Agios awaits FDA filing verdict on mitapivat after mixed RISE UP results
The sNDA rests on a hemoglobin-response win but a missed pain-crisis co-primary, testing whether accelerated approval and a confirmatory trial can carry the drug in sickle cell disease.
Executive Summary
- Agios is waiting on the FDA to confirm it has accepted a sickle cell disease filing for mitapivat and to set a review clock, the next procedural step after submitting for accelerated approval built on a Phase 3 trial that split its two primary endpoints.
- The pivotal trial met its hemoglobin-response goal but missed significance on the pain-crisis rate, the endpoint most directly tied to how patients experience the disease, so the filing leans on a surrogate marker rather than a clean win on symptoms.
- Accelerated approval built on a partial result carries a mandatory confirmatory trial, and Agios has already reached agreement with the FDA on that trial's design, a step that derisks the conversion path rather than leaving it undefined.
- Mitapivat's approvals in two other rare hemolytic anemias give it a track record the sickle cell competitors lack, even as those competitors run their own late-stage trials in a still-small field of direct pyruvate kinase-targeted rivals.
The catalyst
Agios Pharmaceuticals, Inc. submitted a supplemental New Drug Application to the FDA in May 2026 seeking U.S. accelerated approval of mitapivat, an oral pyruvate kinase activator, for sickle cell disease. The company expects to receive notice of filing acceptance and an anticipated review timeline in the third quarter of 2026, following the FDA's standard 60-day filing review period. That notice, not a decision on the drug itself, is the event now pending. AgiosAgios Submits sNDA to FDA for U.S. Accelerated Approval of Mitapivat in Sickle Cell DiseaseMay 12, 2026
Probability of SuccessBased on the AppliedXL Probability of Success model. For more information about the methodology, read the research here.
What RISE UP showed
The filing draws on RISE UP, a randomized, double-blind, placebo-controlled trial spanning Phase 2 and Phase 3 (NCT05031780) that enrolled 286 patients with sickle cell disease across 16 countries. The trial carried four registered primary endpoints split across its two phases, including Phase 3 hemoglobin response and the annualized rate of sickle cell pain crises. Mitapivat met the hemoglobin-response endpoint, showing a statistically significant improvement in hemoglobin concentration and reduced hemolysis versus placebo, translating into benefits in pain crises and hospitalizations for patients who achieved that hemoglobin response. The pain-crisis rate itself, the trial's second primary endpoint, showed a reduction that did not reach statistical significance. NCT05031780+1A Study Evaluating the Efficacy and Safety of Mitapivat (AG-348) in Participants With Sickle Cell Disease (RISE UP)NCT05031780Agios Submits sNDA to FDA for U.S. Accelerated Approval of Mitapivat in Sickle Cell DiseaseMay 12, 2026
The confirmatory trial
Because the sNDA seeks accelerated approval, a pathway reserved for serious conditions with unmet need, Agios must run a confirmatory trial that must already be underway when the FDA decides. The company has reached agreement with the FDA on that trial's design: a global, randomized, double-blind, placebo-controlled 52-week study enrolling approximately 159 patients aged 12 and older, with a primary endpoint of transfusion-free status from Week 4 through Week 52. Chief Medical Officer Sarah Gheuens said the sNDA "is supported by data from the RISE UP clinical program demonstrating that mitapivat significantly improved hemoglobin concentration and reduced hemolysis," calling the anti-hemolytic profile a continuation of the biology that already supported mitapivat's approvals in two other rare hemolytic anemias. AgiosAgios Submits sNDA to FDA for U.S. Accelerated Approval of Mitapivat in Sickle Cell DiseaseMay 12, 2026
Registry churn context
The trial's primary completion date moved four times in the registry, from September 2025 to December 2025, then to October 2025, then back to December 2025, before settling at October 30, 2025. Enrollment held flat within the routine range across the study's life, rising from 267 to 286 patients, a change within the band the operational model treats as typical rather than a shift in trial scope. The trial is now Active, not recruiting, consistent with a program that completed enrollment and is in follow-up rather than one showing signs of abandonment. NCT05031780A Study Evaluating the Efficacy and Safety of Mitapivat (AG-348) in Participants With Sickle Cell Disease (RISE UP)NCT05031780
The competitive field
Pyruvate kinase activation in sickle cell disease remains a narrow field: mitapivat and Novo Nordisk's etavopivat, in a Phase 3 trial (NCT06609226), are the only two direct comparators sharing both the target and mechanism class in this indication. Agios also has a second sickle cell mitapivat trial, an earlier Phase 3 confirmatory-design study (NCT07656415), not yet recruiting, and a nephropathy-focused Phase 2 study that was withdrawn. Beyond pyruvate kinase activators, the broader sickle cell field includes mechanistically distinct approaches: gene therapies, a P-selectin antibody, and hemoglobin polymerization inhibitors, none of which bear directly on how the FDA will weigh mitapivat's own endpoint split.
This analysis was produced using AI-assisted reporting systems, AppliedXL data, and official public records. These systems undergo editorial review, quality checks, and regular audits by human experts. Errors may still occur, as with any automated system. Always consult the linked primary sources. Read our AI Editorial Policy.