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What changed in AGIOS PHARMACEUTICALS, INC.'s 10-K — 2024 vs 2025

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Paragraph-level year-over-year comparison of AGIOS PHARMACEUTICALS, 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.

+602 added−637 removedSource: 10-K (2026-02-12) vs 10-K (2025-02-13)

Top changes in AGIOS PHARMACEUTICALS, INC.'s 2025 10-K

602 paragraphs added · 637 removed · 441 edited across 9 sections

Item 1. Business

Business — how the company describes what it does

161 edited+73 added−50 removed342 unchanged
Biggest changeOur competitors include but are not limited to: BioMarin Pharmaceutical, Inc., or BioMarin; bluebird bio, Inc., or bluebird; Bristol-Myers Squibb Company, or BMS; CRISPR Therapeutics AG, or CRISPR; Emmaus Life Sciences, Inc., or Emmaus; Fulcrum Therapeutics, Inc., or Fulcrum; Geron Corporation, or Geron; Incyte Corporation, or Incyte; Ionis Pharmaceuticals, Inc., or Ionis; Merck & Co., Inc., or Merck; Novartis International AG, or Novartis; Novo Nordisk A/S, or Novo; Otsuka Pharmaceutical Co., Ltd., or Otsuka; Pfizer, Inc., or Pfizer; PharmaEssentia USA Corporation, or PharmaEssentia; Protagonist Therapeutics, Inc., or Protagonist, in collaboration with Takeda, Pharmaceutical Company Limited, or Takeda; PTC Therapeutics, Inc., or PTC; Rocket Pharmaceuticals, Inc., or Rocket Pharma; Silence Therapeutics plc, or Silence; Takeda; and Vertex Pharmaceuticals Incorporated, or Vertex.
Biggest changeOur competitors include but are not limited to: BioMarin Pharmaceutical, Inc., or BioMarin; Bristol-Myers Squibb Company, or BMS; Cellarity, Inc., or Cellarity; CRISPR Therapeutics AG, or CRISPR; DISC Medicine, Inc., or DISC; Emmaus Life Sciences, Inc., or Emmaus; Fulcrum Therapeutics, Inc., or Fulcrum; Genetix Biotherapeutics Inc., or Genetix (formerly bluebird bio, Inc.); Geron Corporation, or Geron; Halia Therapeutics, Inc, Or Halia.; Incyte Corporation, or Incyte; Ionis Pharmaceuticals, Inc., or Ionis, in collaboration with Ono Pharmaceutical Co., Ltd./Deciphera Pharmaceuticals, Inc., or Ono/Deciphera; Italfarmaco S.p.A., or Italfarmaco; Maze Therapeutics, Inc., or Maze; Merck & Co., Inc., or Merck; NGGT Inc., or NGGT; Novartis International AG, or Novartis; Novo Nordisk A/S, or Novo; Otsuka Pharmaceutical Co., Ltd., or Otsuka; Pfizer, Inc., or Pfizer; PharmaEssentia USA Corporation, or PharmaEssentia; Protagonist Therapeutics, Inc., or Protagonist, in collaboration with Takeda, Pharmaceutical Company Limited, or Takeda; PTC Therapeutics, Inc., or PTC; Sanofi S.A., or Sanofi; Silence Therapeutics plc, or Silence; Takeda, in collaboration with Keros Therapeutics, Inc.; and Vertex Pharmaceuticals Incorporated, or Vertex.
A sponsor is required to submit a sNDA if it wishes to make a change to a product that has already been approved under an NDA.
A sponsor is required to submit an sNDA if it wishes to make a change to a product that has already been approved under an NDA.
Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan designation, although the FDA has recently taken steps to limit what it considers abuse of this statutory exemption in PREA by announcing that it does not intend to grant any additional orphan drug designations for rare pediatric subpopulations of what is otherwise a common disease.
Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan designation, although the FDA has taken steps to limit what it considers abuse of this statutory exemption in PREA by announcing that it does not intend to grant any additional orphan drug designations for rare pediatric subpopulations of what is otherwise a common disease.
It also requires the submission to the relevant competent authorities of a MAA and granting of a marketing authorization by these authorities before the product can be marketed and sold in the EU. Preclinical Studies Non-clinical studies are performed to demonstrate the health or environmental safety of new chemical or biological substances.
It also requires the submission to the relevant competent authorities of an MAA and granting of a marketing authorization by these authorities before the product can be marketed and sold in the EU. Preclinical Studies Non-clinical studies are performed to demonstrate the health or environmental safety of new chemical or biological substances.
A sponsor seeking approval to market and distribute a new drug in the United States generally must satisfactorily complete each of the following steps before the product candidate will be approved by the FDA: • preclinical testing including laboratory tests, animal studies and formulation studies which must be performed in accordance with the FDA’s good laboratory practice, or GLP, regulations and standards; • design of a clinical protocol and submission to the FDA of an IND for human clinical testing, which must become effective before human clinical trials may begin; • approval by an independent institutional review board, or IRB, representing each clinical site before each clinical trial may be initiated; • performance of adequate and well-controlled human clinical trials to establish the safety and efficacy of the product candidate for each proposed indication, in accordance with current good clinical practices, or GCP; • preparation and submission to the FDA of an NDA, or a sNDA for a change to a previously approved drug product, which submissions include not only the results of the clinical trials, but also, detailed information on the chemistry, manufacture and quality controls for the product candidate and proposed labeling for one or more proposed indication(s); • review of the product candidate by an FDA advisory committee, where appropriate or if applicable; • satisfactory completion of FDA inspection of the manufacturing facility or facilities, including those of third parties, at which the product candidate or components thereof are manufactured to assess compliance with current good manufacturing practices, or cGMP, requirements and to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity; • satisfactory completion of any FDA audits of the non-clinical and clinical trial sites to assure compliance with GCP and the integrity of clinical data in support of the NDA; • payment of user fees pursuant to PDUFA; • approval of an NDA for the new drug product authorizing marketing of the new drug product for particular indications in the United States; and • compliance with any post-approval requirements, including the potential requirement to implement risk evaluation and mitigation strategies, or REMS, and the potential requirement to conduct any post-approval studies required by the FDA.
A sponsor seeking approval to market and distribute a new drug in the United States generally must satisfactorily complete each of the following steps before the product candidate will be approved by the FDA: • preclinical testing including laboratory tests, animal studies and formulation studies which must be performed in accordance with the FDA’s good laboratory practice, or GLP, regulations and standards; • design of a clinical protocol and submission to the FDA of an IND for human clinical testing, which must become effective before human clinical trials may begin; • approval by an independent institutional review board, or IRB, representing each clinical site before each clinical trial may be initiated; • performance of adequate and well-controlled human clinical trials to establish the safety and efficacy of the product candidate for each proposed indication, in accordance with current good clinical practices, or GCP; • preparation and submission to the FDA of an NDA, or a sNDA for a change to a previously approved drug product, which submissions include not only the results of the clinical trials, but also, detailed information on the chemistry, manufacture and quality controls for the product candidate and proposed labeling for one or more proposed indication(s); • review of the product candidate by an FDA advisory committee, where appropriate or if applicable; • satisfactory completion of FDA inspection of the manufacturing facility or facilities, including those of third parties, at which the product candidate or components thereof are manufactured to assess compliance with current good manufacturing practices, or cGMP, requirements and to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity; • satisfactory completion of any FDA audits of the non-clinical and clinical trial sites to assure compliance with GCP and the integrity of clinical data in support of the NDA; • payment of user fees pursuant to PDUFA; • approval of an NDA for the new drug product authorizing marketing of the new drug product for particular indications in the United States; and • compliance with any approval or post-approval requirements, including the potential requirement to implement REMS, and the potential requirement to conduct any post-approval studies required by the FDA.
The key competitive factors affecting the success of PYRUKYND® and any of our product candidates that we develop, if approved, are likely to be their efficacy, safety, convenience, price, the level of generic competition and the availability of reimbursement from government and other third-party payors.
The key competitive factors affecting the success of PYRUKYND®, AQVESME™ and any of our product candidates that we develop, if approved, are likely to be their efficacy, safety, convenience, price, the level of generic competition and the availability of reimbursement from government and other third-party payors.
PYRUKYND® (mitapivat): First-in-Class PK Activator We are developing PYRUKYND® for the treatment of PK deficiency and other hemolytic anemias such as thalassemia and SCD. PYRUKYND® is an orally available small molecule and a potent activator of the wild-type and mutated PK enzymes.
PYRUKYND®/AQVESME™ (mitapivat): First-in-Class PK Activator We are developing mitapivat for the treatment of PK deficiency and other hemolytic anemias such as thalassemia and SCD. Mitapivat is an orally available small molecule and a potent activator of the wild-type and mutated PK enzymes.
PYRUKYND® and any product candidates that we successfully develop and commercialize will compete with existing therapies and new therapies that may become available in the future. We compete in pharmaceutical, biotechnology and other related markets that address rare diseases, particularly hemolytic anemias, PKU and PV.
PYRUKYND®, AQVESME™ and any product candidates that we successfully develop and commercialize will compete with existing therapies and new therapies that may become available in the future. We compete in pharmaceutical, biotechnology and other related markets that address rare diseases, particularly hemolytic anemias, PKU and PV.
We currently, and expect to continue to, rely on third parties for the manufacture and supply of our clinical and preclinical product candidates, as well as for commercial manufacture of PYRUKYND® and any product for which we may receive marketing approval in the future.
We currently, and expect to continue to, rely on third parties for the manufacture and supply of our clinical and preclinical product candidates, as well as for commercial manufacture of PYRUKYND® and AQVESME™ and any product for which we may receive marketing approval in the future.
A copy of our Corporate Governance Guidelines, Code of Business Conduct and Ethics and the charters of the Audit Committee, Compensation and People Committee, Nominating and Corporate Governance Committee, and Science and Technology Committee are posted on our website, www.agios.com, under the heading “Corporate Governance” and are available in print to any person who requests copies by contacting us by calling (617) 649-8600 or by writing to Agios Pharmaceuticals, Inc., 88 Sidney Street, Cambridge, Massachusetts 02139. 35 Table of Content s
A copy of our Corporate Governance Guidelines, Code of Business Conduct and Ethics and the charters of the Audit Committee, Compensation and People Committee, Nominating and Corporate Governance Committee, and Science and Technology Committee are posted on our website, www.agios.com, under the heading “Corporate Governance” and are available in print to any person who requests copies by contacting us by calling (617) 649-8600 or by writing to Agios Pharmaceuticals, Inc., 88 Sidney Street, Cambridge, Massachusetts 02139. 37 Table of Content s
Violations may also result in injunctions and/or criminal prosecution or disqualification from federal grants. 16 Table of Content s Expanded Access to an Investigational Drug for Treatment Use Expanded access, sometimes called “compassionate use,” is the use of investigational new drug products outside of clinical trials to treat patients with serious or immediately life-threatening diseases or conditions when there are no comparable or satisfactory alternative treatment options.
Violations may also result in injunctions and/or criminal prosecution or disqualification from federal grants. 17 Table of Content s Expanded Access to an Investigational Drug for Treatment Use Expanded access, sometimes called “compassionate use,” is the use of investigational new drug products outside of clinical trials to treat patients with serious or immediately life-threatening diseases or conditions when there are no comparable or satisfactory alternative treatment options.
The safety profile observed was consistent with data reported in the healthy volunteer study of tebapivat. 19 patients elected to enroll in the extension period for up to 156 weeks.
The safety profile observed was consistent with data reported in the healthy volunteer study of tebapivat. 19 patients elected to enroll in the extension period of the trial for up to 156 weeks.
We expect that PYRUKYND® and any of our product candidates that may receive marketing approval in the future will be priced at a significant premium over competitive generic medicines. Manufacturing and Supply Chain PYRUKYND®, tebapivat, and AG-181 are organic compounds of low molecular weight, generally called small molecules, and are dosed orally.
We expect that PYRUKYND®, AQVESME™ and any of our product candidates that may receive marketing approval in the future will be priced at a significant premium over competitive generic medicines. Manufacturing and Supply Chain Mitapivat, tebapivat, and AG-181 are organic compounds of low molecular weight, generally called small molecules, and are dosed orally.
It has been shown that small molecule therapies able to specifically correct genetic deficiencies and their associated organ dysfunction may have application in conditions that arise independent of patient genetics but for which identical organ dysfunction occurs. For example, a treatment for a hereditary hemolytic anemia may find direct application in the treatment of a secondarily acquired hemolytic anemia.
It has been shown that small molecule medicines able to specifically correct genetic deficiencies and their associated organ dysfunction may have application in conditions that arise independent of patient genetics but for which identical organ dysfunction occurs. For example, a treatment for a hereditary hemolytic anemia may find direct application in the treatment of a secondarily acquired hemolytic anemia.
In the future, if and when our product candidates receive approval by the FDA or foreign regulatory authorities, we expect to apply for patent term extensions on issued patents covering those products, depending upon the length of the clinical trials for 12 Table of Content s each product candidate and other factors.
In the future, if and when our product candidates receive approval by the FDA or foreign regulatory authorities, we expect to apply for patent term extensions on issued patents covering those products, depending upon the length of the clinical trials for 13 Table of Content s each product candidate and other factors.
As of February 1, 2025, we owned one issued United States patent and two issued foreign patents and have pending patent applications in the United States and in various foreign jurisdictions. The patents that have issued or may issue for our PAH stabilizer program will have a statutory expiration date of at least 2043 to 2044.
As of February 1, 2026, we owned one issued United States patent and two issued foreign patents and have pending patent applications in the United States and in various foreign jurisdictions. The patents that have issued or may issue for our PAH stabilizer program will have a statutory expiration date of at least 2043 to 2044.
The patents that have issued or may issue for PYRUKYND® will have a statutory expiration date of at least 2030 to 2042, and the patents that have issued or may issue for tebapivat will have a statutory expiration date of at least 2038 to 2045. Patent term adjustments or patent term extensions could result in later expiration dates.
The patents that have issued or may issue for mitapivat will have a statutory expiration date of at least 2030 to 2042, and the patents that have issued or may issue for tebapivat will have a statutory expiration date of at least 2038 to 2045. Patent term adjustments or patent term extensions could result in later expiration dates.
Our diversity and inclusion program focuses on valuing three types of differences: • Representative differences (demographic diversity, such as gender, race, ethnicity, sexual orientation) • Experiential differences (identities based on life experiences that may change over time) • Cognitive differences (unique ways of understanding and interpreting the world) We set goals and track our progress to ensure that we continue to incorporate different voices across the business.
Our Valuing Differences Framework focuses on valuing three types of differences: • Representative differences (demographic diversity, such as gender, race, ethnicity, sexual orientation) • Experiential differences (identities based on life experiences that may change over time) • Cognitive differences (unique ways of understanding and interpreting the world) We set goals and track our progress to ensure that we continue to incorporate different voices across the business.
CMS issued a public statement on January 29, 2025, declaring that lowering the cost of prescription drugs is a top priority of the new administration and CMS is committed to considering opportunities to bring greater transparency in the negotiation program.
CMS issued a public statement on January 29, 2025, declaring that lowering the cost of prescription drugs is a top priority of the Trump administration and CMS is committed to considering opportunities to bring greater transparency in the negotiation program.
Available Information Our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and any amendments to these reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, are 34 Table of Content s available free of charge on our website located at www.agios.com as soon as reasonably practicable after they are filed with or furnished to the Securities and Exchange Commission, or SEC.
Available Information Our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and any amendments to these reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, are available free of charge on our website located at www.agios.com as soon as reasonably practicable after they are filed with or furnished to the Securities and Exchange Commission, or SEC.
Many rare diseases are likely to be under-diagnosed given the lack of available therapies or diagnostics, the rarity of the condition, or limited understanding of how the disease genetics relate to the disease phenotype.
Many rare diseases are likely to be under-diagnosed given the lack of available medicines or diagnostics, the rarity of the condition, or limited understanding of how the disease genetics relate to the disease phenotype.
Among the provisions of the ACA of importance to our potential product candidates are: • an annual, nondeductible fee on any entity that manufactures or imports specified branded prescription drugs and biologic agents, apportioned among these entities according to their market share in certain government healthcare programs; • expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to certain individuals with income at or below 133% of the federal poverty level, thereby potentially increasing a manufacturer’s Medicaid rebate liability; • expanded manufacturers’ rebate liability under the Medicaid Drug Rebate Program, or MDRP, by increasing the minimum rebate for both branded and generic drugs, and revising the definition of “average manufacturer price,” or AMP, for calculating and reporting Medicaid drug rebates on outpatient prescription drug prices; • addressed a new methodology by which rebates owed by manufacturers under the MDRP are calculated for drugs that are inhaled, infused, instilled, implanted or injected; • expanded the types of entities eligible for the 340B drug discount program; • established the Medicare Part D coverage gap discount program by requiring manufacturers to provide a point-of-sale-discount (currently 70%) off the negotiated price of applicable brand drugs to eligible beneficiaries during their coverage gap period as a condition for the manufacturers’ outpatient drugs to be covered under Medicare Part D; and 26 Table of Content s • a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research.
Among the provisions of the ACA of importance to our potential product candidates are: • an annual, nondeductible fee on any entity that manufactures or imports specified branded prescription drugs and biologic agents, apportioned among these entities according to their market share in certain government healthcare programs; • expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to certain individuals with income at or below 133% of the federal poverty level, thereby potentially increasing a manufacturer’s Medicaid rebate liability; • expanded manufacturers’ rebate liability under the Medicaid Drug Rebate Program, or MDRP, by increasing the minimum rebate for both branded and generic drugs, and revising the definition of “average manufacturer price,” or AMP, for calculating and reporting Medicaid drug rebates on outpatient prescription drug prices; • addressed a new methodology by which rebates owed by manufacturers under the MDRP are calculated for drugs that are inhaled, infused, instilled, implanted or injected; • expanded the types of entities eligible for the 340B drug discount program; • established the Medicare Part D coverage gap discount program by requiring manufacturers to provide a point-of-sale-discount (currently 70%) off the negotiated price of applicable brand drugs to eligible beneficiaries during their coverage gap period as a condition for the manufacturers’ outpatient drugs to be covered under Medicare Part D; and • a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research. 28 Table of Content s Other legislative changes have been proposed and adopted in the United States since the ACA was enacted.
Among other things, the IRA requires manufacturers of certain drugs to engage in price negotiations with Medicare (beginning in 2026), with prices that can be negotiated subject to a cap; imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation (first due in 2023); and replaces the Part D coverage gap discount program with a 27 Table of Content s new discounting program (beginning in 2025).
Among other things, the IRA requires manufacturers of certain drugs to engage in price negotiations with Medicare (beginning in 2026), with prices that can be negotiated subject to a cap; imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation (first due in 2023); and replaces the Part D coverage gap discount program with a new discounting program (beginning in 2025).
Accordingly, we believe that activation of mutant forms of PKR can restore glycolytic pathway activity and increase RBC health in patients with PK deficiency, and activation of wild-type (non-mutated) PKR can 6 Table of Content s increase ATP which can then meet the increased energy demands resulting from metabolic stress in RBCs of patients with hemolytic anemias such as thalassemia and SCD.
Accordingly, we believe that activation of mutant forms of PKR can restore glycolytic pathway activity and increase RBC health in patients with PK deficiency, and activation of wild-type (non-mutated) PKR can increase ATP which can then meet the increased energy demands resulting from metabolic stress in RBCs of patients with hemolytic anemias such as thalassemia and SCD.
We built our commercial infrastructure to support the commercialization of PYRUKYND® in adult PK deficiency in the United States, and have expanded this infrastructure to support the potential commercial launch of PYRUKYND® in thalassemia in the United States.
We built our commercial infrastructure to support the commercialization of PYRUKYND® in adult PK deficiency in the United States, and have expanded this infrastructure to support the commercial launch of AQVESME™ in thalassemia in the United States.
The legislation also requires manufacturers to pay rebates for drugs in Medicare Part D whose price increases exceed inflation. The new law also caps Medicare out-of-pocket drug costs at an estimated $2,000 beginning in 2025.
The legislation also requires manufacturers to pay rebates for drugs in Medicare Part D whose price increases exceed inflation. The new law also caps Medicare out-of-pocket drug costs at an estimated $2,000, which began in 2025.
The period of market exclusivity may, in addition, be reduced to six years if it can be demonstrated on the basis of available evidence that the original orphan medicinal product is sufficiently profitable not to justify maintenance of market exclusivity. Patent Term Extensions The EU also provides for patent term extension through SPCs.
The period of market exclusivity may, in addition, be reduced to six years if it can be demonstrated on the basis of available evidence that the original orphan medicinal product is sufficiently profitable not to justify maintenance of market exclusivity. 34 Table of Content s Patent Term Extensions The EU also provides for patent term extension through SPCs.
Manufacturers are required to have such systems and processes in place to comply with the DSCSA, but, so as not to disrupt supply chains, the FDA has granted certain exemptions from enhanced drug distribution security requirements for eligible trading partners for particular periods of time.
Manufacturers are required to have such systems and processes in place to comply with the DSCSA, but, so as not to disrupt supply chains, the FDA has granted certain exemptions 24 Table of Content s from enhanced drug distribution security requirements for eligible trading partners for particular periods of time.
Fast Track, Breakthrough Therapy, Priority Review and Regenerative Advanced Therapy Designations The FDA is authorized to designate certain products for expedited review if they are intended to address an unmet medical need in the treatment of a serious or life-threatening disease or condition.
Fast Track, Breakthrough Therapy, Priority Review and Regenerative Advanced Therapy Designations and Commissioner's National Priority Voucher Program The FDA is authorized to designate certain products for expedited review if they are intended to address an unmet medical need in the treatment of a serious or life-threatening disease or condition.
Mutations in PKR cause defects in RBC glycolysis and lead to a hematological rare disease known as PK deficiency. Glycolysis is the only pathway available for RBCs to maintain the production of adenosine triphosphate, or ATP, which is a form of chemical energy within cells.
Mutations in PKR cause defects in RBC glycolysis and lead to a hematological rare disease known as PK deficiency. Glycolysis is the only pathway available for RBCs to maintain the production of adenosine triphosphate, or ATP, which is a 7 Table of Content s form of chemical energy within cells.
Also, in July 2023, we entered into a license agreement with Alnylam for the development and commercialization of products containing or comprised of an siRNA preclinical development candidate discovered by Alnylam and targeting the TMPRSS6 gene, and we have begun preclinical development of a product candidate, AG-236, for the potential treatment of patients with PV.
Also, in July 2023, we entered into a license agreement with Alnylam for the development and commercialization of products containing or comprised of an siRNA preclinical development candidate discovered by Alnylam and targeting the TMPRSS6 gene, and we are developing a product candidate, AG-236, for the potential treatment of patients with PV.
For example, recently approved treatments for thalassemia, SCD, LR MDS, PKU and PV include Reblozyl® from Merck/BMS (formerly Acceleron/BMS); Revlimid® from BMS; Zynteglo® and Lyfgenia® from bluebird; Adakveo® from Novartis; Casgevy® from Vertex/CRISPR; Kuvan® and Palynziq® from BioMarin; Endari® from Emmaus; Besremi® from PharmaEssentia; Jakafi® from Incyte; and Rytelo® from Geron.
For example, recently approved treatments for thalassemia, SCD, LR MDS, PKU and PV include Reblozyl® from Merck/BMS (formerly Acceleron/BMS); Revlimid® from BMS; Zynteglo® and Lyfgenia® from Genetix; Adakveo® from Novartis; Casgevy® from Vertex/CRISPR; Kuvan® and Palynziq® from BioMarin; Endari® from Emmaus; Besremi® from PharmaEssentia; Jakafi® from Incyte; Sephience™ from PTC, and Rytelo® from Geron.
If a company is found to have promoted off-label uses, it may become subject to adverse public relations and administrative and judicial enforcement by the FDA, the Department of Justice, or the DOJ, or the Office of the Inspector General of the 22 Table of Content s Department of HHS, as well as state authorities.
If a company is found to have promoted off-label uses, it may become subject to adverse public relations and administrative and judicial enforcement by the FDA, the Department of Justice, or the DOJ, or the Office of the Inspector General of the Department of HHS, as well as state authorities.
Accelerated assessment might be granted by the CHMP in exceptional cases, when a medicinal product is of major interest from the point of view of public health and from the viewpoint of therapeutic innovation. The timeframe for the evaluation of an MAA under the accelerated assessment procedure is 150 days, excluding stop clocks.
Accelerated assessment might be granted by the CHMP in exceptional cases, when a medicinal product is of major interest from the point of view of public health and from the viewpoint of therapeutic innovation. The timeframe for the evaluation of an MAA under the accelerated assessment procedure is 150 days, excluding clock stops.
Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, with manufacturing processes, or failure to comply with regulatory requirements, may result in: revisions to the approved labeling to add new safety information; imposition of post-market studies or clinical trials to assess safety risks; or imposition of distribution or other restrictions under a REMS program.
Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, with manufacturing processes, or failure to comply with regulatory requirements, may result in: revisions to the approved labeling to add new safety information; imposition of post- 23 Table of Content s market studies or clinical trials to assess safety risks; or imposition of distribution or other restrictions under a REMS.
All of these events occurred within the first six months of exposure to PYRUKYND® and liver tests improved following discontinuation of PYRUKYND®.
All of these events occurred within the first six months of exposure to mitapivat and liver tests improved following discontinuation of mitapivat.
Under the FDA Reauthorization Act of 2017, the FDA must implement a protocol to expedite review of responses to inspection reports pertaining to certain 19 Table of Content s applications, including applications for products in shortage or those for which approval is dependent on remediation of conditions identified in the inspection report.
Under the FDA Reauthorization Act of 2017, the FDA must implement a protocol to expedite review of responses to inspection reports pertaining to certain applications, including applications for products in shortage or those for which approval is dependent on remediation of conditions identified in the inspection report.
We are committed to fostering a welcoming and diverse workplace in which individuals from a variety of backgrounds can thrive.
We are committed to fostering a welcoming and inclusive workplace in which individuals from a variety of backgrounds can thrive.
Business Overview Rare diseases The lead product candidate in our portfolio, PYRUKYND® (mitapivat), is an activator of both wild-type and mutant pyruvate kinase, or PK, enzymes for the potential treatment of hemolytic anemias. PYRUKYND® is approved for use by the U.S.
Business Overview Rare diseases The lead product candidate in our portfolio, mitapivat, is an activator of both wild-type and mutant pyruvate kinase, or PK, enzymes for the potential treatment of hemolytic anemias. Mitapivat is approved in the United States by the U.S.
Nonetheless, from a practical perspective, a sponsor’s failure to follow the FDA’s recommendations for design of a clinical program may put the program at significant risk of failure. In September 2023, the FDA issued draft guidance outlining the terms of such meetings in more detail.
Nonetheless, from a practical perspective, a sponsor’s 19 Table of Content s failure to follow the FDA’s recommendations for design of a clinical program may put the program at significant risk of failure. In September 2023, the FDA issued draft guidance outlining the terms of such meetings in more detail.
The restoration period granted on a patent covering a product is typically one-half the time between the effective date of when a clinical trial involving human beings has begun and the submission date of an application for approval, plus the time between the submission date of an application and the ultimate approval date.
The restoration period granted on a patent covering a product is typically one-half the time between the effective date of when a clinical trial involving human beings has begun and the submission date 26 Table of Content s of an application for approval, plus the time between the submission date of an application and the ultimate approval date.
Chamber of Commerce and pharmaceutical companies, also filed lawsuits in various courts with similar constitutional claims against HHS and CMS. HHS has generally won the substantive disputes in these cases, and various federal district court judges have expressed skepticism regarding the merits of the legal arguments being pursued by the pharmaceutical industry.
Chamber of Commerce and pharmaceutical companies, also filed lawsuits in various courts with similar constitutional claims against HHS and CMS. HHS has generally won the substantive disputes in these cases, and various federal district court judges have expressed skepticism regarding the merits of the legal arguments being pursued by the pharmaceutical industry. Most of these cases are now on appeal.
The Pediatric Committee of the EMA, or PDCO, may grant 31 Table of Content s deferrals for some medicines, allowing a company to delay development of the medicine for children until there is enough information to demonstrate its effectiveness and safety in adults.
The Pediatric Committee of the EMA, or PDCO, may grant deferrals for some medicines, allowing a company to delay development of the medicine for children until there is enough information to demonstrate its effectiveness and safety in adults.
Following this, further marketing authorizations can be progressively sought from other EU countries in a procedure whereby the countries concerned agree to recognize the validity of the original, national marketing authorization produced by the reference member state.
Following this, further marketing authorizations can be progressively sought from other EU countries in a procedure whereby the 32 Table of Content s countries concerned agree to recognize the validity of the original, national marketing authorization produced by the reference member state.
Further, the legislation subjects drug manufacturers to civil monetary penalties and a potential excise tax for failing to comply with the legislation by offering a price that is not equal to or less than the negotiated “maximum fair price” under the law or for taking price increases that exceed inflation.
Further, the legislation subjects drug manufacturers to civil monetary penalties and a potential excise tax for failing to comply with the legislation by offering a price that is not equal to or less than the negotiated “maximum fair price” under the law or for taking price increases 29 Table of Content s that exceed inflation.
We are also developing (i) tebapivat, a novel PK activator, for the potential treatment of lower-risk myelodysplastic syndromes, or LR MDS, and hemolytic anemias; (ii) AG-181, our phenylalanine hydroxylase, or PAH, stabilizer for the potential treatment of phenylketonuria, or PKU; and (iii) AG-236, an siRNA in-licensed 3 Table of Content s from Alnylam Pharmaceuticals, Inc., or Alnylam, targeting the transmembrane serine protease 6, or TMPRSS6 gene for the potential treatment of polycythemia vera, or PV.
We are also developing (i) tebapivat, a novel PK activator, for the potential treatment of lower-risk myelodysplastic syndromes, or LR MDS, and SCD; (ii) AG-181, our phenylalanine hydroxylase, or PAH, stabilizer for the potential treatment of phenylketonuria, or PKU; and (iii) AG-236, an siRNA in-licensed from Alnylam Pharmaceuticals, Inc., or Alnylam, targeting the transmembrane serine protease 6, or TMPRSS6, gene for the potential treatment of polycythemia vera, or PV.
Direct-to-consumer advertising of prescription medicines is prohibited across the EU. 32 Table of Content s General Data Protection Regulation Many countries outside of the United States maintain rigorous laws governing the privacy and security of personal information.
Direct-to-consumer advertising of prescription medicines is prohibited across the EU. General Data Protection Regulation Many countries outside of the United States maintain rigorous laws governing the privacy and security of personal information.
The transaction included the sale of our oncology business, including TIBSOVO®, our clinical-stage product candidates vorasidenib, AG-270 and AG-636, and our oncology research programs, for a payment of approximately $1.8 billion in cash at the closing, subject to certain adjustments, and a payment of $200.0 million in cash, if, prior to January 1, 2027, vorasidenib is granted new drug application, or NDA, approval from the FDA with an approved label that permits vorasidenib’s use as a single agent for the adjuvant treatment of patients with Grade 2 glioma that have an isocitrate dehydrogenase, or IDH, 1 or 2 mutation (and, to the extent required by such approval, the vorasidenib companion diagnostic test is granted an FDA premarket approval), or the Vorasidenib Milestone Payment, as well as a royalty of 5% of U.S. net sales of TIBSOVO® from the close of the transaction through loss of exclusivity, and a royalty of 15% of U.S. net sales of vorasidenib from the first commercial sale of vorasidenib through loss of exclusivity, or the Vorasidenib Royalty Rights.
The transaction included the sale of our entire oncology business, including our clinical-stage product candidate vorasidenib, for a payment of approximately $1.8 billion in cash at the closing, subject to certain adjustments, and a payment of $200.0 million in cash, if, prior to January 1, 2027, vorasidenib is granted new drug application, or NDA, approval from the FDA with an approved label that permits vorasidenib’s use as a single agent for the adjuvant treatment of patients with Grade 2 glioma that have an isocitrate dehydrogenase, or IDH, 1 or 2 mutation (and, to the extent required by such approval, the vorasidenib companion diagnostic test is granted an FDA premarket approval), or the Vorasidenib Milestone Payment, and a royalty of 15% of U.S. net sales of vorasidenib from the first commercial sale of vorasidenib through loss of exclusivity, or the Vorasidenib Royalty Rights.
In addition to currently marketed therapies, there are also several products that are either small molecules, biologics, ERTs or gene therapies in various stages of development to treat hemolytic anemias, PKU and PV.
In addition to currently 14 Table of Content s marketed therapies, there are also several products that are either small molecules, biologics, ERTs or gene therapies in various stages of development to treat hemolytic anemias, PKU and PV.
Although single-arm trials have been commonly used to support accelerated approval, a randomized controlled trial is the preferred approach, as it provides a more robust efficacy and safety assessment and allows for direct comparisons to an available therapy.
Although single-arm trials have been commonly used to support accelerated approval, a randomized controlled trial is the preferred approach, as it provides a more robust efficacy and safety assessment and allows for direct 22 Table of Content s comparisons to an available therapy.
We evaluated the phase 2a trial results and assessed the impact of those results on the phase 2b portion of the protocol, and based on the data generated in the phase 2a portion of the trial, we plan to increase the dosage levels evaluated in the phase 2b portion of the trial, which we initiated in the third quarter of 2024.
We evaluated the phase 2a trial results and assessed the impact of those results on the phase 2b portion of the protocol, and based on the data generated in the phase 2a portion of the trial, we increased the dosage levels evaluated in the phase 2b portion of the trial, which we initiated in the third quarter of 2024.
Current treatment options for LR MDS often require in- 7 Table of Content s office visits and transfusions, and erythropoiesis stimulating agents and Reblozyl® and Rytelo® are the only approved therapies to treat anemia in a subset of patients. Despite approved therapies in subsets of patients, LR MDS associated anemia remains a disease with a high unmet medical need.
Current treatment options for LR MDS often require in-office visits and transfusions, and erythropoiesis stimulating agents and Reblozyl® and Rytelo® are the only approved medicines to treat anemia in a subset of patients. Despite approved medicines in subsets of patients, LR MDS associated anemia remains a disease with a high unmet medical need.
The most common type of MDS is LR MDS, but many existing therapies and therapies under development focus on high risk MDS. Among patients with LR MDS, which accounts for approximately 70% of all MDS cases and are less likely to progress to AML, the primary concern is symptomatic anemia.
The most common type of MDS is LR MDS, but many existing medicines and medicines under development focus on high risk MDS. Among patients with LR MDS, which accounts for approximately 70% of all 8 Table of Content s MDS cases and are less likely to progress to AML, the primary concern is symptomatic anemia.
As indicated above, during the double-blind periods of ENERGIZE and ENERGIZE-T, two patients on PYRUKYND® experienced events of hepatocellular injury. In addition, during the open-label extension periods of both trials, a total of three patients experienced events of hepatocellular injury after switching from placebo to PYRUKYND®.
During the double-blind periods of ENERGIZE and ENERGIZE-T, two patients on mitapivat experienced events of hepatocellular injury. In addition, during the open-label extension periods of both trials, a total of three patients experienced events of hepatocellular injury after switching from placebo to mitapivat.
We are committed to providing employees with an opportunity to choose the right working arrangement for them based on their role: whether remote, hybrid, or onsite in our Cambridge office, and we continue to evaluate how we can enhance these arrangements for an optimal employee experience.
We continue to provide employees with an opportunity to choose the right working arrangement for them based on their role: whether remote, hybrid, or onsite in our Cambridge office, and regularly evaluate how we can enhance these arrangements to support an optimal employee experience.
The primary endpoint of ACTIVATE-kids is percentage of patients with hemoglobin response, defined as ≥1.5 g/dL increase in hemoglobin concentration from baseline that is sustained at two or more scheduled assessments at weeks 12, 16, and 20 during the double-blind period. We announced topline data for ACTIVATE-kids in February 2025.
The primary endpoint of ACTIVATE-kids is percentage of patients with hemoglobin response, defined as ≥1.5 g/dL increase in hemoglobin concentration from baseline that is sustained at two or more scheduled assessments at weeks 12, 16, and 20 during the double-blind period.
In addition, the pre-specified supportive analysis based on traditional methodology comparing the hemoglobin response 10 Table of Content s rate for mitapivat versus placebo provided further evidence that the primary endpoint was met.
In addition, the pre-specified supportive analysis based on traditional methodology comparing the hemoglobin response rate for mitapivat versus placebo provided further evidence that the primary endpoint was met.
A total of 49 patients were enrolled in ACTIVATE-kidsT, with 32 randomized to mitapivat twice-daily and 17 randomized to matched placebo. 30 patients (93.8%) in the mitapivat arm and 16 (94.1%) in the placebo arm completed the 32-week double-blind period of the study.
We announced topline data for ACTIVATE-kidsT in August 2024. A total of 49 patients were enrolled in ACTIVATE-kidsT, with 32 randomized to mitapivat twice-daily and 17 randomized to matched placebo. 30 patients (93.8%) in the mitapivat arm and 16 (94.1%) in the placebo arm completed the 32-week double-blind period of the study.
The safety results from the trial were consistent with the safety profile for mitapivat previously observed for adult patients with PK deficiency who are not regularly transfused. • An extension study evaluating the long-term safety, tolerability and efficacy of treatment with PYRUKYND® in patients from ACTIVATE and ACTIVATE-T, our completed pivotal trials of PYRUKYND® in not regularly transfused and regularly transfused adult patients with PK deficiency. • An extension study evaluating the long-term safety, tolerability and efficacy of treatment with PYRUKYND® in patients from DRIVE PK, our completed global phase 2, first-in-patient, open-label safety and efficacy clinical trial of PYRUKYND® in adult, not regularly transfused patients with PK deficiency.
The safety results from the trial were consistent with the safety profile for mitapivat previously observed for adult patients with PK deficiency who are not regularly transfused. • An extension study evaluating the long-term safety, tolerability and efficacy of treatment with mitapivat in patients from ACTIVATE and ACTIVATE-T, our completed pivotal trials of mitapivat in not regularly transfused and regularly transfused adult patients with PK deficiency. • An extension study evaluating the long-term safety, tolerability and efficacy of treatment with mitapivat in patients from DRIVE PK, our completed global phase 2, first-in-patient, open-label safety and efficacy clinical trial of mitapivat in adult, not regularly transfused patients with PK deficiency. • An extension study evaluating the long-term efficacy and safety of treatment with mitapivat in patients from ENERGIZE and ENERGIZE-T, our completed pivotal trials of mitapivat in adults with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia.
Current treatment strategies focus on managing and preventing acute RBC sickling, and include hydroxyurea, L-glutamine and blood transfusions, as well as recently approved therapies such as Adakveo®, Casgevy®, and Lfygenia®. We believe that activation of wild-type PKR in patients with SCD may reduce hemoglobin polymerization and the sickling process by at least two mechanisms.
Current treatment strategies focus on managing and preventing acute RBC sickling, and include hydroxyurea, L-glutamine and blood transfusions, as well as recently approved medicines such as Adakveo®, Casgevy®, and Lfygenia®. Activation of wild-type PKR in patients with SCD is believed to reduce hemoglobin polymerization and the sickling process by at least two mechanisms.
We have a proven track record of developing new therapeutic approaches and multiple proprietary first-in-class orally available small molecules. 5 Table of Content s The following summarizes our approved product and most advanced clinical product candidates, each of which is described in further detail below.
We have a proven track record of developing novel therapeutic approaches and multiple proprietary first‑in‑class oral small molecules. 6 Table of Content s The following summarizes our approved products and most advanced clinical product candidates, each of which is described in further detail below.
Also in December 2024, we announced that we submitted an MAA to the EMA and regulatory applications to the Kingdom of Saudi Arabia and United Arab Emirates health authorities for PYRUKYND® for the treatment of adult patients with non-transfusion dependent and transfusion-dependent alpha- or beta-thalassemia.
In December 2024, we announced that we submitted an MAA to the EMA and a regulatory application to the United Arab Emirates health authorities for PYRUKYND® for the treatment of adult patients with non-transfusion dependent and transfusion-dependent alpha- or beta-thalassemia.
The benefits of a regenerative advanced therapy designation include early interactions with 20 Table of Content s FDA to expedite development and review, benefits available to breakthrough therapies, potential eligibility for priority review and accelerated approval based on surrogate or intermediate endpoints.
The benefits of a regenerative advanced therapy designation include early interactions with FDA to expedite development and review, benefits available to breakthrough therapies, potential eligibility for priority review and accelerated approval based on surrogate or intermediate endpoints. • Commissioner’s National Priority Voucher .
We have an active cross-functional diversity council that furthers our commitment to building a diverse and inclusive organization by: • Representing and reflecting the different voices in the Agios community • Furthering the work of diversity, equity and inclusion at Agios and in our communities • Working in partnership with our leadership, human resources and employee resource groups to share, drive and lead our diversity, equity and inclusion efforts We are a majority female organization and maintain significant representation at all levels, including the Board of Directors.
We have an active cross-functional diversity council that furthers our commitment to building an inclusive organization by: • Representing and reflecting the different voices in the Agios community • Deepening the focus on inclusion at Agios and in our communities • Working in partnership with our leadership, human resources and employee resource groups to share, drive and lead our inclusion and belonging efforts 36 Table of Content s We are a majority female organization and maintain significant representation at all levels, including the Board of Directors.
On January 17, 2025, CMS announced the selection of 15 additional drugs covered by Medicare Part D for the second cycle of negotiations. This second cycle of negotiations with participating drug companies will occur during 2025, and any negotiated prices for this second set of drugs will be effective starting January 1, 2027.
On January 17, 2025, CMS announced the selection of 15 additional drugs covered by Medicare Part D for the second cycle of negotiations. Any negotiated prices for this second set of drugs will be effective starting January 1, 2027.
Sale of Oncology Business to Servier and Sale of Contingent Payments On March 31, 2021, we completed the sale of our oncology business to Servier Pharmaceuticals, LLC, or Servier, which represented a discontinued operation.
Sale of Oncology Business to Servier and Sale of Contingent Payments On March 31, 2021, we completed the sale of our oncology business to Servier Pharmaceuticals, LLC, or Servier.
Due to the volatility of the supply networks globally, we have gained regulatory approval for redundant supply of raw materials and active pharmaceutical ingredient, or API, for PYRUKYND®, and have an ongoing program to ensure this risk mitigation remains effective, including establishing safety stocks.
Due to the volatility of the supply networks globally, we have gained regulatory approval for redundant supply of raw materials and active pharmaceutical ingredient, or API, for PYRUKYND® and AQVESME™, and have an ongoing program to monitor supply, including establishing safety stocks.
We believe that the activation of wild-type PKR may increase ATP production and improve red cell fitness and survival of thalassemic RBCs, by increasing the clearance globin chain aggregates through ATP-dependent proteolytic mechanisms.
Activation of wild-type PKR is believed to increase ATP production and improve red cell fitness and survival of thalassemic RBCs, by increasing the clearance globin chain aggregates through ATP-dependent proteolytic mechanisms.
PYRUKYND® is approved for use by the FDA for the treatment of hemolytic anemia in adults with PK deficiency in the United States and by the European Commission for the treatment of PK deficiency in adult patients in the EU.
The FDA approved mitapivat, under the brand name PYRUKYND®, for the treatment of hemolytic anemia in adults with PK deficiency in the United States and by the European Commission for the treatment of PK deficiency in adult patients in the EU.
Products from small- and medium-sized enterprises may qualify for earlier entry into the 29 Table of Content s PRIME scheme than larger companies.
Products from small- and medium-sized enterprises may qualify for earlier entry into the PRIME scheme than larger companies.
Under federal law, the submission of most NDAs is subject to an application user fee, which for federal fiscal year 2025 is approximately $4.31 million. The sponsor of an approved NDA is also subject to an annual program fee, which for fiscal year 2025 is $403,889 per product.
Under federal law, the submission of most NDAs is subject to an application user fee, which for federal fiscal year 2026 is approximately $4.7 million. The sponsor of an approved NDA is also subject to an annual program fee, which for fiscal year 2026 is $442,213 per product.
As of December 19, 2024, the FDA has issued six notices of non-compliance, signaling the government’s willingness to enforce these requirements against non-compliant clinical trial sponsors.
As of December 30, 2025, the FDA has issued eight notices of non-compliance, signaling the government’s willingness to enforce these requirements against non-compliant clinical trial sponsors.
Whether or not it obtains FDA approval for a product, a sponsor will need to obtain the necessary approvals by the comparable non-U.S. regulatory authorities before it can commence clinical trials or marketing of the product in those countries or jurisdictions.
Whether or not it obtains FDA approval for a product, a sponsor will need to obtain the necessary approvals by the comparable regulatory authorities of foreign countries or economic areas, such as the EU, before it can commence clinical trials or marketing of the product in those countries or jurisdictions.
Once the submission is accepted for filing, the FDA begins an in-depth substantive review. Under the goals and policies agreed to by the FDA under the PDUFA, applications seeking approval of New Molecular Entities, or NMEs, are meant to be reviewed within ten months from the date on which the FDA accepts the application for filing.
Under the goals and policies agreed to by the FDA under the PDUFA, applications seeking approval of New Molecular Entities, or NMEs, are meant to be reviewed within ten months from the date on which the FDA accepts the application for filing.
As of February 1, 2025, we owned 17 issued United States patents and 434 issued foreign patents, and have pending patent applications in the United States and in various foreign jurisdictions.
As of February 1, 2026, we owned 19 issued United States patents and 447 issued foreign patents, and have pending patent applications in the United States and in various foreign jurisdictions.
This foundation helps our people push the boundaries of our science and create transformative medicines, which we believe will provide long-term benefits for all our stakeholders. Our connections – with each other and with external parties – fuel the development of new therapies for the people who need them.
This foundation helps our people push the boundaries of our science and create transformative medicines, which we believe will provide long-term benefits for all our stakeholders. Our connections – with each other and with the rare disease community we serve – fuel the development of new medicines.
In addition, the Right to Try Act, among other things, provides a federal framework for certain patients to access certain investigational new drug products that have completed a Phase 1 clinical trial and are undergoing investigation for FDA approval.
In October 2025, the FDA issued final guidance further clarifying the statutory and regulatory requirements governing expanded access. In addition, the Right to Try Act, among other things, provides a federal framework for certain patients to access certain investigational new drug products that have completed a Phase 1 clinical trial and are undergoing investigation for FDA approval.
The FDA or the sponsor may request an amendment to the plan at any time. 18 Table of Content s For drugs intended to treat a serious or life-threatening disease or condition, the FDA must, upon the request of a sponsor, meet to discuss preparation of the initial pediatric study plan or to discuss deferral or waiver of pediatric assessments.
For drugs intended to treat a serious or life-threatening disease or condition, the FDA must, upon the request of a sponsor, meet to discuss preparation of the initial pediatric study plan or to discuss deferral or waiver of pediatric assessments.
Clinical Trial Approval Under the Clinical Trials Regulation (EU) No 536/2014, or the Clinical Trials Regulation, the sponsor of a clinical trial to be conducted in more than one Member State of the EU, or EU Member State, is only required to submit a single application for approval.
These GLP standards reflect the Organisation for Economic Co-operation and Development requirements. Clinical Trial Approval Under the Clinical Trials Regulation (EU) No 536/2014, or the Clinical Trials Regulation, the sponsor of a clinical trial to be conducted in more than one Member State of the EU, or EU Member State, is only required to submit a single application for approval.
We received feedback from employees that helped inform how we approach programs and opportunities to improve the employee experience heading into 2024. In addition, we track important human capital metrics such as turnover rate. Voluntary and involuntary turnover rates across all levels (executives / senior managers, mid-level managers and professionals) are in alignment with the industry average.
We regularly solicit feedback from employees that helps inform our approach to programs and identify opportunities to improve the employee experience. In addition, we track important human capital metrics such as turnover rate. Voluntary and involuntary turnover rates across all levels (executives / senior managers, mid-level managers and professionals) are aligned with industry norms.

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Item 1A. Risk Factors

Risk Factors — what could go wrong, per management

164 edited+62 added−98 removed233 unchanged
Biggest changeFor example, Merck and Bristol-Myers Squibb Company, or BMS, are marketing a therapy to treat beta thalassemia and LR MDS, and are conducting clinical trials for alpha thalassemia and LR MDS patients that are erythropoeisis-stimulating agent naïve and non-transfusion dependent; Geron Corporation recently announced FDA approval of a treatment for adults with LR MDS with transfusion-dependent anemia; Novartis International AG, or Novartis, and Emmaus Life Sciences are each marketing therapies to treat SCD; BioMarin Pharmaceutical Inc., or BioMarin, is marketing and conducting clinical trials for therapies to treat PKU; Pfizer is conducting clinical trials for therapies in SCD; Novo Nordisk is conducting clinical trials for the treatment of alpha and beta thalassemia and SCD; bluebird is marketing a gene therapy to treat transfusion-dependent beta-thalassemia and SCD; Vertex, with CRISPR, is marketing a gene therapy targeting SCD and transfusion-dependent beta-thalassemia; Fulcrum is conducting clinical trials for a potential treatment for SCD; PTC and Otsuka and are conducting clinical trials for potential treatments for PKU; PharmaEssentia Corp, or PharmaEssentia, and Incyte Corporation, or Incyte, are marketing therapies to treat PV, and Protagonist with Takeda, Ionis, Italfarmaco S.p.A., Disc Medicine, Merck, and Silence are developing therapies to treat PV; Rocket Pharma is developing a therapy for the treatment of PK deficiency; and a number of other biotechnology companies have product candidates in clinical development in similar indications as ours.
Biggest change(formerly bluebird bio) is marketing a gene therapy to treat transfusion-dependent beta-thalassemia and SCD; Vertex, with CRISPR, is marketing a gene therapy targeting SCD and transfusion- 44 Table of Content s dependent beta-thalassemia; DISC Medicine, Inc., or DISC, is conducting a clinical trial for a potential treatment for SCD; Fulcrum Therapeutics Inc. is conducting clinical trials for a potential treatment for SCD; BMS is conducting clinical trials for a potential treatment for SCD; Otsuka Pharmaceutical Co., Ltd., NGGT Inc., and Maze Therapeutics, Inc. are conducting clinical trials for potential treatments for PKU; PharmaEssentia Corp and Incyte Corporation are marketing therapies to treat PV, and Protagonist Therapeutics in collaboration with Takeda, Ionis in collaboration with Ono/Deciphera, Italfarmaco S.p.A., DISC, Merck, and Silence Therapeutics are developing therapies to treat PV; and a number of other biotechnology companies have product candidates in clinical development in similar indications as ours.
Our relationships with healthcare providers, physicians and third-party payors are subject to applicable anti-kickback, fraud and abuse and other healthcare laws and regulations, which, in the event of a violation, could expose us to criminal sanctions, civil penalties, contractual damages, reputational harm and diminished profits and future earnings.
Our relationships with healthcare providers, physicians and third-party payors are subject to applicable anti-kickback, fraud and abuse and other healthcare laws and regulations, which, in the event of a violation, could expose us to criminal sanctions, civil penalties, contractual damages, reputational harm and diminished future profits and future earnings.
Cost-control initiatives could cause us, or any collaborators, to decrease the price we, or they, might establish for products, which could result in lower than anticipated product revenue. If the prices for our products, if any, decrease or if governmental and other third-party payors do not provide coverage or adequate reimbursement, our prospects for revenue and profitability will suffer.
Cost-control initiatives could cause us, or any collaborators, to decrease the price we, or they, might establish for products, which could result in lower than anticipated product revenue. If the prices for our products decrease or if governmental and other third-party payors do not provide coverage or adequate reimbursement, our prospects for revenue and profitability will suffer.
We expect that current laws, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price that we, or any collaborators, may receive for any approved products.
We expect that current laws, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and additional downward pressure on the price that we, or any collaborators, may receive for any approved products.
Patient enrollment is also affected by other factors including: • prevalence and severity of the disease under investigation; • availability and efficacy of approved medications for the disease under investigation; • eligibility criteria for the study in question; • perceived risks and benefits of the product candidate under study; • efforts to facilitate timely enrollment in clinical trials; • patient referral practices of physicians; • the ability to monitor patients adequately during and after treatment; • proximity and availability of clinical trial sites for prospective patients; and • the impact of any health epidemics, pandemics or other contagious outbreaks or geopolitical events, such as war.
Patient enrollment is affected by factors including: • prevalence and severity of the disease under investigation; • availability and efficacy of approved medications for the disease under investigation; • eligibility criteria for the study in question; • perceived risks and benefits of the product candidate under study; • efforts to facilitate timely enrollment in clinical trials; • patient referral practices of physicians; • the ability to monitor patients adequately during and after treatment; • proximity and availability of clinical trial sites for prospective patients; and • the impact of any health epidemics, pandemics or other contagious outbreaks or geopolitical events, such as war.
In the United States and foreign jurisdictions, there have been a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of our product candidates, restrict or regulate post-approval activities and affect our ability, or the ability of any collaborators, to profitably sell PYRUKYND® or any other product candidate for which we, or they, obtain marketing approval.
In the United States and foreign jurisdictions, there have been a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of our product candidates, restrict or regulate post-approval activities and affect our ability, or the ability of any collaborators, to profitably sell PYRUKYND®, AQVESME™ or any other product candidate for which we, or they, obtain marketing approval.
In addition, increasingly, 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 cannot be sure that coverage will be available for PYRUKYND® or any product candidate that we, or any collaborator, may commercialize and, if available, that the reimbursement rates will be adequate.
In addition, increasingly, 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 cannot be sure that coverage will be available for PYRUKYND®, AQVESME™ or any product candidate that we, or any collaborator, may commercialize and, if available, that the reimbursement rates will be adequate.
Our future arrangements with healthcare providers, physicians and third-party payors may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which we market, sell and distribute PYRUKYND® and any other medicines for which we obtain marketing approval.
Our future arrangements with healthcare providers, physicians and third-party payors may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which we market, sell and distribute PYRUKYND®, AQVESME™ and any other medicines for which we obtain marketing approval.
If we are unable to maintain sales and marketing capabilities or enter into agreements with third parties to sell and market our product candidates, we may not be successful in commercializing PYRUKYND® or any of our product candidates if they are approved. We have limited experience in the sale, marketing and distribution of pharmaceutical products.
If we are unable to maintain sales and marketing capabilities or enter into agreements with third parties to sell and market our product candidates, we may not be successful in commercializing PYRUKYND®, AQVESME™ or any of our product candidates if they are approved. We have limited experience in the sale, marketing and distribution of pharmaceutical products.
Failure to comply with these requirements could result in reputational risk, public reprimands, administrative penalties, fines or imprisonment. PYRUKYND® or any product candidate that we commercialize may become subject to unfavorable pricing regulations and third-party reimbursement practices, which would harm our business.
Failure to comply with these requirements could result in reputational risk, public reprimands, administrative penalties, fines or imprisonment. PYRUKYND®, AQVESME™ or any product candidate that we commercialize may become subject to unfavorable pricing regulations and third-party reimbursement practices, which would harm our business.
We or others may later discover that PYRUKYND®, or any of our product candidates that may receive marketing approval in the future, is less effective than previously believed or causes undesirable side effects that were not previously identified, which could compromise our ability, or that of any collaborators, to market the product.
We or others may later discover that PYRUKYND®, AQVESME™ or any of our product candidates that may receive marketing approval in the future, is less effective than previously believed or causes undesirable side effects that were not previously identified, which could compromise our ability, or that of any collaborators, to market the product.
For example, two of the European patents in our mitapivat portfolio, neither being the primary compound patent, have been challenged in opposition proceedings in the European Patent Office. The revocation of either of these European patents could potentially allow additional competitor drugs, if approved, to enter the European marketplace earlier than anticipated.
For example, two of the European patents in our mitapivat portfolio, neither being the primary compound patent, have been challenged in opposition proceedings. The revocation of either of these European patents could potentially allow additional competitor drugs, if approved, to enter the European marketplace earlier than anticipated.
The commercial success of PYRUKYND® or of any of our product candidates will depend substantially, both domestically and abroad, on the extent to which the costs of our product candidates will be paid by third-party payors, including government health administration authorities and private health coverage insurers.
The commercial success of PYRUKYND®, AQVESME™ or of any of our product candidates will depend substantially, both domestically and abroad, on the extent to which the costs of our product candidates will be paid by third-party payors, including government health administration authorities and private health coverage insurers.
This could result in a delay in approval, or rejection, of our marketing applications by the FDA or comparable foreign regulatory authority, as the case may be, and may ultimately lead to the denial of marketing approval of one or more of our product candidates. 54 Table of Content s Further, the process of obtaining marketing approvals, both in the United States and abroad, is expensive, may take many years if additional clinical trials are required, if approval is obtained at all, and can vary substantially based upon a variety of factors, including the type, complexity and novelty of the product candidates involved.
This could result in a delay in approval, or rejection, of our marketing applications by the FDA or comparable foreign regulatory authority, as the case may be, and may ultimately lead to the denial of marketing approval of one or more of our product candidates. 55 Table of Content s Further, the process of obtaining marketing approvals, both in the United States and abroad, is expensive, may take many years if additional clinical trials are required, if approval is obtained at all, and can vary substantially based upon a variety of factors, including the type, complexity and novelty of the product candidates involved.
PYRUKYND®, or any of our product candidates that may receive marketing approval in the future, may fail to achieve the degree of market acceptance by physicians, patients, healthcare payors and others in the medical community necessary for commercial success.
PYRUKYND®, AQVESME™ or any of our product candidates that may receive marketing approval in the future, may fail to achieve the degree of market acceptance by physicians, patients, healthcare payors and others in the medical community necessary for commercial success.
The price of our common stock is likely to be volatile, which could result in substantial losses for purchasers of our common stock. The trading price of our common stock has been, and may continue to be, volatile and could be subject to wide fluctuations in response to various factors, some of which are beyond our control.
The price of our common stock is volatile, which could result in substantial losses for purchasers of our common stock. The trading price of our common stock has been, and may continue to be, volatile and could be subject to wide fluctuations in response to various factors, some of which are beyond our control.
The regulatory approval process outside the United States generally includes all of the risks associated with obtaining FDA approval. In addition, in many countries outside the United States, a product must be approved for reimbursement before the product can be approved for sale in that country.
The regulatory approval process outside the United States generally includes all of the risks associated with obtaining FDA approval. In addition, in many foreign countries, a product must be approved for reimbursement before the product can be approved for sale in that country.
A decline in the value of our company could also cause our stockholders to lose all or part of their investment. Changes in tax laws or in their implementation or interpretation may adversely affect our business and financial condition. Changes in tax law may adversely affect our business or financial condition.
A decline in the value of our company could also cause our stockholders to lose all or part of their investment. Changes in tax laws or in their implementation or interpretation may adversely affect our business and financial condition.
We and any collaborators face a risk of product liability exposure related to our product candidates in human clinical trials and face an even greater risk as we or they commercially sell any medicines, including PYRUKYND®.
We and any collaborators face a risk of product liability exposure related to our product candidates in human clinical trials and face an even greater risk as we or they commercially sell any medicines, including PYRUKYND® and AQVESME™.
Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential information could be compromised by disclosure during this type of litigation. 52 Table of Content s Third parties may initiate legal proceedings alleging that we or our collaborators are infringing their intellectual property rights, the outcome of which would be uncertain and could have a material adverse effect on the success of our business.
Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential information could be compromised by disclosure during this type of litigation. 53 Table of Content s Third parties may initiate legal proceedings alleging that we or our collaborators are infringing their intellectual property rights, the outcome of which would be uncertain and could have a material adverse effect on the success of our business.
Failure to obtain marketing approval in foreign jurisdictions would prevent our medicines from being marketed in such jurisdictions and any of our medicines that are approved for marketing in such jurisdiction will be subject to risk associated with foreign operations.
Failure to obtain marketing approval in foreign jurisdictions would prevent our medicines from being marketed in such jurisdictions and any of our medicines that are approved for marketing in such jurisdictions will be subject to risk associated with foreign operations.
We, or any collaborators, may not be able to obtain orphan drug designation or orphan drug exclusivity for our drug candidates and, even if we do, that exclusivity may not prevent the FDA or the EMA from approving competing drugs.
We, or any collaborators, may not be able to obtain or maintain orphan drug designation or orphan drug exclusivity for our drug candidates and, even if we do, that exclusivity may not prevent the FDA or the EMA from approving competing drugs.
Under Section 382 and 383 of the Code and corresponding provisions of state law, if a company undergoes an “ownership change,” generally defined as a greater than 50% change (by value) in its equity ownership by certain stockholders over a three-year period, the company’s ability to use its pre-change net operating loss carryforwards and other pre-change tax attributes (such as research tax credits) to offset its post-change taxable income may be limited.
Under Sections 382 and 383 of the Code and corresponding provisions of state law, if a company undergoes an “ownership change,” generally defined as a greater than 50% change (by value) in its equity ownership by certain stockholders over a three-year period, the company’s ability to use its pre-change net operating loss carryforwards and other pre-change tax attributes (such as research tax credits) to offset its post-change taxable income may be limited.
Until such time, if ever, as we can generate substantial product revenue, including from sales of PYRUKYND®, we expect to finance our cash needs primarily through cash on hand, potential royalty payments with respect to annual U.S. net sales of vorasidenib in excess of $1.0 billion, or the Retained Earn-Out Rights, and, potentially, collaborations, strategic alliances, licensing arrangements and other nondilutive strategic transactions.
Until such time, if ever, as we can generate substantial product revenue, including from potential future sales of PYRUKYND® and AQVESME™, we expect to finance our cash needs primarily through cash on hand, potential royalty payments with respect to annual U.S. net sales of vorasidenib in excess of $1.0 billion, or the Retained Earn-Out Rights, and, potentially, collaborations, strategic alliances, licensing arrangements and other nondilutive strategic transactions.
These payors may not view our products, if any, as cost-effective, and coverage and reimbursement may not be available to our customers, or those of any collaborators, or may not be sufficient to allow our products, if any, to be marketed on a competitive basis.
These payors may not view our products as cost-effective, and coverage and reimbursement may not be available to our customers, or those of any collaborators, or may not be sufficient to allow our products to be marketed on a competitive basis.
Healthcare providers, physicians and third-party payors will play a primary role in the recommendation and prescription of PYRUKYND® and any product candidates for which we obtain marketing approval.
Healthcare providers, physicians and third-party payors will play a primary role in the recommendation and prescription of PYRUKYND®, AQVESME™ and any product candidates for which we obtain marketing approval.
Our competitors may develop products that are more effective, safer, more convenient or less costly than PYRUKYND® or any product candidates that we are developing or that would render PYRUKYND® or our product candidates obsolete or non-competitive.
Our competitors may develop products that are more effective, safer, more convenient or less costly than PYRUKYND®, AQVESME™ or any product candidates that we are developing or that would render PYRUKYND®, AQVESME™ or our product candidates obsolete or non-competitive.
Even if we are able to establish agreements with third-party manufacturers, reliance on third-party manufacturers entails additional risks, including: • reliance on the third party for regulatory compliance, quality assurance, environmental and safety and pharmacovigilance reporting; • the possible breach of the manufacturing agreement by the third party; and • the possible termination or nonrenewal of the agreement by the third party at a time that is costly or inconvenient for us.
Even if we are able to establish such agreements, reliance on third-party manufacturers entails additional risks, including: reliance on the third party for regulatory compliance, quality assurance, environmental and safety and pharmacovigilance reporting; the possible breach of the manufacturing agreement by the third party; and the possible termination or nonrenewal of the agreement by the third party at a time that is costly or inconvenient for us.
In addition, even where the foreign study data are not intended to serve as the sole basis for approval, the FDA will not accept the data as support for an application for marketing approval unless the study is well-designed and well-conducted in accordance with GCP requirements and the FDA is able to validate the data from the study through an onsite inspection if deemed necessary.
Where the foreign study data are not intended to serve as the sole basis for approval, the FDA will not accept the data as support for an application for marketing approval unless the study is well-designed and well-conducted in accordance with GCP requirements and the FDA is able to validate the data from the study through an onsite inspection if deemed necessary.
As a result, the coverage determination process is often a time-consuming and costly process that will require us to provide scientific and clinical support for the use of our products to each payor separately, with no assurance that coverage and adequate reimbursement will be applied consistently or obtained in the first instance.
As a result, the coverage determination process is often a time-consuming and costly process that requires us to provide scientific and clinical support for the use of our products to each payor separately, with no assurance that coverage and adequate reimbursement will be applied consistently or obtained in the first instance.
We have invested a significant portion of our efforts and financial resources in the identification of our product candidates and the development of our most advanced clinical programs, including PYRUKYND® and tebapivat. Our ability to generate meaningful product revenue will depend heavily on the successful clinical development and eventual commercialization of our current and any future product candidates, including PYRUKYND®.
We have invested a significant portion of our efforts and financial resources in the identification of our product candidates and the development of our most advanced clinical programs, including mitapivat and tebapivat. Our ability to generate meaningful product revenue will depend heavily on the successful clinical development and eventual commercialization of our current and any future product candidates, including mitapivat.
Although these decisions and this hepatic adverse event finding do not affect our ongoing clinical trials for PYRUKYND® or tebapivat, we cannot provide any assurances that there will not be other treatment-related severe adverse events in our other clinical trials, or that our other trials will not be placed on clinical hold in the future.
Although these decisions and this hepatic adverse event finding do not affect our ongoing clinical trials for mitapivat or tebapivat, we cannot provide any assurances that there will not be other treatment-related severe adverse events in our other clinical trials, or that our other trials will not be placed on clinical hold in the future.
We expect that additional state and federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for 59 Table of Content s healthcare products and services, which could result in reduced demand for our product or product candidates or additional pricing pressures.
We expect that additional state and federal healthcare reform 60 Table of Content s measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in reduced demand for our product or product candidates or additional pricing pressures.
While we maintain a broad safety stock of drug product, we do not currently have arrangements in place for redundant supply for drug product. If any one of our current contract manufacturers cannot perform as agreed, we may be required to replace that manufacturer.
While we maintain a broad safety stock of drug substance and drug product, we do not currently have arrangements in place for redundant supply of drug substance and drug product. If any one of our current contract manufacturers cannot perform as agreed, we may be required to replace that manufacturer.
Our financial condition and operating results also may fluctuate from quarter to quarter and year to year due to a variety of factors, many of which are beyond our control. Accordingly, you should not rely upon the results of any quarterly or annual periods as indications of future operating performance.
Our financial condition and operating results also may fluctuate from quarter to quarter and year to year due to a variety of factors, many of which are beyond our control. Accordingly, our stockholders should not rely upon the results of any quarterly or annual periods as indications of future operating performance.
We face substantial competition, which may result in others discovering, developing or commercializing products before or more successfully than we do. We face competition with respect to PYRUKYND® and tebapivat and our other product candidates, and we will face competition with respect to any product candidates that we may seek to develop or commercialize in the future.
We face substantial competition, which may result in others discovering, developing or commercializing products before or more successfully than we do. We face competition with respect to PYRUKYND®, AQVESME™, mitapivat, tebapivat and our other product candidates, and we will face competition with respect to any product candidates that we may seek to develop or commercialize in the future.
Even if our product candidates receive PRIME designation, we may not experience a faster development process, review or approval compared to conventional EMA procedures and it does not assure or increase the likelihood of the EMA’s grant of a marketing authorization.
Even if our product candidates receive PRIME designation, we may not experience a faster development process, review or approval compared to conventional EMA procedures and it does not ensure or increase the likelihood of the EMA’s grant of a marketing authorization.
Accordingly, it is possible that the FDA or EMA may refuse to accept for substantive review any NDA, supplemental NDA or MAA that we submit for our product candidates, or may conclude after review of our data that our marketing application is insufficient to obtain marketing approval of our product candidates.
Accordingly, it is possible that the FDA or EMA may refuse to accept for substantive review any NDA, sNDA or MAA that we submit for our product candidates, or may conclude after review of our data that our marketing application is insufficient to obtain marketing approval of our product candidates.
Our executive officers, directors and principal stockholders maintain the ability to significantly influence all matters submitted to stockholders for approval. As of December 31, 2024, our executive officers, directors and principal stockholders, in the aggregate, beneficially owned shares representing a significant percentage of our capital stock.
Our executive officers, directors and principal stockholders maintain the ability to significantly influence all matters submitted to stockholders for approval. As of December 31, 2025, our executive officers, directors and principal stockholders, in the aggregate, beneficially owned shares representing a significant percentage of our capital stock.
Although we enter into non-disclosure and confidentiality agreements with parties who may have access to patentable aspects of our research and development output, such as our employees, corporate collaborators, outside scientific collaborators, CROs, 51 Table of Content s contract manufacturers, consultants, advisors and other third parties, any of these parties may breach the agreements and disclose such output before a patent application is filed, thereby jeopardizing our ability to seek patent protection.
Although we enter into non-disclosure and confidentiality agreements with parties who may have access to patentable aspects of our research and development output, such as our employees, corporate collaborators, outside scientific collaborators, CROs, contract manufacturers, consultants, advisors and other third parties, any of these parties may breach the agreements and disclose such output before a patent application is filed, thereby jeopardizing our ability to seek patent protection.
We have adopted a Code of Business Conduct and 61 Table of Content s Ethics, but it is not always possible to identify and deter employee misconduct, and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws or regulations.
We have adopted a Code of Business Conduct and Ethics, but it is not always possible to identify and deter employee misconduct, and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws or regulations.
If we do not achieve our projected development or regulatory approval estimates in the timeframes we announce and expect, the commercialization of our products may be delayed and, as a result, our stock price may decline. From time to time, we provide estimates related to the development of PYRUKYND® and our product candidates.
If we do not achieve our projected development or regulatory approval estimates in the timeframes we announce and expect, the commercialization of our products may be delayed and, as a result, our stock price may decline. From time to time, we provide estimates related to the development of mitapivat and our other product candidates.
If coverage and reimbursement is not available, or reimbursement is available only to limited levels, we, or any collaborators, may not be able to successfully commercialize PYRUKYND® or our product candidates.
If coverage and reimbursement are not available, or reimbursement is available only to limited levels, we, or any collaborators, may not be able to successfully commercialize PYRUKYND®, AQVESME™ or our product candidates.
The outcome of preclinical studies and early clinical trials may not be predictive of the success of later clinical trials, and positive results of completed clinical trials do not necessarily predict success in future clinical trials.
Results of preclinical studies and early clinical trials may not be predictive of results of later-stage clinical trials. The outcome of our preclinical studies and early clinical trials may not be predictive of the success of our later clinical trials, and positive results of our completed clinical trials do not necessarily predict success in our future clinical trials.
We built our commercial infrastructure to support the commercialization of PYRUKYND® in adult PK deficiency in the United States, and have expanded this infrastructure to support the potential commercial launch of PYRUKYND® in thalassemia in the United States.
We built our commercial infrastructure to support the commercialization of PYRUKYND® in adult PK deficiency in the United States, and have expanded this infrastructure to support the commercial launch of AQVESME™ in thalassemia in the United States.
Nevertheless, our effective tax rate may be different from previous periods or our current expectations due to numerous factors, including as a result of changes in the mix of our profitability from state to state, the results of examinations and audits of our tax filings, our inability to secure or sustain acceptable agreements with tax authorities, changes in accounting for income taxes and changes in tax laws.
Nevertheless, our effective tax rate may be different from previous periods or our current expectations due to numerous factors, including as a result of changes in the mix of our profitability from state to state, the results of examinations and audits of our tax filings, our inability to secure or sustain 65 Table of Content s acceptable agreements with tax authorities, changes in accounting for income taxes and changes in tax laws.
We may become involved in lawsuits to protect or enforce our patents and other intellectual property rights, which could be expensive, time consuming and unsuccessful. Competitors may infringe our patents and other intellectual property rights. To counter infringement or unauthorized use, we may be required to file infringement claims, which can be expensive and time consuming.
We may become involved in lawsuits to protect or enforce our patents and other intellectual property rights, which could be expensive, time consuming and unsuccessful. Competitors may infringe our patents and other intellectual property rights. To counter infringement or unauthorized use, we may be required to file infringement claims, which can be expensive, time consuming and have uncertain outcomes.
In addition, in an infringement proceeding, a court may decide that a patent of ours is invalid or unenforceable, or may refuse to stop the other party from using the technology at issue on the grounds that our patents do not cover the technology in question.
In addition, a court may decide that a patent of ours is invalid or unenforceable, or may refuse to stop the other party from using the technology at issue on the grounds that our patents do not cover the technology in question.
We also could incur significant costs associated with civil or criminal fines and penalties. Although we maintain workers’ compensation insurance to cover us for costs and expenses we may incur due to injuries to our employees resulting from the use of hazardous materials, this insurance may not provide adequate coverage against potential liabilities.
We also could incur significant costs associated with civil or criminal fines and penalties. 62 Table of Content s Although we maintain workers’ compensation insurance to cover us for costs and expenses we may incur due to injuries to our employees resulting from the use of hazardous materials, this insurance may not provide adequate coverage against potential liabilities.
Provisions in our corporate charter and our bylaws may discourage, delay or prevent a merger, acquisition or other change in control of us that stockholders may consider favorable, including transactions in which you might otherwise receive a premium for your shares.
Provisions in our corporate charter and our bylaws may discourage, delay or prevent a merger, acquisition or other change in control of us that stockholders may consider favorable, including transactions in which stockholders might otherwise receive a premium for their shares.
The FTC has been particularly focused on the unpermitted processing of health and genetic data through its recent enforcement actions and is expanding the types of privacy violations that it interprets to be “unfair” under Section 5 of the FTC Act of 1914, as well as the types of activities it views to trigger the Health Breach Notification Rule (which the FTC also has the authority to enforce).
The FTC has been particularly focused on the unpermitted processing of health and genetic data through its recent enforcement actions and is expanding the types of privacy violations that it interprets to be “unfair” under Section 5 of the FTC Act of 1914, as well as the types of activities it views to trigger the Health Breach Notification Rule.
In particular, regulations promulgated pursuant to the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, establish privacy and security standards that limit the use and disclosure of individually identifiable health information, 45 Table of Content s or protected health information, and require the implementation of administrative, physical and technological safeguards to protect the privacy of protected health information and ensure the confidentiality, integrity and availability of electronic protected health information.
In particular, regulations promulgated pursuant to the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, establish privacy and security standards that limit the use and disclosure of individually identifiable health information, or protected health information, and require the implementation of administrative, physical and technological safeguards to protect the privacy of protected health information and ensure the confidentiality, integrity and availability of electronic protected health information.
Under the Creating and Restoring Equal Access to Equivalent Samples Act of 2019, or the CREATES Act, authorizes sponsors of ANDAs and 505(b)(2) applications to file lawsuits against companies holding NDAs that decline to provide sufficient quantities of an approved reference drug on commercially reasonable, market-based terms.
The Creating and Restoring Equal Access to Equivalent Samples Act of 2019, or the CREATES Act, authorizes sponsors of ANDAs and 505(b)(2) applications to file lawsuits against companies holding NDAs that decline to provide sufficient quantities of an approved reference drug on commercially reasonable, market-based terms, subject to certain exemptions.
Moreover, agreements with physicians often must be the subject of prior notification and approval by the physician’s employer, his or her competent professional organization and/or the regulatory authorities of the individual EU Member States. These requirements are provided in the national laws, industry codes or professional codes of conduct, applicable in the EU Member States.
Moreover, agreements with physicians often must be the subject of prior notification and approval by the physician’s employer, his or her competent professional organization and/or the regulatory authorities of the individual EU Member States. These requirements are provided in the 58 Table of Content s national laws, industry codes or professional codes of conduct, applicable in the EU Member States.
If, following approval of a product candidate, including PYRUKYND®, we, or others, discover that the product is less effective than previously believed or causes undesirable side effects that were not previously identified, any of the following adverse events could occur: • regulatory authorities may withdraw their approval of the product or seize the product; • we, or any collaborators, may be required to recall the product, change the way the product is administered or conduct additional clinical trials; • additional restrictions may be imposed on the marketing of, or the manufacturing processes for, the particular product; • we may be subject to fines, injunctions or the imposition of civil or criminal penalties; • regulatory authorities may require the addition of warnings on the product label; • we, or any collaborators, may be required to create a Medication Guide outlining the risks of the previously unidentified side effects for distribution to patients; • we, or any collaborators, could be sued and held liable for harm caused to patients; • the product may become less competitive; and • our reputation may suffer.
If, following approval of a product candidate, including PYRUKYND® and AQVESME™, we, or others, discover that the product is less effective than previously believed or causes undesirable side effects that were not previously identified, any of the following adverse events could occur: • regulatory authorities may withdraw their approval of the product or seize the product; 43 Table of Content s • we, or any collaborators, may be required to recall the product, change the way the product is administered or conduct additional clinical trials; • additional restrictions may be imposed on the marketing of, or the manufacturing processes for, the particular product; • we may be subject to fines, injunctions or the imposition of civil or criminal penalties; • regulatory authorities may require the addition of warnings on the product label, require a REMS or or modify an existing REMS; • we, or any collaborators, may be required to create a Medication Guide outlining the risks of the previously unidentified side effects for distribution to patients; • we, or any collaborators, could be sued and held liable for harm caused to patients; • the product may become less competitive; and • our reputation may suffer.
Even if marketing approval of a product candidate is granted, the approval may be subject to limitations on the indicated uses for which the medicine may be marketed or to the conditions of approval, or contain requirements for costly post-marketing testing and surveillance to monitor the safety or efficacy of the medicine, including the requirement to implement a REMS.
Even if marketing approval of a product candidate is granted, the approval may be subject to limitations on the indicated uses for which the medicine may be marketed or to the conditions of approval, or contain requirements for costly post-marketing testing and surveillance to monitor the safety or efficacy of the medicine, including the requirement to implement a REMS, such as the required REMS for AQVESME™.
If we are unable to raise additional funds through equity or debt financings when needed or on attractive terms, we may be required to delay, limit, reduce or terminate our product development or future commercialization efforts, or grant rights to develop and market product candidates that we would otherwise prefer to develop and market ourselves.
If we are unable to raise additional funds when needed or on attractive terms, we may be required to delay, limit, reduce or terminate our product development or future commercialization efforts, or grant rights to develop and market product candidates that we would otherwise prefer to develop and market ourselves.
Moreover, despite our efforts, the possibility of these events occurring cannot be eliminated entirely. We cannot guarantee that the measures we have taken to date, and actions we may take in the future, will be sufficient to prevent any cyber-attacks or security breaches.
Moreover, despite our efforts, the possibility of these events occurring cannot be 46 Table of Content s eliminated entirely. We cannot guarantee that the measures we have taken to date, and actions we may take in the future, will be sufficient to prevent any cyber-attacks or security breaches.
If we experience significant delays or an inability to successfully develop and commercialize PYRUKYND®, our business would be materially harmed. 36 Table of Content s We depend heavily on the success of our clinical-stage product candidates, including the potential approval of PYRUKYND® for the treatment of thalassemia or SCD in the United States and in other jurisdictions.
If we experience significant delays or an inability to successfully develop and commercialize PYRUKYND® and AQVESME™, our business would be materially harmed. 38 Table of Content s We depend heavily on the success of our clinical-stage product candidates, including the potential approval of mitapivat for the treatment of thalassemia in the EU, or SCD in the United States and in other jurisdictions.
We also estimate the timing of the anticipated accomplishment of various scientific, preclinical, clinical, regulatory and other product development goals. These estimates may include the commencement or completion of clinical trials, the timing of completing 42 Table of Content s enrollment, the timing for reporting clinical trial results and the timing of submission of regulatory filings in various jurisdictions.
We also estimate the timing of the anticipated accomplishment of various scientific, preclinical, clinical, regulatory and other product development goals. These estimates may include the commencement or completion of clinical trials, the timing of completing enrollment, the timing for reporting clinical trial results and the timing of submission of regulatory filings in various jurisdictions.
Collaborations are complex and time-consuming to negotiate and document. Whether we reach a definitive agreement for a collaboration will depend, among other things, upon our assessment of the collaborator’s resources and expertise, the terms and conditions of the proposed collaboration and the proposed collaborator’s evaluation of a number of factors.
Collaborations are complex and time-consuming to negotiate and document. Whether we reach a definitive agreement for a collaboration will depend, among other things, upon our assessment of the collaborator’s resources and expertise, the terms and conditions of the proposed collaboration and the proposed collaborator’s evaluation of a number of 51 Table of Content s factors.
Further, the net reimbursement for drug products may be subject to additional reductions if there are changes to laws 58 Table of Content s that presently restrict imports of drugs from countries where they may be sold at lower prices than in the United States.
Further, the net reimbursement for drug products may be subject to additional reductions if there are changes to laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the United States.
For example, we are responsible to pay up to $130.0 million in potential development and regulatory milestones, in addition to sales milestones as well as tiered royalties on annual net sales, if any, of any licensed products, under the license agreement with Alnylam.
For example, we are responsible for paying up to $130.0 million in potential development and regulatory milestones, in addition to sales milestones as well as tiered royalties on annual net sales, if any, of any licensed products, under our license agreement with Alnylam.
A 505(b)(2) NDA product, or follow-on-product, may be for a new or improved version of the original reference listed drug. The FDA may not approve an ANDA or 505(b)(2) NDA until any applicable period of regulatory exclusivity for the reference-listed drug has expired.
A 505(b)(2) NDA product, or follow-on-product, may be for a new or improved version of the original reference listed drug. The FDA may not approve an ANDA or 505(b)(2) NDA until any applicable period of regulatory exclusivity for the reference-listed drug has expired, subject to certain exceptions.
The FDA has broad discretion on whether to grant fast track designation and/or priority review designation to a product candidate, so even if we believe a particular product candidate is eligible for such designation or status, the FDA may decide not to grant it.
The FDA has broad discretion on whether to grant fast track designation, priority review designation and/or other expedited review designations or vouchers for a product candidate, so even if we believe a particular product candidate is eligible for such designation or status, the FDA may decide not to grant it.
In addition, because our Board of Directors is responsible for appointing the members of our management team, these provisions may frustrate or prevent any attempts by our stockholders to replace or remove our current management by making it more difficult for stockholders to replace members of our Board of Directors.
In addition, because our Board of Directors is responsible for appointing the members of our management team, these provisions may frustrate or prevent any 63 Table of Content s attempts by our stockholders to replace or remove our current management by making it more difficult for stockholders to replace members of our Board of Directors.
Additionally, the statutory provisions authorize a federal court to award the product developer an amount “sufficient to deter” the NDA holder from refusing to provide sufficient product quantities on commercially reasonable, market-based terms if the 60 Table of Content s court finds, by a preponderance of the evidence, that the NDA holder did not have a legitimate business justification to delay providing the product or failed to comply with the court’s order.
Additionally, the statutory provisions authorize a federal court to award the sponsor an amount “sufficient to deter” the NDA holder from refusing to provide sufficient product quantities on commercially reasonable, market-based terms if the court finds, by a preponderance of the evidence, that the NDA holder did not have a legitimate business justification to delay providing the product or failed to comply with the court’s order.
With the passage of the CREATES Act, we are exposed to possible litigation and damages by competitors who may claim that we are not providing sufficient quantities of our approved products on commercially reasonable, market-based terms for testing in support of their ANDAs and 505(b)(2) applications.
The CREATES Act exposes us to possible litigation and damages by competitors who may claim that we are not providing sufficient quantities of our approved products on commercially reasonable, market-based terms for testing in support of their ANDAs and 505(b)(2) applications.
We anticipate that we will incur significant expenses if and as we: • prepare for and commercially launch PYRUKYND® for approved indications in approved jurisdictions; • continue to establish and maintain a sales, marketing and distribution infrastructure to commercialize PYRUKYND® and other product candidates for which we may obtain marketing approval; 48 Table of Content s • initiate and continue clinical trials for our products and product candidates, including PYRUKYND® in other indications; • continue our research and preclinical development of our product candidates and seek to identify additional product candidates; • seek marketing approvals for our product candidates that successfully complete clinical trials; • require the manufacture of larger quantities of product candidates for clinical development and commercialization; • maintain, expand and protect our intellectual property portfolio; • add additional personnel to support our product research and development and planned future commercialization efforts and our operations; and • acquire or in-license other product candidates, medicines and technologies.
We anticipate that we will incur significant expenses if and as we: • commercialize PYRUKYND® and AQVESME™ for approved indications in approved jurisdictions; • continue to establish and maintain a sales, marketing and distribution infrastructure to commercialize PYRUKYND®, AQVESME™ and other product candidates for which we may obtain marketing approval; • initiate and continue clinical trials for our products and product candidates; • continue our research and preclinical development of our product candidates and seek to identify additional product candidates; • seek marketing approvals for our product candidates that successfully complete clinical trials; • require the manufacture of larger quantities of product candidates for clinical development and commercialization; • maintain, expand and protect our intellectual property portfolio; • add additional personnel to support our product research and development and planned future commercialization efforts and our operations; and • acquire or in-license other product candidates, medicines and technologies.
These licensed patent rights may be valuable to our business, and we may not have the right to control the preparation, filing and prosecution of patent applications, or to maintain the patents, covering technology or medicines underlying such licenses.
These licensed patent rights may be valuable to our business, 52 Table of Content s and we may not have the right to control the preparation, filing and prosecution of patent applications, or to maintain the patents, covering technology or medicines underlying such licenses.
We expect that we will be subject to additional risks in commercializing any of our product candidates that receive marketing approval outside the United States, including tariffs, trade barriers and regulatory requirements; economic weakness, including inflation, or political instability in particular foreign economies and markets; compliance with tax, employment, immigration and labor laws for employees living or traveling abroad; foreign currency fluctuations, which could result in increased operating expenses and reduced revenue, and other obligations incident to doing business in another country; and workforce uncertainty in countries where labor unrest is more common than in the United States.
We expect that we will be subject to additional risks in commercializing any of our product candidates that receive marketing approval outside the United States, including tariffs and trade barriers; economic weakness, including inflation, or political instability in particular foreign economies and markets; compliance with tax, employment, immigration and labor laws for employees living or traveling abroad; foreign currency fluctuations, which could result in increased operating expenses and reduced revenue; and workforce uncertainty in countries where labor unrest is more common than in the United States.
Generally, if a product with an orphan drug designation subsequently receives the first marketing approval for the indication for which it has such designation, the product is entitled to a period of marketing exclusivity, which precludes the EMA or the FDA from approving another marketing application for the same product for that time period.
Generally, if a product with an orphan drug designation subsequently receives the first marketing approval for the indication for which it has such designation, the product is entitled to a period of marketing exclusivity, which precludes the EMA or the FDA from approving another marketing application for the same product for that time period, except in certain limited circumstances.
The market price for our common stock may be influenced by many factors, including: • our success in launching and commercializing PYRUKYND®; 62 Table of Content s • announcements by us or our competitors of significant acquisitions, in-licensing arrangements, strategic partnerships, joint ventures, collaborations or capital commitments; • the timing and results of clinical trials of product candidates, or our competitors’ product candidates; • regulatory actions with respect to our product or product candidates or our competitors’ products and product candidates; • commencement or termination of collaborations for our development programs; • failure or discontinuation of any of our development programs; • regulatory or legal developments in the United States and other countries; • developments or disputes concerning patent applications, issued patents or other proprietary rights; • the recruitment or departure of key personnel; • the level of expenses related to any of our products, product candidates or development programs; • the results of our efforts to develop additional product candidates and products; • actual or anticipated changes in estimates as to financial results or development timelines; • announcement or expectation of additional financing efforts; • sales of our common stock by us, our insiders or other stockholders; • variations in our financial results or results of companies that are perceived to be similar to us; • changes in estimates, evaluations or recommendations by securities analysts, that cover our stock or the failure by one or more securities analysts to continue to cover our stock; • changes in the structure of healthcare payment systems; • the societal and economic impact of public health epidemics or pandemics, and any recession, depression or sustained market event resulting from such epidemics or pandemics; • market conditions in the pharmaceutical and biotechnology sectors; • general economic, industry and market conditions; and • the other factors described in this “Risk Factors” section.
The market price for our common stock may be influenced by many factors, including: • our success in launching and commercializing PYRUKYND® and AQVESME™; • announcements by us or our competitors of significant acquisitions, in-licensing arrangements, strategic partnerships, joint ventures, collaborations or capital commitments; • the timing and results of clinical trials of product candidates, or our competitors’ product candidates; • regulatory actions with respect to our or our competitors’ products or product candidates; • commencement or termination of collaborations for our development programs; • failure or discontinuation of any of our development programs; • regulatory or legal developments in the United States and other countries; • developments or disputes concerning patent applications, issued patents or other proprietary rights; • the recruitment or departure of key personnel; • the level of expenses related to any of our products, product candidates or development programs; • the results of our efforts to develop additional product candidates and products; • actual or anticipated changes in estimates as to financial results or development timelines; • announcement or expectation of additional financing efforts; • sales of our common stock by us, our insiders or other stockholders; 64 Table of Content s • variations in our financial results or results of companies that are perceived to be similar to us; • changes in estimates, evaluations or recommendations by securities analysts, that cover our stock or the failure by one or more securities analysts to continue to cover our stock; • changes in the structure of healthcare payment systems; • market conditions in the pharmaceutical and biotechnology sectors; • general economic, political, industry and market conditions; and • the other factors described in this “Risk Factors” section.
Our future capital requirements will depend on many factors, including: 47 Table of Content s • the amount and timing of future revenue received from commercial sales of PYRUKYND® and any of our other product candidates for which we may receive marketing approval; • the amount of payments, if any, we may receive on account of the Retained Earn-Out Rights; • the costs and timing of our ongoing and future commercialization activities, including product manufacturing, sales, marketing and distribution, for PYRUKYND® in the approved jurisdictions and for any product candidate for which we may receive approval; • the scope, progress, results and costs of preclinical development, laboratory testing and clinical trials for our product candidates; • the costs associated with in-licensing or acquiring assets for pipeline growth, including the amount and timing of future milestone and royalty payments payable to Alnylam pursuant to the license agreement; • the costs, timing and outcome of regulatory review of our product candidates, including with respect to regulatory submissions for PYRUKYND® for the treatment of thalassemia; • the costs of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property rights and defending intellectual property-related claims; • our ability to establish and maintain collaborations on favorable terms, if at all; • our ability to successfully execute on our strategic plans; • operational delays due to public health epidemics; and • operational delays, disruptions and/or increased costs associated with global economic and political developments, rising global energy prices or energy shortages or rationing.
Our future capital requirements will depend on many factors, including: • the amount and timing of future revenue received from commercial sales of PYRUKYND®, AQVESME™ or any of our other product candidates for which we may receive marketing approval; • the amount of payments, if any, we may receive on account of the Retained Earn-Out Rights; • the costs and timing of our ongoing and future commercialization activities, including product manufacturing, sales, marketing and distribution, for PYRUKYND® and AQVESME™ in the approved jurisdictions and indications and for any product candidate for which we may receive approval; • the scope, progress, results and costs of preclinical development, laboratory testing and clinical trials for our product candidates; • the costs associated with in-licensing or acquiring assets for pipeline growth, including the amount and timing of future milestone and royalty payments payable to Alnylam pursuant to the license agreement; • the costs, timing and outcome of regulatory review of our product candidates; • the costs of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property rights and defending intellectual property-related claims; 48 Table of Content s • our ability to establish and maintain collaborations on favorable terms, if at all; • our ability to successfully execute on our strategic plans; and • operational delays, disruptions and/or increased costs associated with public health pandemics, global economic and political developments.
Regulatory authorities in some jurisdictions, including the United States and the E.U., may designate drugs and biologics for relatively small patient populations as orphan drugs.
Regulatory authorities in some jurisdictions, including the United States and the EU, may designate drugs and biologics for relatively small patient populations as orphan drugs.
In addition, we do not have experience commercializing products outside of the United States and such efforts may depend on our ability to find a suitable collaborator.
In addition, we do not have direct experience commercializing products outside of the United States and such efforts may depend on our ability to find a suitable distribution partner.
Bribery Act 2010. Infringement of these laws could result in substantial fines and imprisonment. 57 Table of Content s Payments made to physicians in certain EU Member States must be publicly disclosed.
Bribery Act 2010. Infringement of these laws could result in substantial fines and imprisonment. Payments made to physicians in certain EU Member States must be publicly disclosed.
Conducting clinical trials outside the U.S. also exposes us to additional risks, including risks associated with: • additional foreign regulatory requirements; • foreign exchange fluctuations; • compliance with foreign manufacturing, customs, shipment and storage requirements; • cultural differences in medical practice and clinical research; • diminished protection of intellectual property in some countries; and 40 Table of Content s • interruptions or delays in our trials resulting from geopolitical events, such as war or terrorism.
Conducting clinical trials outside the United States also exposes us to additional risks, including risks associated with foreign exchange fluctuations, compliance with foreign manufacturing, customs, shipment and storage requirements, cultural differences in medical practice and clinical research, diminished protection of intellectual property in some countries, and interruptions or delays in our trials resulting from geopolitical events, such as war or terrorism.
If either we or any third parties on which we rely are adversely impacted by geopolitical events, rising global energy costs or energy shortages or rationing, delays may occur in our product development activities, which delays could have a material adverse impact on our business, financial condition and prospects.
If either we or any third parties on which we rely are adversely impacted by geopolitical events, delays may occur in our product development activities, which delays could have a material adverse impact on our business, financial condition and prospects.
In many countries, the pricing review period begins after marketing or product licensing approval is granted. In some foreign markets, prescription pharmaceutical pricing remains subject to continuing governmental control even after initial approval is granted. In these countries, pricing negotiations with governmental authorities can take considerable time after the receipt of marketing approval for a product.
In some foreign markets, prescription pharmaceutical pricing remains subject to continuing governmental control even after initial approval is granted. In these countries, pricing negotiations with governmental authorities can take considerable time after the receipt of marketing approval for a product.

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Item 1C. Cybersecurity

Cybersecurity — threats and controls disclosure

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Biggest changeThe Audit Committee receives periodic updates from management regarding cybersecurity matters, and is notified between such updates regarding significant new cybersecurity threats or incidents. 64 Table of Content s Our Vice President, Information Technology and Facilities, or the VP of IT, leads the operational oversight of company-wide cybersecurity strategy, policy, standards and processes and works across relevant departments to assess and help prepare us and our employees to address cybersecurity risks.
Biggest changeOur Senior Director, Technology Services, referred to herein as the Head of Cybersecurity, leads the operational oversight of company-wide cybersecurity strategy, policy, standards and processes and works across relevant departments to assess and help prepare us and our employees to address cybersecurity risks.
We periodically assess our processes against cybersecurity frameworks, such as the National Institute of Standards and Technology, or NIST, Cybersecurity Framework, Center for Internet Security, or CIS, Controls, and International Organization for Standardization, or ISO, 27001.
We periodically assess our processes against cybersecurity frameworks, such as the National Institute of Standards and Technology, or NIST, Cybersecurity Framework, Center for Internet Security, or CIS, Controls, International Organization for Standardization, or ISO, 27001 and the MITRE ATT&CK framework.
We also use technology-based tools that are designed to mitigate cybersecurity risks and to bolster our employee-based cybersecurity programs.
We also use technology-based tools that are designed to mitigate cybersecurity risks and to bolster our employee-based cybersecurity programs. 66 Table of Content s
Our VP of IT has worked in the information technology field for over 20 years at both biotechnology companies and management consulting firms, and holds a Bachelor of Science in Management and a Masters of Business Administration.
Our Head of Cybersecurity has worked in the information technology field for over 30 years at both biotechnology companies and internet service providers, and holds a Bachelor of Science in Mathematics.
Added
The Audit Committee receives periodic updates from management regarding cybersecurity matters, and is notified between such updates regarding significant new cybersecurity threats or incidents.

Item 2. Properties

Properties — owned and leased real estate

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Biggest changeIn May 2023, we entered into a long-term sublease agreement for 7,407 square feet of office space on the first floor of 64 Sidney Street, Cambridge, Massachusetts, with the term of the lease running through April 2025. We believe our existing facilities are adequate for our current needs.
Biggest changeIn July 2025, we entered into a long-term sublease agreement with a new tenant for 7,407 square feet of office space on the first floor of 64 Sidney Street, Cambridge, Massachusetts, which began in November 2025 with the term of the sublease running through February 2028. We believe our existing facilities are adequate for our current needs.
Removed
In August 2021, we entered into a long-term sublease agreement for the 13,000 square feet at 38 Sidney Street, Cambridge, Massachusetts, which expired on December 31, 2024. In April 2022, we entered into a long-term sublease agreement for 27,000 square feet of office space at 64 Sidney Street, Cambridge, Massachusetts, with the term of the lease running through April 2025.

Item 3. Legal Proceedings

Legal Proceedings — active lawsuits and investigations

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Biggest changeWe are not a party to any material proceedings in which any director, member of senior management or affiliate of ours is either a party adverse to us or our subsidiaries or has a material interest adverse to us or our subsidiaries. Item 4. Mine Safety Disclosures Not applicable. 65 Table of Content s PART II
Biggest changeWe are not a party to any material proceedings in which any director, member of senior management or affiliate of ours is either a party adverse to us or our subsidiaries or has a material interest adverse to us or our subsidiaries. Item 4. Mine Safety Disclosures Not applicable. 67 Table of Content s PART II
Item 3. Legal Proceedings As of December 31, 2024, we were not a party to any material legal or arbitration proceedings. No governmental proceedings are pending or, to our knowledge, contemplated against us.
Item 3. Legal Proceedings As of December 31, 2025, we were not a party to any material legal or arbitration proceedings. No governmental proceedings are pending or, to our knowledge, contemplated against us.

Item 4. Mine Safety Disclosures

Mine Safety Disclosures — required of mining issuers

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Biggest changeItem 4. Mine Safety Disclosures 65 PART II Item 5. Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities 66 Item 6. Reserved 67 Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations 68 Item 7A. Quantitative and Qualitative Disclosures about Market Risk 82 Item 8.
Biggest changeItem 4. Mine Safety Disclosures 67 PART II Item 5. Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities 68 Item 6. Reserved 69 Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations 70 Item 7A. Quantitative and Qualitative Disclosures about Market Risk 84 Item 8.

Item 5. Market for Registrant's Common Equity

Market for Common Equity — stock, dividends, buybacks

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Biggest changeHolders As of February 7, 2025, there were nine holders of record of our common stock. This number does not include beneficial owners whose shares are held by nominees in street name. Dividends We have not declared or paid any cash dividends on our capital stock since our inception.
Biggest changeHolders As of February 6, 2026, there were ten holders of record of our common stock. This number does not include beneficial owners whose shares are held by nominees in street name. Dividends We have not declared or paid any cash dividends on our capital stock since our inception.
The stock price performance included in this graph is not necessarily indicative of future stock price performance. 66 Table of Content s Recent Sales of Unregistered Securities None. Purchases of Equity Securities by the Issuer or Affiliated Purchasers None.
The stock price performance included in this graph is not necessarily indicative of future stock price performance. 68 Table of Content s Recent Sales of Unregistered Securities None. Purchases of Equity Securities by the Issuer or Affiliated Purchasers None.
The comparison assumes $100 was invested after the market closed on December 31, 2019 in our common stock and in each of the foregoing indices, and it assumes reinvestment of dividends, if any.
The comparison assumes $100 was invested after the market closed on December 31, 2020 in our common stock and in each of the foregoing indices, and it assumes reinvestment of dividends, if any.
The following graph compares the performance of our common stock to the NASDAQ Composite Index and the NASDAQ Biotechnology Index from December 31, 2019 through December 31, 2024.
The following graph compares the performance of our common stock to the NASDAQ Composite Index and the NASDAQ Biotechnology Index from December 31, 2020 through December 31, 2025.

Item 7. Management's Discussion & Analysis

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

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Biggest changeResearch and Development Expenses Our research and development expenses, by major program, are outlined in the table below: (In thousands) 2024 2023 2022 PK activator (PYRUKYND®) $ 112,720 $ 101,322 $ 83,271 Novel PK activator (tebapivat) 14,544 18,267 15,747 In-process research and development — 17,500 — Other research and platform programs 20,730 11,492 26,837 Total direct research and development expenses 147,994 148,581 125,855 Compensation and related expenses 114,618 108,484 109,248 Facilities and IT related expenses & other 38,674 38,461 43,290 Other expenses - transition services — — 1,517 Total indirect research and development expenses 153,292 146,945 154,055 Total research and development expense $ 301,286 $ 295,526 $ 279,910 Total Research and Development Expenses – 2024 vs. 2023 – The increase in research and development expenses of $5.8 million in 2024 compared to 2023 was due to a $6.3 million increase in our indirect expenses, partially offset by a $0.6 million decrease in our direct expenses.
Biggest changeTotal Operating Expenses – 2024 vs 2023 – The increase in total operating expenses of $43.9 million in 2024 compared to 2023 was primarily due to an increase of $36.9 million in selling, general and administrative expenses, driven by an increase in commercial-related activities as we prepared for the potential approval of PYRUKYND® in thalassemia, and an increase of $5.8 million in research and development expenses, which is described below under Research and Development Expenses . 79 Table of Content s Research and Development Expenses Our research and development expenses, by major program, are outlined in the table below: (In thousands) 2025 2024 2023 PK activator (PYRUKYND®/AQVESME™) $ 108,087 $ 112,720 $ 101,322 Novel PK activator (tebapivat) 31,639 14,544 18,267 PAH stabilizer (AG-181) 5,992 2,912 740 siRNA targeting TMPRSS6 (AG-236) 12,490 11,985 2,664 In-process research and development 10,000 — 17,500 Other research and platform programs 7,820 5,833 8,088 Total direct research and development expenses 176,028 147,994 148,581 Compensation and related expenses 121,645 114,618 108,484 Facilities and IT related expenses & other 41,862 38,674 38,461 Total indirect research and development expenses 163,507 153,292 146,945 Total research and development expense $ 339,535 $ 301,286 $ 295,526 Total Research and Development Expenses – 2025 vs. 2024 – The increase in research and development expenses of $38.2 million in 2025 compared to 2024 was due to a $28.0 million increase in our direct expenses and a $10.2 million increase in our indirect expenses.
In September 2024, we received the Vorasidenib Milestone Payment from Servier and recognized income of $200.0 million within the milestone payment from gain on sale of oncology business line item in our consolidated statements of operations for the year ended December 31, 2024.
In September 2024, we received the Vorasidenib Milestone Payment from Servier and recognized income of $200.0 million within the milestone payment from gain on sale of oncology business line item in our consolidated statements of operations for the year ended December 31, 2024.
In May 2024, we entered into a purchase and sale agreement to sell the Vorasidenib Royalty Rights to Royalty Pharma Investments 2019 ICAV, or Royalty Pharma, for $905.0 million in cash, or the Upfront Payment. The sale was contingent upon FDA approval of vorasidenib and other customary closing conditions.
In May 2024, we entered into a purchase and sale agreement to sell the Vorasidenib Royalty Rights to Royalty Pharma Investments 2019 ICAV, or Royalty Pharma, for $905.0 million in cash, or the Upfront Payment. The sale was contingent upon FDA approval of vorasidenib and other customary closing conditions.
Upon consummation of the sale in August 2024, Royalty Pharma acquired 100% of the Vorasidenib Royalty Rights payments made by Servier on account of up to $1.0 billion in U.S. net sales for each calendar year.
Upon consummation of the sale in August 2024, Royalty Pharma acquired 100% of the Vorasidenib Royalty Rights payments made by Servier on account of up to $1.0 billion in U.S. net sales for each calendar year.
In addition, any such Vorasidenib Royalty Rights payments made by Servier on account of U.S. net sales in each calendar year in excess of $1.0 billion will be split, with Royalty Pharma having the rights to a 12% earn-out on those excess payments and Agios retaining the rights to a 3% earn-out on those excess payments, or the Retained Earn-Out Rights.
In addition, any such Vorasidenib Royalty Rights payments made by Servier on account of U.S. net sales in each calendar year in excess of $1.0 billion will be split, with Royalty Pharma having the rights to a 12% earn-out on those excess payments and Agios retaining the rights to a 3% earn-out on those excess payments, or the Retained Earn-Out Rights.
As a result of the sale, we recognized income of $889.1 million ($905.0 million net of fees of $15.9 million) within the gain on sale of contingent payments line item in our consolidated statements of operations for the year ended December 31, 2024.
As a result of the sale, we recognized income of $889.1 million ($905.0 million net of fees of $15.9 million) within the gain on sale of contingent payments line item in our consolidated statements of operations for the year ended December 31, 2024.
The cash provided by investing activities for the year ended December 31, 2023 was primarily due to higher proceeds from maturities and sales of marketable securities than purchases of marketable securities, partially offset by the $17.5 million up-front payment associated with the Alnylam license agreement discussed above under Overview.
Cash provided by investing activities for the year ended December 31, 2023 was primarily due to higher proceeds from maturities and sales of marketable securities than purchases of marketable securities, partially offset by the $17.5 million up-front payment associated with the Alnylam license agreement discussed above under Overview.
The cash provided by financing activities for the year ended December 31, 2023 was due to $5.4 million of proceeds received from stock option exercises and purchases made pursuant to our employee stock purchase plan.
Cash provided by financing activities for the year ended December 31, 2023 was due to $5.4 million of proceeds received from stock option exercises and purchases made pursuant to our employee stock purchase plan.
Government rebates include Medicare, TriCare, and Medicaid rebates, which we estimate using the expected value method, based upon a range of possible outcomes that are probability-weighted for the estimated payor mix. These reserves are recorded in the same period the related revenue is recognized, resulting in a reduction of product revenue.
Government rebates include Medicare, TriCare, and Medicaid rebates, which we estimate using the expected value method, based upon a range of possible outcomes that are probability-weighted for the estimated payor mix. These reserves are recorded in the same period the related revenue is recognized, resulting in a reduction of product revenue. Returns .
Net cash provided by investing activities Cash provided by investing activities of $363.4 million during the year ended December 31, 2024 was primarily due to the proceeds from the Upfront Payment from Royalty Pharma and the Vorasidenib Milestone Payment from Servier, partially offset by higher purchases of marketable securities than proceeds from maturities and sales of marketable securities as a result of the proceeds from the Upfront Payment and the Vorasidenib Milestone Payment.
Cash provided by investing activities of $363.4 million during the year ended December 31, 2024 was primarily due to the proceeds from the Upfront Payment from Royalty Pharma and the Vorasidenib Milestone Payment from Servier, partially offset by higher purchases of marketable securities than proceeds from maturities and sales of marketable securities as a result of the proceeds from the Upfront Payment and the Vorasidenib Milestone Payment.
Based on our policy to expense costs associated with the manufacturing of our products prior to regulatory approval, certain of the manufacturing costs associated with product shipments of PYRUKYND® recorded during the years ended December 31, 2024, December 31, 2023 and December 31, 2022 were expensed prior to February 17, 2022, and, therefore, are not included in costs of sales during the years ended December 31, 2024, December 31, 2023 and December 31, 2022.
Based on our policy to expense costs associated with the manufacturing of our products prior to regulatory approval, certain of the manufacturing costs associated with product shipments of PYRUKYND® recorded during the years ended December 31, 2025, December 31, 2024 and December 31, 2023 were expensed prior to February 17, 2022, and, therefore, are not included in costs of sales during the years ended December 31, 2025, December 31, 2024 and December 31, 2023.
For further discussion of our revenue recognition policy, see Note 2, Summary of Significant Accounting Polices and Note 8, Product Revenue , to the consolidated financial statements in this Annual Report on Form 10-K. In the future, we expect to continue to generate revenue from product sales.
For further discussion of our revenue recognition policy, see Note 2, Summary of Significant Accounting Polices and Note 8, Product Revenue , to the consolidated financial statements in this Annual Report on Form 10-K. In the future, we expect to continue to generate revenue from product sales of PYRUKYND®.
We anticipate that our selling, general and administrative expenses will increase in the future to support continued research and development activities, and ongoing and future commercialization activities related to our portfolio, including the ongoing commercialization of PYRUKYND® and any of our other product candidates, which may include the hiring of additional personnel.
We anticipate that our selling, general and administrative expenses will increase in the future to support continued research and development activities, and ongoing and future commercialization activities related to our portfolio, including the ongoing commercialization of PYRUKYND®, AQVESME™ and any of our other product candidates, which may include the hiring of additional personnel.
Net cash provided by financing activities The cash provided by financing activities for the year ended December 31, 2024 was due to $14.4 million of proceeds received from stock option exercises and purchases made pursuant to our employee stock purchase plan.
Cash provided by financing activities for the year ended December 31, 2024 was due to $14.4 million of proceeds received from stock option exercises and purchases made pursuant to our employee stock purchase plan.
The safety profile observed was consistent with data reported in the healthy volunteer study of tebapivat. 19 patients elected to enroll in the extension period for up to 156 weeks.
The safety profile observed was consistent with data reported in the healthy volunteer study of tebapivat. 19 patients elected to enroll in the extension period of the trial for up to 156 weeks.
We currently estimate product return 75 Table of Content s liabilities using the expected value method, based on available industry data, including our visibility into the inventory remaining in the distribution channel. Accrued Research and Development Expenses As part of the process of preparing our consolidated financial statements, we are required to estimate our accrued expenses.
We currently estimate product return liabilities using the expected value method, based on available industry data, including our visibility into the inventory remaining in the distribution channel. 77 Table of Content s Accrued Research and Development Expenses As part of the process of preparing our consolidated financial statements, we are required to estimate our accrued expenses.
Expired inventory is disposed of, and the related costs are recognized as cost of sales in our consolidated statements of operations, when, based on the expiry date, we do not believe we are able to sell the inventory. We have not reserved for excess or obsolete inventory during the years ended December 31, 2024 and December 31, 2023.
Expired inventory is disposed of, and the related costs are recognized as cost of sales in our consolidated statements of operations, when, based on the expiry date, we do not believe we are able to sell the inventory. We have not reserved for excess or obsolete inventory during the years ended December 31, 2025 and December 31, 2024.
The following summarizes our most advanced programs: PYRUKYND® (mitapivat): First-in-Class PK Activator We are developing PYRUKYND® for the treatment of PK deficiency and other hemolytic anemias such as thalassemia and SCD. PYRUKYND® is an orally available small molecule and a potent activator of the wild-type and mutated PK enzymes.
The following summarizes our products and most advanced programs: PYRUKYND®/AQVESME™ (mitapivat): First-in-Class PK Activator We are developing mitapivat for the treatment of PK deficiency and other hemolytic anemias such as thalassemia and SCD. Mitapivat is an orally available small molecule and a potent activator of the wild-type and mutated PK enzymes.
As such, at this time, we cannot reasonably estimate or know the nature, timing and estimated costs of the efforts that will be necessary to complete the development of and to commercialize these product candidates. We are unable to predict the amount of net cash inflows from PYRUKYND® or any of our product candidates.
As such, at this time, we cannot reasonably estimate or know the nature, timing and estimated costs of the efforts that will be necessary to complete the development of and to commercialize these product candidates. We are unable to predict the amount of net cash inflows from any of our products or product candidates.
Financial Operations Overview General Since inception, our operations have primarily focused on organizing and staffing our company, business planning, raising capital, assembling our core capabilities in cellular metabolism and classical hematology, identifying potential product candidates, undertaking preclinical studies, conducting clinical trials, establishing a commercial infrastructure, preparing for and executing on the commercial launch of PYRUKYND® and, prior to the sale of our oncology business to Servier on March 31, 2021, marketing TIBSOVO® and IDHIFA®.
Financial Operations Overview General Since inception, our operations have primarily focused on organizing and staffing our company, business planning, raising capital, assembling our core capabilities in cellular metabolism and classical hematology, identifying potential product candidates, undertaking preclinical studies, conducting clinical trials, establishing a commercial infrastructure, preparing for and executing on the commercial launches of PYRUKYND® and AQVESME™ and, prior to the sale of our oncology business to Servier on March 31, 2021, marketing TIBSOVO® and IDHIFA®.
The amounts excluded from cost of sales were not significant during the years ended December 31, 2024, December 31, 2023 and December 31, 2022. Inventories are reviewed periodically to identify excess or obsolete inventory based on projected sales activity as well as product shelf-life.
The amounts excluded from cost of sales were not significant during the years ended December 31, 2025, December 31, 2024 and December 31, 2023. Inventories are reviewed periodically to identify excess or obsolete inventory based on projected sales activity as well as product shelf-life.
The expected volatility has been determined using Agios' historical volatilities for a period equal to the expected term of the option grant. Risk-free rate. The risk-free rate is based on the yield curve of U.S. Treasury securities with periods commensurate with the expected term of the options being valued. Dividends.
The expected volatility has been determined using our historical volatilities for a period equal to the expected term of the option grant. Risk-free rate. The risk-free rate is based on the yield curve of U.S. Treasury securities with periods commensurate with the expected term of the options being valued. Dividends.
We are also developing (i) tebapivat, a novel PK activator, for the potential treatment of lower-risk myelodysplastic syndromes, or LR MDS, and hemolytic anemias; (ii) AG-181, our phenylalanine hydroxylase, or PAH, stabilizer for the potential treatment of phenylketonuria, or PKU; and (iii) AG-236, an siRNA in-licensed from Alnylam Pharmaceuticals, Inc., or Alnylam, targeting the transmembrane serine protease 6, or TMPRSS6 gene for the potential treatment of polycythemia vera, or PV.
We are also developing (i) tebapivat, a novel PK activator, for the potential treatment of lower-risk myelodysplastic syndromes, or LR MDS, and SCD; (ii) AG-181, our phenylalanine hydroxylase, or PAH, stabilizer for the potential treatment of phenylketonuria, or PKU; and (iii) AG-236, an siRNA in-licensed from Alnylam Pharmaceuticals, Inc., or Alnylam, targeting the transmembrane serine protease 6, or TMPRSS6, gene for the potential treatment of polycythemia vera, or PV.
Our expectations regarding our long-term funding requirements are 80 Table of Content s based on assumptions that may prove to be wrong, and we may need additional capital resources to fund our operating plans and capital expenditure requirements.
Our expectations regarding 82 Table of Content s our long-term funding requirements are based on assumptions that may prove to be wrong, and we may need additional capital resources to fund our operating plans and capital expenditure requirements.
We built our commercial infrastructure to support the commercialization of PYRUKYND® in adult PK deficiency in the United States, and have expanded this infrastructure to support the potential commercial launch of PYRUKYND® in thalassemia in the United States.
We built our commercial infrastructure to support the commercialization of PYRUKYND® in adult PK deficiency in the United States, and have expanded this infrastructure to support the commercial launch of AQVESME™ in thalassemia in the United States.
(3) Relates to payment obligations under a development and manufacturing services agreement for drug product. Arrangement is for a contractual term of five years, however, the total funds can be allocated in any manner to meet the agreement terms.
(3) Relates to payment obligations under a development and manufacturing services agreement for drug product. Arrangement is for a remaining contractual term of four years, however, the total funds can be allocated in any manner to meet the agreement terms.
Royalty income related to the Retained Earn-Out Rights, if any, will be recognized in the period when realizable. Our cash, cash equivalents and marketable securities balance was $1.5 billion at December 31, 2024. The Retained Earn-Out Rights discussed above are our only committed potential external sources of funds.
Royalty income related to the Retained Earn-Out Rights, if any, will be recognized in the period when realizable. Our cash, cash equivalents and marketable securities balance was $1.2 billion at December 31, 2025. The Retained Earn-Out Rights discussed above are our only committed potential external sources of funds.
On an ongoing basis, we evaluate our estimates and judgments. We base our estimates on historical experience and various other factors that we believe are reasonable under the circumstances, the results of which form the basis for making judgments about the carrying value of assets and liabilities that are not readily apparent from other sources.
On an ongoing basis, we evaluate our estimates and judgments. We base our estimates on historical experience and various other factors that we believe are reasonable under the circumstances, the results of which form the basis for making judgments about the carrying value of 76 Table of Content s assets and liabilities that are not readily apparent from other sources.
Also, in July 2023, we entered into a license agreement with Alnylam for the development and commercialization of products containing or comprised of an siRNA preclinical development candidate discovered by Alnylam and targeting the TMPRSS6 gene, and we have begun preclinical development of a product candidate, AG-236, for the potential treatment of patients with PV.
Also, in July 2023, we entered into a license agreement with Alnylam for the development and commercialization of products containing or comprised of an siRNA preclinical development candidate discovered by Alnylam and targeting the TMPRSS6 gene, and we are developing a product candidate, AG-236, for the potential treatment of patients with PV.
Under the license agreement, we may be required to pay up to $130.0 million in potential development and regulatory milestones, in addition to sales milestones as well as tiered royalties on annual net sales, if any, of licensed products, which may be subject to specified reductions and offsets.
Under the license agreement, we may be required to pay up to an additional $120.0 million in potential development and regulatory milestones, in addition to sales milestones as well as tiered royalties on annual net sales, if any, of licensed products, which may be subject to specified reductions and offsets.
Our future capital requirements will depend on many factors, including: • the amount and timing of future revenue received from commercial sales of PYRUKYND® or any of our product candidates for which we may receive marketing approval; • the amount of payments, if any, we may receive on account of the Retained Earn-Out Rights; • the costs and timing of our ongoing and future commercialization activities, including product manufacturing, sales, marketing and distribution for PYRUKYND® in the approved jurisdictions and for any product candidate for which we may receive approval; • the scope, progress, results and costs of preclinical development, laboratory testing and clinical trials for our product candidates; • the costs associated with in-licensing or acquiring assets for pipeline growth, including the amount and timing of future milestone and royalty payments potentially payable to Alnylam pursuant to the license agreement; • the costs, timing and outcome of regulatory review of our product candidates, including with respect to regulatory submissions for PYRUKYND® for the treatment of thalassemia; • the costs of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property rights and defending intellectual property-related claims; • our ability to establish and maintain collaborations on favorable terms, if at all; • our ability to successfully execute on our strategic plans; • operational delays due to public health epidemics; and • operational delays, disruptions and/or increased costs associated with global economic and political developments, rising global energy prices or energy shortages or rationing.
Our future capital requirements will depend on many factors, including: • the amount and timing of future revenue received from commercial sales of PYRUKYND®, AQVESME™ or any of our other product candidates for which we may receive marketing approval; • the amount of payments, if any, we may receive on account of the Retained Earn-Out Rights; • the costs and timing of our ongoing and future commercialization activities, including product manufacturing, sales, marketing and distribution for PYRUKYND® and AQVESME™ in the approved jurisdictions and indications and for any product candidate for which we may receive approval; • the scope, progress, results and costs of preclinical development, laboratory testing and clinical trials for our product candidates; • the costs associated with in-licensing or acquiring assets for pipeline growth, including the amount and timing of future milestone and royalty payments potentially payable to Alnylam pursuant to the license agreement; • the costs, timing and outcome of regulatory review of our product candidates; • the costs of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property rights and defending intellectual property-related claims; • our ability to establish and maintain collaborations on favorable terms, if at all; • our ability to successfully execute on our strategic plans; • operational delays due to public health epidemics; and • operational delays, disruptions and/or increased costs associated with global economic and political developments.
Until such time, if ever, as we can generate substantial product revenue, we expect to finance our cash needs primarily through cash on hand, potential royalty payments with respect to the Retained Earn-Out Rights, the actual and potential future sales of PYRUKYND® and, potentially, collaborations, strategic alliances, licensing arrangements and other nondilutive strategic transactions.
Until such time, if ever, as we can generate substantial product revenue, we expect to finance our cash needs primarily through cash on hand, potential royalty payments with respect to the Retained Earn-Out Rights, the actual and potential future sales of PYRUKYND®, the potential future sales of AQVESME™ if successfully launched by us and, potentially, collaborations, strategic alliances, licensing arrangements and other nondilutive strategic transactions.
This is due to the numerous risks and uncertainties associated with developing medicines, including the uncertainty of: • establishing an appropriate safety profile with an investigational new drug application, or IND, and/or NDA-enabling toxicology and clinical trials; • successfully enrolling in, and completion of, clinical trials; • receiving marketing approvals from applicable regulatory authorities; • establishing compliant commercial manufacturing capabilities or making arrangements with third-party manufacturers; • obtaining and maintaining patent and trade secret protection and regulatory exclusivity for our product candidates; • launching commercial sales of the products, if and when approved, in the United States or in other jurisdictions, whether alone or in collaboration with others, including pursuant to the NewBridge Agreement; and • maintaining an acceptable safety profile of the products following approval.
This is due to the numerous risks and uncertainties associated with developing medicines, including the uncertainty of: • establishing an appropriate safety profile with an investigational new drug application, or IND, and/or NDA-enabling toxicology and clinical trials; • successfully enrolling in, and completion of, clinical trials; • receiving marketing approvals from applicable regulatory authorities; • establishing compliant commercial manufacturing capabilities or making arrangements with third-party manufacturers; • obtaining and maintaining patent and trade secret protection and regulatory exclusivity for our product candidates; • launching commercial sales of the products, if and when approved, in the United States or in other jurisdictions, whether alone or in collaboration with others, including pursuant to the NewBridge Agreement and Avanzanite Agreement; • maintaining an acceptable safety profile of the products following approval; and 72 Table of Content s • complying with any approval or post-approval requirements.
All of these events occurred within the first six months of exposure to PYRUKYND® and liver tests improved following discontinuation of PYRUKYND®.
All of these events occurred within the first six months of exposure to mitapivat and liver tests improved following discontinuation of mitapivat.
Following the sale of our oncology business to Servier on March 31, 2021, we have financed and expect to continue to finance our operations primarily through cash on hand, potential royalty payments with respect to the Retained Earn-Out Rights, the actual and potential future sales of PYRUKYND® and, potentially, collaborations, strategic alliances, licensing arrangements and other nondilutive strategic transactions.
Following the sale of our oncology business to Servier on March 31, 2021, we have financed and expect to continue to finance our operations primarily through cash on hand, potential royalty payments with respect to the Retained Earn-Out Rights, the actual and potential future sales of PYRUKYND®, the potential future sales of AQVESME™ if successfully launched by us and, potentially, collaborations, strategic alliances, licensing arrangements and other nondilutive strategic transactions.
Following the sale of our oncology business to Servier on March 31, 2021, we have financed and expect to continue to finance our operations primarily through cash on hand, potential royalty payments with respect to the Retained Earn-Out Rights, the actual and potential future sales of PYRUKYND® and, potentially, collaborations, strategic alliances, licensing arrangements and other nondilutive strategic transactions.
Following the sale of our oncology business to Servier on March 31, 2021, we have financed and expect to continue to finance our operations primarily through cash on hand, potential royalty payments with respect to the Retained Earn-Out Rights, the actual and potential future sales of PYRUKYND®, the potential future sales of AQVESME™ if successfully launched by us and, potentially, collaborations, strategic alliances, licensing arrangements and other nondilutive strategic transactions.
Also in December 2024, we announced that we submitted a marketing authorization application, or MAA, to the European Medicines Agency, or EMA, and regulatory applications to the Kingdom of Saudi Arabia and United Arab Emirates health authorities for PYRUKYND® for the treatment of adult patients with non-transfusion dependent and transfusion-dependent alpha- or beta-thalassemia.
In December 2024, we announced that we submitted a marketing authorization application, or MAA, to the European Medicines Agency, or EMA, and a regulatory application to the United Arab Emirates health authorities for PYRUKYND® for the treatment of adult patients with non-transfusion dependent and transfusion-dependent alpha- or beta-thalassemia.
The preparation of these consolidated financial statements requires us to make estimates and assumptions that affect the reported amounts of assets and liabilities and the disclosure of contingent assets and liabilities at the date of the financial 74 Table of Content s statements, as well as the reported amounts of revenue and expenses during the reporting periods.
The preparation of these consolidated financial statements requires us to make estimates and assumptions that affect the reported amounts of assets and liabilities and the disclosure of contingent assets and liabilities at the date of the financial statements, as well as the reported amounts of revenue and expenses during the reporting periods.
Funding Requirements We expect our expenses to increase as we continue the research, development and clinical trials of, seek marketing approvals for, and commercialize our product candidates in our portfolio, including as we continue to commercialize PYRUKYND®.
Funding Requirements We expect our expenses to increase as we continue the research, development and clinical trials of, seek marketing approvals for, and commercialize our product candidates in our portfolio, including as we continue to commercialize PYRUKYND® and AQVESME™ for their approved indications.
We evaluated the phase 2a trial results and assessed the impact of those results on the phase 2b portion of the protocol, and based on the data generated in the phase 2a portion of the trial, we plan to increase the dosage levels evaluated in the phase 2b portion of the trial, which we initiated in the third quarter of 2024.
We evaluated the phase 2a trial results and assessed the impact of those results on the phase 2b portion of the protocol, and based on the data generated in the phase 2a portion of the trial, we increased the dosage levels evaluated in the phase 2b portion of the trial, which we initiated in the third quarter of 2024.
The transaction included the sale of our oncology business, including TIBSOVO®, our clinical-stage product candidates vorasidenib, AG-270 and AG-636, and our oncology research programs for a payment of approximately $1.8 billion in cash at the closing, subject to certain adjustments, and a payment of $200.0 million in cash, if, prior to January 1, 2027, vorasidenib is granted new drug application, or NDA, approval from the FDA with an approved label that permits vorasidenib’s use as a single agent for the adjuvant treatment of patients with Grade 2 glioma that have an isocitrate dehydrogenase, or IDH, 1 or 2 mutation (and, to the extent required by such approval, the vorasidenib companion diagnostic test is granted an FDA premarket approval), or the Vorasidenib Milestone Payment, as well as a royalty of 5% of U.S. net sales 68 Table of Content s of TIBSOVO® from the close of the transaction through loss of exclusivity, and a royalty of 15% of U.S. net sales of vorasidenib from the first commercial sale of vorasidenib through loss of exclusivity, or the Vorasidenib Royalty Rights.
The transaction included the sale of our entire oncology business, including our clinical-stage product candidate vorasidenib, for a payment of approximately $1.8 billion in cash at the closing, subject to certain adjustments, and a payment of $200.0 million in 70 Table of Content s cash, if, prior to January 1, 2027, vorasidenib is granted new drug application, or NDA, approval from the FDA with an approved label that permits vorasidenib’s use as a single agent for the adjuvant treatment of patients with Grade 2 glioma that have an isocitrate dehydrogenase, or IDH, 1 or 2 mutation (and, to the extent required by such approval, the vorasidenib companion diagnostic test is granted an FDA premarket approval), or the Vorasidenib Milestone Payment, and a royalty of 15% of U.S. net sales of vorasidenib from the first commercial sale of vorasidenib through loss of exclusivity, or the Vorasidenib Royalty Rights.
As indicated above, during the double-blind periods of ENERGIZE and ENERGIZE-T, two patients on PYRUKYND® experienced events of hepatocellular injury. In addition, during the open-label extension periods of both trials, a total of three patients experienced events of hepatocellular injury after switching from placebo to PYRUKYND®.
During the double-blind periods of ENERGIZE and ENERGIZE-T, two patients on mitapivat experienced events of hepatocellular injury. In addition, during the open-label extension periods of both trials, a total of three patients experienced events of hepatocellular injury after switching from placebo to mitapivat.
In addition, improvements in changes from baseline for markers of hemolysis (indirect bilirubin, 73 Table of Content s lactate dehydrogenase and haptoglobin) were observed in the mitapivat arm compared to the placebo arm.
In addition, improvements in changes from baseline for markers of hemolysis (indirect bilirubin, lactate dehydrogenase and haptoglobin) were observed in the mitapivat arm compared to the placebo arm.
The primary endpoint of ACTIVATE-kids is percentage of patients with hemoglobin response, defined as ≥1.5 g/dL increase in hemoglobin concentration from baseline that is sustained at two or more scheduled assessments at weeks 12, 16, and 20 during the double-blind period. We announced topline data for ACTIVATE-kids in February 2025.
The primary endpoint of ACTIVATE-kids is percentage of patients with hemoglobin response, defined as ≥1.5 g/dL increase in hemoglobin concentration from baseline that is sustained at two or more scheduled assessments at weeks 12, 16, and 20 during the double-blind period.
The cash provided by financing activities for the year ended December 31, 2022 was primarily due to $2.7 million of proceeds received from stock option exercises and purchases made pursuant to our employee stock purchase plan.
Net cash provided by financing activities Cash provided by financing activities for the year ended December 31, 2025 was due to $8.7 million of proceeds received from stock option exercises and purchases made pursuant to our employee stock purchase plan.
A total of 49 patients were enrolled in ACTIVATE-kidsT, with 32 randomized to mitapivat twice-daily and 17 randomized to matched placebo. 30 patients (93.8%) in the mitapivat arm and 16 (94.1%) in the placebo arm completed the 32-week double-blind period of the study.
We announced topline data for ACTIVATE-kidsT in August 2024. A total of 49 patients were enrolled in ACTIVATE-kidsT, with 32 randomized to mitapivat twice-daily and 17 randomized to matched placebo. 30 patients (93.8%) in the mitapivat arm and 16 (94.1%) in the placebo arm completed the 32-week double-blind period of the study.
The safety results from the trial were consistent with the safety profile for mitapivat previously observed for adult patients with PK deficiency who are not regularly transfused. • An extension study evaluating the long-term safety, tolerability and efficacy of treatment with PYRUKYND® in patients from ACTIVATE and ACTIVATE-T, our completed pivotal trials of PYRUKYND® in not regularly transfused and regularly transfused adult patients with PK deficiency. • An extension study evaluating the long-term safety, tolerability and efficacy of treatment with PYRUKYND® in patients from DRIVE PK, our completed global phase 2, first-in-patient, open-label safety and efficacy clinical trial of PYRUKYND® in adult, not regularly transfused patients with PK deficiency.
The safety results from the trial were consistent with the safety profile for mitapivat previously observed for adult patients with PK deficiency who are not regularly transfused. • An extension study evaluating the long-term safety, tolerability and efficacy of treatment with mitapivat in patients from ACTIVATE and ACTIVATE-T, our completed pivotal trials of mitapivat in not regularly transfused and regularly transfused adult patients with PK deficiency. • An extension study evaluating the long-term safety, tolerability and efficacy of treatment with mitapivat in patients from DRIVE PK, our completed global phase 2, first-in-patient, open-label safety and efficacy clinical trial of mitapivat in adult, not regularly transfused patients with PK deficiency. • An extension study evaluating the long-term efficacy and safety of treatment with mitapivat in patients from ENERGIZE and ENERGIZE-T, our completed pivotal trials of mitapivat in adults with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia.
In July 2024, we entered into a distribution agreement, or the NewBridge Agreement, with NewBridge Pharmaceuticals FZ-LLC, or NewBridge, pursuant to which we granted NewBridge the right to commercialize PYRUKYND® in Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates, or the GCC region.
In July 2024, we entered into a distribution agreement, or the NewBridge Agreement, with NewBridge Pharmaceuticals FZ-LLC, or NewBridge, pursuant to which we granted NewBridge the right to commercialize PYRUKYND® in Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates, also known as the Gulf Council Countries, or GCC.
The increase in milestone payment from gain on sale of oncology business was due to the receipt of the Vorasidenib Milestone Payment in 2024 as discussed above in Overview . The $14.7 million increase in interest income, net in 2024 compared to 2023 is primarily attributable to increased return on our investments.
The decrease in milestone payment from gain on sale of oncology business was due to the receipt of the Vorasidenib Milestone Payment in 2024 as discussed above in Overview . The $8.3 million increase in interest income, net in 2025 compared to 2024 is primarily attributable to increased return on our investments.
Also in December 2024, we announced that we submitted an MAA to the EMA and regulatory applications to the Kingdom of Saudi Arabia and United Arab Emirates health authorities for PYRUKYND® for the treatment of adult patients with non-transfusion dependent and transfusion-dependent alpha- or beta-thalassemia.
In December 2024, we announced that we submitted an MAA to the EMA and a regulatory application to the United Arab Emirates health authorities for PYRUKYND® for the treatment of adult patients with non-transfusion dependent and transfusion-dependent alpha- or beta-thalassemia.
These Customers subsequently resell PYRUKYND® to pharmacies or dispense PYRUKYND® directly to patients. In addition to distribution agreements with Customers, we enter into arrangements with healthcare providers and payors that provide for government-mandated and/or privately-negotiated rebates, chargebacks and discounts with respect to the purchase of PYRUKYND®.
In addition to distribution agreements with Customers, we enter into arrangements with healthcare providers and payors that provide for government-mandated and/or privately-negotiated rebates, chargebacks and discounts with respect to the purchase of PYRUKYND®.
Sale of Oncology Business to Servier Pharmaceuticals, LLC (Servier) and Sale of Contingent Payments On March 31, 2021, we completed the sale of our oncology business to Servier Pharmaceuticals, LLC, or Servier, which represented a discontinued operation.
Sale of Oncology Business to Servier Pharmaceuticals, LLC (Servier) and Sale of Contingent Payments On March 31, 2021, we completed the sale of our oncology business to Servier Pharmaceuticals, LLC, or Servier.
We cannot predict what success, if any, Servier may have in the United States with respect to the sale of vorasidenib, and consequently, we cannot estimate the amount of payments, if any, we may receive on account of the Retained Earn-Out Rights. 79 Table of Content s Cash Flows The following table provides information regarding our cash flows for the years ended December 31, 2024, 2023 and 2022: (In thousands) 2024 2023 2022 Net cash used in operating activities $ (389,841) $ (296,062) $ (309,478) Net cash provided by investing activities 363,441 239,575 243,261 Net cash provided by financing activities 14,442 5,433 2,350 Net change in cash and cash equivalents $ (11,958) $ (51,054) $ (63,867) Net cash used in operating activities Cash used in operating activities of $389.8 million during the year ended December 31, 2024 was primarily due to operating expenses driven by research and development costs described above under Research and Development Expenses, partially offset by cash received related to interest income of $43.5 million and cash received from product revenues of $37.8 million.
We cannot predict what success, if any, Servier may have in the United States with respect to the sale of vorasidenib, and consequently, we cannot estimate the amount of payments, if any, we may receive on account of the Retained Earn-Out Rights. 81 Table of Content s Cash Flows The following table provides information regarding our cash flows for the years ended December 31, 2025, 2024 and 2023: (In thousands) 2025 2024 2023 Net cash used in operating activities $ (372,977) $ (389,841) $ (296,062) Net cash provided by investing activities 377,184 363,441 239,575 Net cash provided by financing activities 8,676 14,442 5,433 Net change in cash and cash equivalents $ 12,883 $ (11,958) $ (51,054) Net cash used in operating activities Cash used in operating activities of $373.0 million during the year ended December 31, 2025 was primarily due to operating expenses driven by research and development costs described above under Research and Development Expenses, partially offset by cash received related to interest income of $59.0 million and cash received from product revenues of $50.5 million.
Our net income for the year ended December 31, 2024 was $673.7 million, our net loss for the year ended December 31, 2023 was $352.1 million and our net loss for the year ended December 31, 2022 was $231.8 million. As of December 31, 2024, we had an accumulated deficit of $148.9 million.
Our net loss for the year ended December 31, 2025 was $412.8 million, our net income for the year ended December 31, 2024 was $673.7 million and our net loss for the year ended December 31, 2023 was $352.1 million. As of December 31, 2025, we had an accumulated deficit of $561.7 million.
PYRUKYND® is approved for use by the FDA for the treatment of hemolytic anemia in adults with PK deficiency in the United States and by the European Commission for the treatment of PK deficiency in adult patients in the EU.
The FDA approved mitapivat, under the brand name PYRUKYND®, for the treatment of hemolytic anemia in adults with PK deficiency in the United States and by the European Commission for the treatment of PK deficiency in adult patients in the EU.
A change in the outcome of any of these variables with respect to the development of any of our product candidates would significantly change the costs and timing associated with the development of that product candidate. 70 Table of Content s Research and development expenses consist primarily of costs incurred for our research activities, including our drug discovery efforts, and the development of our product candidates, which include: • employee-related expenses, including salaries, benefits and stock-based compensation expense; • expenses incurred under agreements with third parties, including contract research organizations, or CROs, that conduct research and development and both preclinical and clinical activities on our behalf, and the cost of consultants; • the cost of lab supplies and acquiring, developing and manufacturing preclinical study and clinical trial materials; and • facilities, depreciation, and other expenses, which include direct and allocated expenses for rent and the maintenance of facilities, insurance and other operating costs.
Research and development expenses consist primarily of costs incurred for our research activities, including our drug discovery efforts, and the development of our product candidates, which include: • employee-related expenses, including salaries, benefits and stock-based compensation expense; • expenses incurred under agreements with third parties, including contract research organizations, or CROs, that conduct research and development and both preclinical and clinical activities on our behalf, and the cost of consultants; • the cost of lab supplies and acquiring, developing and manufacturing preclinical study and clinical trial materials; and • facilities, depreciation, and other expenses, which include direct and allocated expenses for rent and the maintenance of facilities, insurance and other operating costs.
We expect that our existing cash, cash equivalents and marketable securities as of December 31, 2024, together with anticipated product revenue and interest income, will provide the financial independence to prepare for potential PYRUKYND® commercial launches in thalassemia and SCD, advance our existing programs, and opportunistically expand our pipeline through both internally and externally discovered assets.
We expect that our existing cash, cash equivalents and marketable securities as of December 31, 2025, together with anticipated product revenue and interest income, will provide the financial independence to commercially launch AQVESME™ in the United States, prepare for the potential U.S. commercial launch of mitapivat in SCD, advance our existing clinical programs, and opportunistically expand our pipeline through both internally and externally discovered assets.
If we obtain additional marketing approvals for PYRUKYND® in thalassemia or in other indications, or outside of the United States or for any of our product candidates, we expect to incur significant commercialization expenses related to product sales, marketing, manufacturing and distribution.
If we obtain additional marketing approvals for mitapivat in sickle cell disease or in other indications, or for any of our other product candidates, we expect to incur significant commercialization expenses related to product sales, marketing, manufacturing and distribution.
In July 2024, we entered into a distribution agreement with NewBridge Pharmaceuticals FZ-LLC, or the NewBridge Agreement, pursuant to which we granted NewBridge the right to commercialize PYRUKYND® in the GCC region. We expect to fund the future development and commercialization costs related to this program.
In July 2024, we entered into a distribution agreement, or the NewBridge Agreement, with NewBridge Pharmaceuticals FZ-LLC, or NewBridge, pursuant to which we granted NewBridge the right to commercialize PYRUKYND® in the GCC region.
Prescribing Information, or USPI, for PYRUKYND® for the treatment of hemolytic anemia in adults with PK deficiency to reflect the aforementioned hepatocellular injury and monitoring. • RISE UP, a phase 2/3 study evaluating the efficacy and safety of PYRUKYND® in SCD patients who are 16 years of age or older, have had between two and 10 sickle cell pain crises, or SCPCs, in the past 12 months, and have hemoglobin within the range of 5.5 to 10.5 g/dL during screening.
RISE UP, a phase 2/3 study evaluating the efficacy and safety of mitapivat in SCD patients who are 16 years of age or older, have had between two and 10 sickle cell pain crises, or SCPCs, in the past 12 months, and have hemoglobin within the range of 5.5 to 10.5 g/dL during screening.
Net Income (Loss) (In thousands) 2024 2023 2022 Net income (loss) before taxes $ 717,969 $ (352,088) $ (231,801) Income tax expense 44,244 — — Net income (loss) 673,725 (352,088) (231,801) Net Income (Loss) – 2024 vs 2023 – The increase in net income in 2024 compared to 2023 was primarily driven by the sale of the Vorasidenib Royalty Rights in 2024 discussed above in Overview and the receipt of the Vorasidenib Milestone Payment in 2024 discussed above in Overview , partially offset by the increase in income tax expense as a result of the income related to the sale of the Vorasidenib Royalty Rights and the receipt of the Vorasidenib Milestone Payment.
Net (Loss) Income – 2024 vs 2023 – The increase in net income in 2024 compared to 2023 was primarily driven by the sale of the Vorasidenib Royalty Rights in 2024 discussed above in Overview and the receipt of the Vorasidenib Milestone Payment in 2024 discussed above in Overview , partially offset by the increase in income tax expense as a result of the income related to the sale of the Vorasidenib Royalty Rights and the receipt of the Vorasidenib Milestone Payment.
In August 2024, the FDA approved vorasidenib for adult and pediatric patients 12 years and older with Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation, following surgery including biopsy, sub-total resection, or gross total resection.
The Vorasidenib Milestone Payment and Vorasidenib Royalty Rights are referred to as contingent payments and recognized as income when realizable. In August 2024, the FDA approved vorasidenib for adult and pediatric patients 12 years and older with Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation, following surgery including biopsy, sub-total resection, or gross total resection.
We expect that we will continue to incur significant expenses as we continue to advance and expand clinical development and commercialization activities for PYRUKYND®, including with respect to the review by the FDA and other regulatory authorities of our regulatory submissions made, which we announced in December 2024, for the treatment of thalassemia; continue to advance and expand clinical development of tebapivat, our novel PK activator; continue to advance clinical development of AG-181, our PAH stabilizer; continue preclinical development of AG-236, a licensed siRNA development candidate pursuant to our license agreement with Alnylam; expand and protect our intellectual property portfolio, including by in-licensing or acquiring assets for pipeline growth; and hire additional commercial and development personnel. 69 Table of Content s Revenues Our wholly owned product, PYRUKYND®, received approval from the FDA on February 17, 2022, for the treatment of hemolytic anemia in adults with PK deficiency in the United States.
We expect that we will continue to incur significant expenses as we continue to advance and expand our commercialization activities for PYRUKYND®; continue our commercialization activities for AQVESME™; continue to advance clinical development and regulatory activities for mitapivat, tebapivat, AG-181 and AG-236; expand and protect our intellectual property portfolio, including by in-licensing or acquiring assets for pipeline growth; and hire additional commercial and development personnel. 71 Table of Content s Revenues Our wholly owned product, PYRUKYND®, received approval from the FDA on February 17, 2022, for the treatment of hemolytic anemia in adults with PK deficiency in the United States.
In August 2024, the FDA approved vorasidenib for adult and pediatric patients 12 years and older with Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation, following surgery including biopsy, sub-total resection, or gross total resection.
The Vorasidenib Milestone Payment and Vorasidenib Royalty Rights are referred to as contingent payments and recognized as income when realizable. In August 2024, the FDA approved vorasidenib for adult and pediatric patients 12 years and older with Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation, following surgery including biopsy, sub-total resection, or gross total resection.
Off-Balance Sheet Arrangements We did not have, during the periods presented, and we do not currently have, any off-balance sheet arrangements, as defined under applicable SEC rules. 81 Table of Content s Contractual Obligations The following table summarizes our significant contractual obligations as of the payment due date by period at December 31, 2024: Payments due by period (In thousands) Total Less than 1 year 1-3 years 3-5 years More than 5 years Operating lease obligations (1) $ 62,328 $ 17,943 $ 40,906 $ 3,479 $ — Manufacturing arrangements (2) 942 314 628 — — Service arrangements (3) 6,625 3,142 1,742 1,741 — (1) Relates to payment obligations under lease agreements covering approximately 146,000 square feet at 88 Sidney Street, 43,000 square feet at 64 Sidney Street, and 13,000 square feet at 38 Sidney Street, Cambridge, Massachusetts.
Off-Balance Sheet Arrangements We did not have, during the periods presented, and we do not currently have, any off-balance sheet arrangements, as defined under applicable SEC rules. 83 Table of Content s Contractual Obligations The following table summarizes our significant contractual obligations as of the payment due date by period at December 31, 2025: Payments due by period (In thousands) Total Less than 1 year 1-3 years 3-5 years More than 5 years Operating lease obligations (1) $ 42,745 $ 18,511 $ 24,234 $ — $ — Manufacturing arrangements (2) 674 337 337 — — Service arrangements (3) 4,351 1,088 2,175 1,088 — (1) Relates to payment obligations under lease agreements covering approximately 146,000 square feet at 88 Sidney Street, 43,000 square feet at 64 Sidney Street, and 13,000 square feet at 38 Sidney Street, Cambridge, Massachusetts.
Other Income and Expense (In thousands) 2024 2023 2022 Gain on sale of contingent payments $ 889,136 $ — $ 127,853 Milestone payment from gain on sale of oncology business 200,000 — — Royalty income from gain on sale of oncology business — — 9,851 Interest income, net 48,083 33,344 12,793 Other income, net 6,487 6,055 6,749 Other Income and Expense – 2024 vs. 2023 – The increase in gain on sale of contingent payments in 2024 compared to 2023 was due to the sale of the Vorasidenib Royalty Rights in 2024 discussed above in O verview .
Other Income and Expense (In thousands) 2025 2024 2023 Gain on sale of contingent payments $ — $ 889,136 $ — Milestone payment from gain on sale of oncology business — 200,000 — Interest income, net 56,379 48,083 33,344 Other income, net 1,956 6,487 6,055 Other Income and Expense – 2025 vs. 2024 – The decrease in gain on sale of contingent payments in 2025 compared to 2024 was due to the sale of the Vorasidenib Royalty Rights in 2024 discussed above in Overview .
In connection with our regulatory approvals in the EU and Great Britain, we are currently providing access to PYRUKYND® on a free of charge basis for eligible patients in those jurisdictions through a global managed access program.
In connection with our regulatory approvals in the EU, Great Britain and Saudi Arabia, we provide access to PYRUKYND® to eligible patients through the Avanzanite Agreement and the NewBridge Agreement, as applicable, and on either a free of charge or for charge basis for eligible patients in those jurisdictions and other jurisdictions through a global managed access program.
Cash used in operating activities of $309.5 million during the year ended December 31, 2022 was primarily due to operating expenses driven by research and development costs described above under Research and Development Expenses, partially offset by cash received from revenues of $13.3 million, cash received related to interest income of $11.6 million and cash received from royalties on U.S. net sales of TIBSOVO® of $8.6 million.
Cash used in operating activities of $389.8 million during the year ended December 31, 2024 was primarily due to operating expenses driven by research and development costs described above under Research and Development Expenses, partially offset by cash received related to interest income of $43.5 million and cash received from product revenues of $37.8 million.
Total Research and Development Expenses – 2023 vs 2022 – The increase in research and development expenses of $15.6 million in 2023 compared to 2022 was due to a $22.7 million increase in our direct expense offset by a $7.1 million decrease in our indirect expenses.
Total Research and Development Expenses – 2024 vs 2023 – The increase in research and development expenses of $5.8 million in 2024 compared to 2023 was due to a $6.3 million increase in our indirect expenses, partially offset by a $0.6 million decrease in our direct expenses.
The decrease in direct expenses was due to the $17.5 million up-front payment in 2023 associated with the Alnylam license agreement discussed above under Overview 77 Table of Content s and a decrease of $3.7 million in tebapivat costs due to decreased costs associated with clinical trials of tebapivat in patients with SCD and MDS, offset by an $11.4 million increase in PYRUKYND® costs and a $9.2 million increase in other research and platform programs.
The decrease in direct expenses was due to the $17.5 million up-front payment in 2023 associated with the Alnylam license agreement discussed above under Overview and a decrease of $3.7 million in tebapivat costs due to decreased costs associated with clinical trials of tebapivat in patients with SCD and LR MDS, offset by an $11.4 million increase in PYRUKYND® costs and a $9.3 million increase in AG-236, the in-licensed siRNA TMPRSS6 program for PV, primarily driven by higher process development expenses.
We expect to complete enrollment in this phase 2b trial in late 2025. Other Programs In addition to the aforementioned development programs, we are developing AG-181, a PAH stabilizer for the potential treatment of PKU, for which we filed an IND in December 2023.
Other Programs In addition to the aforementioned development programs, we are developing AG-181, a PAH stabilizer for the potential treatment of PKU, for which we filed an investigational new drug application, or IND, in December 2023.
We initiated a phase 1 clinical trial of AG-181 in healthy volunteers in the first quarter of 2024.
We initiated a phase 1 clinical trial of AG-181 in healthy volunteers in the first quarter of 2024, initiated the multiple ascending dose portion of the trial in the second quarter of 2025, and completed the trial in December 2025.
Total Operating Expenses (In thousands) 2024 2023 2022 Operating expenses Cost of sales $ 4,165 $ 2,881 $ 1,704 Research and development 301,286 295,526 279,910 Selling, general and administrative 156,784 119,903 121,673 Total Operating Expenses $ 462,235 $ 418,310 $ 403,287 Total Operating Expenses – 2024 vs. 2023 – The increase in total operating expenses of $43.9 million in 2024 compared to 2023 was primarily due to an increase of $36.9 million in selling, general and administrative expenses, driven by an increase in commercial-related activities as we prepare for the potential approval of PYRUKYND® in thalassemia, and an increase of $5.8 million in research and development expenses, which is described below under Research and Development Expenses.
Total Operating Expenses (In thousands) 2025 2024 2023 Operating expenses Cost of sales $ 6,345 $ 4,165 $ 2,881 Research and development 339,535 301,286 295,526 Selling, general and administrative 180,280 156,784 119,903 Total operating expenses $ 526,160 $ 462,235 $ 418,310 Total Operating Expenses – 2025 vs. 2024 – The increase in total operating expenses of $63.9 million in 2025 compared to 2024 was primarily due to an increase of $38.2 million in research and development expenses, which is described below under Research and Development Expenses , and an increase of $23.5 million in selling, general and administrative expenses, driven by an increase in commercial-related activities as we prepared for the approval of AQVESME™ in thalassemia, which was approved by the FDA on December 23, 2025.
The primary endpoints of the phase 2 portion of the trial were hemoglobin response, defined as ≥ 1 g/dL increase in average hemoglobin concentration from week 10 to week 12 compared to baseline, and safety.
The primary endpoints of the phase 3 portion of the trial were (i) hemoglobin response, defined as ≥1 g/dL increase in average hemoglobin from week 24 through week 52 compared to baseline, and (ii) annualized rate of SCPCs.
For awards subject to performance-based vesting conditions, we recognize stock-based compensation expense if the performance condition is considered probable of achievement using management’s best estimates. 76 Table of Content s Results of Operations Comparison of years ended December 31, 2024, 2023 and 2022 Revenues (In thousands) 2024 2023 2022 Revenues: Product revenue, net $ 36,498 $ 26,823 $ 11,740 Milestone revenue — — 2,500 Total revenue $ 36,498 $ 26,823 $ 14,240 Total Revenue – 2024 vs. 2023 – The increase in total revenue of $9.7 million in 2024 compared to 2023 was due to increased volume associated with PYRUKYND®.
For awards subject to performance-based vesting conditions, we recognize stock-based compensation expense if the performance condition is considered probable of achievement using management’s best estimates. 78 Table of Content s Results of Operations Comparison of years ended December 31, 2025, 2024 and 2023 Revenues (In thousands) 2025 2024 2023 Revenues: Product revenue, net U.S. $ 49,170 $ 36,395 $ 26,823 Rest of world 4,858 103 — Total product revenue, net 54,028 36,498 26,823 Total revenue $ 54,028 $ 36,498 $ 26,823 Total Revenue – 2025 vs. 2024 – The increase in total revenue of $17.5 million in 2025 compared to 2024 was due to an increase of $12.8 million in U.S. product revenue and an increase of $4.7 million in rest of world product revenue.
We have completed a phase 1 clinical trial evaluating tebapivat in healthy volunteers and patients with SCD, and we expect to dose the first patient in a phase 2 clinical trial of tebapivat in adult patients with SCD in mid-2025.
We have completed a phase 1 clinical trial evaluating tebapivat in healthy volunteers and patients with SCD, and we have completed enrollment in the phase 2 clinical trial of tebapivat in adult patients with SCD. We expect to announce topline data for this trial in the second half of 2026.
Alnylam License Agreement In accordance with the license agreement with Alnylam, in the year ended December 31, 2023, we made an up-front payment to Alnylam and recognized in-process research and development of $17.5 million which was recorded in research and development expense within our consolidated statements of operations and classified as investing activities within our consolidated statements of cash flows.
In accordance with the license agreement, we made an up-front payment to Alnylam and recognized in-process research and development of $17.5 million in the year ended December 31, 2023. We will also pay Alnylam for certain expenses associated with the development of AG-236, and these will be recorded in our consolidated statements of operations as incurred.
The transaction included the sale of our oncology business, including TIBSOVO®, our clinical-stage product candidates vorasidenib, AG-270 and AG-636, and our oncology research programs for a payment of approximately $1.8 billion in cash at the closing, subject to certain adjustments, and the right to the Vorasidenib Milestone Payment, as well as a royalty of 5% of U.S. net sales of TIBSOVO® from the close of the transaction through loss of exclusivity, and the Vorasidenib Royalty Rights.
The transaction included the sale of our entire oncology business, including our clinical-stage product candidate vorasidenib, for a payment of approximately $1.8 billion in cash at the closing, subject to certain adjustments, and the right to the Vorasidenib Milestone Payment and the Vorasidenib Royalty Rights.
In October 2023, we enrolled the first patient in the phase 3 portion of this trial and we have since enrolled over 200 patients worldwide. The phase 3 portion includes a 52-week randomized, placebo-controlled period in which participants will be randomized in a 2:1 ratio to receive the recommended (100 mg twice daily) PYRUKYND® dose level or the placebo.
We enrolled 207 patients in the phase 3 portion of the trial, which included a 52-week double blind, randomized, placebo-controlled period in which participants were randomized in a 2:1 ratio to receive the recommended (100 mg twice daily) mitapivat dose level or the placebo.
Additionally, PYRUKYND® has received orphan drug designation from the FDA for the treatment of thalassemia and SCD, orphan medicinal product designation from the EMA for the treatment of SCD, and breakthrough medicine designation from the Saudi Food and Drug Authority for the treatment of thalassemia.
Additionally, mitapivat has received orphan drug designation from the FDA for the treatment of thalassemia and SCD, and orphan medicinal product designation from the EMA for the treatment of SCD. Mitapivat was granted orphan drug designation for the treatment of PK deficiency by the FDA and EMA.

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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 changeItem 7A. Quantitative and Qualitative Disclosures about Market Risk We are exposed to market risk related to changes in interest rates. As of December 31, 2024 and December 31, 2023, we had cash, cash equivalents and marketable securities of $1.5 billion and $0.8 billion, respectively, consisting primarily of investments in U.S.
Biggest changeItem 7A. Quantitative and Qualitative Disclosures about Market Risk We are exposed to market risk related to changes in interest rates. As of December 31, 2025 and December 31, 2024, we had cash, cash equivalents and marketable securities of $1.2 billion and $1.5 billion, respectively, consisting primarily of investments in U.S.
As of December 31, 2024 and December 31, 2023, we had minimal or no liabilities denominated in foreign currencies.
As of December 31, 2025 and December 31, 2024, we had minimal or no liabilities denominated in foreign currencies.

Other AGIO 10-K year-over-year comparisons