FDA Pushes Mitapivat's Sickle Cell Decision to February Over Liver Safety
Agios won a decisive hemoglobin response in sickle cell but missed the pain-crisis endpoint. A liver-safety question has now pushed the mitapivat decision to February.
Agios Pharmaceuticals now waits until February 1, 2027, for an FDA decision on mitapivat in sickle cell disease, three months beyond the original November 1, 2026 goal date. The extra quarter follows a late-cycle safety question, not a verdict on the efficacy data. On October 9, three weeks before the first PDUFA date, the agency asked whether a Risk Evaluation and Mitigation Strategy is needed because of the liver injury seen in the thalassemia trials. Agios answered on October 19 with roughly nine months of updated safety data through October 9, pulled from the open-label extensions of the RISE UP program. With that follow-up, the company says there are still no sickle cell cases of hepatocellular injury matching the pattern and severity observed in thalassemia, and that the benefit-risk profile is unchanged. On October 28, the FDA classified the response as a major amendment and added three months.
The clock change is administrative. The filing underneath it still rests on a trial that proved hemolysis control while missing the symptom most patients actually feel.
A decisive hemoglobin win, a miss on pain crises
RISE UP, registered as NCT05031780, enrolled 207 patients aged 16 or older, randomized 2:1 to mitapivat 100 mg twice daily (n=138) or placebo (n=69) across a 52-week double-blind period. Mitapivat activates pyruvate kinase, raising ATP and lowering 2,3-DPG inside red blood cells. It is already marketed in the United States as PYRUKYND for pyruvate kinase deficiency (2022) and thalassemia (2025).
The hemoglobin-response endpoint was emphatic. An improvement of at least 1.0 g/dL in average hemoglobin from week 24 through week 52 occurred in 40.6% of mitapivat patients versus 2.9% on placebo (p<0.0001). Mean hemoglobin climbed 7.69 g/L versus 0.26 g/L, and indirect bilirubin, a hemolysis marker, fell 16.03 micromol/L versus a 0.88 micromol/L rise on placebo. Both of those key secondaries cleared p<0.0001.
The co-primary endpoint did not. The annualized rate of sickle cell pain crises was 2.62 events on mitapivat versus 3.05 on placebo (p=0.1213), short of statistical significance. PROMIS Fatigue registered -2.72 versus -2.25 (p=0.7112). A post hoc cut among mitapivat patients found hemoglobin responders had an annualized crisis rate of 2.20 versus 2.98 in non-responders (rate ratio 0.74), hospitalizations of 1.16 versus 1.76 (rate ratio 0.66), and a fatigue change of -5.19 versus -2.55, with responders crossing a -4.1 threshold treated as clinically meaningful. That cut is not the prespecified test. The full results were published in The Lancet.
The REMS question follows clean sickle cell liver data
Serious treatment-emergent adverse events hit 20.3% of mitapivat patients versus 29.0% on placebo. Discontinuations for adverse events ran 4.3% versus 2.9%. Three patients (2.2%) died on mitapivat and two (2.9%) on placebo, none considered treatment-related. Liver abnormalities in RISE UP did not suggest drug-induced hepatocellular injury, unlike the ENERGIZE and ENERGIZE-T thalassemia trials.
The FDA raised the REMS question regardless. Sickle cell disease affects roughly 100,000 people in the United States, which chief executive Brian Goff called the largest indication Agios has pursued for mitapivat. The sNDA went in under accelerated approval and earned Priority Review. The open question is whether thalassemia's liver history should shadow the drug into a much larger population even though the sickle cell file has not reproduced it.
What accelerated approval would lock in
Accelerated approval would rest on hemoglobin response and hemolysis markers, not on a win against annualized pain crises. The confirmatory trial required on that path is REIGNITE (NCT07656415), with the first patient dosed in July 2026. It is built to show clinical benefit by cutting transfusion burden in patients aged 12 and older, a different endpoint from the crisis miss.
February 1 will not reopen the crisis p-value. It will decide whether a hemoglobin-anchored accelerated approval, with REIGNITE still enrolling and a potential REMS hanging over the label, is enough to put an oral pyruvate kinase activator in front of the U.S. sickle cell population. Mitapivat can raise hemoglobin and cut hemolysis. It has not yet shown it reduces the crises that define the disease in the clinic. The extra quarter is the FDA deciding how much safety scaffolding that gap still requires.
