Mitapivat sNDA Seeks FDA Accelerated Approval in Sickle Cell Disease

Agios has submitted a Supplemental New Drug Application (sNDA) to the US Food and Drug Administration (FDA) seeking accelerated approval of mitapivat for sickle cell disease, according to a company announcement issued on May 12, 2026. The filing places the oral pyruvate kinase activator under FDA review for a potential new hematology indication after prior approvals in other rare hemolytic anemias.

“The submission of the mitapivat sNDA represents an important milestone for the sickle cell community, which urgently needs new treatments that can address key underlying aspects of this debilitating and deadly disease,” said Sarah Gheuens, MD, PhD.1

Agios said the application follows agreement with the FDA on a required confirmatory trial under the accelerated approval pathway.1 The company expects to learn in the third quarter of 2026 whether the filing is accepted for review and what timeline the agency assigns.1

What the FDA accelerated approval filing includes

According to Agios, the submission is supported by data from the RISE UP phase 2 and phase 3 programs in sickle cell disease.1 The company’s announcement focused primarily on topline phase 3 findings and on the design of a confirmatory study intended to satisfy accelerated approval requirements.1

Accelerated approval allows FDA to clear therapies for serious conditions on the basis of a surrogate or intermediate clinical endpoint reasonably likely to predict clinical benefit, with postmarketing confirmation required.2 In this case, Agios said FDA and the company have aligned on a randomized, double-blind, placebo-controlled, 52-week confirmatory trial enrolling about 159 patients aged 12 years or older with sickle cell disease.1 The primary endpoint is transfusion-free status from week 4 through week 52.1

The confirmatory trial design appears to reflect an attempt to establish a direct clinical benefit endpoint after mixed results in RISE UP. In the phase 3 study, mitapivat met one co-primary endpoint, hemoglobin response, defined as at ≥ 1.0-g/dL increase from baseline in average hemoglobin concentration from week 24 through week 52.1 However, the other co-primary endpoint, annualized rate of sickle cell pain crises, was reduced versus placebo but did not reach statistical significance.1

Agios also reported improvements in hemolysis markers and stated that patients who achieved hemoglobin response had reductions in pain crises, hospitalizations, and fatigue, although full data were not included in the press release.1 Results are scheduled for oral presentation at the European Hematology Association Congress on June 13, 2026.1

What the phase 3 RISE UP trial showed

RISE UP, registered as NCT05031780, enrolled patients aged ≥ 16 years of age and randomly assigned 207 participants in a 2:1 ratio to oral mitapivat 100 mg twice daily or placebo for 52 weeks.1,3

The trial included 2 primary endpoints, hemoglobin response and annualized sickle cell pain crisis rate, along with 5 key secondary endpoints, including hemoglobin concentration, indirect bilirubin, fatigue, hospitalizations for pain crises, and reticulocyte percentage.1

The key limitation for clinicians interpreting the filing is the current absence of a peer-reviewed full report or detailed numerical efficacy results from phase 3. The press release did not provide absolute response rates, effect sizes, confidence intervals, or a detailed safety table.1 As a result, the degree of benefit, subgroup consistency, and adverse event profile cannot yet be independently assessed from the public materials accompanying the submission. Still, the study population, duration, and double-blind design are notable in a disease area where new therapies have often shown discordant effects across laboratory, pain, and utilization endpoints.

Mitapivat activates red blood cell pyruvate kinase, increasing adenosine triphosphate production and lowering diphosphoglycerate levels, a mechanism intended to improve red cell health and reduce sickling propensity.1,4 The drug is already FDA approved for adults with pyruvate kinase deficiency and for adults with transfusion-dependent and non–transfusion-dependent alpha- or beta-thalassemia, providing prior regulatory experience with the agent outside sickle cell disease.4

Whether the sickle cell application will be viewed as suitable for accelerated approval may depend on how FDA interprets the hemoglobin and hemolysis findings as surrogates and on the feasibility of the agreed confirmatory transfusion-burden study.

Mitapivat safety and next regulatory steps in sickle cell disease

Agios said the safety profile in RISE UP was consistent with prior mitapivat trials in sickle cell disease.1 During the 52-week double-blind period, 87.0% of patients in the mitapivat group and 81.2% in the placebo group completed treatment; 174 of 176 completers entered the open-label extension.1 No further breakdown of adverse events, serious adverse events, discontinuations due to toxicity, or laboratory abnormalities was disclosed in the release.1

That leaves several unanswered questions ahead of any FDA filing decision: whether the application will receive priority or standard review, what endpoint FDA will regard as the principal basis for accelerated approval, and whether the forthcoming EHA presentation clarifies the magnitude of benefit on hemolysis, fatigue, hospitalization, and transfusion-related outcomes. The agency has increasingly scrutinized accelerated approvals in hematology and oncology when confirmatory pathways are uncertain.2 For now, the regulatory update is best understood as the start of a review process rather than an approval decision.

References

1. Agios Pharmaceuticals. Agios submits sNDA to FDA for U.S. accelerated approval of mitapivat in sickle cell disease. GlobeNewswire. Published May 12, 2026. Accessed May 12, 2026. https://www.globenewswire.com/news-release/2026/05/12/3293011/31990/en/agios-submits-snda-to-fda-for-u-s-accelerated-approval-of-mitapivat-in-sickle-cell-disease.html

2. US Food and Drug Administration. Accelerated approval program. Accessed May 12, 2026. https://www.fda.gov/drugs/information-health-care-professionals-drugs/accelerated-approval-program

3. ClinicalTrials.gov. A study of AG-348 in participants with sickle cell disease (RISE UP). NCT05031780. Accessed May 12, 2026. https://clinicaltrials.gov/study/NCT05031780

4. US Food and Drug Administration. Pyrukynd (mitapivat) prescribing information. Accessed May 12, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216196s000lbl.pdf