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 results, 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, a mixed result for Agios Pharmaceuticals as it seeks to expand use of the drug to sickle cell disease. The study met one of its two primary endpoints; the results are under FDA review.
Among participants assigned to mitapivat, 41% had a hemoglobin response, compared with 3% of those given placebo, a statistically significant difference (P<0.0001). The response was defined as an increase of at least 1 gram per deciliter in average hemoglobin from baseline during weeks 24 to 52.
The other primary endpoint was not met. The annualized rate of sickle cell pain crises was 2.6 with mitapivat and 3.1 with placebo; the difference was not statistically significant (P=0.1213). The trial enrolled 207 people older than 16 with anemia and recurrent crises. Participants were randomized in a 2:1 ratio to receive mitapivat 100 mg twice daily or placebo across 69 sites in 15 countries.
Researchers led by Biree Andemariam of the New England Sickle Cell Institute at the University of Connecticut Health reported improvements in measures of hemolysis and reduced transfusion burden, as well as other benefits among participants who responded on hemoglobin. The study authors did not report an improvement in patient-reported fatigue across the trial. These secondary findings do not change the result on the pain-crisis endpoint.
A Hemoglobin Gain Without Fewer Crises
The results leave an important clinical question unresolved: whether raising hemoglobin with mitapivat will reduce the painful episodes that drive urgent care and hospitalization. The trial’s overall comparison did not show a statistically significant reduction in crises, so the findings do not establish that the drug prevents them.
At the same time, the hemoglobin response gives regulators and clinicians evidence of a biological effect in this population. The distinction matters for people weighing a potential treatment: a laboratory measure improved, but the trial did not show a significant benefit on one of the disease outcomes patients may most directly experience. The drug’s benefit-risk profile and the FDA’s review will determine whether that result supports an expanded indication.
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Mitapivat’s Existing Uses and Safety Review
Mitapivat, marketed as Aqvesme, is an oral pyruvate kinase activator approved in the United States for anemia in adults with alpha- or beta-thalassemia. Its labeling carries a boxed warning for liver injury and includes a risk evaluation and mitigation strategy, or REMS. The FDA has asked Agios to analyze whether a REMS would also be needed for use in sickle cell disease.
The development comes after setbacks for other sickle cell medicines. Crizanlizumab remains available in the United States but lost marketing authorization in Europe after a randomized trial did not show superiority to placebo for vaso-occlusive crises. Voxelotor, which received accelerated approval in 2019, was withdrawn from global markets after trial data showed an imbalance in deaths and acute crises. Those histories make the evidence for both benefit and safety relevant to the current review.
In RISE UP, participants had a median age of 25, and average baseline hemoglobin was about 8.5 g/dL. They averaged 3.4 pain crises per year before the study. The reported safety results showed grade 3 or higher adverse events in 33% of mitapivat recipients and 41% of placebo recipients, and serious adverse events in 20% and 29%, respectively. Some liver-related events led to treatment discontinuation, despite no reported pattern of liver injury matching the concern in the thalassemia trials.
“There could be clinical benefit”
— Jennifer Knight-Madden and Zachary Ramsay, commentators from the University of the West Indies
Responder Benefits and Liver Risk
It is not yet clear whether the apparent benefits among people whose hemoglobin improved will hold up in further analyses or translate into reliable reductions in crises. The commentators described lower crisis rates, fewer related hospitalizations and emergency visits, longer times to subsequent crises, and lower fatigue scores among responders in post-hoc analyses. They also cautioned that these comparisons were not the trial’s primary test and may reflect differences between patients who did and did not respond.
The study was not designed to determine which patients are likely to achieve a hemoglobin response. The commentators said genetic and epigenetic factors, red-cell metabolism, or inherited red-cell variants could help explain differences, but the trial does not establish which factors predict response. The FDA’s assessment of liver safety and whether a REMS is appropriate for a sickle cell indication also remains pending. A small number of liver-related adverse events led to discontinuation; the reported trial results do not settle the longer-term risk.
Deaths occurred in 2% of the mitapivat group and 3% of the placebo group, and investigators did not consider any treatment-related. The supplied results do not establish what the FDA will conclude from the full submission or how any eventual label would describe the drug’s benefits and risks.
FDA Review and Decision Ahead
The RISE UP data are under FDA review, and a decision on mitapivat for sickle cell disease is expected by February 2027. The agency’s consideration will include the split primary-endpoint results and the drug’s safety profile, including the existing boxed warning and the question of whether a REMS should apply to this use.
Until the FDA acts, mitapivat remains approved for the stated thalassemia indications, not sickle cell disease. Any expansion would depend on the agency’s review; the study results alone do not establish that the drug will be approved for this population.
Key Questions
What did the RISE UP trial find?
It found that 41% of participants taking mitapivat met the hemoglobin-response definition, compared with 3% taking placebo. Mitapivat did not significantly reduce the annualized rate of sickle cell pain crises.
Did mitapivat reduce pain crises?
Not significantly in the trial’s overall comparison. The annualized rates were 2.6 with mitapivat and 3.1 with placebo, with P=0.1213. Post-hoc findings among hemoglobin responders are exploratory and do not replace the primary endpoint result.
Is mitapivat approved for sickle cell disease?
No. The source reports that mitapivat is approved for anemia in adults with alpha- or beta-thalassemia. Its sickle cell disease results are under FDA review.
When could the FDA decide on the sickle cell application?
An FDA decision is expected by February 2027, according to the report. Whether the agency will approve the drug, and what safety requirements might apply, remain unknown.
What safety issue is being reviewed?
Mitapivat carries a boxed warning for liver injury in its current labeling, along with a REMS program. The FDA has requested an analysis of whether a REMS would be needed for sickle cell disease; the study also reported some liver-related events that led to treatment discontinuation.
Source: medpagetoday.com
