRIT Biotechnology, Immatics, Immunocore, Intima Bioscience, KSQ Therapeutics, Lyell Immunopharma, Marker Therapeutics, Obsidian Therapeutics, TILT Biotherapeutics, and others.
AbelZeta Pharma, Alaunos Therapeutics, Biosyngen, GRIT Biotechnology, Immatics, Immunocore, Intima Bioscience, KSQ Therapeutics, Marker Therapeutics, Obsidian Therapeutics, and others are developing T cell therapies based on genetically engineered T cell receptors rendered reactive against tumor-associated antigens, other genetically engineered TIL products, and TIL products designed to be reactive to specific neoantigens. ● Novel IL-2 treatments in development .
In addition, government programs like Medicaid include substantial penalties for increasing commercial prices over the rate of inflation, which can affect realization and return on investment. 29 Table of Contents In the U.S., Europe, and other potentially significant markets for our products and product candidates, government authorities and private third-party payors are increasingly attempting to limit or regulate the price of medical products and services, particularly for new and innovative products and therapies, which often has resulted in average selling prices lower than they would otherwise be.
We cannot predict whether the IRA, in whole or in part, will be overturned, repealed, replaced, or amended. 26 Table of Contents In the U.S., Europe, and other potentially significant markets for our products and product candidates, government authorities and private third-party payors are increasingly attempting to limit or regulate the price of medical products and services, particularly for new and innovative products and therapies, which often has resulted in average selling prices lower than they would otherwise be.

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Item 1A. Risk Factors

Risk Factors — what could go wrong, per management

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Biggest changeThe CCPA and CPRA, among other things, create new data privacy obligations for covered companies and provides new privacy rights to California residents, including the right to opt out of certain disclosures of their information. The CCPA also created a private right of action with statutory damages for certain data breaches, thereby potentially increasing risks associated with a data breach.
Biggest changeFor example, the California Consumer Privacy Act, or CCPA, which went into effect January 1, 2020, and as amended and expanded by the California Privacy Rights Act, or CPRA, which went into effect on January 1, 2023, among other things, create new data privacy obligations for covered companies and provides new privacy rights to California residents, including the right to opt out of certain disclosures of their information.
If we are unable to successfully increase the manufacturing capacity for a product candidate (as a result of lack of approval from, or capacity limitations imposed by, the FDA, or otherwise), the resulting capacity limitations could have a material adverse effect on our results of operations and financial condition.
If we are unable to successfully increase the manufacturing capacity for a product or product candidate (as a result of lack of approval from, or capacity limitations imposed by, the FDA, or otherwise), the resulting capacity limitations could have a material adverse effect on our results of operations and financial condition.
Seeking prior authorization and negotiating the single-case agreement may take anywhere from days to months to obtain, if at all, and may cause ATCs, clinics, and patients to decline to use our products.
Seeking prior authorization and negotiating the single-case agreement may take anywhere from days to months to obtain, if at all, and may cause ATCs, clinics, and patients to decline to use our products.
Moreover, it is unclear how regulations and sub-regulatory policy, which fluctuate continually, may affect interpretation and further implementation of the existing law and its practical effects on our business.
Moreover, it is unclear how regulations and sub-regulatory policy, which fluctuate continually, may affect the interpretation and further implementation of the existing law and its practical effects on our business.
Changing regulatory policies resulting from the changing political environment could impact our regulatory and compliance costs and future revenues, all of which could materially and adversely affect our business, financial condition, and operating results.
Changing regulatory policies resulting from the political environment could impact our regulatory and compliance costs and future revenues, all of which could materially and adversely affect our business, financial condition, and operating results.
Factors that may inhibit our efforts to commercialize our current or future products and product candidates and generate significant product revenues include: ● if a health epidemic or pandemic occurs it may negatively impact our ability to establish commercial operations, educate and interact with healthcare professionals, and successfully launch our product on a timely basis; ● the inability of sales personnel to obtain access to physicians or physicians do not prescribe our current or future product candidates; ● our inability to effectively oversee a geographically dispersed sales and marketing team; ● the costs and time associated with the initial and ongoing training of sales and marketing personnel on legal and regulatory compliance matters and monitoring their actions; ● an inability to secure adequate or any coverage and reimbursement by government and private health plans; ● the clinical indications for which the products are approved and the claims that we may make for the products; ● limitations or warnings, including distribution or use restrictions, contained in the products’ approved labeling; ● any distribution and use restrictions imposed by the FDA or to which we agree as part of a mandatory REMS or voluntary risk management plan; ● liability for sales or marketing personnel who fail to comply with the applicable legal and regulatory requirements; ● the lack of complementary products to be offered by sales personnel, which may put us at a competitive disadvantage relative to companies with more extensive product lines; and ● unforeseen costs and expenses associated with creating an independent sales and marketing organization or engaging a contract sales organization.
Factors that may inhibit our efforts to commercialize our current or future products and product candidates and generate significant product revenues include: ● if a health epidemic or pandemic occurs it may negatively impact our ability to establish commercial operations, educate, and interact with healthcare professionals, and successfully launch our product on a timely basis; ● the inability of sales personnel to obtain access to physicians or physicians do not prescribe our current or future product candidates; ● our inability to effectively oversee a geographically dispersed sales and marketing team; ● the costs and time associated with the initial and ongoing training of sales and marketing personnel on legal and regulatory compliance matters and monitoring their actions; ● an inability to secure adequate or any coverage and reimbursement by government and private health plans; ● the clinical indications for which the products are approved and the claims that we may make for the products; ● limitations or warnings, including distribution or use restrictions, contained in the products’ approved labeling; ● any distribution and use restrictions imposed by the FDA or to which we agree as part of a mandatory REMS or voluntary risk management plan; ● liability for sales or marketing personnel who fail to comply with the applicable legal and regulatory requirements; ● the lack of complementary products to be offered by sales personnel, which may put us at a competitive disadvantage relative to companies with more extensive product lines; and ● unforeseen costs and expenses associated with an independent sales and marketing organization or engaging a contract sales organization.
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.
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; 48 Table of Contents ● 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. ​ 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.
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.
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; 59 Table of Contents ● 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 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.
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.
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 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.
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.
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.
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.
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; 52 Table of Contents ● 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 potential health epidemics and pandemics; ● 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. ​ If prolonged government shutdowns, inadequate funding, loss of employees, changes in regulations or policies by the new U.S. administration or other disruptions were to occur at the FDA, final FDA approval of our product candidates may be delayed.
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.
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 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.
Reliance on third-party manufacturers entails exposure to risks to which we would not be subject if we manufactured the products and product candidates exclusively by ourselves, including: 39 Table of Contents ● inability to negotiate manufacturing and quality agreements with third parties under commercially reasonable terms; ● reduced day-to-day control over the manufacturing process for our product candidates as a result of using third-party manufacturers for all aspects of manufacturing activities; ● reduced control over the protection of our trade secrets and know-how from misappropriation or inadvertent disclosure; ● termination or nonrenewal of manufacturing agreements with third parties in a manner or at a time that may be costly or damaging to us or result in delays in the development or commercialization of our products and/or product candidates; ● disruptions to the operations of our third-party manufacturers or suppliers caused by conditions unrelated to our business or operations, including the bankruptcy of the manufacturer or supplier; ● international or multi-national activities that are related to business activities outside of our scope, but may have an impact on a CMO’s ability to conduct business in a manner consistent with governmental or our regulatory and ethical standards; and ● our ability to synchronize operations and standards to ensure that all aspects of manufacturing are consistent without deviations across facilities. ​ In addition, the manufacturing process and facilities for any products and product candidates that we may develop at the i CTC and or our CMOs is subject to FDA and foreign regulatory authority approval processes, and we or our CMOs will need to meet all applicable FDA and foreign regulatory authority requirements, including cGMP, on an ongoing basis.
Reliance on third-party manufacturers entails exposure to risks to which we would not be subject if we manufactured the products and product candidates exclusively by ourselves, including: ● inability to negotiate manufacturing and quality agreements with third parties under commercially reasonable terms; ● reduced day-to-day control over the manufacturing process for our product candidates as a result of using third-party manufacturers for all aspects of manufacturing activities; ● reduced control over the protection of our trade secrets and know-how from misappropriation or inadvertent disclosure; ● termination or nonrenewal of manufacturing agreements with third parties in a manner or at a time that may be costly or damaging to us or result in delays in the development or commercialization of our products and/or product candidates; ● disruptions to the operations of our third-party manufacturers or suppliers caused by conditions unrelated to our business or operations, including the bankruptcy of the manufacturer or supplier; ● international or multi-national activities that are related to business activities outside of our scope, but may have an impact on a CMO’s ability to conduct business in a manner consistent with governmental or our regulatory and ethical standards; and ● our ability to synchronize operations and standards to ensure that all aspects of manufacturing are consistent without deviations across facilities. ​ In addition, the manufacturing process and facilities for any products and product candidates that we may develop at the i CTC or at our CMOs is subject to FDA and foreign regulatory authority approval processes, and we or our CMOs will need to meet all applicable FDA and foreign regulatory authority requirements, including cGMP, on an ongoing basis.
Acquiring and thereafter operating larger new businesses will also increase our management, operating and reporting costs and burdens. In addition, if we undertake acquisitions, we may issue dilutive securities, assume or incur debt obligations, incur large one-time expenses and acquire intangible assets that could result in significant future amortization expense.
Acquiring and thereafter operating larger new businesses will also increase our management, operating and reporting costs and burdens. In addition, if we undertake acquisitions, we may issue dilutive securities, assume or incur debt obligations, incur large one-time expenses and acquire intangible assets that could result in significant future amortization expenses.
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. In both domestic and foreign markets, sales of our product candidates, if approved, depend on the availability of coverage and adequate reimbursement from third-party payors.
Coverage and reimbursement may be limited or unavailable in certain market segments for our products or product candidates, which could make it difficult for us to sell our product candidates profitably. In both domestic and foreign markets, sales of our product candidates, if approved, depend on the availability of coverage and adequate reimbursement from third-party payors.
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.
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.
In the U.S., engaging in the impermissible promotion of our products, following approval, for off-label uses can also subject us to false claims and other litigation under federal and state statutes, including fraud and abuse and consumer protection laws, which can lead to civil and criminal penalties and fines, agreements with governmental authorities that materially restrict the manner in which we promote or distribute therapeutic products and do business through, for example, corporate integrity agreements, suspension or exclusion from participation in federal and state healthcare programs, and debarment from government contracts and refusal of future orders under existing contracts.
In the U.S., engaging in the impermissible promotion of our products, following approval, for off-label uses can also subject us to false claims and other litigation under federal and state statutes, including fraud and abuse and consumer protection laws, which can lead to civil and criminal penalties, damages, fines, and actions, agreements with governmental authorities that materially restrict the manner in which we promote or distribute therapeutic products and do business through, for example, corporate integrity agreements, suspension or exclusion from participation in federal and state healthcare programs, and debarment from government contracts and refusal of future orders under existing contracts.
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 extent and duration of the conflicts in Ukraine, the Middle East and other global conflicts, 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.
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.
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, the Middle East and other global conflicts, geopolitical tensions, or inflation.
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.
Regardless of the merits or eventual outcome, liability claims may result in: 40 Table of Contents ● 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.
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.
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 ● 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.
Following the change in U.S. administration, there is uncertainty regarding future legislative and regulatory changes and policies related to matters such as taxation and importation, including tariffs, and any such proposed or enacted regulations, taxes, or tariffs by the current or a future U.S. administration, Congress, or taxing and importation authorities in other jurisdictions could adversely impact the global economy and materially affect our tax obligations, tariff obligations, and operating results.
There is uncertainty regarding future legislative and regulatory changes and policies related to matters such as taxation and importation, including tariffs, and any such proposed or enacted regulations, taxes, or tariffs by the current or a future U.S. administration, Congress, or taxing and importation authorities in other jurisdictions could adversely impact the global economy and materially affect our tax obligations, tariff obligations, and operating results.
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.
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, 2025, we experienced multiple ownership changes.
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.
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; 56 Table of Contents ● 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 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.
If these third parties fail to perform as expected or to comply with legal and regulatory requirements, our ability to commercialize our current or future products will be significantly impacted and we may be subject to regulatory sanctions; ● We may be unable to successfully or sufficiently expand our manufacturing capacity to meet demand for our products; ● We depend on the success of our product candidates and cannot guarantee that these product candidates will successfully complete development, receive regulatory approval, or be successfully commercialized; ● 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; ● A Fast Track, breakthrough therapy, or regenerative medicines advanced therapy product designations, or other designation to facilitate product candidate development may not lead to faster development or a faster regulatory review or approval process, and it does not increase the likelihood that our product candidates will receive marketing approval; ● While in the U.S. 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; ● We may encounter substantial delays in our clinical trials, not be able to conduct our clinical trials on the timelines we expect, and be required to conduct additional clinical trials or modify current or future clinical trials based on feedback we receive from the FDA and foreign regulatory authorities; ● It may take longer and cost more to complete our clinical trials than we project, or we may not be able to complete them at all; ● Our clinical trials may fail to demonstrate adequately the safety and efficacy of our product candidates, which would prevent or delay regulatory approval and commercialization; ● 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; ● We rely on and collaborate with governmental, academic, and corporate partners or agencies to approve, improve, and develop TIL cell therapies for new indications for use in combination with other therapies and to evaluate new TIL manufacturing methods, the results of which, because the manufacturing processes are not within our control, and may be incorrect or unreliable; ● We have global operations, which expose us to additional risks, and any adverse event could have a material adverse effect on our results of operations and financial condition; and ● We are currently operating in a period of economic uncertainty and capital markets disruption, which has been significantly impacted by geopolitical instability, ongoing military conflicts between Russia and Ukraine and between Israel and Hamas, Hezbollah, and the Houthis, and inflation.
If these third parties fail to perform as expected or to comply with legal and regulatory requirements, our ability to commercialize our current or future products will be significantly impacted and we may be subject to regulatory sanctions; ● We may be unable to successfully or sufficiently expand our manufacturing capacity to meet demand for our products and product candidates; ● We depend on the success of our product candidates and cannot guarantee that these product candidates will successfully complete development, receive regulatory approval, or be successfully commercialized; ● 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; ● A Fast Track, breakthrough therapy, or regenerative medicines advanced therapy product designations, or other designation to facilitate product candidate development may not lead to faster development or a faster regulatory review or approval process, and it does not increase the likelihood that our product candidates will receive marketing approval; ● While in the U.S. 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; ● We may encounter substantial delays in our clinical trials, not be able to conduct our clinical trials on the timelines we expect, and be required to conduct additional clinical trials or modify current or future clinical trials based on feedback we receive from the FDA and foreign regulatory authorities; ● It may take longer and cost more to complete our clinical trials than we project, or we may not be able to complete them at all; ● Our clinical trials may fail to demonstrate adequately the safety and efficacy of our product candidates, which would prevent or delay regulatory approval and commercialization; ● 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; 30 Table of Contents ● We rely on and collaborate with governmental, academic, and corporate partners or agencies to approve, improve, and develop TIL cell therapies for new indications for use in combination with other therapies and to evaluate new TIL manufacturing methods, the results of which, because the manufacturing processes are not within our control, may be incorrect or unreliable; ● We have global operations, which expose us to additional risks, and any adverse event could have a material adverse effect on our results of operations and financial condition; and ● We are currently operating in a period of economic uncertainty and capital markets disruption, which has been significantly impacted by geopolitical instability, ongoing military conflicts, and inflation.
If we, or any of our third-party manufacturers encounter such difficulties, our ability to provide supply of our product candidates for clinical trials or our products for patients could be delayed or stopped, or we may be unable to maintain a commercially viable cost structure; ● Cell-based therapies and biologics rely on the availability of biological raw materials (including live cells), chemicals and agents used for manufacturing, reagents, specialized equipment, and other specialty materials, which may not be available to us on acceptable terms or at all.
If we, or any of our third-party manufacturers encounter such difficulties, our ability to provide supply of our product candidates for clinical trials or our products for patients could be delayed or stopped, or we may be unable to maintain a commercially viable cost structure; 29 Table of Contents ● Cell-based therapies and biologics rely on the availability of biological raw materials (including live cells), chemicals and agents used for manufacturing, reagents, specialized equipment, and other specialty materials, which may not be available to us on acceptable terms or at all.
In addition, in order to supplement our own efforts to improve TIL manufacturing and develop TIL cell therapies in new indications in clinical trials, we currently work and collaborate with government and academic research institutions, medical institutions, and corporate partners such as the NCI, Moffitt, Memorial Sloan Kettering Cancer Center, Cellectis, and Novartis.
In addition, in order to supplement our own efforts to improve TIL manufacturing and develop TIL cell therapies in new indications in clinical trials, we currently work and collaborate with government and academic research institutions, medical institutions, and corporate partners such as the NCI, Moffitt, Memorial Sloan Kettering Cancer Center, or MSKCC, Cellectis, and Novartis.
However, because the majority of our collaborations are conducted at outside laboratories and we do not have complete control over how the studies are conducted or reported or over the manufacturing methods used to manufacture TIL product, the results of such studies, which we may use as the basis for our conclusions, projections or decisions with respect to our current or future products and product candidates, may be incorrect or unreliable, or may have a negative impact on us if the results of such studies are imputed to our products or proposed indications, even if such imputation is improper.
However, because the majority of our collaborations are conducted at outside laboratories and we do not have complete control over how the studies are conducted or reported or over the manufacturing methods used to manufacture TIL product, the results of such studies, which we may use as the basis for our conclusions, projections or decisions with respect to our current or future products and product candidates, may be incorrect or unreliable, or may have a negative impact on us if the results of such 60 Table of Contents studies are imputed to our products or proposed indications, even if such imputation is improper.
No assurance can be given that the NIH has not previously licensed, or that the NIH hereafter will not license to other biotechnology companies some or all of the non-exclusive technologies available to us under the NIH License Agreement. In addition, one pending U.S. patent application in the NIH License Agreement is not owned solely by the NIH.
No assurance can be given that the NIH has not previously licensed, or that the NIH hereafter will not license to other biotechnology companies some or all of the non-exclusive technologies available to us under the NIH License Agreement. In addition, one U.S. patent in the NIH License Agreement is not owned solely by the NIH.
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.
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.
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 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.
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, the Middle East and other global conflicts, geopolitical tensions, or inflation. ​ 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 products or 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.
For example, the tax relief measures under the CARES Act for businesses include a five-year net operating loss carryback, suspension of annual deduction limitation of 80% of taxable income from net operating losses generated in a tax year beginning after December 31, 2017, changes in the deductibility of interest, acceleration of alternative minimum tax credit refunds, payroll tax relief, and a technical correction to allow accelerated deductions for qualified improvement property.
For example, the tax relief measures under the CARES Act for businesses include a five-year net operating loss carryback, suspension of annual deduction limitation of 80% of taxable income from net operating losses generated in a tax year beginning after December 31, 2017, changes in the deductibility of interest, acceleration of 34 Table of Contents alternative minimum tax credit refunds, payroll tax relief, and a technical correction to allow accelerated deductions for qualified improvement property.
Moreover, while we are expanding our capabilities to enable more internal manufacturing, should we continue to use CMOs, we may not succeed in maintaining our relationships with our current CMO or establishing relationships with additional or alternative CMOs. Our products and product candidates may compete with other products and product candidates for access to manufacturing facilities.
Moreover, while we are expanding our capabilities to enable more internal manufacturing, should we continue to use CMOs, we may not succeed in maintaining our relationships with CMOs or establishing relationships with additional or alternative CMOs. Our products and product candidates may compete with other products and product candidates for access to manufacturing facilities.
No assurance can be given that NIH’s co-owner of the certain pending U.S. patent application in the NIH License Agreement has not previously licensed, or that the co-owner thereafter will not license, to other biotechnology companies some or all of the technologies available to us.
No assurance can be given that NIH’s co-owner of the certain U.S. patent in the NIH License Agreement has not previously licensed, or that the co-owner thereafter will not license, to other biotechnology companies some or all of the technologies available to us.
If we adopt alternative names, we would lose the benefit of any existing trademark applications for such product and/or product candidate and may be required to expend significant additional resources in an effort to identify a suitable product name that would qualify under applicable trademark laws, not infringe the existing rights of third parties, and be acceptable to 47 Table of Contents the FDA and foreign regulatory authorities.
If we adopt alternative names, we would lose the benefit of any existing trademark applications for such product and/or product candidate and may be required to expend significant additional resources in an effort to identify a suitable product name that would qualify under applicable trademark laws, not infringe the existing rights of third parties, and be acceptable to the FDA and foreign regulatory authorities.
These trials, which we refer to as IOV-LUN-202 Cohorts 1 and 2 in the case of advanced NSCLC and TILVANCE-301 in the case of advanced melanoma, are currently underway and have been the subject of formal FDA meetings and communications.
The ongoing trials, which we refer to as IOV-LUN-202 Cohorts 1 and 2 in the case of advanced NSCLC and TILVANCE-301 in the case of advanced melanoma, are currently underway and have been the subject of formal FDA meetings and communications.
Other than the Gen 2 manufacturing process, our licensed rights, and our method of use rights in certain indications, 81 Table of Contents we currently do not own any exclusive rights on our entire product portfolio that could be used to fully prevent third parties from duplicating our business plan or from otherwise directly competing against us.
Other than the Gen 2 manufacturing process, our licensed rights, and our method of use rights in certain indications, we currently do not own any exclusive rights on our entire product portfolio that could be used to fully prevent third parties from duplicating our business plan or from otherwise directly competing against us.
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.
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.
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.
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. 46 Table of Contents Additionally, we may contract with a third-party to calculate and report pricing information mandated by various government programs.
Although both the internal and external facilities were approved by the FDA for commercial manufacturing of Amtagvi ® , there is no guarantee that we or our CMOs will be able to successfully pass all aspects of surveillance or pre-approval inspections by the FDA or other foreign regulatory authorities for Amtagvi ® or future product candidates.
Although both the internal and external facilities were approved by the FDA for commercial manufacturing of Amtagvi ® , there is no guarantee that we or our CMOs will be 37 Table of Contents able to successfully pass all aspects of surveillance or pre-approval inspections by the FDA or other foreign regulatory authorities for Amtagvi ® or future product candidates.
Raimondo, 603 U.S. 369 (2024) and Corner Post, Inc. v. Board of Governors of the Federal Reserve System, 603 U.S. 799 (2024), will impact the FDA’s enforcement and decision-making authority. Loper Bright explicitly overturned Chevron deference, which previously gave 77 Table of Contents judicial deference to administrative action by agencies in the executive branch.
Raimondo, 603 U.S. 369 (2024) and Corner Post, Inc. v. Board of Governors of the Federal Reserve System, 603 U.S. 799 (2024), will impact the FDA’s enforcement and decision-making authority. Loper Bright explicitly overturned Chevron deference, which previously gave judicial deference to administrative action by agencies in the executive branch.
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.
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. 32 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.
There is no assurance that we will be successful in meeting these milestones on a timely basis, or at all. 61 Table of Contents We are dependent on third parties to support our research, development, and supplement our internal manufacturing activities and, therefore, are subject to the efforts of these parties and our ability to successfully collaborate with these third parties.
There is no assurance that we will be successful in meeting these milestones on a timely basis, or at all. We are dependent on third parties to support our research, development, and supplement our internal manufacturing activities and, therefore, are subject to the efforts of these parties and our ability to successfully collaborate with these third parties.
For instance, on December 22, 2023, the FDA placed a clinical hold on the IOV-LUN-202 trial in response to a reported Grade 5 (fatal) serious adverse event potentially related to the non-myeloablative lymphodepletion pre-conditioning regimen, and we paused enrollment and the lifileucel treatment regimen for new patients in IOV-LUN-202 during the clinical hold.
For instance, on December 22, 2023, the FDA placed a clinical hold on the IOV-LUN-202 trial in response to a reported Grade 5 (fatal) serious adverse event potentially related to the non-myeloablative lymphodepletion, or NMA-LD, pre-conditioning regimen, and we paused enrollment and the lifileucel treatment regimen for new patients in IOV-LUN-202 during the clinical hold.
Changes to implement an 70 Table of Contents independent review committee and assay validation and implementation, and the data within these clinical trials may not ultimately be supportive of product approval, all of which could result in significant delays to our currently anticipated timeline for development and approval of the lifileucel product candidate or prevent their approval.
Changes to implement an independent review committee and assay validation and implementation, and the data within these clinical trials may not ultimately be supportive of product approval, all of which could result in significant delays to our currently anticipated timeline for development and approval of the lifileucel product candidate or prevent their approval.
In addition, given our current net loss and net loss carryforwards, we may not be able to realize the full benefit of these tax advantages before they expire. 37 Table of Contents Risks Related to the Manufacturing and Commercialization of Our Products and Product Candidates Even though our lead product Amtagvi ® is approved and commercialized, we may not become profitable.
In addition, given our current net loss and net loss carryforwards, we may not be able to realize the full benefit of these tax advantages before they expire. Risks Related to the Manufacturing and Commercialization of Our Products and Product Candidates Even though our lead product Amtagvi ® is approved and commercialized, we may not become profitable.
We may not be able to obtain rights to such materials on commercially reasonable terms, or at all, and if we are unable to alter our process in a commercially viable manner to avoid the use of such materials or find a suitable substitute, it would have a material adverse effect on our business.
We may not be able to obtain rights to such materials on commercially reasonable terms, or at all, and if we are unable to alter our process in a commercially viable manner to avoid the use of 38 Table of Contents such materials or find a suitable substitute, it would have a material adverse effect on our business.
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.
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.
On March 4, 2024, the FDA lifted the partial clinical hold on the IOV-LUN-202 trial, permitting us to resume patient enrollment. A failure of one or more clinical trials can occur at any stage of testing, and our future 54 Table of Contents clinical studies may not be successful.
On March 4, 2024, the FDA lifted the partial clinical hold on the IOV-LUN-202 trial, permitting us to resume patient enrollment. A failure of one or more clinical trials can occur at any stage of testing, and our future clinical studies may not be successful.
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.
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.
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.
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.
Certain changes, however, and supplements to an approved BLA, and subsequent applications filed by the same sponsor, manufacturer, licensor, predecessor in interest, or other related entity do not qualify for the 12-year exclusivity period. Our products and product candidates may qualify for the BPCIA’s 12-year period of exclusivity.
Certain changes, however, and supplements to an approved BLA, and subsequent applications filed by the same sponsor, manufacturer, licensor, predecessor in interest, or other related entity do not qualify for the 12-year exclusivity period. 44 Table of Contents Our products and product candidates may qualify for the BPCIA’s 12-year period of exclusivity.
Likewise, in the absence of a long-term agreement with an insurance company, there is no guarantee that an insurance company will enter into a single-case agreement with us or otherwise provide prior authorization for a particular case, in which case there may be no or inadequate coverage and reimbursement for our products.
Likewise, in the absence of a long-term agreement with an insurance company, there is no guarantee that an insurance company will enter into a single-case agreement with us or otherwise provide prior authorization for a particular case, in which case there may be no or 39 Table of Contents inadequate coverage and reimbursement for our products.
Our treatment centers may not be able to obtain necessary supplies, such as lymphodepleting chemotherapy agents, because of shortages. Our commercial products and investigational therapies will rely heavily on our ability to train centers and the centers’ ability to choose suitable patients and deliver a 50 Table of Contents complex regimen.
Our treatment centers may not be able to obtain necessary supplies, such as lymphodepleting chemotherapy agents, because of shortages. Our commercial products and investigational therapies will rely heavily on our ability to train centers and the centers’ ability to choose suitable patients and deliver a complex regimen.
Moreover, following product approval, orphan exclusivity may be lost if the FDA determines, among other reasons, that the request for designation was materially defective or if the manufacturer is unable to assure sufficient quantity of the product to meet the needs of patients with the rare disease or condition.
Moreover, following product approval, orphan exclusivity may be lost if the FDA determines, among other reasons, that the request for designation was materially defective or if the manufacturer is unable to assure sufficient quantity of the product to meet the needs 49 Table of Contents of patients with the rare disease or condition.
Events like these, such as the ongoing war between Russia and Ukraine and rising conflict in the Middle East, could result in material adverse effects on macroeconomic conditions, currency exchange rates and financial markets, and may adversely affect our business, results of operations, and financial condition.
Events like these, such as the ongoing war between Russia and Ukraine, rising conflict in the Middle East and other global conflicts, could result in material adverse effects on macroeconomic conditions, currency exchange rates and financial markets, and may adversely affect our business, results of operations, and financial condition.
The FDA may take a restrictive approach when regulating cell therapy manufacturing facilities that could result in delays, product release challenges, shortages, or capacity restraints. Our current manufacturing strategy involves the use of CMOs in conjunction with our internal manufacturing capacity at the i CTC.
The FDA may take a restrictive approach when regulating cell therapy manufacturing facilities that could result in delays, product release challenges, shortages, or capacity restraints. 36 Table of Contents Our current manufacturing strategy involves the use of CMOs in conjunction with our internal manufacturing capacity at the i CTC.
Moreover, the FDA and comparable foreign regulatory authorities require us to comply with Good Clinical Practices, or GCPs, for conducting, recording, and reporting the results of clinical trials to assure that data and reported results are credible and accurate and that the rights, integrity, and confidentiality of clinical trial participants are protected.
Moreover, the FDA and comparable foreign regulatory authorities require us to comply with Good Clinical Practices, or GCPs, for conducting, recording, and reporting the results of clinical trials to assure that data and reported results are credible and accurate and that the rights, integrity, and confidentiality of clinical trial 50 Table of Contents participants are protected.
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.
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.
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.
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 70 Table of Contents business.
If we or our future collaborators do not lawfully promote our approved products, if any, we may become subject to such 74 Table of Contents litigation and, if we do not successfully defend against such actions, those actions may have a material adverse effect on our business, financial condition, results of operations and prospects.
If we or our future collaborators do not lawfully promote our approved products, if any, we may become subject to such litigation and, if we do not successfully defend against such actions, those actions may have a material adverse effect on our business, financial condition, results of operations and prospects.
A prevailing party in that case may not offer us a license on commercially acceptable terms. We cannot prevent other companies from licensing most of the same intellectual properties that we have licensed or from otherwise duplicating our business model and operations.
A prevailing party in that case may not offer us a license on commercially acceptable terms. 79 Table of Contents We cannot prevent other companies from licensing most of the same intellectual properties that we have licensed or from otherwise duplicating our business model and operations.
The outcome of this and other future litigation is uncertain. ​ Our Board of Directors could issue one or more additional series of preferred stock without stockholder approval with the effect of diluting existing stockholders and impairing their voting and other rights. ​ Our certificate of incorporation, as amended, authorizes the issuance of up to 50,000,000 shares of “blank check” preferred stock (of which only 17,000 shares were issued as Series A Convertible Preferred Stock and 11,500,000 shares were issued as Series B Convertible Preferred Stock) with designations, rights, and preferences as may be determined from time to time by our Board of Directors.
The outcome of these and other future litigation is uncertain. ​ Our Board of Directors could issue one or more additional series of preferred stock without stockholder approval with the effect of diluting existing stockholders and impairing their voting and other rights. ​ Our certificate of incorporation, as amended, authorizes the issuance of up to 50,000,000 shares of “blank check” preferred stock (of which only 17,000 shares were authorized for issuance as Series A Convertible Preferred Stock and 11,500,000 shares were authorized for issuance as Series B Convertible Preferred Stock) with designations, rights, and preferences as may be determined from time to time by our Board of Directors.
As a result, we cannot give any assurance that the Gen 2 process or any future process that we select will be a manufacturing process that can produce our products in compliance with the applicable regulatory requirements, at a cost or in quantities necessary to make them commercially viable.
As a result, we cannot give any assurance that the Gen 2 process or any future process that we select will be a manufacturing process that can produce our product candidates in compliance with the applicable regulatory requirements, at a cost or in quantities necessary to make them commercially viable.
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.
These changes may require 53 Table of Contents 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.
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.
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.
If we obtain FDA approval of any of our product candidates and begin commercializing those products in the U.S., our potential exposure under such laws will increase significantly, and our costs associated with compliance with such laws are also likely to increase.
If we obtain FDA approval of any of our product candidates and begin commercializing those products in the U.S., our potential exposure under such laws will increase significantly, and our costs 77 Table of Contents associated with compliance with such laws are also likely to increase.
In addition, new regulation or legislative actions regarding data privacy and security (together with applicable industry standards) may increase our costs of doing business.
In addition, new regulations or legislative actions regarding data privacy and security (together with applicable industry standards) may increase our costs of doing business.
Although we may apply for special government programs and prepare the market for product approval, there is no way to ensure that healthcare providers, insurance companies, or other third parties will reimburse our product at an expeditious rate.
Although we may apply for special government programs and prepare the market for product approval, there is no way to ensure that HCPs, insurance companies, or other third parties will reimburse our product at an expeditious rate.
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.
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.
As a result, we may not be able to successfully or sufficiently increase the manufacturing capacity for our product candidates or modify our manufacturing processes.
As a result, we may not be able to successfully or sufficiently increase the manufacturing capacity for our products and product candidates or modify our manufacturing processes.
As an example, of changes enacted by a new administration, the Inflation Reduction Act, or the IRA, was signed into law in August 2022 by President Biden, which makes significant changes to how drugs are covered and paid for under the Medicare program, including the creation of financial penalties for drugs whose prices rise faster than the rate of inflation, redesign of the Medicare Part D program to require manufacturers to bear more of the liability for certain drug benefits, and government price-setting for certain Medicare Part D drugs, starting in 2026, and Medicare Part B drugs starting in 2028.
As an example, of changes enacted by a new administration, the IRA, or the IRA, was signed into law in August 2022 by President Biden, 75 Table of Contents which makes significant changes to how drugs are covered and paid for under the Medicare program, including the creation of financial penalties for drugs whose prices rise faster than the rate of inflation, redesign of the Medicare Part D program to require manufacturers to bear more of the liability for certain drug benefits, and government price-setting for certain Medicare Part D drugs, which started in 2026, and Medicare Part B drugs starting in 2028.
Product candidates in later stages of clinical trials may fail to show the desired safety and efficacy traits despite having progressed through preclinical studies and initial clinical trials. Preclinical studies may also reveal unfavorable product candidate characteristics, including safety concerns.
Product candidates in later stages of clinical trials 55 Table of Contents may fail to show the desired safety and efficacy traits despite having progressed through preclinical studies and initial clinical trials. Preclinical studies may also reveal unfavorable product candidate characteristics, including safety concerns.
Furthermore, we are required to make certain future payments under the Proleukin ® acquisition agreement that are denominated in non-U.S. dollars, including future deferred consideration and earnout payments based on Proleukin ® sales. As such, we face exposure to adverse movements in foreign currency exchange rates, including movements in foreign currency for the future milestone payment.
Furthermore, we are required to make certain future payments under the Proleukin ® acquisition agreement that are denominated in non-U.S. dollars, including future deferred consideration and earnout payments based 65 Table of Contents on Proleukin ® sales. As such, we face exposure to adverse movements in foreign currency exchange rates, including movements in foreign currency for the future milestone payment.
The market price of our common stock is likely to be volatile and could fluctuate widely in response to many factors, including but not limited to: ● volatility and instability in the capital markets due to the COVID-19 pandemic; ● announcements of the results of clinical trials by us, our collaborators, or our competitors, or negative developments with respect to similar products, including those being developed by our collaborators; ● developments with respect to patents or proprietary rights; ● announcements of technological innovations by us or our competitors; ● announcements of new products or new contracts by us or our competitors; ● actual or anticipated variations in our operating results due to the level of development expenses and other factors; ● changes in financial estimates by equities research analysts and whether our earnings meet or exceed such estimates; ● conditions and trends in the pharmaceutical, biotechnology and other industries; ● receipt, or lack of receipt, of funding in support of conducing our business; ● regulatory developments within, and outside of, the U.S.; ● litigation or arbitration; ● general volatility in the financial markets; ● general economic, political and market conditions and other factors; and ● the occurrence of any of the risks described in this Annual Report on Form 10-K.
The market price of our common stock is likely to be volatile and could fluctuate widely in response to many factors, including but not limited to: ● volatility and instability in the capital markets due to potential health epidemics and pandemics; ● announcements of the results of clinical trials by us, our collaborators, or our competitors, or negative developments with respect to similar products, including those being developed by our collaborators; ● developments with respect to patents or proprietary rights; 81 Table of Contents ● announcements of technological innovations by us or our competitors; ● announcements of new products or new contracts by us or our competitors; ● actual or anticipated variations in our operating results due to the level of development expenses and other factors; ● changes in financial estimates by equities research analysts and whether our earnings meet or exceed such estimates; ● conditions and trends in the pharmaceutical, biotechnology and other industries; ● receipt, or lack of receipt, of funding in support of conducing our business; ● regulatory developments within, and outside of, the U.S.; ● litigation or arbitration; ● general volatility in the financial markets; ● general economic, political and market conditions and other factors; and ● the occurrence of any of the risks described in this Annual Report on Form 10-K.
Even if we are successful in defending against these claims, litigation could result in substantial costs and be a distraction to management and other employees. Provisions in our amended and restated bylaws could limit our stockholders’ ability to obtain a favorable judicial forum for disputes with us or our directors, officers or employees.
Even if we are successful in defending against these claims, litigation could result in substantial costs and be a distraction to management and other employees. 84 Table of Contents Provisions in our amended and restated bylaws could limit our stockholders’ ability to obtain a favorable judicial forum for disputes with us or our directors, officers or employees.
For example, we continue to recruit a new Chief Executive Officer. However, competition for qualified employees among companies in the biotechnology and biopharmaceutical industry is intense, and no assurance can be given that we will be able attract, hire, retain, and motivate the highly skilled employees that we need.
For example, we continue to recruit a new Chief Executive Officer. However, competition for qualified employees among companies in the biotechnology and biopharmaceutical industry is intense, and no assurance can be given that we will be able attract, 45 Table of Contents hire, retain, and motivate the highly skilled employees that we need.
Approval procedures vary among jurisdictions and can involve requirements and administrative review periods different from, and greater than, those in the U.S., including additional preclinical studies or clinical trials as clinical studies conducted in one jurisdiction may not be accepted by regulatory authorities in 71 Table of Contents other jurisdictions.
Approval procedures vary among jurisdictions and can involve requirements and administrative review periods different from, and greater than, those in the U.S., including additional preclinical studies or clinical trials as clinical studies conducted in one jurisdiction may not be accepted by regulatory authorities in other jurisdictions.
Additionally, the costs associated with development of cell therapy products may be significant due to the length of treatment and the supportive therapies provided to the patient during the treatment process. Supportive therapies may impact costs and patient viability and may potentially limit availability.
Additionally, the costs associated with development of cell therapy products may be significant due to the length of treatment and the supportive 47 Table of Contents therapies provided to the patient during the treatment process. Supportive therapies may impact costs and patient viability and may potentially limit availability.
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.
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, 42 Table of Contents which will take time and require significant financial expenditures, and we may not be successful in doing so.

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Item 1C. Cybersecurity

Cybersecurity — threats and controls disclosure

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Biggest changeCybersecurity 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 .
Biggest changeCybersecurity 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. ● 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 .
As cybersecurity threats become more sophisticated and coordinated, it is reasonably likely that we will be required to expend greater resources to continue to modify and enhance our protective measures as we pursue our business strategies. Governance: ● Board of Directors The Audit Committee operates under a written charter adopted by the Company’s Board of Directors.
As cybersecurity threats become more sophisticated and coordinated, it is reasonably likely that we will be required to expend greater resources to continue to modify and enhance our protective measures as we pursue our business strategies. 85 Table of Contents Governance: ● Board of Directors The Audit Committee operates under a written charter adopted by the Company’s Board of Directors.

Item 2. Properties

Properties — owned and leased real estate

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Biggest changeItem 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.
Biggest changeItem 2. Properties San Carlos Headquarters Lease On November 15, 2024, we entered into a sublease agreement, or the 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 Headquarters Lease, we will lease approximately 16,731 rentable square feet of space in the Building.
Philadelphia Office Lease On May 2, 2019, we entered into an agreement to lease approximately 1,500 square feet of office space in Philadelphia, Pennsylvania until July 1, 2019, for a rate of $2,000 a month, and then approximately 4,500 square feet of office space for the remainder of a three-year term at an initial rate of $11,063 per month, subject to annual increases of 2.5%.
Former Philadelphia Office Lease On May 2, 2019, we entered into an agreement to lease approximately 1,500 square feet of office space in Philadelphia, Pennsylvania until July 1, 2019, for a rate of $2,000 a month, and then approximately 4,500 square feet of office space for the remainder of a three-year term at an initial rate of $11,063 per month, subject to annual increases of 2.5%.
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.
On December 22, 2021, we entered into a second 86 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.
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.
The Headquarters Lease is for a term of 24 months and commenced on December 12, 2024. The 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 Headquarters Lease.
On September 1, 2021, we entered into an agreement to extend the lease term for an additional three years to July 31, 2025, for approximately $11,900 a month, effective as of June 1, 2022, subject to annual increases of 2.5%.
On September 1, 2021, we entered into an agreement to extend the lease term for an additional three years to July 31, 2025, for approximately $11,900 a month, effective as of June 1, 2022, subject to annual increases of 2.5%. The lease agreement expired at the end of July 2025 and was not further extended.
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 lease payments are approximately $41,000, subject to annual increases of 3.75%. 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 2025 to extend the lease term through July 28, 2026.
Beginning on the commencement date, our monthly base rent under the New Headquarters Lease will be $0.1 million during the term.
Beginning on the commencement date, our monthly base rent under the Headquarters Lease will be $0.1 million during the term. We are also responsible for paying operating expenses such as common area maintenance.
Removed
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.
Added
On July 28, 2025, we entered into a third amendment, to extend the lease term through January 2028. Lease payments are approximately $50,000 per month.
Removed
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.
Added
We have since entered into various lease amendments to expand the rentable square feet of office space and lab space. Most recently, in May 2025, we amended the lease agreement to extend the lease term to July 31, 2029, with the option to subsequently extend for an additional two years.
Removed
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.
Removed
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.
Removed
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.
Removed
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.
Removed
In addition, the lessor has provided a tenant improvement allowance of up to $8.2 million, of which, to date, we have received reimbursements associated with this tenant improvement allowance totaling $8.1 million. We do not expect to receive any additional reimbursements associated with this tenant improvement allowance.
Removed
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.
Removed
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.
Removed
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.
Removed
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 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
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 17 to our consolidated financial statements for the year ended December 31, 2025, 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 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.
Item 3. Legal Proceedings The information in Note 17 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 5. Market for Registrant's Common Equity

Market for Common Equity — stock, dividends, buybacks

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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.
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.
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] ​
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. ​ 88 Table of Contents ​ Equity Compensation Plan Information Information regarding our equity compensation plans is incorporated by reference from the information in our Proxy Statement for our 2026 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] ​
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.
Repurchases of Common Stock There were no share repurchases during the year ended December 31, 2025. Stock Performance Graph ​ The following graph illustrates a comparison of the total cumulative stockholder return on our common stock since December 31, 2020, to two indices: the Russell 3000 and the NASDAQ Biotechnology Index.
Dividends We have never declared or paid any cash dividends on our common stock or any other securities. We anticipate that we will retain all available funds and any future earnings, if any, for use in the operation of our business and do not anticipate paying cash dividends in the foreseeable future.
We anticipate that we will retain all available funds and any future earnings, if any, for use in the operation of our business and do not anticipate paying cash dividends in the foreseeable future.
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.
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, 2025, there were approximately 18 holders of record of our common stock. 87 Table of Contents Dividends We have never declared or paid any cash dividends on our common stock or any other securities.
Added
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

95 edited+35 added−66 removed73 unchanged
Biggest changeCosts and expenses The following table summarizes the period-over-period changes in our costs and expenses: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Years Ended December 31, ​ Increase (Decrease) (in thousands) 2024 2023 ​ $ % Cost of sales ​ $ 123,995 ​ $ 10,755 ​ 113,240 ​ 1,053 Research and development expense ​ ​ 282,336 ​ ​ 344,077 ​ (61,741) ​ (18) Selling, general, and administrative expense ​ 153,017 ​ 106,916 ​ 46,101 ​ 43 ​ Cost of sales Cost of sales for the year ended December 31, 2024, increased by $113.2 million, or 1,053% driven by the increase in sales of Amtagvi ® and Proleukin ® , as well as costs related to the manufacturing of Amtagvi ® .
Biggest changeWhile such Proleukin ® sales are not directly indicative of future Amtagvi ® revenues because of the timing of stocking activities by specialty distributors and because of sales that are not related to Amtagvi ® infusions, such as sales of Proleukin ® utilized in clinical manufacturing or clinical trials, such sales are one indicator of future Amtagvi ® revenues. ​ 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) ​ 2024 ​ ​ ​ 2023 ​ $ ​ % Costs and expenses ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Cost of sales ** ​ $ 93,248 ​ $ 1,033 ​ 92,215 ​ 8,927 Research and development ** ​ ​ 276,228 ​ ​ 333,194 ​ (56,966) ​ (17) Selling, general, and administrative ** ​ ​ 152,269 ​ ​ 106,098 ​ 46,171 ​ 44 Depreciation and amortization ​ ​ 37,603 ​ ​ 21,423 ​ 16,180 ​ 76 Total costs and expenses ​ $ 559,348 ​ $ 461,748 ​ 97,600 ​ 21 ** Excludes depreciation and amortization ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Cost of sales Cost of sales, excluding depreciation and amortization, for the year ended December 31, 2024, increased by $92.2 million, or 8,927%, driven by the increase in sales of Amtagvi ® and Proleukin ® products, as well as costs related to the manufacturing of Amtagvi ® .
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, 2024 was $390.7 million compared to net cash provided of $463.0 million for the same period in 2023.
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.
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.
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.
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.
Our owned and licensed intellectual property portfolio 91 Table of Contents 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.
These decreases were partially offset by (i) a $29.5 million increase in payroll and related costs, including stock-based compensation, primarily driven by an increase in the number of employees and the number of stock awards granted at a higher average stock price, (ii) a $5.0 million charge for the impairment of leasehold improvements driven by the early termination of our headquarters lease during the fourth quarter of 2024 (exclusive of the gain on lease termination which is recorded in interest and other income, net), (iii) a $2.6 million increase in lab and consumable costs for the development of next generation candidates, (iii) a $2.9 million increase in license costs related to the expansion of our information technology infrastructure to support our clinical activities, and (iv) a $1.3 million increase in other costs, including travel and facility related costs.
These decreases were partially offset by (i) a $19.8 million increase in payroll and related costs, including stock-based compensation, primarily driven by an increase in the number of employees and the number of stock awards granted at a higher average stock price, (ii) a $5.0 million charge for the impairment of leasehold improvements driven by the early termination of our headquarters lease during the fourth quarter of 2024 (exclusive of the gain on lease termination which is recorded in interest and other income, net), (iii) a $2.6 million increase in lab and consumable costs for the development of next generation candidates, (iv) a $2.9 million increase in license costs related to the expansion of our information technology infrastructure to support our clinical activities, and (v) a $1.3 million increase in other costs, including travel and facility related costs.
These estimates are typically based on contracted amounts, patient visit data, discussions with internal clinical stakeholders and outside service providers, and historical look-back analysis of actual payments made to date. ​ We make judgements and estimates in determining the accrual balance in each reporting period.
These estimates are typically based on contracted amounts, patient visit data, discussions with internal clinical stakeholders and outside service providers, and historical look-back analysis of actual payments made to date. ​ We make judgments and estimates in determining the accrual balance in each reporting period.
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.
If the screen test is met, the transaction is accounted for as an asset acquisition. If the screen test is not met, further 103 Table of Contents 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.
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.
More than 50 of these patents are related to our Gen 2 TIL manufacturing processes and have terms that we anticipate will extend to October 2037 or January 2038, not including any patent term extensions or adjustments that may be available.
In addition, it reflects a decrease in non-cash charges of $17.3 million primarily driven by lower stock-based compensation expenses and accretion of discount on investments, partially offset by increases in amortization of intangible assets driven primarily by the amortization associated with the developed technology intangible asset acquired as part of the Acquisition and in depreciation expense resulting primarily from additional fixed assets put in service at the i CTC.
In addition, it reflects a decrease in non-cash charges of $17.3 million primarily driven by lower stock-based compensation expenses and accretion of discount on investments, partially offset by increases in amortization of intangible assets 101 Table of Contents driven primarily by the amortization associated with the developed technology intangible asset acquired as part of the Acquisition and in depreciation expense resulting primarily from additional fixed assets put in service at the i CTC.
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.
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, 2025, we had no obligations that would require disclosure as off-balance sheet arrangements.
In addition, to a lesser extent, such costs included period costs incurred for the first few quarters after the launch of Amtagvi ® related to overhead and manufacturing costs at the i CTC during the period from approval resulting from under absorption of overhead costs during the period, which was driven by our decision to launch with capacity sufficient to address anticipated commercial demand in 2024 and beyond.
In addition, to a lesser extent, such costs included period costs incurred for the first few quarters after the launch of Amtagvi ® related to overhead and manufacturing 97 Table of Contents costs at the i CTC during the period from approval resulting from under absorption of overhead costs during the period, which was driven by our decision to launch with capacity sufficient to address anticipated commercial demand in 2024 and beyond.
The Proleukin ® inventory that was previously with distributors at the time of the Acquisition to support the U.S. market has been substantially sold, and, as a result, we experienced significant re-stocking demand from specialty distributors in both the second and third quarter of 2024 to support ongoing and anticipated infusions related to the strong commercial launch of Amtagvi ® .
The Proleukin ® inventory that was previously with distributors at the time of the Acquisition to support the U.S. market has been substantially depleted, and, as a result, we experienced significant re-stocking demand from U.S. specialty distributors in both the second and third quarter of 2024 to support ongoing and anticipated infusions related to the commercial launch of Amtagvi ® .
We are currently evaluating the impact of ASU 2024-03 on our consolidated financial statements.
We are currently evaluating the impact of adopting ASU 2024-03 on our consolidated financial statements.
The issuance and sale, if any, of shares of our common stock under the 2023 Sale Agreement was or will be made pursuant to a prospectus supplement dated June 16, 2023 to our Registration Statement on Form S-3ASR, which became effective immediately upon filing with the U.S. Securities and Exchange Commission on June 16, 2023.
The issuance and sale, if any, of shares of our common stock under the Sale Agreement was or will be made pursuant to a prospectus supplement dated August 22, 2025 to our Registration Statement on Form S-3ASR, which became effective immediately upon filing with the U.S. Securities and Exchange Commission on June 16, 2023, or the Registration Statement.
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.
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 92 Table of Contents may result in an uneven payment flow.
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.
We expect to continue to incur significant expenses to support commercial activities for 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.
Further, net cash used in operating activities related to changes in operating assets and liabilities increased by $124.0 million, driven primarily by an increase in trade accounts receivable, resulting from the sale of our products and a decrease in accounts payable and accrued expenses, resulting from cash utilized for payments associated with the continued growth in the business, including our increased workforce, timing of vendor invoicing and related payments, and cash used for purchases of raw material inventory in support of the commercial launch of Amtagvi ® .
Further, net cash used in operating activities related to changes in operating assets and liabilities increased by $128.5 million, driven primarily by an increase in trade accounts receivable, resulting from the sale of our products and a decrease in accounts payable and accrued expenses, resulting from cash utilized for payments associated with the continued growth in the business, including our increased workforce, timing of vendor invoicing and related payments, and cash used for purchases of raw material inventory in support of the commercial launch of Amtagvi ® .
In addition, it reflects a net increase in non-cash charges of $53.0 million, primarily driven by higher stock-based compensation expense and amortization of intangible assets, the latter of which is driven primarily by the amortization associated with the developed technology intangible asset recorded as part of the Acquisition and intellectual property license intangible assets associated with Amtagvi ® , and an impairment charge of the long-lived assets that resulted from an early termination of our corporate headquarters lease.
In addition, it reflects a net increase in non-cash charges of $57.5 million, primarily driven by higher stock-based compensation expense and amortization of intangible assets, the latter of which is driven primarily by the amortization associated with the developed technology intangible asset recorded as part of the Acquisition and intellectual property license intangible assets associated with Amtagvi ® , and an impairment charge of the long-lived assets that resulted from an early termination of our corporate headquarters lease.
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 currently own more than 90 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.
Our payment terms to customers range from 45 to 105 days; payment terms differ by customer and by product. 107 Table of Contents Revenue is reduced at the time of recognition for expected chargebacks, product returns, discounts, rebates, and sales allowances, collectively referred to as gross to net adjustments, or GTN adjustments.
Our payment terms to customers range from 45 to 105 days; payment terms differ by customer and by product. 104 Table of Contents Revenue is reduced at the time of recognition for expected chargebacks, discounts, rebates, and sales allowances, collectively referred to as gross to net adjustments, or GTN adjustments.
We focus significant effort and attention on working with the treatment centers during the onboarding process regarding these matters, as well as on our internal manufacturing processes. ​ Research and development ​ Research and development expenses include personnel and facility-related expenses, outside contracted services including clinical trial costs, manufacturing and process development costs, research costs, and other consulting services.
We focus significant effort and attention on working with the treatment centers regarding these matters, as well as on our internal manufacturing processes. ​ Research and development expense ​ Research and development expenses include personnel and facility-related expenses, outside contracted services including clinical trial costs, manufacturing and process development costs, research costs, and other consulting services.
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.
Net cash used in investing activities for the year ended December 31, 2024, was $96.4 million compared to net cash used in investing activities of $155.2 million for the same period in 2023.
The decrease was primarily attributable to (i) a $97.7 million decrease in clinical manufacturing costs, driven by capitalization of qualified costs for Amtagvi ® manufacturing resulting from our BLA approval and the transition to commercial manufacturing to support the commercial launch of Amtagvi ® , (ii) a $4.4 million decrease in costs associated with the reclassification of certain activities supporting Amtagvi ® into general and administrative expenses upon BLA approval based on their function, and (iii) a $0.9 million decrease in clinical costs, driven primarily by lower patient enrollment across certain studies.
The decrease was primarily attributable to (i) an $83.3 million decrease in clinical manufacturing costs, driven by capitalization of qualified costs for Amtagvi ® manufacturing resulting from our BLA approval and the transition to commercial manufacturing to support the commercial launch of Amtagvi ® , (ii) a $4.4 million decrease in costs associated with the reclassification of certain activities supporting Amtagvi ® into general and administrative expenses upon BLA approval based on their function, and (iii) a $0.9 million decrease in clinical costs, driven primarily by lower patient enrollment across certain studies.
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.
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 or impaired intangible assets existed as of December 31, 2025 or December 31, 2024.
The increase was primarily attributable to (i) a $28.0 million increase in payroll and related expenses, including stock-based compensation, driven by an increase in headcount to support the growth in the overall business as well as to support the commercialization of Amtagvi ® , an increased number of stock awards granted at a higher average stock price, and the reclassification of costs of certain employees previously supporting research and development activities into general and administrative expense upon BLA approval based on their functional activities, (ii) a $3.8 million increase in legal costs driven by a reduction in legal costs in 2023 resulting from the capitalization of previously expensed costs directly associated with the Acquisition, (iii) a $7.0 million increase in costs incurred in support of the distribution and commercialization of Amtagvi ® and Proleukin ® , and (iv) a $2.4 million charge for the impairment of the leasehold improvements driven by the early termination of our headquarters lease during the fourth quarter of 2024 (exclusive of the gain on lease termination which is recorded in interest and other income, net), and (v) a $4.9 million increase in other costs, including costs associated with increased travel, software licenses related to the expansion of our information technology infrastructure, and professional fees. ​ Interest and other income, net ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Years Ended December 31, Increase (Decrease) (in thousands) 2024 2023 $ % Interest and other income, net ​ $ 20,273 $ 13,043 7,230 ​ 55 ​ Interest and other income, net for the year ended December 31, 2024, increased by $7.2 million, or 55%, compared to the same period in 2023.
The increase was primarily attributable to (i) a $27.9 million increase in payroll and related expenses, including stock-based compensation, driven by an increase in headcount to support the growth in the overall business as well as to support the commercialization of Amtagvi ® , an increased number of stock awards granted at a higher average stock price, and the reclassification of costs of certain employees previously supporting research and development activities into general and administrative expense upon BLA approval based on their functional activities, (ii) a $3.8 million increase in legal costs driven by a reduction in legal costs in 2023 resulting from the capitalization of previously expensed costs directly associated with the Acquisition, (iii) a $7.0 million increase in costs incurred in support of the distribution and commercialization of Amtagvi ® and Proleukin ® , and (iv) a $2.4 million charge for the impairment of the leasehold improvements driven by the early termination of our headquarters lease during the fourth quarter of 2024 (exclusive of the gain on lease termination which is recorded in interest and other income, net), and (v) a $5.1 million increase in other costs, including costs associated with increased travel, software licenses related to the expansion of our information technology infrastructure, and professional fees. ​ Depreciation and amortization ​ Depreciation and amortization expense for the year ended December 31, 2024, increased $16.2 million, or 76% compared to the same period in 2023.
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.
Research and development activities are central to our business model. 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.
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.
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; 11,141,434;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; 11,293,009; 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; 11,401,507; 11,433,097; 11,517,592; 11,529,372; 11,541,077; 11,631,483; 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; 11,998,568; 12,023,355; 12,024,718; 12,031,157; 12,104,172; 12,121,541; 12,159,700; 12,170,134; 12,188,048; 12,194,061; 12,226,434; 12,226,522; 12,230,378; 12,230,379; 12,233,075; 12,280,140; 12,343,380 ; 12,485,145; and 12,495,791.
Components of Operating Results ​ Revenues ​ Revenues for the year ended December 31, 2024 represent product sales of Amtagvi ® , as well as Proleukin ® , primarily driven from sales in the U.S. to support the ongoing commercial launch of Amtagvi ® , which received FDA approval in February 2024.
Components of Operating Results ​ Revenue ​ Revenue for the year ended December 31, 2025 represents product sales of Amtagvi ® , as well as Proleukin ® , primarily driven from sales in the U.S. to support the ongoing commercial launch of Amtagvi ® , which received FDA approval in February 2024.
We determine excess or obsolete inventory based on multiple factors, including an estimate of recent sales forecast compared to quantities on hand and the expiration date of the product and materials. Revenue Recognition We recognize revenue from product sales in accordance with Topic ASC 606, Revenue from Contracts with Customers, or ASC 606.
We determine excess or obsolete inventory based on multiple factors, including our most recent sales and manufacturing forecast compared to quantities on hand and the expiration date of the product and materials. Revenue Recognition We recognize revenue from product sales in accordance with ASC 606, Revenue from Contracts with Customers .
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.
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, 2025, was $302.4 million compared to $353.0 million for the same period in 2024.
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.
Net loss ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Years Ended December 31, ​ ​ ​ (Increase) Decrease (in thousands) ​ ​ ​ 2024 ​ ​ ​ 2023 ​ ​ ​ $ ​ ​ ​ % Net loss ​ $ (372,177) ​ $ (444,037) ​ 71,860 ​ ​ ​ 16 ​ 99 Table of Contents Net loss for the year ended December 31, 2024 decreased by $71.9 million, or 16%, compared to the year ended December 31, 2023.
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.
If any of the securities covered by the 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. 100 Table of Contents Cash Flows Cash flows from operating, investing and financing activities (in thousands): ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Years Ended December 31, ​ ​ ​ ​ 2025 ​ ​ ​ 2024 ​ ​ ​ 2023 Net cash (used in) provided by: ​ ​ ​ ​ ​ ​ Operating activities ​ $ (302,408) ​ $ (352,977) ​ $ (361,820) Investing activities ​ 47,496 ​ (96,411) ​ (155,242) Financing activities ​ 300,773 ​ 390,664 ​ 462,959 Net increase (decrease) in cash, cash equivalents and restricted cash* ​ $ 45,861 ​ $ (58,724) ​ $ (54,103) * 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.
Under the terms of the 2023 Sale Agreement, we may, from time to time, in our sole discretion, issue and sell up to $450.0 million of shares of our common stock pursuant to the “at the market” offering program. The 2023 Sale Agreement superseded and replaced in its entirety the 2022 Sale Agreement, which was terminated by the Company.
Under the terms of the 2025 Sale Agreement, we may, from time to time, in our sole discretion, issue and sell up to $350.0 million of shares of our common stock pursuant to the “at the market” offering program. The 2025 Sale Agreement superseded and replaced in its entirety the 2023 Sale Agreement.
As such, we do not maintain information regarding those costs incurred on a project specific basis. 98 Table of Contents ​ The table below summarizes our research and development expenses by therapeutic area (in thousands): ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Years Ended December 31, ​ Increase (Decrease) ​ ​ 2024 2023 ​ $ % Direct research and development expense by product candidate ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ TIL, including combination therapy ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Lifileucel monotherapy ​ $ 65,573 ​ $ 76,873 ​ ​ (11,300) ​ -15% Combination Therapy ​ ​ 16,299 ​ ​ 17,809 ​ ​ (1,510) ​ -8% Next Generation ​ ​ 7,361 ​ ​ 9,987 ​ ​ (2,626) ​ -26% Others clinical, preclinical, and research programs under development ​ ​ 17,391 ​ ​ 16,983 ​ ​ 408 ​ 2% ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Indirect research and development expense ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Personnel related (excluding stock-based compensation) ​ ​ 77,442 ​ ​ 116,628 ​ ​ (39,186) ​ -34% Stock-based compensation expense ​ ​ 49,274 ​ ​ 34,926 ​ ​ 14,348 ​ 41% Contractors and outside services ​ ​ 6,557 ​ ​ 20,636 ​ ​ (14,079) ​ -68% Office and facilities ​ ​ 42,439 ​ ​ 50,235 ​ ​ (7,796) ​ -16% Total research and development ​ $ 282,336 ​ $ 344,077 ​ ​ (61,741) ​ -18% ​ Selling, general, and administrative expense ​ Selling, general and administrative expense for the year ended December 31, 2024, increased by $46.1 million, or 43%, compared to the same period in 2023.
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) ​ ​ 2024 ​ ​ ​ 2023 ​ $ ​ % Direct research and development expense by product candidate ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ TIL, including combination therapy ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Lifileucel monotherapy ​ $ 65,573 ​ $ 35,487 ​ ​ 30,086 ​ 85% Lifileucel ​ ​ ​ ​ ​ 41,386 ​ ​ (41,386) ​ -100% Combination Therapy ​ ​ 16,299 ​ ​ 17,809 ​ ​ (1,510) ​ -8% Next Generation ​ ​ 7,361 ​ ​ 9,987 ​ ​ (2,626) ​ -26% Others clinical, preclinical, and research programs under development ​ ​ 17,391 ​ ​ 16,983 ​ ​ 408 ​ 2% Indirect research and development expenses ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Personnel related (excluding stock-based compensation) ​ ​ 77,442 ​ ​ 116,628 ​ ​ (39,186) ​ -34% Stock-based compensation expense ​ ​ 49,270 ​ ​ 34,926 ​ ​ 14,344 ​ 41% Contractors and outside services ​ ​ 6,557 ​ ​ 20,636 ​ ​ (14,079) ​ -68% Office and facilities ​ ​ 36,335 ​ ​ 39,352 ​ ​ (3,017) ​ -8% Total Research and Development ​ $ 276,228 ​ $ 333,194 ​ ​ (56,966) ​ -17% 98 Table of Contents Selling, general, and administrative expense ​ Selling, general and administrative expense for the year ended December 31, 2024, increased by $46.2 million, or 44%, compared to the same period in 2023.
The outstanding shares of Series A Convertible Preferred Stock are currently convertible into 97,000 shares of our common stock, and the outstanding shares of Series B Convertible Preferred Stock are currently convertible into 2,842,158 shares of our common stock.
The outstanding shares of Series A Convertible Preferred Stock are currently convertible into 97,000 shares of our common stock, and the outstanding shares of Series B Convertible Preferred Stock are currently convertible into 1,932,667 shares of our common stock.
In November 2024, the FASB issued ASU 2024-03, Income Statement-Reporting Comprehensive Income-Expense Disaggregation Disclosures (Subtopic 220-40): Disaggregation of Income Statement Expenses, which requires the disaggregation of certain expense captions into specified categories in disclosures within the notes to the financial statements to provide enhanced transparency into the expense captions presented on the face of the income statement.
See Note 14 to the consolidated financial statements included in the Annual Report on Form 10-K. 105 Table of Contents In November 2024, the FASB issued ASU 2024-03, Income Statement-Reporting Comprehensive Income-Expense Disaggregation Disclosures (Subtopic 220-40): Disaggregation of Income Statement Expenses, which requires the disaggregation of certain expense captions into specified categories in disclosures within the notes to the financial statements to provide enhanced transparency into the expense captions presented on the face of the income statement.
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.
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. Overview ​ We are a commercial-stage biopharmaceutical company pioneering a transformational approach to treating cancer.
In addition to the non-cash amortization expense, cost of sales included $14.2 million of 97 Table of Contents royalties payable related to sales of our products for the year ended December 31, 2024. There were no royalties payable for the year ended December 31, 2023.
Cost of sales included $14.2 million of royalties payable related to sales of our products for the year ended December 31, 2024. There were no royalties payable for the year ended December 31, 2023.
With the approval of our BLA, we expect to continue to generate revenue from the sale of our product, Amtagvi ® .
With the approval of our BLA, we have to date and expect to continue to generate revenue from the sale of our first internally developed product, Amtagvi ® .
(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.
(2) We have purchase obligations of $61.9 million related to manufacturing and supply agreements for Proleukin ® under a contract we inherited as part of the Acquisition, which was subsequently extended through 2028.
Liquidity and Capital Resources As of December 31, 2024, we had $330.1 million in cash, cash equivalents, investments, and restricted cash ($115.7 million in cash and cash equivalents, $208.1 million in short-term investments, and $6.4 million in restricted cash). We have incurred losses and generated negative cash flows from operations since inception.
Liquidity and Capital Resources As of December 31, 2025, we had $303.0 million in cash, cash equivalents, short-term investments, and restricted cash ($163.1 million of cash and cash equivalents, $133.9 million in short-term investments, and $6.0 million in restricted cash). We have incurred losses and generated negative cash flows from operations since inception.
However, if the out-of-specifications product can be administered as part of a clinical trial, in an expanded or early access program, or single-patient IND, as requested by the treating physician, the costs of the product are recorded as research and development expense based on the fact that we receive clinical data related to these infusions.
However, if the out-of-specifications product can be administered as part of a clinical trial, in an expanded or early access program, or single-patient investigational new drug submission, as requested by the treating physician, the costs of the product are recorded as research and development expense based on the fact that we receive clinical data related to these infusions. ​ The manufacturing process for Amtagvi ® is highly complex and subject to stringent FDA guidelines and requirements, as well as internal specifications and quality guidelines.
When contingent consideration is a component of the cost of an asset acquisition, we capitalize the amount of incremental cost from the contingent consideration related to the intangible asset acquired in the period the underlying contingency is resolved.
We amortize our intangible assets on a straight-line basis over their estimated useful lives. When contingent consideration is a component of the cost of an asset acquisition, we capitalize the amount of incremental cost from the contingent consideration related to the intangible asset acquired in the period the underlying contingency is resolved.
Net cash used in operating activities for the year ended December 31, 2022, was $292.8 million compared to $227.9 million for the same period in 2021.
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.
Furthermore, as Proleukin ® inventory that was previously with distributors in the U.S. market at the time of the Acquisition has been substantially depleted, we also began to sell Proleukin ® into the U.S. market, where product margins are substantially higher than in other markets, to support ongoing and anticipated infusions related to the continued strong commercial launch of Amtagvi ® .
Furthermore, starting in 2024 we began selling Proleukin ® into the U.S. market, where product margins are substantially higher than in other markets, to support ongoing and anticipated infusions related to the continued strong commercial launch of Amtagvi ® .
This expense is recorded as the units acquired in the Acquisition are sold, and we expect this amount to decrease over the next six to twelve months as this inventory is sold.
This expense is recorded as the units acquired in the Acquisition are sold, and we expect this amount to decrease over the next six to twelve months as this inventory is sold. Restructuring charges ​ There were no restructuring charges recorded for the year ended December 31, 2024 and the comparable period December 31, 2023.
Our mission is to be the global leader in innovating, developing, and delivering tumor infiltrating lymphocyte, or TIL, cell therapies for patients with solid tumor cancers.
Our mission is to be the global leader in innovating, developing, and delivering tumor infiltrating lymphocyte, or TIL, cell therapies for patients with solid tumor cancers. TIL cell therapies harness the individual immune system’s ability to recognize and destroy diverse cancer cells that are unique to each patient.
Proleukin ® is also licensed in multiple countries around the world for treatment of patients with metastatic renal cell carcinoma and/or metastatic melanoma.
Proleukin ® is approved in the U.S., and licensed in multiple international markets, for treatment of adults with metastatic renal cell carcinoma and/or metastatic melanoma.
Prior to May 2023, we had not recognized any revenue. ​ Amtagvi ® revenue is recognized upon patient infusion, while Proleukin ® revenue is recognized upon shipment or delivery to customers, which include specialty distributors, clinical manufacturers, research organizations, and ATCs.
Proleukin ® , which we acquired the worldwide rights to in May 2023, is also sold in markets outside the U.S., primarily in the EU and UK. ​ Amtagvi ® revenue is recognized upon patient infusion, while Proleukin ® revenue is recognized upon shipment or delivery to customers, which include specialty distributors, clinical manufacturers, research organizations, and ATCs.
Intangible Assets ​ Our intangible assets are initially measured based on an allocation of the cost of the acquisition to the assets acquired on a relative fair value basis and are recorded net of accumulated amortization. We amortize the intangible assets on a straight-line basis over their estimated useful lives.
Intangible Assets ​ Our acquired intangible assets are initially measured based on an allocation of the cost of the acquisition to the assets acquired on a relative fair value basis and are recorded net of accumulated amortization, while intangible assets recorded as the result of milestone or license payments are recorded at the amount paid.
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.
However, it is difficult to determine with certainty the duration and completion costs of our current or future preclinical programs and clinical trials of our product candidates. ​ Selling, general, and administrative expense ​ Selling, general, and administrative expenses consist primarily of salaries and other related costs, including 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.
We are conducting two ongoing registrational trials to support a supplementary BLA, or sBLA, of lifileucel in frontline advanced melanoma and in advanced non-small cell lung cancer, or NSCLC, following standard of care chemo-immunotherapy.
We are conducting two ongoing registrational trials in frontline advanced melanoma and previously treated advanced non-small cell lung cancer, or NSCLC.
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.
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.
Details of related agreements are provided in the Research, Development, Manufacturing and License Agreements for TIL Cell Therapy section of this Annual Report on Form 10-K. ​ TIL Cell T herapy Clinical Development in Advanced, Metastatic or Unresectable Solid Tumor Cancers Our TIL cell therapy platform and manufacturing process have been initially validated through the FDA approval of Amtagvi ® .
Details of related agreements are provided in the Research, Development, Manufacturing and License Agreements in this Annual Report on Form 10-K. ​ TIL Cell Therapy Platforms for Advanced, or Metastatic or Unresectable, Solid Tumor Cancers ​ Our T cell-based immunotherapy technology platform of TIL cell therapies leverages patient-specific cells to recognize and attack diverse cancer cells that are unique to each patient.
Net cash (used in) / provided by investing activities primarily consists of purchases, maturities of our investments and capital expenditures. Net cash provided by investing activities for the year ended December 31, 2022 was $256.5 million compared to net cash provided by investing activities of $0.1 million for the same period in 2021.
Investing Activities Net cash provided by investing activities for the year ended December 31, 2025, was $47.5 million compared to net cash used by investing activities of $96.4 million for the same period in 2024.
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.
Based on the funds we have available as of the date our consolidated financial statements for the year ended December 31, 2025 are issued, 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.
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.
Amtagvi ® returns billions of individualized patient T cells back to the body to fight cancer and is administered as part of a treatment regimen. Amtagvi ® is indicated for the treatment of adult patients with advanced melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor.
No cost of sales was incurred for the year ended December 31, 2022. ​ Research and development expense ​ Research and development expense for the year ended December 31, 2023 increased by $49.3 million, or 17%, compared to the year ended December 31, 2022.
Research and development expense ​ Research and development expense for the year ended December 31, 2024, decreased by $57.0 million, or 17%, compared to the same period in 2023.
In addition, cost of sales includes royalties payable on 95 Table of Contents sales of our products, as well as non-cash expenses including amortization of the fair value step-up of acquired Proleukin ® inventory which is recognized as the acquired inventory units are sold, amortization expense for the developed technology intangible asset and the milestone payment recorded as part of the Acquisition, and the intellectual property license intangible assets. ​ In the event that the manufactured product does not meet specifications, or a patient is unable to receive the infusion, the Amtagvi ® product is destroyed and the costs associated with manufacturing and inventory associated with the product is generally required to be expensed as cost of sales.
In addition, non-U.S. government programs may include different pricing schemes such as cost caps and volume discounts. ​ Costs and Expenses ​ Cost of sales ​ Cost of sales includes cost of inventories sold, including overhead and manufacturing costs of Amtagvi ® , reserves for excess and obsolete inventory, royalties payable on the sales of our products and other costs that are directly associated with the purchase and sales of Proleukin ® . ​ In the event that the manufactured product does not meet specifications, or a patient is unable to receive the infusion, the Amtagvi ® product is generally destroyed and the costs associated with manufacturing and inventory associated with the product is generally required to be expensed as cost of sales.
Beyond the U.S., we plan to launch Amtagvi ® into additional markets with a high prevalence of advanced melanoma, including the European Union, or EU, United Kingdom, or UK, Canada, Switzerland, and Australia. In June 2024, we submitted a centralized marketing authorization application, or MAA, to the European Medicines Agency, or the EMA, for lifileucel.
Amtagvi ® is approved in the U.S. and Canada, and we plan to launch into additional markets with a high prevalence of advanced melanoma. Potential approvals are pending in the United Kingdom, or UK, and Australia in the first half of 2026 and Switzerland in 2027.
During the year ended December 31, 2024, we received $200.0 million in net proceeds, after offering costs, through the sale of 23,127,726 shares of common stock through the 2023 Sale Agreement. 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.
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.
ASC 2023-07 was effective for us in our annual reporting for fiscal year 2024 and for interim period reporting beginning in fiscal year 2025 on a retrospective basis, which we adopted as of December 31, 2024.
ASU 2023-09 was effective for us in our annual reporting for fiscal year 2025 and for interim period reporting beginning in fiscal year 2026.
Our medical affairs team is also educating key opinion leaders, or KOLs, about Amtagvi ® and TIL cell therapy, as well as presenting and publishing our clinical results. ​ We are focusing ongoing Amtagvi ® commercialization efforts on four primary areas: ● supporting operations and patient enrollment at authorized treatment centers, or ATCs, in the U.S. and activating ATCs in the EU, UK, and Canada to prepare for anticipated 2025 regulatory approvals in those markets; ● educating, training, and collaborating with healthcare professionals, or HCPs, who will be administering our product, as well as community oncologists who will be referring patients to our ATCs and larger community practices that may become ATCs; ● operational excellence in launch execution, commercial manufacturing, and delivery of therapy; and ● continuous communication with payors about the value of Amtagvi ® to facilitate strong reimbursement and patient access. ​ U.S.
Our top priority is to drive commercial success of Amtagvi ® for previously treated advanced melanoma across four primary areas: ● Educating, training, and collaborating with healthcare professionals, or HCPs, who will be administering our product at academic and community authorized treatment centers, or ATCs, as well as community oncologists and advocacy groups who will refer patients to our ATCs; ● Providing operational and patient support at ATCs in the U.S. and onboarding ATCs in preparation for anticipated regulatory approvals and product launches in additional global markets; ● Collaborating with payors about the value of Amtagvi ® to continue to facilitate strong reimbursement and patient access; and ● Driving operational excellence in launch execution, commercial manufacturing success, and delivery of therapy. ​ U.S.
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.
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 requires public entities, on an annual basis, to provide disclosure of specific categories in the rate reconciliation, as well as disclosure of income taxes paid disaggregated by jurisdiction.
This was offset by cash used of $2.6 million for tax payments related to vested RSUs. 105 Table of Contents Contractual Obligations ​ The following table summarizes our non-cancellable contractual obligations as of December 31, 2024 and the effects that such obligations are expected to have on our liquidity and cash flows in future periods (in thousands): ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Payments due by period ​ Total 2025 2026 2027 2028 2029 Thereafter Operating lease obligations - facilities (1) ​ $ 82,168 ​ $ 6,039 ​ $ 5,452 ​ $ 4,307 ​ $ 4,393 ​ $ 4,481 ​ $ 57,496 Purchase obligations (2) ​ ​ 27,199 ​ ​ 13,599 ​ ​ 7,159 ​ ​ 6,440 ​ ​ — ​ ​ — ​ ​ — Total (3) ​ $ 109,367 ​ $ 19,638 ​ $ 12,611 ​ $ 10,747 ​ $ 4,393 ​ $ 4,481 ​ $ 57,496 ​ ​ ​ (1) Our operating lease obligations consist of obligations under non-cancellable operating leases for our facilities in Philadelphia, Pennsylvania, and Tampa, Florida, and our non-cancellable operating sublease in San Carlos, California.
These increases were partially offset by a $1.6 million decrease in proceeds from the issuance of common stock upon the exercise of stock options. 102 Table of Contents Contractual Obligations ​ The following table summarizes our non-cancellable contractual obligations as of December 31, 2025 and the effects that such obligations are expected to have on our liquidity and cash flows in future periods (in thousands): ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Payments due by period ​ ​ ​ ​ Total ​ ​ ​ 2026 ​ ​ ​ 2027 ​ ​ ​ 2028 ​ ​ ​ 2029 ​ ​ ​ 2030 ​ ​ ​ Thereafter Operating lease obligations - facilities (1) ​ $ 79,903 ​ $ 6,577 ​ $ 5,469 ​ $ 5,016 ​ $ 4,838 ​ $ 4,610 ​ $ 53,393 Purchase obligations (2) ​ ​ 61,933 ​ ​ 16,699 ​ ​ 23,954 ​ ​ 21,280 ​ ​ — ​ ​ — ​ ​ — Total (3) ​ $ 141,836 ​ $ 23,276 ​ $ 29,423 ​ $ 26,296 ​ $ 4,838 ​ $ 4,610 ​ $ 53,393 ​ ​ ​ (1) Our operating lease obligations consist of obligations under non-cancellable operating leases for our facilities in San Carlos, California, Philadelphia, Pennsylvania, and Tampa, Florida.
We received $301.7 million in proceeds, net of offering costs, through the sale of 44,080,226 shares of our common stock during 2023.
During the year ended December 31, 2025, we received $306.3 million in net proceeds, net of offering costs, through the sale of 101,899,334 shares of common stock cumulatively through the 2023 and 2025 Sale Agreements.
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.
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) ​ ​ 2025 ​ ​ ​ 2024 ​ $ ​ % Direct research and development expense by product candidate ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ TIL, including combination therapy ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Lifileucel monotherapy ​ $ 73,206 ​ $ 65,573 ​ ​ 7,633 ​ 12% Combination Therapy ​ ​ 15,023 ​ ​ 16,299 ​ ​ (1,276) ​ -8% Next Generation ​ ​ 9,787 ​ ​ 7,361 ​ ​ 2,426 ​ 33% Others clinical, preclinical, and research programs under development ​ ​ 24,981 ​ ​ 17,391 ​ ​ 7,590 ​ 44% Indirect research and development expense ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Personnel related (excluding stock-based compensation) ​ ​ 109,657 ​ ​ 77,442 ​ ​ 32,215 ​ 42% Stock-based compensation expense ​ ​ 26,959 ​ ​ 49,270 ​ ​ (22,311) ​ -45% Contractors and outside services ​ ​ 9,559 ​ ​ 6,557 ​ ​ 3,002 ​ 46% Office and facilities ​ ​ 31,098 ​ ​ 36,335 ​ ​ (5,237) ​ -14% Total research and development ​ $ 300,270 ​ $ 276,228 ​ ​ 24,042 ​ 9% ​ Selling, general, and administrative expense ​ Selling, general and administrative expense for the year ended December 31, 2025, was flat as compared to the same period in 2024.
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.
We believe this approach is the emerging backbone for immuno-oncology approaches to treat solid tumor cancers. We have investigated TIL cell therapy in global, multicenter Iovance-sponsored clinical trials in various treatment settings in advanced melanoma, NSCLC, cervical cancer, endometrial cancer, and head and neck squamous cell carcinoma, or HNSCC.
On November 18, 2022, we entered into a new Open Market Sale Agreement, or the 2022 Sale Agreement, with Jefferies with respect to an “at the market” offering program.
The shares of Series A Convertible Preferred Stock and Series B Convertible Preferred Stock do not have voting rights or accrue dividends. On August 22, 2025, we entered into an Amended and Restated Open Market Sale Agreement, or the 2025 Sale Agreement, with Jefferies with respect to an “at the market” offering program.
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.
The Company recognizes charges related to restructuring plans when the liabilities have been incurred and can be reasonably estimated. ​ 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. ​ 93 Table of Contents Results of Operations for the Years Ended December 31, 2025 and 2024 ​ Revenue ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ Increase (Decrease) (in thousands) ​ ​ ​ 2025 ​ ​ ​ 2024 ​ ​ ​ $ ​ ​ ​ % Amtagvi ® ​ $ 220,024 ​ $ 103,567 ​ 116,457 ​ 112 Proleukin ® ​ ​ 43,478 ​ ​ 60,503 ​ (17,025) ​ (28) Total product revenue ​ $ 263,502 ​ $ 164,070 ​ 99,432 ​ 61 ​ Revenue for the year ended December 31, 2025, increased by $99.4 million, or 61% compared to the same period in 2024.
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.
Applying our expertise in TIL cell therapy, our next-generation technology platforms are designed to optimize outcomes with TIL cell therapy across three key initiatives: genetic modifications, potency, and new treatment regimens using an improved IL-2. Intellectual Property We have established a leading intellectual property portfolio developed internally and licensed from third parties.
Cost of sales included $21.0 million for the year ended December 31, 2024, compared to $9.7 million for the year ended December 31, 2023, of non-cash amortization expense for the developed technology intangible asset and the milestone payment recorded as part of the Acquisition as well as intellectual property license intangible assets.
The increase was primarily related to non-cash amortization expense for the developed technology intangible asset and the milestone payment recorded as part of the Acquisition as well as intellectual property license intangible assets, and non-cash amortization expense of the fair value step-up of acquired Proleukin ® inventory sold as the acquired inventory continues to be depleted.
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.
Commercial Launch of the First TIL Cell Therapy in Advanced Melanoma Amtagvi ® Amtagvi ® (lifileucel) is the first one-time, individualized T cell therapy approved for a solid tumor cancer and for the treatment of adult patients with previously treated advanced melanoma.
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 also believe that the i CTC is the only current Good Manufacturing Practice, or cGMP, facility with a centralized, scalable TIL manufacturing process. To date, more than 1,500 patients have been treated with commercial and investigational TIL cell therapies manufactured using Iovance processes.
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.
The decrease in cash used of $143.9 million was driven by a $114.1 million increase associated with changes in the timing of maturities and purchases of investments, and a $22.8 million increase in cash utilized to fund capital expenditures. These increases were partially offset by a $52.6 million decrease in cash used for the Acquisition, net of cash acquired.
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.
The decrease in net cash provided by financing activities of $89.9 million was primarily driven by a decrease in net proceeds of $91.0 million received through the sales of common stock through our “at the market” offering program during the year ended December 31, 2025, as compared to the net proceeds received from our public offering in February 2024 and through the sales of common stock through our “at the market” offering program during the year ended December 31, 2024.
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.
Our vision is to pioneer this transformational approach to cure solid tumor cancers. We are committed to continuous innovation to develop TIL cell therapies and optimize TIL treatment regimens that may extend and improve life for patients with cancer.
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.
Amtagvi ® is administered as part of a treatment regimen that includes lymphodepletion and a short course of Proleukin ® . ​ Globally, Amtagvi ® has the potential to address more than 30,000 previously treated advanced melanoma patients annually.

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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 changeHowever, 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. ​
Biggest changeNevertheless, foreign currency transaction gains and losses were immaterial for the years ended December 31, 2025 and 2024. No foreign currency exchange risk existed for the years ended December 31, 2025 and 2024. ​
Inflation 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.
Inflation Risk Inflation has not had a material effect on our business, financial condition or results of operations during the years ended December 31, 2025, 2024, or 2023. ​ 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.
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.
If interest rates had varied by 1% in the year ended December 31, 2025, the fair value of our investment portfolio would increase or decrease by approximately $0.3 million.
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.
As of December 31, 2025, we had $194.4 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. ​ The majority of our product sales during the year ended December 31, 2024 were denominated in the U.S. dollar.
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, 2025 were denominated in the U.S. dollar, however, we do have some sales denominated in foreign currencies.

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