TL;DR
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The phase III RISE UP trial found that mitapivat improved hemoglobin response in people with sickle cell disease, meeting one of its two primary endpoints. It did not significantly reduce the annualized rate of pain crises compared with placebo; the FDA is reviewing the data, with a decision expected by February 2027.
Mitapivat improved hemoglobin response but did not significantly reduce sickle cell pain crises in the phase III RISE UP trial, which tested the oral drug in people with sickle cell disease. The split results mean the study met one of its two primary endpoints as the U.S. Food and Drug Administration reviews whether to approve the drug for this condition.
Among the 207 participants, 41% of those assigned to mitapivat had a hemoglobin response, compared with 3% assigned to placebo, a statistically significant difference (P<0.0001). The trial defined response as an increase of at least 1 g/dL in average hemoglobin from baseline over weeks 24 to 52.
The second primary endpoint was the annualized rate of sickle cell pain crises. Participants in the mitapivat group averaged 2.6 crises per year, compared with 3.1 in the placebo group; the difference was not statistically significant (P=0.1213). Researchers led by Biree Andemariam, MD, of the New England Sickle Cell Institute at the University of Connecticut Health reported the results in The Lancet.
The study also reported improved markers of hemolysis and reduced transfusion burden with mitapivat, but no improvement in patient-reported fatigue overall. The drug was associated with lower rates of grade 3 or higher adverse events than placebo, 33% versus 41%, and serious adverse events, 20% versus 29%. These group-level findings do not remove the need to weigh individual risks, including the drug’s existing liver-injury warning.
What the Split Endpoints Mean
The results offer evidence of an effect on hemoglobin levels, but they do not establish that mitapivat reduces pain crises across the trial population. Pain crises can involve urgent care and hospitalization, so the lack of a statistically significant result on that endpoint leaves a central question about the drug’s potential clinical role unanswered.
The distinction also matters for the FDA’s review. The findings may support consideration of the hemoglobin response, while the missed pain-crisis endpoint and the safety profile are relevant to decisions about an expanded indication. The trial does not, by itself, show how regulators will weigh those results or whether approval would carry additional safety measures.
Two commentators said post-hoc analyses pointed to possible benefits among people who achieved a hemoglobin response, including fewer crises and related hospital visits. Those analyses were not the trial’s primary comparison and cannot establish in advance who will respond. The overall randomized result remains that the pain-crisis rate was not significantly different from placebo.
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Trial Design and Drug Background
RISE UP enrolled people older than 16 with anemia and recurrent sickle cell pain crises at 69 sites in 15 countries. Participants were assigned in a 2-to-1 ratio to mitapivat, taken twice daily at 100 mg, or placebo. At the start of the study, the median age was 25, mean hemoglobin was about 8.5 g/dL, and participants averaged 3.4 pain crises a year.
Mitapivat, marketed as Aqvesme, is an oral pyruvate kinase activator already approved for anemia in adults with alpha- or beta-thalassemia. Its labeling includes a boxed warning for liver injury and a risk evaluation and mitigation strategy program. Agios Pharmaceuticals said no cases in this sickle cell trial followed the pattern or severity seen in its thalassemia trials; that is the company’s account, and the study also recorded some liver-related adverse events that led to treatment discontinuation.
The results arrive as other sickle cell drug decisions have drawn attention to the need for clear clinical evidence. Crizanlizumab lost marketing authorization in Europe after a randomized trial failed to show superiority to placebo on vaso-occlusive crises, while voxelotor was withdrawn from global markets after trial data found an imbalance in deaths and acute crises among treated patients. These histories provide context, but do not determine mitapivat’s outcome.
“There could be clinical benefit.”
— Jennifer Knight-Madden, MBBS, PhD, and Zachary Ramsay, MBBS, University of the West Indies
Questions for FDA Review
It remains unclear how the FDA will weigh the positive hemoglobin result against the failure to show a statistically significant reduction in pain crises. The agency has also asked for an analysis of whether a risk evaluation and mitigation strategy would be needed if mitapivat is approved for sickle cell disease.
The trial was not designed to determine which patients are most likely to achieve a hemoglobin response. The commentators said response differences could relate to genetic or epigenetic factors, red-cell metabolism, or inherited red-cell variants, but those explanations were not established by the study. Nor do the post-hoc results prove that responders will reliably experience fewer crises in clinical practice.
Although the researchers reported no treatment-related deaths, liver-related events occurred, and one serious adverse event in the mitapivat group was considered treatment-related. More detail on the FDA’s assessment, any requested analyses, and potential labeling is not yet available in the supplied report.
FDA Decision Expected by February
The RISE UP data are under FDA review, and a decision on mitapivat for sickle cell disease is expected by February 2027, according to the report. The agency has requested an analysis of whether a risk evaluation and mitigation strategy would be needed if the drug is approved for this condition.
Until that review is complete, the trial results do not establish that mitapivat is approved for sickle cell disease. Further details from the regulatory process could clarify how the FDA interprets the hemoglobin response, the pain-crisis findings, and the possible benefits suggested by analyses of responders.
Key Questions
What did the RISE UP trial find?
Mitapivat improved the rate of hemoglobin response versus placebo, with responses in 41% versus 3% of participants. It did not significantly reduce the annualized rate of pain crises: 2.6 per year with mitapivat versus 3.1 with placebo.
Did mitapivat meet the trial’s primary goals?
It met one of two primary endpoints: hemoglobin response. The difference in pain-crisis rates was not statistically significant.
Is mitapivat approved for sickle cell disease?
The supplied report says the sickle cell data are under FDA review, with an approval decision expected by February 2027. Mitapivat is currently approved for anemia in adults with alpha- or beta-thalassemia, not sickle cell disease.
What safety issue is being reviewed?
Mitapivat carries a boxed warning for liver injury and has a risk evaluation and mitigation strategy for its current use. The FDA has asked whether such a program would also be needed for a sickle cell indication; some liver-related events led to discontinuation in the trial.
Source: medpagetoday.com
