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Item 2. Management’s Discussion and Analysis

2025-10-30 compared with 2025-07-31 · 102 added, 87 removed, 268 unchanged (41% of the section changed)

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Forward-looking Information

The following discussion of our financial condition and results of operations should be read in conjunction with our unaudited condensed consolidated financial statements as of June 30, 2025 and for the three and six months ended June 30, 2025 and 2024, and related notes included in Part I, Item 1 of this Quarterly Report on Form 10-Q, as well as the audited consolidated financial statements and notes and Management’s Discussion and Analysis of Financial Condition and Results of Operations, included in our Annual Report on Form 10-K for the year ended December 31, 2024 filed with the SEC on February 13, 2025.

The following discussion of our financial condition and results of operations should be read in conjunction with our unaudited condensed consolidated financial statements as of September 30, 2025 and for the three and nine months ended September 30, 2025 and 2024, and related notes included in Part I, Item 1 of this Quarterly Report on Form 10-Q, as well as the audited consolidated financial statements and notes and Management’s Discussion and Analysis of Financial Condition and Results of Operations, included in our Annual Report on Form 10-K for the year ended December 31, 2024 filed with the SEC on February 13, 2025.

This Management’s Discussion and Analysis of Financial Condition and Results of Operations contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995.

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We undertake no obligation to revise the forward-looking statements contained herein to reflect events or circumstances after the date hereof or to reflect the occurrence of unanticipated events, except as required by law.

We are a biopharmaceutical company committed to transforming patients’ lives through leadership in the field of cellular metabolism, with the goal of creating differentiated medicines for rare diseases, with a focus on classical hematology.

With a history of focused study on cellular metabolism, we have a deep and mature understanding of this biology, which is involved in the healthy functioning of nearly every system in the body.

Building on this expertise, these learnings can be rapidly applied to our clinical trials with the goal of developing medicines that can have a significant impact for patients.

We accelerate the impact of our portfolio by cultivating connections with patient communities, healthcare professionals, partners and colleagues to discover, develop and deliver potential therapies for rare diseases.

We are a commercial-stage biopharmaceutical company dedicated to redefining the future of rare disease treatment.

We champion an inclusive culture that fosters bold innovation and collaboration, both within our teams and with the rare disease communities we serve.

By building deep connections and trusted partnerships with patients, advocates, and healthcare professionals, we advance our understanding of the unique priorities and needs of these communities.

These real-world insights, combined with our biological expertise, allow us to develop and deliver innovative medicines with the potential to transform lives.

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.

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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® for the treatment of sickle cell disease, or SCD.

We are also developing (i) tebapivat, a novel PK activator, for the potential treatment of lower-risk myelodysplastic syndromes, or LR MDS, and SCD;

The FDA accepted the sNDA and granted a Prescription Drug User Fee Act, or PDUFA, goal date of September 7, 2025, which the FDA subsequently extended to December 7, 2025 following our submission of a proposed Risk Evaluation and Mitigation Strategy, or REMS, to mitigate the risk of hepatocellular injury that was described in the original sNDA filing.

The submission of the REMS is a major amendment to the PYRUKYND® sNDA, resulting in the three-month review extension.

The extension was not the result of new or additional efficacy or safety data requested by the FDA or submitted by us.

In December 2024, we also 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 the United Arab Emirates health authorities for PYRUKYND® for the treatment of adult patients with non-transfusion dependent and transfusion-dependent alpha- or beta-thalassemia.

In August 2025, we announced that the Saudi Food and Drug Authority approved PYRUKYND® for the treatment of adult patients with non-transfusion dependent and transfusion-dependent alpha- or beta-thalassemia.

In October 2025, we announced that the Committee for Medicinal Products for Human Use, or the CHMP, of the EMA adopted a positive opinion for the new indication for PYRUKYND® in adults for the treatment of anemia associated with transfusion-dependent and non-transfusion-dependent alpha- or beta-thalassemia.

The European Commission will now review the CHMP’s opinion, with the final decision expected by early 2026.

In addition, we are currently evaluating PYRUKYND® 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 SCD;

(ii) AG-181, our phenylalanine hydroxylase, or PAH, stabilizer for the potential treatment of phenylketonuria, or PKU;

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In accordance with the license agreement, 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.

In the three months ended June 30, 2025, we achieved a regulatory milestone that triggered a $10.0 million payment to Alnylam, which we recorded within research and development expenses in our condensed consolidated statements of operations.

In the nine months ended September 30, 2025, we achieved a regulatory milestone that triggered a $10.0 million payment to Alnylam, which we recorded within research and development expenses in our condensed consolidated statements of operations.

Sale of Oncology Business to Servier and Sale of Contingent Payments

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Financial Operations Overview

Since inception, our operations have primarily focused on organizing and staffing our company, business planning, raising capital, assembling our core capabilities in cellular metabolism and classical hematology, identifying potential product candidates, undertaking preclinical studies, conducting clinical trials, establishing a commercial infrastructure, preparing for and executing on the commercial launch of PYRUKYND® and, prior to the sale of our oncology business to Servier on March 31, 2021, marketing TIBSOVO® and IDHIFA®.

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.

candidates, undertaking preclinical studies, conducting clinical trials, establishing a commercial infrastructure, preparing for and executing on the commercial launch of PYRUKYND® and, prior to the sale of our oncology business to Servier on March 31, 2021, marketing TIBSOVO® and IDHIFA®.

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, 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.

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

Our net loss for the six months ended June 30, 2025 was $201.3 million and our net loss for the six months ended June 30, 2024 was $177.7 million.

As of June 30, 2025, we had an accumulated deficit of $350.2 million.

Our net loss for the nine months ended September 30, 2025 was $304.7 million and our net income for the nine months ended September 30, 2024 was $770.2 million.

As of September 30, 2025, we had an accumulated deficit of $453.7 million.

The net income we generated in the nine months ended September 30, 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.

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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 three and six months ended June 30, 2025 and 2024 were expensed prior to February 17, 2022, and, therefore, are not included in costs of sales during the three and six months ended June 30, 2025 and 2024.

The amounts excluded from cost of sales were not significant during the three and six months ended June 30, 2025 and 2024.

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 three and nine months ended September 30, 2025 and 2024 were expensed prior to February 17, 2022, and, therefore, are not included in costs of sales during the three and nine months ended September 30, 2025 and 2024.

The amounts excluded from cost of sales were not significant during the three and nine months ended September 30, 2025 and 2024.

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 three and six months ended June 30, 2025 and 2024.

We have not reserved for excess or obsolete inventory during the three and nine months ended September 30, 2025 and 2024.

Research and Development Expenses

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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.

are unable to predict the amount of net cash inflows from PYRUKYND® or any of our 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:

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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.

The FDA accepted the sNDA and granted a PDUFA goal date of September 7, 2025, which the FDA subsequently extended to December 7, 2025 following our submission of a proposed REMS to mitigate the risk of hepatocellular injury that was described in the original PYRUKYND® sNDA.

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.

October 2025, we announced that the CHMP of the EMA adopted a positive opinion for the new indication for PYRUKYND® in adults for the treatment of anemia associated with transfusion-dependent and non-transfusion-dependent alpha- or beta-thalassemia.

The European Commission will now review the CHMP’s opinion, with the final decision expected by early 2026.

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

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

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

We have full ownership rights to PYRUKYND® and expect to fund the future development and commercialization costs related 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 Gulf Cooperation Council region.

In June 2025, we entered into a distribution agreement with Avanzanite Bioscience B.V., or the Avanzanite Agreement, pursuant to which we granted Avanzanite the right to commercialize PYRUKYND® in the European Economic Area, Switzerland, and the U.K.

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, 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 either a free of charge or for 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.

Beyond the global managed access program, we have entered into the NewBridge Agreement and the Avanzanite Agreement for commercialization of PYRUKYND® in certain regions outside of the United States and we continue to evaluate other options for the commercialization of PYRUKYND® outside of the United States, including through exploring potential partnership opportunities.

In connection with our regulatory approvals in the EU, Great Britain and Saudi Arabia, we provide access to PYRUKYND® to eligible patients through the Avanzanite Agreement and the NewBridge Agreement, as applicable, and on either a free of charge or for charge basis for eligible patients in those jurisdictions and other jurisdictions through a global managed access program.

To date, none of the NewBridge Agreement, the Avanzanite Agreement or our global managed access program have had a significant impact on our business, financial condition or results of operations.

We continue to evaluate other options for the commercialization of PYRUKYND® outside of the United States, including through exploring potential partnership opportunities.

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

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(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).

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.

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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 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.

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Prescribing Information, or USPI, for PYRUKYND® for the treatment of hemolytic anemia in adults with PK deficiency to reflect the aforementioned risk of hepatocellular injury and recommended monitoring.

In September 2025, we announced that, following an information request from the FDA, we submitted a proposed REMS to mitigate the risk of hepatocellular injury that was described in the original PYRUKYND® sNDA.

• 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.

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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 week 24 through week 52 compared to baseline, and annualized rate of SCPCs.

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.

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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.

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.

In November 2023, we announced that we achieved clinical proof-of-concept in the phase 2a portion of the trial.

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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.

19 patients elected to enroll in the extension period for up to 156 weeks.

We evaluated the phase 2a trial results and assessed the impact of those results on the phase 2b portion of the protocol, and based on the data generated in the phase 2a portion of the trial, we increased the dosage levels evaluated in the phase 2b portion of the trial, which we initiated in the third quarter of 2024.

We expect to complete enrollment in this phase 2b trial in late 2025.

We completed enrollment in the phase 2b portion of the trial in September 2025 and expect to announce topline data for this trial in early 2026.

Other Programs

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Also, in July 2023, we entered into a license agreement with Alnylam for the development and commercialization of products containing or comprised of an siRNA preclinical development candidate discovered by Alnylam and targeting the TMPRSS6 gene, and we are developing a product candidate, AG-236, for the potential treatment of patients with PV.

We filed an IND with the FDA for AG-236 for the treatment of PV which cleared in June 2025.

We initiated a phase 1 clinical trial evaluating AG-236 in healthy volunteers in July 2025.

We filed an IND with the FDA for AG-236 for the treatment of PV which cleared in June 2025, and we initiated a phase 1 clinical trial evaluating AG-236 in healthy volunteers in July 2025.

Selling, General and Administrative Expenses

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We have determined that our most critical accounting estimates are those relating to revenue recognition, accrued research and development expenses and stock-based compensation.

As of June 30, 2025, there have been no material changes to our existing critical accounting estimates discussed in Part II, Item 7 of our Annual Report on Form 10-K for the year ended December 31, 2024.

As of September 30, 2025, there have been no material changes to our existing critical accounting estimates discussed in Part II, Item 7 of our Annual Report on Form 10-K for the year ended December 31, 2024.

Results of Operations

Comparison of the three and six months ended June 30, 2025 and 2024

Three Months Ended June 30, Six Months Ended June 30,

Comparison of the three and nine months ended September 30, 2025 and 2024

Three Months Ended September 30, Nine Months Ended September 30,

(In thousands) 2025 2024 2025 2024

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Total revenue $ 12,880 $ 8,964 $ 34,061 $ 25,768

Total Revenue - Three Months Ended June 30, 2025 vs.

Three Months Ended June 30, 2024 – The increase in total revenue of $3.8 million for the three months ended June 30, 2025 compared to the three months ended June 30, 2024 was due to increased volume associated with PYRUKYND®.

Total Revenue - Six Months Ended June 30, 2025 vs.

Six Months Ended June 30, 2024 – The increase in total revenue of $4.4 million for the six months ended June 30, 2025 compared to the six months ended June 30, 2024 was due to increased volume associated with PYRUKYND®.

Total Revenue - Three Months Ended September 30, 2025 vs.

Three Months Ended September 30, 2024 – The increase in total revenue of $3.9 million for the three months ended September 30, 2025 compared to the three months ended September 30, 2024 was due to increased volume associated with PYRUKYND®.

Total Revenue - Nine Months Ended September 30, 2025 vs.

Nine Months Ended September 30, 2024 – The increase in total revenue of $8.3 million for the nine months ended September 30, 2025 compared to the nine months ended September 30, 2024 was due to increased volume associated with PYRUKYND®.

Total Operating Expenses

Three Months Ended June 30, Six Months Ended June 30,

Three Months Ended September 30, Nine Months Ended September 30,

(In thousands) 2025 2024 2025 2024

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Total operating expenses $ 129,749 $ 111,775 $ 384,615 $ 326,468

Total Operating Expenses - Three Months Ended June 30, 2025 vs.

Three Months Ended June 30, 2024 – The increase in total operating expenses of $25.1 million for the three months ended June 30, 2025 compared to the three months ended June 30, 2024 was primarily due to an increase in research and development expenses of $14.5 million, which is described below under Research and Development Expenses, and an increase in selling, general and administrative expenses of $10.3 million, driven by an increase in commercial-related activities as we prepare for the potential approval of PYRUKYND® in thalassemia.

Total Operating Expenses - Six Months Ended June 30, 2025 vs.

Six Months Ended June 30, 2024 – The increase in total operating expenses of $40.2 million for the six months ended June 30, 2025 compared to the six months ended June 30, 2024 was primarily due to an increase in selling, general and administrative expenses of $20.8 million, driven by an increase in commercial-related activities as we prepare for the potential approval of PYRUKYND® in thalassemia, and an increase in research and development expenses of $18.7 million which is described below under Research and Development Expenses.

Total Operating Expenses - Three Months Ended September 30, 2025 vs.

Three Months Ended September 30, 2024 – The increase in total operating expenses of $18.0 million for the three months ended September 30, 2025 compared to the three months ended September 30, 2024 was primarily due to an increase in research and development expenses of $14.3 million, which is described below under Research and Development Expenses, and an increase in selling, general and administrative expenses of $2.7 million, driven by an increase in commercial-related activities as we prepare for the potential approval of PYRUKYND® in thalassemia.

Total Operating Expenses - Nine Months Ended September 30, 2025 vs.

Nine Months Ended September 30, 2024 – The increase in total operating expenses of $58.1 million for the nine months ended September 30, 2025 compared to the nine months ended September 30, 2024 was primarily due to an increase in research and development expenses of $33.0 million which is described below under Research and Development Expenses, and an increase in selling, general and administrative expenses of $23.6 million, driven by an increase in commercial-related activities as we prepare for the potential approval of PYRUKYND® in thalassemia.

Research and Development Expenses

Our research and development expenses, by major program, are outlined in the table below:

Three Months Ended June 30, Six Months Ended June 30,

Three Months Ended September 30, Nine Months Ended September 30,

(In thousands) 2025 2024 2025 2024

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Total research and development expense $ 86,796 $ 72,455 $ 251,479 $ 218,476

Total Research and Development Expenses - Three Months Ended June 30, 2025 vs.

Three Months Ended June 30, 2024 – The increase in total research and development expenses of $14.5 million for the three months ended June 30, 2025 compared to the three months ended June 30, 2024 was primarily due to a $13.3 million increase in our direct expenses.

Total Research and Development Expenses - Six Months Ended June 30, 2025 vs.

Six Months Ended June 30, 2024 – The increase in total research and development expenses of $18.7 million for the six months ended June 30, 2025 compared to the six months ended June 30, 2024 was due to a $11.9 million increase in our direct expenses and a $6.8 million increase in our indirect expenses.

The increase in direct expenses was primarily due to in-process research and development as a result of the $10.0 million milestone payment associated with the agreement with Alnylam discussed above under Overview , and an increase in tebapivat costs due to increased costs associated with clinical trials of tebapivat in patients with SCD and LR MDS.

These increases were partially offset by a decrease in PYRUKYND® costs due to lower process development expenses, lower costs associated with the phase 3 ACTIVATE-Kids and ACTIVATE-KidsT trials, and lower costs associated with the phase 3 ENERGIZE and ENERGIZE-T trials, partially offset by increased professional expenses.

Total Research and Development Expenses - Three Months Ended September 30, 2025 vs.

Three Months Ended September 30, 2024 – The increase in total research and development expenses of $14.3 million for the three months ended September 30, 2025 compared to the three months ended September 30, 2024 was primarily due to a $10.8 million increase in our direct expenses.

The increase in direct expenses was primarily due to an increase in tebapivat costs driven by increased costs associated with clinical trials of tebapivat in patients with SCD and higher process development expenses, and an increase in PYRUKYND® costs driven by start-up costs associated with clinical trials in pediatric patients with thalassemia.

Total Research and Development Expenses - Nine Months Ended September 30, 2025 vs.

Nine Months Ended September 30, 2024 – The increase in total research and development expenses of $33.0 million for the nine months ended September 30, 2025 compared to the nine months ended September 30, 2024 was due to a $22.7 million increase in our direct expenses and a $10.3 million increase in our indirect expenses.

The increase in direct expenses was primarily due to an increase in tebapivat costs driven by increased costs associated with clinical trials of tebapivat in patients with SCD and LR MDS and higher process development expenses, and an increase in in-process research and development as a result of the $10.0 million milestone payment associated with the agreement with Alnylam discussed above under Overview .

PYRUKYND® costs for the nine months ended September 30, 2025 were relatively consistent with the nine months ended September 30, 2024.

Included in the change in PYRUKYND® costs was increased professional expenses, and start-up costs associated with clinical trials in pediatric patients with thalassemia, partially offset by lower process development expenses.

The increase in our indirect expenses was primarily due to an increase in compensation and related expenses, driven principally by workforce-related expenses.

Other Income and Expense

Three Months Ended June 30, Six Months Ended June 30,

Three Months Ended September 30, Nine Months Ended September 30,

(In thousands) 2025 2024 2025 2024

Gain on sale of contingent payments $ — $ 889,136 $ — $ 889,136

Milestone payment from gain on sale of oncology business — 200,000 — 200,000

Interest income, net 13,369 13,059 43,969 30,068

Other income, net 67 1,651 1,843 4,864

Other Income and Expense - Three Months Ended June 30, 2025 vs.

Three Months Ended June 30, 2024 – The increase in interest income, net in the three months ended June 30, 2025 compared to the three months ended June 30, 2024 was primarily attributable to increased return on our investments and an increased investment balance.

Other Income and Expense - Six Months Ended June 30, 2025 vs.

Six Months Ended June 30, 2024 – The increase in interest income, net in the six months ended June 30, 2025 compared to the six months ended June 30, 2024 was primarily attributable to increased return on our investments and an increased investment balance.

Three Months Ended June 30, Six Months Ended June 30,

Other Income and Expense - Three Months Ended September 30, 2025 vs.

Three Months Ended September 30, 2024 – The decrease in gain on sale of contingent payments was due to the sale of the Vorasidenib Royalty Rights in the three months ended September 30, 2024 discussed above in Overview .

The decrease in milestone payment from gain on sale of oncology business was due to the receipt of the Vorasidenib Milestone Payment in the three months ended September 30, 2024 discussed above in Overview .

Other Income and Expense - Nine Months Ended September 30, 2025 vs.

Nine Months Ended September 30, 2024 – The decrease in gain on sale of contingent payments was due to the sale of the Vorasidenib Royalty Rights in the nine months ended September 30, 2024 discussed above in Overview .

The decrease in milestone payment from gain on sale of oncology business was due to the receipt of the Vorasidenib Milestone Payment in the nine months ended September 30, 2024 discussed above in Overview .

The increase in interest income, net in the nine months ended September 30, 2025 compared to the nine months ended September 30, 2024 was primarily attributable to increased return on our investments.

Net (Loss) Income

Three Months Ended September 30, Nine Months Ended September 30,

(In thousands) 2025 2024 2025 2024

Net loss $ (112,020) $ (96,118) $ (201,309) $ (177,667)

Net Loss - Three Months Ended June 30, 2025 vs.

Three Months Ended June 30, 2024 – The increase in net loss for the three months ended June 30, 2025 compared to the three months ended June 30, 2024 was primarily driven by the increase in research and development expenses discussed above in Research and Development Expenses , and the increase in selling, general and administrative expenses discussed above in Total Operating Expenses, partially offset by the increase in interest income, net discussed above in Other Income and Expense , and the increase in product revenue discussed above in Revenue .

Net Loss - Six Months Ended June 30, 2025 vs.

Six Months Ended June 30, 2024 – The increase in net loss for the six months ended June 30, 2025 compared to the six months ended June 30, 2024 was primarily driven by the increase in selling, general and administrative expenses discussed above in Total Operating Expenses and the increase in research and development expenses discussed above in Research and Development Expenses , partially offset by the increase in interest income, net discussed above in Other Income and Expense, and the increase in product revenue discussed above in Revenue .

Net (loss) income $ (103,433) $ 947,915 $ (304,742) $ 770,248

Net (Loss) Income - Three Months Ended September 30, 2025 vs.

Three Months Ended September 30, 2024 – The increase in net loss for the three months ended September 30, 2025 compared to the three months ended September 30, 2024 was primarily driven by the sale of the Vorasidenib Royalty Rights and the receipt of the Vorasidenib Milestone Payment in the three months ended September 30, 2024 discussed above in Overview , partially offset by the income tax expense in the three months ended September 30, 2024 as a result of the income related to the Vorasidenib Royalty Rights and Vorasidenib Milestone Payment.

Net (Loss) Income - Nine Months Ended September 30, 2025 vs.

Nine Months Ended September 30, 2024 – The increase in net loss for the nine months ended September 30, 2025 compared to the nine months ended September 30, 2024 was primarily driven by the sale of the Vorasidenib Royalty Rights and the receipt of the Vorasidenib Milestone Payment in the nine months ended September 30, 2024 discussed above in Overview , partially offset by the income tax expense in the nine months ended September 30, 2024 as a result of the income related to the Vorasidenib Royalty Rights and Vorasidenib Milestone Payment.

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.

collaborations, strategic alliances, licensing arrangements and other nondilutive strategic transactions.

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

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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 $1.3 billion at June 30, 2025.

Our cash, cash equivalents and marketable securities balance was $1.3 billion at September 30, 2025.

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.

The following table provides information regarding our cash flows for the six months ended June 30, 2025 and 2024:

Six Months Ended June 30,

The following table provides information regarding our cash flows for the nine months ended September 30, 2025 and 2024:

Nine Months Ended September 30,

(In thousands) 2025 2024

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Net cash used in operating activities.

Cash used in operating activities of $188.6 million during the six months ended June 30, 2025 was primarily due to operating expenses driven by research and development costs described above under Research and Development Expenses , partially offset by cash received from i nterest income of $31.5 million and product revenues of $22.0 million .

Cash used in operating activities of $172.5 million during the six months ended June 30, 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 from interest income of $19.3 million and product revenues of $17.6 million.

Cash used in operating activities of $276.8 million during the nine months ended September 30, 2025 was primarily due to operating expenses driven by research and development costs described above under Research and Development Expenses , partially offset by cash received from i nterest income of $45.8 million and product revenues of $35.8 million .

Cash used in operating activities of $256.7 million during the nine months ended September 30, 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 from product revenues of $28.0 million and interest income of $26.3 million.

Net cash provided by investing activities .

Cash provided by investing activities of $191.6 million during the six months ended June 30, 2025 was primarily due to higher proceeds from maturities and sales of marketable securities than purchases of marketable securities.

Cash provided by investing activities of $161.8 million during the six months ended June 30, 2024 was primarily due to higher proceeds from maturities and sales of marketable securities than purchases of marketable securities.

Cash provided by investing activities of $287.1 million during the nine months ended September 30, 2025 was primarily due to higher proceeds from maturities and sales of marketable securities than purchases of marketable securities.

Cash provided by investing activities of $412.6 million during the nine months ended September 30, 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.

Net cash provided by financing activities .

Cash provided by financing activities of $1.7 million during the six months ended June 30, 2025, was due to net proceeds received from stock option exercises and purchases made pursuant to our 2013 Employee Stock Purchase Plan, or 2013 ESPP.

Cash provided by financing activities of $7.0 million during the six months ended June 30, 2024 was due to net proceeds received from stock option exercises and purchases made pursuant to our 2013 ESPP.

Cash provided by financing activities of $6.1 million during the nine months ended September 30, 2025, was due to net proceeds received from stock option exercises and purchases made pursuant to our 2013 Employee Stock Purchase Plan, or 2013 ESPP.

Cash provided by financing activities of $9.6 million during the nine months ended September 30, 2024, was due to net proceeds received from stock option exercises and purchases made pursuant to our 2013 ESPP.

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 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 June 30, 2025, 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.

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 other 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 September 30, 2025, 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 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.

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• 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.

• operational delays, disruptions and/or increased costs associated with global economic and political developments.

Until such time, if ever, as we can generate substantial product revenue, we expect to finance our cash needs primarily through cash on hand, potential royalty payments with respect to the Retained Earn-Out Rights, the actual and potential future sales of PYRUKYND® and, potentially, collaborations, strategic alliances, licensing arrangements and other nondilutive strategic transactions.

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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.

If we are unable to raise additional funds through equity or debt financings

when needed or on attractive terms, we may be required to delay, limit, reduce or terminate our product development or future commercialization efforts, or grant rights to develop and market product candidates that we would otherwise prefer to develop and market ourselves.

If we are unable to raise additional funds through equity or debt financings when needed or on attractive terms, we may be required to delay, limit, reduce or terminate our product development or future commercialization efforts, or grant rights to develop and market product candidates that we would otherwise prefer to develop and market ourselves.

Contractual Obligations

During the six months ended June 30, 2025, there were no material changes to our contractual obligations and commitments described under Management's Discussion and Analysis of Financial Condition and Results of Operations in our Annual Report on Form 10-K for the year ended December 31, 2024.

During the nine months ended September 30, 2025, there were no material changes to our contractual obligations and commitments described under Management's Discussion and Analysis of Financial Condition and Results of Operations in our Annual Report on Form 10-K for the year ended December 31, 2024.

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-Q

Item 2. Management’s Discussion and Analysis