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Item 2. Management’s Discussion and Analysis

2025-07-31 compared with 2025-05-01 · 87 added, 71 removed, 268 unchanged (37% 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 March 31, 2025 and for the three months ended March 31, 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 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.

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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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 a phase 3 clinical trial for the treatment of sickle cell disease, or SCD.

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;

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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

On July 28, 2023, we entered into a license agreement with Alnylam under which we acquired the rights to develop and commercialize Alnylam’s novel preclinical siRNA targeting the TMPRSS6 gene, as a potential disease-modifying treatment for patients with PV.

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.

Sale of Oncology Business to Servier and Sale of Contingent Payments

On March 31, 2021, we completed the sale of our oncology business to Servier Pharmaceuticals, LLC, or Servier, which represented a discontinued operation.

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.

The transaction included the sale of our oncology business, including TIBSOVO®, our clinical-stage product candidates vorasidenib, AG-270 and AG-636, and our oncology research programs, for a payment of approximately $1.8 billion in cash at the closing, subject to certain adjustments, and a payment of $200.0 million in cash, if, prior to January 1, 2027, vorasidenib is granted new drug application, or NDA, approval from the FDA with an approved label that permits vorasidenib’s use as a single agent for the adjuvant treatment of patients with Grade 2 glioma that have an isocitrate dehydrogenase, or IDH, 1 or 2 mutation (and, to the extent required by such approval, the vorasidenib companion diagnostic test is granted an FDA premarket approval), or the Vorasidenib Milestone Payment, as well as a royalty of 5% of U.S.

net sales of TIBSOVO® from the close of the transaction through loss of exclusivity, and a royalty of 15% of U.S.

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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.

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 has 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.

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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.

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 three months ended March 31, 2025 was $89.3 million and our net loss for the three months ended March 31, 2024 was $81.5 million.

As of March 31, 2025, we had an accumulated deficit of $238.2 million.

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.

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®, 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;

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 for the treatment of thalassemia, which we announced in December 2024;

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;

continue clinical 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.

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

For further discussion of our revenue recognition policy, see Note 8, Product Revenue , to the condensed consolidated financial statements in this Quarterly Report on Form 10-Q.

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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 months ended March 31, 2025 and 2024 were expensed prior to February 17, 2022, and, therefore, are not included in costs of sales during the three months ended March 31, 2025 and 2024.

The amounts excluded from cost of sales were not significant during the three months ended March 31, 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 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.

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 months ended March 31, 2025 and 2024.

We have not reserved for excess or obsolete inventory during the three and six months ended June 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.

We are unable to predict the amount of net cash inflows from PYRUKYND® or any of our product candidates.

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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• obtaining and maintaining patent and trade secret protection and regulatory exclusivity for our product candidates;

• launching commercial sales of the products, if and when approved, in the United States or in other jurisdictions, whether alone or in collaboration with others, including pursuant to the NewBridge Agreement;

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

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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.

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

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.

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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.

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 continue to evaluate options for the commercialization of PYRUKYND® outside of the United States, including through exploring potential partnership opportunities, such as the NewBridge Agreement.

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.

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

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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 hemoglobin 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) 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.

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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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• 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.

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 ≥ 1 g/dL increase in average hemoglobin concentration from week 10 to week 12 compared to baseline, and safety.

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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.

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;

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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 begin patient enrollment in a phase 2 clinical trial of tebapivat in adult patients with SCD in mid-2025.

We have completed a phase 1 clinical trial evaluating tebapivat in healthy volunteers and patients with SCD, and initiated a phase 2 clinical trial of tebapivat in adult patients with SCD in the second quarter of 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.

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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.

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.

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.

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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 IND with the FDA for AG-236 for the treatment of PV in mid-2025.

We initiated a phase 1 clinical trial of AG-181 in healthy volunteers in the first quarter of 2024, and initiated the multiple ascending dose portion of the trial in the second quarter of 2025.

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.

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 March 31, 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 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.

Results of Operations

Comparison of the three months ended March 31, 2025 and 2024

Three Months Ended March 31,

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

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

(In thousands) 2025 2024 2025 2024

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Total revenue $ 12,455 $ 8,615 $ 21,181 $ 16,804

Total Revenue - Three Months Ended March 31, 2025 vs.

Three Months Ended March 31, 2024 – The increase in total revenue of $0.5 million for the three months ended March 31, 2025 compared to the three months ended March 31, 2024 was due to increased volume associated with PYRUKYND®.

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 Operating Expenses

Three Months Ended March 31,

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

(In thousands) 2025 2024 2025 2024

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Total operating expenses $ 139,511 $ 114,432 $ 254,866 $ 214,693

Total Operating Expenses - Three Months Ended March 31, 2025 vs.

Three Months Ended March 31, 2024 – The increase in total operating expenses of $15.1 million for the three months ended March 31, 2025 compared to the three months ended March 31, 2024 was primarily due to an increase in selling, general and administrative expenses of $10.5 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 $4.1 million which is described below under Research and Development Expenses.

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.

Research and Development Expenses

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

Three Months Ended March 31,

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

(In thousands) 2025 2024 2025 2024

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Novel PK activator (tebapivat) 7,852 4,488 13,240 6,383

In-process research and development 10,000 — 10,000 —

Other research and platform programs 5,394 7,270 8,838 10,955

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Total research and development expense $ 91,940 $ 77,401 $ 164,683 $ 146,021

Total Research and Development Expenses - Three Months Ended March 31, 2025 vs.

Three Months Ended March 31, 2024 – The increase in total research and development expenses of $4.1 million for the three months ended March 31, 2025 compared to the three months ended March 31, 2024 was primarily due to a $5.6 million increase in our indirect expenses, partially offset by a $1.5 million decrease in our direct expenses.

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.

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

The decrease in direct expenses was primarily due to a decrease in PYRUKYND® costs due to lower process development expenses, lower costs associated with the phase 3 ENERGIZE and ENERGIZE-T trials and lower costs associated with the phase 3 ACTIVATE-Kids and ACTIVATE-KidsT trials.

This was partially offset by an increase in tebapivat costs due to increased costs associated with clinical trials of tebapivat in patients with LR MDS, increased process development expenses and increased costs associated with clinical trials of tebapivat in patients with SCD.

Other Income and Expense

Three Months Ended March 31,

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

(In thousands) 2025 2024 2025 2024

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Other income, net 523 1,579 1,776 3,213

Other Income and Expense - Three Months Ended March 31, 2025 vs.

Three Months Ended March 31, 2024 – The increase in interest income, net in the three months ended March 31, 2025 compared to the three months ended March 31, 2024 was primarily attributable to increased return on our investments and an increased investment balance.

Three Months Ended March 31,

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,

(In thousands) 2025 2024 2025 2024

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

Net Loss - Three Months Ended March 31, 2025 vs.

Three Months Ended March 31, 2024 – The increase in net loss for the three months ended March 31, 2025 compared to the three months ended March 31, 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 .

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 .

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

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 three months ended September 30, 2024.

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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 $1.4 billion at March 31, 2025.

Our cash, cash equivalents and marketable securities balance was $1.3 billion at June 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 three months ended March 31, 2025 and 2024:

Three Months Ended March 31,

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

Six Months Ended June 30,

(In thousands) 2025 2024

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Net cash used in operating activities.

Cash used in operating activities of $111.5 million during the three months ended March 31, 2025 was primarily due to operating expenses driven by research and development costs described above under Research and Development Expenses, partially offset by cash received from i nterest income of $16.1 million and product revenues of $10.4 million.

Cash used in operating activities of $99.9 million during the three months ended March 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 from interest income of $10.5 million and product revenues of $8.6 million.

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.

Net cash provided by investing activities .

Cash provided by investing activities of $112.6 million during the three months ended March 31, 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 $124.6 million during the three months ended March 31, 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 $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.

Net cash provided by financing activities .

Cash provided by financing activities of $1.6 million during the three months ended March 31, 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 $5.9 million during the three months ended March 31, 2024 was the result of net proceeds received from stock option exercises and purchases made pursuant to our 2013 ESPP.

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.

Funding Requirements

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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 March 31, 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.

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.

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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• 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 costs and timing of our ongoing and future commercialization activities, including product manufacturing, sales, marketing and distribution for PYRUKYND® in the approved jurisdictions and indications and for any product candidate for which we may receive approval;

• the scope, progress, results and costs of preclinical development, laboratory testing and clinical trials for our product candidates;

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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 three months ended March 31, 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 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.

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