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Item 7. Management’s Discussion and Analysis

2025-02-13 compared with 2024-02-15 · 214 added, 184 removed, 247 unchanged (62% of the section changed)

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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.

In February 2022, the U.S.

Food and Drug Administration, or FDA, approved PYRUKYND® for the treatment of hemolytic anemia in adults with PK deficiency in the United States.

In November 2022, we received marketing authorization from the European Commission for PYRUKYND® for the treatment of PK deficiency in adult patients in the European Union, or EU.

In December 2022, we received marketing authorization in Great Britain for PYRUKYND® for the treatment of PK deficiency in adult patients under the European Commission Decision Reliance Procedure.

In addition, we are currently evaluating PYRUKYND® in clinical trials for the treatment of thalassemia, sickle cell disease, or SCD, and in pediatric patients with PK deficiency.

We are also developing (i) AG-946, a novel PK activator, for the potential treatment of lower-risk myelodysplastic syndrome, or LR MDS, and hemolytic anemias, and (ii) AG-181, our phenylalanine hydroxylase, or PAH, stabilizer for the potential treatment of phenylketonuria, or PKU.

In addition to the aforementioned development programs, in July 2023 we entered into a license agreement with Alnylam Pharmaceuticals, Inc., or Alnylam for the development and commercialization of products containing or comprised of an siRNA preclinical development candidate discovered by Alnylam and targeting the transmembrane serine protease 6, or TMPRSS6, gene and we intend to pursue development of a licensed product for the potential disease-modifying treatment of patients with polycythemia vera, or PV, a rare blood disorder.

PYRUKYND® is approved for use by the U.S.

Food and Drug Administration, or 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 European Union, or EU.

Additionally, we received marketing authorization in Great Britain for PYRUKYND® for the treatment of PK deficiency in adult patients under the European Commission Decision Reliance Procedure.

In December 2024, we announced that we submitted a supplemental new drug application, or sNDA, to the FDA for PYRUKYND® for the treatment of adult patients with non-transfusion dependent and transfusion-dependent alpha- or beta-thalassemia, which was accepted with standard review by the FDA and granted a Prescription Drug User Fee Act, or PDUFA, goal date of September 7, 2025.

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 addition, we are currently evaluating PYRUKYND® in Phase 3 clinical trials for the treatment of sickle cell disease, or SCD, and in pediatric patients with PK deficiency.

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.

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.

We will also pay Alnylam for certain expenses associated with the development of the TMPRSS6 gene and these will be recorded in our Consolidated Statements of Operations as incurred.

We will also pay Alnylam for certain expenses associated with the development of AG-236, an siRNA targeting the TMPRSS6 gene, and these will be recorded in our consolidated statements of operations as incurred.

Additionally, 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 licensed products, which may be subject to specified reductions and offsets.

Because the acquired assets under the license agreement with Alnylam do not meet the definition of a business in accordance with ASC 805, Business Combinations, we accounted for the agreement as an asset acquisition.

Because the acquired assets under the license agreement with Alnylam do not meet the definition of a business in accordance with Accounting Standards Codification, or ASC, 805, Business Combinations , we accounted for the agreement as an asset acquisition.

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.

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 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 1 or 2 mutation (and, to the extent required by such approval, the vorasidenib companion diagnostic test is granted an FDA premarket approval), 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, with these royalties referred to as contingent payments and recognized as income when

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.

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Servier also acquired our co-commercialization rights for Bristol Myers Squibb’s IDHIFA® and the right to receive a $25.0 million potential milestone payment under our prior collaboration agreement with Celgene Corporation, or Celgene, and Servier is responsible for conducting certain clinical development activities within the IDHIFA® development program.

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 Vorasidenib Milestone Payment, Vorasidenib Royalty Rights and royalty payments related to TIBSOVO® are referred to as contingent payments and recognized as income when realizable.

Servier also acquired our co-commercialization rights for Bristol Myers Squibb’s IDHIFA® and the right to receive a $25.0 million potential milestone payment under our prior collaboration agreement with Celgene Corporation, or Celgene, and following the sale Servier agreed to conduct certain clinical development activities within the IDHIFA® development program.

In October 2022, we sold our rights to future contingent payments associated with the royalty of 5% of U.S.

net sales of TIBSOVO® from the close of the transaction through the loss of exclusivity to entities affiliated with Sagard Healthcare Partners, or Sagard, and recognized income of $127.9 million within the gain on sale of contingent payments line item in our consolidated statements of operations for the year ended December 31, 2022.

We retain our rights to the potential milestone payment and royalties from Servier if a new drug application for vorasidenib is approved by the FDA.

In November 2023, Servier announced that it was planning to submit a new drug application, or NDA, for vorasidenib for the treatment of IDH-mutant diffuse glioma to the FDA by the end of 2023 and to the European Medicines Agency, or EMA, in early 2024.

The oncology business met the criteria within Accounting Standards Codification 205-20 to be reported as discontinued operations because the transaction was a strategic shift in business that had a major effect on our operations and financial results.

Therefore, we have reported the historical results of the oncology business including the results of operations and cash flows as discontinued operations, and related assets and liabilities were retrospectively reclassified as assets and liabilities of discontinued operations for all periods presented herein.

Refer to Note 15, Discontinued Operations of our consolidated financial statements included in this Annual Report on Form 10-K for additional information.

A more complete description of our business prior to the consummation of the transaction is included in Item 1.

“Business”, in Part I of our Annual Report on Form 10-K for the year ended December 31, 2020 that was previously filed with the Securities and Exchange Commission, or SEC, on February 25, 2021.

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.

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.

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.

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.

Royalty income related to the Retained Earn-Out Rights, if any, will be recognized in the period when realizable.

Financial Operations Overview

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Through March 31, 2021, we financed our operations primarily through proceeds from the sale of our royalty rights, commercial sales of TIBSOVO®, funding received from our collaboration agreements, private placements of our preferred stock, our initial public offering of our common stock and concurrent private placement of common stock to an affiliate of Celgene, and our follow-on public offerings.

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, royalty payments from Servier with respect to U.S.

net sales of TIBSOVO® prior to the sale of these contingent payments to Sagard, proceeds from the sale of contingent payments to Sagard, a potential milestone payment and royalties from Servier if a new drug application for vorasidenib is approved by the FDA with a 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 1 or 2 mutation, 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® and, potentially, collaborations, strategic alliances, licensing arrangements and other nondilutive strategic transactions.

In addition, we may pursue opportunistic debt offerings, and equity or equity-linked offerings.

Additionally, since inception, we have incurred significant operating losses.

Our net loss for the year ended December 31, 2023 was $352.1 million, our net loss for the year ended December 31, 2022 was $231.8 million and our net income for the year ended December 31, 2021 was $1.6 billion.

Additionally, since inception, we have historically incurred significant operating losses.

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.

The net income we generated in the year ended December 31, 2021 was due to the sale of our oncology business to Servier.

We expect to incur significant expenses and net losses until such time we are able to report profitable results.

The net income we generated in the year ended December 31, 2024 was primarily due to the sale of the Vorasidenib Royalty Rights to Royalty Pharma and our receipt of the Vorasidenib Milestone Payment discussed above in Overview .

We expect to continue to incur significant expenses and net losses until such time we are able to report profitable results.

Our net losses may fluctuate significantly from year to year.

We expect that we will continue to incur significant expenses as we continue to advance and expand clinical development and commercialization activities for PYRUKYND®;

advance and expand clinical development of AG-946;

continue to prioritize advancement of AG-181, our PAH stabilizer;

initiate preclinical development of a licensed siRNA development candidate pursuant to our license agreement with Alnylam;

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;

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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 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.

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 a combination of product sales, and we may potentially generate revenue from royalties on product sales, milestone payments, and upfront payments under existing arrangements or future collaborations or licensing agreements.

In the future, we expect to continue to generate revenue from product sales.

We may also generate revenue from milestone payments, upfront payments or royalties on product sales under collaborations or licensing agreements that we may enter into in the future.

Cost of Sales

Cost of sales consists primarily of manufacturing costs for sales of PYRUKYND®.

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, 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, 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, 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.

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.

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.

Research and Development Expenses

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However, the successful development of our product candidates is highly uncertain.

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 remainder of the development and to commercialize these 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 PYRUKYND® or any of our product candidates.

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 new drug application, or NDA, enabling toxicology and clinical trials;

• the successful enrollment in, and completion of, clinical trials;

• the receipt of marketing approvals from applicable regulatory authorities;

• 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, whether alone or in collaboration with others;

• 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;

• maintaining an acceptable safety profile of the products following approval.

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.

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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 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 and clinical study materials;

• 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;

• facilities, depreciation, and other expenses, which include direct and allocated expenses for rent and the maintenance of facilities, insurance and other operating costs.

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In May 2022, we announced our determination to evolve our approach to exploratory research and drug discovery to focus on our existing late-lead optimization programs and to prioritize in-licensing or acquiring assets for pipeline growth.

We reduced approximately 45 roles focused on exploratory research in connection with this evolution of our research organization, and retained an internal research team focused on roles critical to advancing our current and future late-stage research and early clinical programs.

The following summarizes our most advanced programs:

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PYRUKYND® is an orally available small molecule and a potent activator of the wild-type and mutated PK enzymes.

In February 2022, the FDA approved PYRUKYND® for the treatment of hemolytic anemia in adults with PK deficiency in the United States.

In November 2022, we received marketing authorization from the European Commission for PYRUKYND® for the treatment of PK deficiency in adult patients in the EU.

In December 2022, we received marketing authorization in Great Britain for PYRUKYND® for the treatment of PK deficiency in adult patients under the European Commission Decision Reliance Procedure.

In addition, we are currently evaluating PYRUKYND® in clinical trials for the treatment of thalassemia, SCD, and in pediatric patients with PK deficiency.

We have worldwide development and commercial rights to PYRUKYND® and expect to fund the future development and commercialization costs related to this program.

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.

Additionally, we received marketing authorization in Great Britain for PYRUKYND® for the treatment of PK deficiency in adult patients under the European Commission Decision Reliance Procedure.

In December 2024, we announced that we submitted an sNDA to the FDA for PYRUKYND® for the treatment of adult patients with non-transfusion dependent and transfusion-dependent alpha- or beta-thalassemia, which was accepted with standard review by the FDA and granted a PDUFA goal date of September 7, 2025.

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 addition, we are currently evaluating PYRUKYND® in clinical trials for the treatment of SCD and in pediatric patients with PK deficiency.

We have worldwide development and commercial rights to PYRUKYND®.

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.

PYRUKYND® has been granted orphan drug designation for the treatment of PK deficiency by the FDA and the EMA.

Additionally, PYRUKYND® has received orphan drug designation from the FDA for the treatment of thalassemia and SCD.

We have built our commercial infrastructure to support the commercial launch of PYRUKYND® in adult PK deficiency in the United States.

In connection with our regulatory approvals in the EU and Great Britain, we are currently providing access to PYRUKYND® free of charge for eligible patients in those jurisdictions through a global managed access program.

We may provide access to PYRUKYND® for adult patients with PK deficiency in other jurisdictions upon request through the global managed access program, on either a free of charge or for charge basis.

Beyond the global managed access program, we continue to evaluate options for the commercialization of PYRUKYND® outside of the United States, including through exploring potential partnership opportunities.

We are evaluating PYRUKYND® in the following clinical trials:

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.

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.

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.

We provide access to PYRUKYND® for adult patients with PK deficiency in other jurisdictions upon request through the global managed access program, on either a free of charge or for charge basis.

Our global managed access program has not had a significant impact on our business, financial condition or results of operations.

We are evaluating PYRUKYND® in numerous clinical trials, including the following:

• An extension study evaluating the long-term safety, tolerability and efficacy of treatment with PYRUKYND® in patients from ENERGIZE, our completed phase 3, double-blind, randomized, placebo-controlled multicenter study pivotal trial of PYRUKYND® in adults with non-transfusion-dependent alpha- or beta-thalassemia.

We announced topline data for ENERGIZE in January 2024.

A total of 194 patients were enrolled in the study, with 130 randomized to PYRUKYND® 100 mg twice-daily, and 64 randomized to matched placebo.

We announced topline data for ENERGIZE in January 2024 and a more detailed analysis of the data in June 2024.

A total of 194 patients were enrolled in the study, with 130 randomized to PYRUKYND® 100 mg twice-daily, or BID, and 64 randomized to matched placebo.

122 patients (93.8%) in the PYRUKYND® arm and 62 patients (96.9%) in the placebo arm completed the 24-week double-blind period of the study.

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Treatment with PYRUKYND® also demonstrated statistically significant improvements compared to placebo for both key secondary endpoints:

(i) change from baseline in average Functional Assessment of Chronic Illness Therapy-Fatigue, or FACIT-Fatigue, subscale score from week 12 to week 24 and (ii) change from baseline in average emoglobin concentration from week 12 to week 24.

(i) change from baseline in average Functional Assessment of Chronic Illness Therapy-Fatigue, or FACIT-Fatigue, subscale score from week 12 to week 24 and (ii)

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change from baseline in average hemoglobin concentration from week 12 to week 24.

During the 24-week double-blind period, four (3.1%) subjects in the PYRUKYND® arm experienced adverse events, or AEs, leading to discontinuation, and there were no AEs in the placebo arm leading to discontinuation.

We plan to provide a more detailed analysis of the data from this trial at an upcoming medical meeting and we aim to submit an NDA for PYRUKYND® in thalassemia to the FDA by the end of 2024.

• ENERGIZE-T, a phase 3, double-blind, randomized, placebo-controlled multicenter study evaluating the efficacy and safety of PYRUKYND® as a potential treatment for adults with transfusion-dependent alpha- or beta-thalassemia, defined as 6 to 20 RBC units transfused and ≤ six-week transfusion-free period during the 24-week period before randomization.

AEs that led to discontinuation in the PYRUKIND® arm were thrombocytopenia, arthralgia, abdominal distension, and 5 concurrent laboratory adverse events (alanine aminotransferase increase, aspartate aminotransferase increase, blood bilirubin increase, blood LDH increase, and international normalized ratio increase), all in one patient each.

• An extension study evaluating the long-term safety, tolerability and efficacy of treatment with PYRUKYND® in patients from ENERGIZE-T, our completed phase 3, double-blind, randomized, placebo-controlled multicenter study evaluating the efficacy and safety of PYRUKYND® as a potential treatment for adults with transfusion-dependent alpha- or beta-thalassemia, defined as 6 to 20 red blood cell, or RBC, units transfused and ≤ six-week transfusion-free period during the 24-week period before randomization.

The primary endpoint of the trial is percentage of patients with transfusion reduction response, defined as a ≥50% reduction in transfused RBC units with a reduction of ≥2 units of transfused RBCs in any consecutive 12-week period through week 48 compared with baseline.

Secondary endpoints include additional transfusion reduction measures and percentage of participants with transfusion-independence.

This trial has completed enrollment and we plan to announce topline data from this trial in mid-2024.

• 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 in the past 12 months, and have hemoglobin within the range of 5.5 to 10.5 g/dL during screening.

We announced topline data for ENERGIZE-T in June 2024 and a more detailed analysis of the data in December 2024.

A total of 258 patients were enrolled in the study, with 171 randomized to PYRUKYND® 100 mg twice-daily and 87 randomized to matched placebo.

155 patients (90.6%) in the PYRUKYND® arm and 83 patients (95.4%) in the placebo arm completed the 48-week double-blind period of the study.

The study met the primary endpoint of transfusion reduction response, where treatment with PYRUKYND® demonstrated a statistically significant reduction in transfusion burden compared to placebo, as 30.4% of patients achieved a transfusion reduction response, compared to 12.6% of patients in the placebo arm (2-sided p=0.0003).

Treatment with PYRUKYND® also demonstrated a statistically significant reduction in additional measures of transfusion reduction response compared to placebo as assessed by the three key secondary endpoints:

(i) ≥50% reduction in transfused RBC units in any consecutive 24-week period through week 48 compared with baseline, (ii) ≥33% reduction in transfused RBC units from week 13 through week 48 compared with baseline, and (iii) ≥50% reduction in transfused RBC units from week 13 through week 48 compared with baseline.

In addition, a higher proportion of patients in the PYRUKYND® arm (9.9%) compared to the placebo arm (1.1%) achieved the secondary endpoint of transfusion independence (transfusion-free for ≥8 consecutive weeks through week 48).

The proportion of patients with any treatment-emergent adverse events, or TEAEs, was 90.1% in patients on PYRUKYND® and 83.5% in patients on placebo.

The most frequent TEAEs that occurred in at least 10% of patients on PYRUKYND® were headache, upper respiratory tract infection, initial insomnia, diarrhea and fatigue.

Serious TEAEs were reported in 11.0% and 15.3% of patients on PYRUKYND® and placebo, respectively;

2.3% and 1.2%, respectively, were considered treatment-related.

During the 48-week double-blind period, 5.8% of the patients in the PYRUKYND® arm experienced a TEAE leading to discontinuation compared to 1.2% of patients in the placebo arm.

The TEAEs leading to discontinuation of PYRUKYND®, each of which occurred in one patient, were diarrhea, paresthesia oral, concurrent anxiety and insomnia, initial insomnia, supraventricular tachycardia, fatigue, hypertransaminasemia, hepatitis C, hepatic cancer, and renal mass.

The TEAE that led to discontinuation of the one patient on placebo was blood creatine phosphokinase increase.

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®.

All of these events occurred within the first six months of exposure to PYRUKYND® and liver tests improved following discontinuation of PYRUKYND®.

Based on the results of the ENERGIZE and ENERGIZE-T trials, in December 2024 we announced that we filed regulatory applications for PYRUKYND® for the treatment of adult patients with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia with the FDA, EMA and Kingdom of Saudi Arabia and United Arab Emirates health authorities and we included in our regulatory applications hepatocellular injury as an important potential risk of PYRUKYND® in patients with thalassemia and proposed monthly monitoring of liver tests for the first six months of treatment with PYRUKYND®.

We updated our PYRUKYND® clinical trial protocols across all indications to incorporate monthly monitoring of liver tests for the first six months of treatment and updated the U.S.

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.

We enrolled 79 patients in the phase 2 portion of the trial, with 26 patients in the 50 mg twice daily mitapivat arm, 26 patients in the 100 mg twice daily mitapivat arm and 27 patients in the placebo arm.

The primary endpoints of the phase 2 portion of the trial were hemoglobin response, defined as defined as ≥ 1 g/dL

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.

In June 2023,

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increase in average hemoglobin concentration from week 10 to week 12 compared to baseline, and safety.

In June 2023, we announced the phase 2 portion of this trial had achieved its primary endpoint of hemoglobin response in patients in both 50 mg and 100 mg twice daily mitapivat arms.

we announced the phase 2 portion of this trial had achieved its primary endpoint of hemoglobin response in patients in both the 50 mg and 100 mg twice daily mitapivat arms.

46.2% of patients (n=12) in the 50 mg twice daily mitapivat arm and 50.0% of patients (n=13) in the 100 mg twice daily mitapivat arm achieved a hemoglobin response, compared to 3.7% of patients (n=1) in the placebo arm (2-sided p=0.0003 and 0.0001, respectively).

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(i) the least-squares mean (95% confidence interval) for average change from baseline in hemoglobin levels, from week 10 through week 12, for patients in the 50 mg twice daily mitapivat, 100 mg twice daily mitapivat, and placebo arms, respectively, was 1.11 (0.77, 1.45) g/dL, 1.13 (0.79, 1.47) g/dL, and 0.05 (−0.28, 0.39) g/dL;

(ii) we observed improvements in annualized rates of sickle cell pain crises as the annualized rate of sickle cell pain crises (95% confidence interval) for patients in the 50 mg twice daily and 100 mg twice daily mitapivat arms, respectively, was 0.83 (0.34, 1.99) and 0.51 (0.16, 1.59), compared to 1.71 (0.95, 3.08) for patients in the placebo arm;

(ii) we observed improvements in annualized rates of SCPCs as the annualized rate of SCPCs (95% confidence interval) for patients in the 50 mg twice daily and 100 mg twice daily mitapivat arms, respectively, was 0.83 (0.34, 1.99) and 0.51 (0.16, 1.59), compared to 1.71 (0.95, 3.08) for patients in the placebo arm;

(iii) we observed improvement in patient-reported fatigue scores in the 50 mg twice daily mitapivat arm compared to the placebo arm, and the least-squares mean (95% confidence interval) for average changes from baseline in patient-reported fatigue score, from week 10 through week 12, for patients in the 50 mg twice daily mitapivat, 100 mg twice daily mitapivat, and placebo arms, respectively, was −3.80 (−7.16, −0.45), −0.10 (−3.27, 3.08), and −0.17 (−3.40, 3.07).

The safety profile for mitapivat observed in the phase 2 portion of the trial was generally consistent with previously reported data in other studies of SCD and other hemolytic anemias.

The most common treatment-emergent AEs in the 50 mg BID, 100 mg BID, and placebo arms, respectively, were:

The most common TEAEs in the 50 mg BID, 100 mg BID, and placebo arms, respectively, were:

headache (n=6, 6, 7), arthralgia (n=3, 5, 9), dysmenorrhea (n=0, 3, 0), pain (n=3, 3, 2), pain in extremity (n=1, 3, 6), back pain (n=4, 2, 3), nausea (n=1, 2, 4), fatigue (n=4, 1, 5), and influenza-like illness (n=1, 1, 3).

There were no serious treatment-emergent adverse events, or TEAEs, attributed to mitapivat and there were no adverse events leading to drug reduction, discontinuation, interruption or death in either the mitapivat or the placebo arms.

There were no serious TEAEs attributed to mitapivat and there were no AEs leading to drug reduction, discontinuation, interruption or death in either the mitapivat or the placebo arms.

Of the 79 patients enrolled in the study, 73 continued into the Phase 2 open-label extension period.

In October 2023, we enrolled the first patient in the phase 3 portion of this trial.

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.

The primary endpoints are hemoglobin response, defined as ≥1 g/dL increase in average hemoglobin from baseline to week 52, and annualized rate of sickle cell pain crises.

The primary endpoints are hemoglobin response, defined as ≥1 g/dL increase in average hemoglobin from week 24 through week 52 compared to baseline, and annualized rate of SCPCs.

The secondary endpoints include additional clinical efficacy measures related to anemia, hemolysis, erythropoiesis, patient-reported fatigue and pain, annualized frequency of hospitalizations for SCPCs, and change from baseline in six minute walk test.

Participants who complete either the phase 2 or phase 3 portion will have the option to move into a 216-week open-label extension period to continue to receive PYRUKYND®.

We anticipate completing enrollment by the end of 2024 and announcing topline data for this trial in 2025.

We have completed enrollment and expect to announce topline data for this trial in late 2025, with a potential U.S.

commercial launch in 2026, if approved.

• ACTIVATE-kids and ACTIVATE-kidsT, double-blind phase 3 studies evaluating the efficacy and safety of PYRUKYND® as a potential treatment for PK deficiency in not regularly transfused and regularly transfused patients between one and 18 years old, respectively.

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.

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 primary endpoint of ACTIVATE-kidsT is transfusion reduction response, defined as ≥33% reduction in total RBC transfusion volume from week 9 through week 32 of the double-blind period.

ACTIVATE-kidsT has completed enrollment and we expect to announce topline data for this trial by the end of 2024.

ACTIVATE-kids is currently enrolling patients, we expect to complete enrollment for this trial by mid-2024, and we anticipate announcing topline data for this trial in 2025.

We announced topline data for ACTIVATE-kidsT in August 2024.

Using Bayesian methodology, the prespecified statistical criterion for the primary endpoint in ACTIVATE-kidsT was not met using low or moderate borrowing of data from the ACTIVATE-T study in adults.

In the study, 28.1% of patients in the mitapivat arm achieved the primary endpoint of transfusion reduction response, compared to 11.8% of patients in the placebo arm.

Transfusion-free response and normal hemoglobin response were secondary endpoints in this study and only observed in patients in the mitapivat arm.

In the 32-week double-blind treatment period, mitapivat was generally safe and well-tolerated, with safety results consistent with the safety profile for mitapivat previously observed in adults with PK deficiency who are regularly transfused.

A total of 30 patients were enrolled in ACTIVATE-kids, with 19 randomized to mitapivat twice-daily and 11 randomized to matched placebo.

All patients in both treatment arms completed the 20-week double-blind period of the study.

We announced topline data for ACTIVATE-kids in February 2025.

Using Bayesian methodology, the prespecified statistical criterion for the primary endpoint in ACTIVATE-kids was met using a range of relative borrowing from the adult ACTIVATE study, for all possible borrowing weights (ranging from 0 to 1).

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.

There were 31.6% of patients in the mitapivat arm achieving a hemoglobin response compared to 0% of patients in the placebo arm;

the 95% confidence interval for the difference in hemoglobin response rates between mitapivat and placebo was >0 (95% CI=10.8% to 52.7%).

In addition, improvements in changes from baseline for markers of hemolysis (indirect bilirubin,

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lactate dehydrogenase and haptoglobin) were observed in the mitapivat arm compared to the placebo arm.

In the 20-week double-blind period of the study, a similar proportion of patients had AEs in the mitapivat and placebo arms and there were no discontinuations of study treatment due to AEs or for any reason.

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.

• An extension study evaluating the safety, tolerability and efficacy of treatment with PYRUKYND® in patients from our completed phase 2, open-label safety and efficacy clinical trial of PYRUKYND® in adults with non-transfusion-dependent alpha- and beta-thalassemia.

• In collaboration with the Company, the National Institutes of Health, or NIH, is evaluating PYRUKYND® in a phase 1 trial in patients with SCD pursuant to a cooperative research and development agreement.

The core trial period has completed, and the long-term extension study is ongoing.

In June 2020, clinical proof of concept was established based on a preliminary analysis of the data from this trial.

• In collaboration with the Company, University Medical Center Utrecht, or UMC Utrecht, is evaluating PYRUKYND® in patients with SCD pursuant to an investigator sponsored trial agreement.

The trial has completed enrollment and patient follow-up is ongoing, and a 2-year extension study has been initiated for patients who complete the follow-up period.

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Novel PK Activator

We are developing AG-946, a novel PK activator, for the potential treatment of LR MDS and hemolytic anemias.

We are evaluating AG-946 in a phase 1 trial of AG-946 in healthy volunteers and in patients with SCD.

We have presented data from the healthy volunteer cohorts, and we have initiated the SCD patient cohort of this phase 1 trial.

We initiated a phase 2a clinical trial of AG-946 in adults with LR MDS in the third quarter of 2022, and the trial has completed enrollment with 22 patients, including 12 patients classified as non-transfused and 10 patients classified as low transfusion burden.

Patients received 5 mg of AG-946 once daily for up to 16 weeks.

We are developing tebapivat, a novel PK activator for the potential treatment of LR MDS and hemolytic anemias.

Tebapivat has been granted orphan drug designation for the treatment of MDS by the FDA.

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 also initiated a phase 2a clinical trial of tebapivat in adults with LR MDS in the third quarter of 2022, and the trial has completed enrollment with 22 patients, including 12 patients classified as non-transfused and 10 patients classified as low transfusion burden.

Patients received 5 mg of tebapivat once daily for up to 16 weeks.

The two primary endpoints of the trial were transfusion independence (for patients classified as low transfusion burden), defined as transfusion-free for ≥ eight consecutive weeks during the 16-week treatment period, and hemoglobin response, defined as a ≥ 1.5 g/dL increase from baseline in the average hemoglobin concentration measured from week 8 through week 16.

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We observed that four of the 10 patients with low transfusion burden achieved the transfusion independence endpoint, and one of the 22 patients achieved the hemoglobin response endpoint in the 16-week treatment period.

The safety profile observed was consistent with data reported in the healthy volunteer study of AG-946.

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.

We intend to complete a full evaluation of the phase 2a trial results and assess the impact on the phase 2b portion of the protocol in 2024.

We anticipate initiating a phase 2b trial of AG-946 in adults with LR MDS in mid-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 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 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 investigational new drug, or IND, application in December 2023, and plan to initiate a phase 1 study in healthy volunteers in the first half of 2024.

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 intend to pursue development of a licensed product for the potential treatment of patients with PV.

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.

We initiated a phase 1 clinical trial of AG-181 in healthy volunteers in the first quarter of 2024.

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.

We expect to file an investigational new drug application, or IND, with the FDA for AG-236 for the treatment of PV in mid-2025.

Selling, General and Administrative Expenses

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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.

Impact of COVID-19 on our Business

As of December 31, 2023, we have not experienced a significant financial or supply chain impact directly related to the recent COVID-19 pandemic, but have experienced some disruptions to clinical operations and certain clinical and research activities at our contract research organizations, or CROs.

Although the public health emergency declaration related to COVID-19 ended on May 11, 2023, the extent of the effect of any future pandemics or public health emergencies on our operational and financial performance will depend in large part on future developments, which cannot be predicted and are out of our control.

Critical Accounting Policies and Significant Judgments and Estimates

Our management’s discussion and analysis of our financial condition and results of operations are based on our consolidated financial statements, which we have prepared in accordance with accounting principles generally accepted in the United States.

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.

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statements, as well as the reported amounts of revenue and expenses during the reporting periods.

On an ongoing basis, we evaluate our estimates and judgments.

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While our significant accounting policies are described in more detail in the notes to our consolidated financial statements included in this Annual Report on Form 10-K, we believe that the following accounting policies are the most critical in fully understanding and evaluating our financial condition and results of operations and are policies that require a significant level of judgment and estimates.

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Revenue recognition

Under Accounting Standards Codification 606, Revenue from Contracts with Customers , or ASC 606, revenue is recognized when the customer obtains control of promised goods or services, in an amount that reflects the consideration that we expect to receive in exchange for those goods or services.

Under ASC 606, Revenue from Contracts with Customers , or ASC 606, revenue is recognized when the customer obtains control of promised goods or services, in an amount that reflects the consideration that we expect to receive in exchange for those goods or services.

To determine revenue recognition for arrangements that have been determined to be within the scope of ASC 606, we perform the following five steps:

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We estimate the amount of product sales that may be returned by Customers and record this estimate as a reduction of revenue in the period the related product revenue is recognized.

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.

We currently estimate product return

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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

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Examples of estimated accrued research and development expenses include fees paid to:

(i) CROs and other third parties in connection with clinical studies and preclinical development activities;

(ii) investigative sites in connection with clinical studies;

(i) CROs and other third parties in connection with clinical trials and preclinical development activities;

(ii) investigative sites in connection with clinical trials;

and (iii) third parties related to product manufacturing, development and distribution of clinical supplies.

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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.

Discontinued Operations

We accounted for the sale of our oncology business in the first quarter of 2021 in accordance with ASC 205, Discontinued Operations and Accounting Standards Update, or ASU, No.

2014-08, Reporting of Discontinued Operations and Disclosures of Disposals of Components of an Entity .

We followed the held-for-sale criteria as defined in ASC 360, Property, Plant and Equipment, and ASC 205.

ASC 205 requires that a component of an entity that has been disposed of or is classified as held for sale and has operations and cash flows that can be clearly distinguished from the rest of the entity be reported as assets held for sale and discontinued operations.

In the period a component of an entity has been disposed of or classified as held for sale, the results of operations for the periods presented are reclassified into separate line items in the consolidated statements of operations.

Assets and liabilities are also reclassified into separate line items on the related consolidated balance sheets for the

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periods presented.

The statements of cash flows for the periods presented are also reclassified to reflect the results of discontinued operations as separate line items.

ASU 2014-08 requires that only a disposal of a component of an entity, or a group of components of an entity, that represents a strategic shift that has, or will have, a major effect on the reporting entity’s operations and financial results be reported in the financial statements as discontinued operations.

ASU 2014-08 also provides guidance on the financial statement presentations and disclosures of discontinued operations.

Due to the sale of our oncology business during the first quarter of 2021, in accordance with ASC 205, we have classified the results of the oncology business as discontinued operations in our consolidated statements of operations and cash flows for all periods presented, and refer to Note 15, Discontinued Operations .

All amounts included in the notes to the consolidated financial statements relate to continuing operations unless otherwise noted.

Results of Operations

Certain prior-year amounts have been reclassified to conform with current presentation.

Comparison of years ended December 31, 2024, 2023 and 2022

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Total Revenue – 2024 vs.

2022 – The increase in total revenue of $12.6 million in 2023 compared to 2022 was due to increased product revenue associated with PYRUKYND®, which was approved by the FDA in February 2022, partially offset by revenue recognized in 2022 associated with the licensing of intellectual property for our Friedreich's Ataxia preclinical program.

2023 – The increase in total revenue of $9.7 million in 2024 compared to 2023 was due to increased volume associated with PYRUKYND®.

Total Revenue – 2023 vs.

2021 – The increase in total revenue of $14.2 million in 2022 compared to 2021 was due to product revenue associated with PYRUKYND®, which was approved in February 2022, and revenue recognized associated with the licensing of intellectual property for our Friedreich's Ataxia preclinical program.

Total Operating Expenses

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Total Operating Expenses – 2024 vs.

2022 – The increase in total operating expenses of $15.0 million in 2023 compared to 2022 was primarily due to an increase of $15.6 million in research and development expenses, which is described below under Research and Development Expenses.

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 – 2023 vs 2022 – The increase in total operating expenses of $15.0 million in 2023 compared to 2022 was primarily due to an increase of $15.6 million in research and development expenses, which is described below under Research and Development Expenses.

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Research and Development Expenses

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PK activator (PYRUKYND®) $ 112,720 $ 101,322 $ 83,271

Novel PK activator (AG-946) 18,267 15,747 10,658

Novel PK activator (tebapivat) 14,544 18,267 15,747

In-process research and development — 17,500 —

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Total Research and Development Expenses – 2024 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.

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 increase in indirect expenses was primarily due to a $6.1 million increase in compensation and related expenses due to an increase in workforce related 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

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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 increase in PYRUKYND® costs was primarily due to increased process development expenses and increased costs associated with clinical trials for patients with SCD, partially offset by lower costs associated with the phase 3 clinical trials of PYRUKYND® in patients with thalassemia, ENERGIZE and ENERGIZE-T.

The increase in other research and platform programs was primarily a result of costs associated with AG-236, the in-licensed siRNA TMPRSS6 program for PV.

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.

The increase in direct expenses was primarily due to a $18.1 million increase in PYRUKYND® costs and in-process research and development from the $17.5 million up-front payment associated with the license agreement with Alnylam discussed above under Overview, offset by a $15.3 million decrease in other research and platform programs.

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The decrease in indirect expenses was primarily due to a $4.8 million decrease in facilities and IT related expenses & other due to a reduction in facility expenses associated with the evolution of our research organization, and the $1.5 million of reimbursable transition related services we provided to Servier in 2022 related to the sale of the oncology business for discovery, clinical development, technical operations, and related activities, which were completed during the three months ended March 31, 2022.

Total Research and Development Expenses – 2022 vs 2021 – The increase in research and development expenses of $22.9 million in 2022 compared to 2021 was due to an $18.2 million increase in our direct expenses and a $4.7 million increase in our indirect expenses.

The increase in direct expenses was due to a $9.3 million increase in PYRUKYND® costs, a $5.1 million increase in AG-946 costs, and a $3.9 million increase in other research and platform programs.

The increase in PYRUKYND® costs was primarily due to increased costs for the phase 3 trials of PYRUKYND® in patients with thalassemia, ENERGIZE and ENERGIZE-T, the phase 3 trials of PYRUKYND® in pediatric patients with PK deficiency, ACTIVATE-kids and ACTIVATE-kidsT, and the phase 2/3 trial of PYRUKYND® in patients with SCD, RISE UP, offset by closeouts of the ACTIVATE and ACTIVATE-T studies.

The increase in AG-946 costs was primarily due to start-up costs for the phase 2 trial of AG-946 in patients with LR MDS and increased spend for the phase 1 trial of AG-946 in h ealthy volunteers and in patients with SCD.

The increase in other research and platform programs was primarily driven by increased activity associated with our preclinical PAH program as well as increased activity on various other exploratory activities.

The increase in indirect expenses was primarily due to a $14.1 million increase in compensation and related expenses primarily due to increased headcount, as well as certain workforce-related expenses associated with the evolution of our research organization.

Th is increase was partially offset by $7.9 million of additional reimbursable transition related services we provided to Servier in 2021 compared to 2022 related to the sale of the oncology business for discovery, clinical development, technical operations, and related activities, which were completed during the three months ended March 31, 2022.

Other Income and Expense

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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

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Other Income and Expense – 2024 vs.

2022 – The decrease in gain on sale of contingent payments and royalty income from gain on sale of oncology business in 2023 compared to 2022 was due to the sale to Sagard in the fourth quarter of 2022 of our rights to future contingent payments associated with royalties on U.S.

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 .

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.

Other Income and Expense – 2023 vs 2022 – The decrease in gain on sale of contingent payments and royalty income from gain on sale of oncology business in 2023 compared to 2022 was due to the sale to Sagard in the fourth quarter of 2022 of our rights to future contingent payments associated with royalties on U.S.

next sales of TIBSOVO®.

The $20.6 million increase in

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interest income, net in 2023 compared to 2022 is primarily attributable to an increase in interest rates.

The $20.6 million increase in interest income, net in 2023 compared to 2022 is primarily attributable to an increase in interest rates.

The $0.7 million decrease in other income, net in 2023 compared to 2022 primarily related to approximately $2.6 million of reimbursable transition related services and fees for the sale of the oncology business in 2022, partially offset by sublease income of $6.1 million in 2023 compared to $4.1 million in 2022.

Other Income and Expense – 2022 vs 2021 – The $127.9 million gain on sale of contingent payments in 2022 was due to the October 27, 2022 sale of future contingent payments to entities affiliated with Sagard.

The $12.0 million increase in interest income, net in 2022 compared to 2021 was primarily attributable to an increase in interest rates.

The $3.2 million increase in royalty income from gain on sale of oncology business related to higher income from royalties on U.S.

net sales of TIBSOVO® by Servier in 2022 compared to 2021.

The $7.7 million decrease in other income, net in 2022 compared to 2021 primarily related to approximately $13.8 million of reimbursable transition related services and fees for the sale of the oncology business in 2021 compared to $2.6 million in 2022, partially offset by sublease income of $4.1 million in 2022 compared to $0.5 million in 2021.

Loss from Operations and Net (Loss) Income

Net Income (Loss)

(In thousands) 2024 2023 2022

Net loss from continuing operations $ (352,088) $ (231,801) $ (356,510)

Net income from discontinued operations, net of tax — — 1,961,225

Net (loss) income (352,088) (231,801) 1,604,715

Loss from Operations and Net Loss – 2023 vs 2022 – The $120.3 million increase in net loss from continuing operations in 2023 compared to 2022 was primarily driven by the gain on sale of contingent payments in 2022 described above in Other Income and Expense, higher research and development expenses discussed above under Research and Development Expenses, which includes the $17.5 million up-front payment associated with the license agreement with Alnylam discussed above under Overview, and the decrease in royalty income from gain on sale of oncology business described above in Other Income and Expense.

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 Income (Loss) – 2023 vs 2022 – The $120.3 million increase in net loss in 2023 compared to 2022 was primarily driven by the gain on sale of contingent payments in 2022 described above in Other Income and Expense, higher research and development expenses discussed above under Research and Development Expenses, which includes the $17.5 million up-front

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payment associated with the license agreement with Alnylam discussed above under Overview, and the decrease in royalty income from gain on sale of oncology business described above in Other Income and Expense.

These were partially offset by the increase in interest income, net discussed above in Other Income and Expense and the increase in revenue discussed above under Revenues.

Loss from Operations and Net (Loss) Income – 2022 vs 2021 – The $124.7 million decrease in net loss from continuing operations in 2022 compared to 2021 was primarily driven by the gain on sale of contingent payments in 2022 described above in Other Income and Expense, the increase in revenue in 2022 compared to 2021 discussed above under Revenues, and the increase in interest income, net and royalty income from gain on sale of oncology business discussed above under Other Income and Expense.

These were partially offset by higher research and development expenses discussed above under Research and Development Expenses and a decrease in other income, net discussed above under Other Income and Expense.

The change in net income from discontinued operations and net (loss) income in 2022 compared to 2021 was primarily driven by the sale of our oncology business to Servier for approximately $1.8 billion in cash in the first quarter of 2021, which is included within net income from discontinued operations.

Liquidity and Capital Resources

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Since our inception, and through March 31, 2021, we financed our operations primarily through proceeds from the sale of our royalty rights, commercial sales of TIBSOVO®, funding received from our collaboration agreements, private placements of our preferred stock, our initial public offering of our common stock and concurrent private placement of common stock to an affiliate of Celgene, and our follow-on public offerings.

net sales of TIBSOVO® prior to the sale of these contingent payments to Sagard, proceeds from the sale of contingent payments to Sagard, a potential milestone payment and royalties from Servier if a new drug application for vorasidenib is approved by the FDA with a 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 1 or 2 mutation, the actual and potential future sales of PYRUKYND® and, potentially, collaborations, strategic alliances, licensing arrangements and other nondilutive strategic transactions.

In addition, we may pursue opportunistic debt offerings, and equity or equity-linked offerings.

On March 31, 2021, we completed the sale of our oncology business to Servier.

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 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 1 or 2 mutation (and, to the extent required by such approval, the vorasidenib companion

net sales of TIBSOVO® from the close of the transaction through loss of exclusivity, and the Vorasidenib Royalty Rights.

The Vorasidenib Milestone Payment, Vorasidenib Royalty Rights and royalty payments related to TIBSOVO® are referred to as contingent payments and recognized as income when realizable.

Servier a lso acquired our co-commercialization rights for Bristol Myers Squibb's IDHIFA® and the right to receive a $25.0 million potential milestone payment under our prior collaboration agreement with Celgene, and following the sale Servier has agreed to conduct certain clinical development activities within the IDHIFA® development progra m.

As discussed in Note 1, Nature of Business to the consolidated financial statements in this Annual Report on Form 10-K, in October 2022, we sold our rights to the royalty on U.S.

net sales of TIBSOVO® to Sagard for $131.8 million, but we retained our rights to the Vorasidenib Milestone Payment and Vorasidenib Royalty Rights.

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.

In addition, any such Vorasidenib Royalty Rights payments made by Servier on account of U.S.

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.

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.

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diagnostic test is granted an FDA premarket approval), 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.

The milestone payment for approval of vorasidenib and royalty payments related to vorasidenib and TIBSOVO® represent contingent consideration.

Servier also acquired our co-commercialization rights for Bristol Myers Squibb's IDHIFA® and the right to receive a $25.0 million potential milestone payment under our prior collaboration agreement with Celgene, and following the sale Servier is responsible for conducting certain clinical development activities within the IDHIFA® development progra m.

As discussed below in Note 1, Na t ure of Business , in October 2022, we sold our rights to the royalty on U.S.

net sales of TIBSOVO® to Sagard for $131.8 million.

We retained our rights to the potential milestone payment and royalties from Servier if a new drug application for vorasidenib is approved by the FDA.

In November 2023, Servier announced that it planned to submit a new drug application for vorasidenib for the treatment of IDH-mutant diffuse glioma to the FDA by the end of 2023 and to the European Medicines Agency, or EMA, in early 2024.

Our cash, cash equivalents and marketable securities balance was $806.4 million at December 31, 2023.

The $200.0 million milestone payment and royalty payments discussed above are our only committed potential external sources of funds.

Whether the regulatory approval milestone for vorasidenib will be achieved is subject to various risks and uncertainties, which are outside our control.

Furthermore, we cannot predict what success, if any, Servier may have in the United States with respect to sales of vorasidenib, if approved, and consequently we cannot estimate the amount of royalty payments that we can expect to receive from Servier prior to the loss of exclusivity of vorasidenib.

The following table provides information regarding our cash flows for the years ended December 31, 2024, 2023 and 2022:

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Net cash provided by investing activities 363,441 239,575 243,261

Net cash provided by (used in) financing activities 5,433 2,350 (765,768)

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 $296.1 million during the year ended December 31, 2023, of which all was used by continuing operations, 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 $31.2 million and cash received from revenues of $28.6 million.

Cash used in operating activities of $309.5 million during the year ended December 31, 2022, of which all was used by continuing operations, 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.

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.

Cash used in operating activities of $296.1 million during the year ended December 31, 2023 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 $31.2 million and cash received from revenues of $28.6 million.

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 $407.3 million during the year ended December 31, 2021, of which $314.1 million was used by continuing operations and $93.2 million was used by discontinued operations, was primarily due to operating expenses driven by research and development costs described above in Research and Development Expenses, offset by cash received of $39.5 million from sales of TIBSOVO®, and $1.2 million in cost reimbursements related to our collaboration agreements with Celgene.

Net cash provided by investing activities

The cash provided by investing activities for the year ended December 31, 2023, of which all was provided by continuing operations, 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 investing activities for the year ended December 31, 2022, of which all was provided by continuing operations, was primarily due to cash received of $131.8 million from the sale of future contingent payments described above in Other Income and Expense and higher proceeds from maturities and sales of marketable securities than purchases of marketable securities.

The cash provided by investing activities for the year ended December 31, 2021, of which $1,802.9 million was provided by discontinued operations and $554.2 million was used by continuing operations was primarily due to the approximately $1.8

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billion in cash proceeds received from the sale of our oncology business to Servier that was completed on March 31, 2021, and the result of higher purchases of marketable securities than proceeds from maturities and sales of marketable securities.

Net cash provided by (used in) financing 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.

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.

The cash provided by investing activities for the year ended December 31, 2022 was primarily due to cash received of $131.8 million from the sale of future contingent payments described above in Other Income and Expense and higher proceeds from maturities and sales of marketable securities than purchases of marketable securities.

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.

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.

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.

The cash used in financing activities for the year ended December 31, 2021 was primarily the due to the repurchase of common stock under our Repurchase Program of $802.5 million, partially offset by $37.3 million of proceeds received from stock option exercises and purchases made pursuant to our employee stock purchase plan.

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®.

If we obtain additional marketing approvals for PYRUKYND® 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.

We expect that our existing cash, cash equivalents and marketable securities as of December 31, 2023, together with anticipated product revenue, interest income and the potential vorasidenib milestone will enable us to fund our operating expenses and capital expenditures through several value-creating milestones and at least into 2026.

This guidance does not include cash inflows from potential royalties or royalty monetization from vorasidenib, commercializing mitapivat outside of the United States through one or more partnerships, or other potential strategic business or financial agreements.

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.

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.

Our expectations regarding our long-term funding requirements are

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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 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 contingent consideration we ultimately receive from Servier;

• the costs and timing of our ongoing commercialization activities, including product manufacturing, sales, marketing and distribution for PYRUKYND® for the treatment of hemolytic anemia in adults with PK deficiency in approved jurisdictions;

• 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;

• 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;

• the costs and timing of future commercialization activities, including product manufacturing, sales, marketing and distribution, for any of our product candidates for which we may receive marketing approval;

• 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, including the recent COVID-19 pandemic;

• operational delays, disruptions and/or increased costs associated with global economic developments, rising global energy prices or energy shortages or rationing.

Until such time, if ever, as we can generate substantial product revenue, we expect to finance our cash needs primarily through cash on hand, the potential milestone payment and royalties from Servier if vorasidenib is approved by the FDA, the actual and potential future sales of PYRUKYND® and, potentially, collaborations, strategic alliances, licensing arrangements and other nondilutive strategic transactions.

• operational delays due to public health epidemics;

• operational delays, disruptions and/or increased costs associated with global economic and political developments, rising global energy prices or energy shortages or rationing.

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.

In addition, we may pursue opportunistic debt offerings, and equity or equity-linked offerings.

We do not have any committed external source of funds other than the potential milestone and royalty payments that we are eligible to receive with respect to vorasidenib under our purchase agreement with Servier.

We do not have any committed external source of funds other than the Retained Earn-Out Rights.

To the extent that we raise additional capital through the sale of equity or convertible debt securities, the ownership interest of our stockholders will be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect the rights of our common stockholders.

Debt financing, if available, may involve agreements that include covenants limiting or restricting our

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ability to take specific actions, such as incurring additional debt, selling or licensing our assets, making capital expenditures or declaring dividends.

Debt financing, if available, may involve agreements that include covenants limiting or restricting our ability to take specific actions, such as incurring additional debt, selling or licensing our assets, making capital expenditures or declaring dividends.

If we raise funds through collaborations, strategic alliances or licensing arrangements with third parties, we may have to relinquish valuable rights to our technologies, future revenue streams, research programs or product candidates, or grant licenses on terms that may not be favorable to us.

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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.

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Contractual Obligations

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Arrangement is for a contractual term of five years, however, the total funds can be allocated in any manner to meet the agreement terms.

Amounts included assume equal payments each year.

We also enter into agreements in the normal course of business with CROs for clinical trials and contract manufacturing organizations, or CMOs, for supply manufacturing, and with vendors for preclinical research studies and other services and products for operating purposes.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 7. Management’s Discussion and Analysis