Agios Announces Topline Results from RISE UP Phase 3 Trial of Mitapivat in Sickle Cell Disease

Trial met primary endpoint of hemoglobin response and key secondary endpoints of change from baseline in hemoglobin concentration and indirect bilirubin

Trial showed trend favoring mitapivat but did not meet statistical significance in primary endpoint of annualized rate of SCPCs (pain crises), and the key secondary endpoint of change from baseline in PROMIS Fatigue was not met

Patients in the mitapivat arm who achieved hemoglobin response had clinically meaningful benefits in SCPC-related endpoints and PROMIS Fatigue

Favorable safety profile observed in RISE UP Phase 3 trial was consistent with that observed in prior mitapivat sickle cell disease trials

Company will share the comprehensive results from the RISE UP clinical program with the FDA and intends to submit for potential U.S. regulatory approval

Company will host investor conference call and webcast today at 8:00 a.m. ET

CAMBRIDGE, Mass., Nov. 19, 2025 (GLOBE NEWSWIRE) -- Agios Pharmaceuticals, Inc. (Nasdaq: AGIO), a commercial-stage biopharmaceutical company focused on delivering innovative medicines for patients with rare diseases, today announced topline results from the 52-week double-blind period of the global RISE UP Phase 3 trial of mitapivat, an oral pyruvate kinase (PK) activator, in patients aged 16 years or older with sickle cell disease. RISE UP was designed with two primary endpoints and five key secondary endpoints to evaluate objective measures of hemolysis improvement as well as additional parameters of sickle cell disease. This comprehensive design enabled a broad assessment of the potential benefits of mitapivat across multiple aspects of the disease.

The trial met its primary endpoint of hemoglobin response, with mitapivat demonstrating a statistically significant improvement compared to placebo. While mitapivat also showed a reduction in the primary endpoint of annualized rate of sickle cell pain crises (SCPCs) compared to placebo, this trend did not achieve statistical significance.

Mitapivat also demonstrated statistically significant improvements in the first two key secondary endpoints, Week 24 through Week 52 average change from baseline in hemoglobin concentration and levels of indirect bilirubin, a marker of hemolysis, compared with placebo. The third key secondary endpoint of Week 24 through Week 52 average change from baseline on Patient Reported Outcome Measurement Information System Fatigue 13a (PROMIS Fatigue) score was not met.

The subset of patients in the mitapivat arm who achieved hemoglobin response also experienced clinically meaningful benefits in the endpoints of annualized rate of SCPCs, annualized rate of hospitalizations for SCPCs (the fourth key secondary endpoint of the trial), and PROMIS Fatigue, based on a post hoc analysis.

The safety profile of mitapivat in the RISE UP Phase 3 trial was consistent with that seen in prior mitapivat sickle cell disease trials.

“Sickle cell disease is a complex and devastating condition that has long lacked innovation. As a result, patients have very few effective treatments, contributing to poor outcomes and shortened lifespans,” said Biree Andemariam, M.D., Professor of Medicine and American Red Cross Endowed Chair in Transfusion Medicine, University of Connecticut Health, and a RISE UP trial investigator. “The data from RISE UP demonstrate that treatment with mitapivat significantly improved hemoglobin concentration and reduced hemolysis. We also see that patients who achieved the threshold of hemoglobin response also experienced clinically meaningful benefits in the rate of sickle cell pain crises and hospital visits for those events, as well as in fatigue. These strong results, coupled with a favorable safety profile, support the potential of mitapivat as a novel treatment option for patients with sickle cell disease.”

RISE UP Phase 3 Trial Results The double-blind, randomized, placebo-controlled RISE UP Phase 3 trial enrolled 207 patients aged 16 years or older who are representative of the global sickle cell disease population. Participants were randomized 2:1 to receive mitapivat twice daily or matched-placebo. The 52-week double-blind treatment period was completed by 87.0% (n=120/138) of patients in the mitapivat arm and 81.2% (n=56/69) of patients in the placebo arm. All but two of these patients (174/176) opted to enter the ongoing 216-week open-label extension period of the study.

Primary Efficacy Endpoint Results

Hemoglobin Response: 40.6% of patients in the mitapivat arm achieved a hemoglobin response, defined as a ≥1.0 g/dL increase from baseline in average hemoglobin from Week 24 through Week 52, compared to 2.9% of patients in the placebo arm, a statistically significant improvement (2-sided p5x upper limit of normal (ULN) with or without jaundice. All patients discontinued treatment with PYRUKYND, and these events improved upon treatment discontinuation.

Obtain liver tests prior to the initiation of PYRUKYND and monthly thereafter for the first 6 months and as clinically indicated. Interrupt PYRUKYND if clinically significant increases in liver tests are observed or alanine aminotransferase is >5x ULN. Discontinue PYRUKYND if hepatic injury due to PYRUKYND is suspected.

Adverse Reactions: The most common adverse reactions including laboratory abnormalities (≥10%) in patients with PK deficiency were estrone decreased (males), increased urate, back pain, estradiol decreased (males), and arthralgia.

Drug Interactions:

Strong CYP3A Inhibitors and Inducers: Avoid concomitant use.

Moderate CYP3A Inhibitors: Do not titrate PYRUKYND beyond 20 mg twice daily.

Moderate CYP3A Inducers: Consider alternatives that are not moderate inducers. If there are no alternatives, adjust PYRUKYND dosage.

Sensitive CYP3A, CYP2B6, CYP2C Substrates Including Hormonal Contraceptives: Avoid concomitant use with substrates that have narrow therapeutic index.

UGT1A1 Substrates: Avoid concomitant use with substrates that have narrow therapeutic index.

P-gp Substrates: Avoid concomitant use with substrates that have narrow therapeutic index.

Hepatic Impairment: Avoid use of PYRUKYND in patients with moderate and severe hepatic impairment.

Please see full Prescribing Information for PYRUKYND.

About Agios: Fueled by Connections to Transform Rare Diseases™ At Agios, our vision is to redefine the future of rare disease treatment. Fueled by connections, we build trusted partnerships with communities – collaborating to develop and deliver innovative medicines that have the potential to transform lives. With a foundation in hematology, we combine biological expertise with real-world insights to advance a growing pipeline of rare disease medicines that reflect the priorities of the people we serve. Agios is a commercial-stage biopharmaceutical company headquartered in Cambridge, Massachusetts. To learn more, visit www.agios.com and follow us on LinkedIn and X .

Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding the potential benefits of mitapivat; Agios’ plans for future meetings with, or submissions to, regulators, including the FDA; Agios’ plans for the development of mitapivat; and Agios’ strategic plans and focus. The words “anticipate,” “expect,” “goal,” “hope,” “milestone,” “plan,” “potential,” “possible,” “strategy,” “will,” “vision,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from Agios’ current expectations and beliefs. For example, there can be no guarantee that any product candidate Agios is developing will successfully commence or complete necessary preclinical and clinical development phases, or that development of any of Agios’ product candidates will successfully continue. There can be no guarantee that any positive developments in Agios’ business will result in stock price appreciation. Management’s expectations and, therefore, any forward-looking statements in this press release could also be affected by risks and uncertainties relating to a number of other important factors, including, without limitation: the content and timing of decisions made by the U.S. FDA, the EMA or other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies; Agios’ results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; risks and uncertainties related to the impact of pandemics or other public health emergencies to Agios’ business, operations, strategy, goals and anticipated milestones, including its ongoing and planned research activities, ability to conduct ongoing and planned clinical trials, clinical supply of current or future drug candidates, commercial supply of current or future approved products, and launching, marketing and selling current or future approved products; Agios’ ability to obtain and maintain requisite regulatory approvals and to enroll patients in its planned clinical trials; unplanned cash requirements and expenditures; competitive factors; Agios’ ability to obtain, maintain and enforce patent and other intellectual property protection for any product candidates it is developing; Agios’ ability to establish and maintain key collaborations; uncertainty regarding any royalty payments related to the sale of its oncology business or any milestone or royalty payments related to its in-licensing of AG-236, and the uncertainty of the timing of any such payments; uncertainty of the results and effectiveness of the use of Agios’ cash and cash equivalents; and general economic and market conditions. These and other risks are described in greater detail under the caption “Risk Factors” included in Agios’ public filings with the Securities and Exchange Commission. Any forward-looking statements contained in this press release speak only as of the date hereof, and Agios expressly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

Contacts:

Investor Contact Morgan Sanford, Vice President, Investor Relations Agios Pharmaceuticals morgan.sanford@agios.com

Media Contact Eamonn Nolan, Senior Director, Corporate Communications Agios Pharmaceuticals eamonn.nolan@agios.com