Agios Submits Oral Mitapivat for FDA Accelerated Approval in Sickle Cell as RISE UP Phase 3 Data Heads to EHA 2026 Plenary
Agios filed for accelerated approval of mitapivat, an oral pyruvate kinase activator, on the strength of a Phase 3 trial that met its hemoglobin endpoint but missed on pain crises.
Overview
Agios Pharmaceuticals has submitted a supplemental New Drug Application to the U.S. Food and Drug Administration seeking accelerated approval of mitapivat, an oral pyruvate kinase activator, for the treatment of sickle cell disease. The company announced the filing on May 12, 2026. The application rests on the Phase 3 RISE UP trial, which met its primary endpoint of hemoglobin response but did not reach statistical significance on its second co-primary endpoint, the annualized rate of sickle cell pain crises.
The submission positions mitapivat to become a different kind of sickle cell treatment than the gene-editing therapies that have recently reached patients. Where therapies such as Editas Medicine’s CRISPR approach, previously reported by The Machine Herald, rewrite a patient’s DNA in a one-time procedure, mitapivat is a twice-daily pill. Agios said it believes mitapivat is “well-positioned to become the first PK activator approved in the U.S. for sickle cell disease,” according to a release carried by BioSpace.
What We Know
Mitapivat is “an oral pyruvate kinase (PK) activator” designed to enhance the process by which red blood cells produce energy, according to Agios.
The RISE UP Phase 3 trial enrolled 207 participants who were randomized 2:1 to receive oral mitapivat at 100 mg twice daily (n=138) or matched placebo (n=69) during a 52-week, double-blind, randomized, placebo-controlled period, as detailed in the filing announcement. The trial carried two primary endpoints, hemoglobin response and the annualized rate of sickle cell pain crises, according to Agios.
When the company first reported topline results, it disclosed that 40.6% of patients in the mitapivat arm achieved a hemoglobin response, defined as a 1.0 g/dL or greater increase from baseline in average hemoglobin from Week 24 through Week 52, compared with 2.9% of patients in the placebo arm, a statistically significant improvement at a two-sided p-value below 0.0001, according to the November 2025 topline release.
The trial also met secondary endpoints tied to hemolysis and hemoglobin levels. The average change from baseline in hemoglobin concentration from Week 24 through Week 52 was 7.69 g/L in the mitapivat arm versus 0.26 g/L in the placebo arm, and the change in indirect bilirubin, a marker of red blood cell destruction, was -16.03 µmol/L versus 0.88 µmol/L, both statistically significant, the topline release stated.
The pain endpoint was the weak point. The annualized rate of sickle cell pain crises was 2.62 in the mitapivat arm and 3.05 in the placebo arm, with a two-sided p-value of 0.1213, a trend favoring mitapivat that did not meet statistical significance, per the topline data. Agios said the safety profile of mitapivat in RISE UP “was consistent with that seen in prior mitapivat sickle cell disease trials,” according to the same release.
Because Agios is pursuing the accelerated approval pathway, the submission follows agreement with the FDA on a required confirmatory trial. That global, randomized, double-blind, placebo-controlled, 52-week study will enroll approximately 159 patients aged 12 years or older with sickle cell disease, with a primary endpoint of being transfusion-free from Week 4 through Week 52, according to BioSpace. Agios said it expects to receive notice of the sNDA filing acceptance and the anticipated review timeline in the third quarter of 2026, following the FDA’s 60-day filing review period, BioSpace reported.
Sarah Gheuens, M.D., Ph.D., chief medical officer and head of R&D at Agios, said the submission “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,” according to BioSpace.
What Comes Next
Detailed RISE UP results are set for a high-profile venue. Agios said the trial data will be presented orally during the Plenary Abstracts Session at the 31st European Hematology Association Congress in Stockholm, Sweden, running June 11-14, 2026, and that “the RISE UP abstract was one of only six selected for this distinguished plenary session” out of thousands of submissions, according to the company. Agios plans to host an investor conference call during the congress on Saturday, June 13, at 9:00 a.m. ET, the company said.
The EHA presentation gives clinicians their first detailed look at efficacy and safety beyond the topline numbers, and it precedes the FDA’s decision on whether to accept the filing for review.
What We Don’t Know
Agios has not disclosed a target action date for the sNDA; the company said only that it expects notice of filing acceptance and the review timeline in the third quarter of 2026, according to BioSpace. It is also not yet clear how the FDA will weigh a hemoglobin-based accelerated approval given that the trial’s pain-crisis co-primary endpoint did not reach statistical significance, per the topline data. The confirmatory trial’s transfusion-free endpoint will be the measure used to establish clinical benefit, according to BioSpace, but its results lie years ahead.