TL;DR
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The phase III RISE UP trial met its hemoglobin-response goal for mitapivat but did not show a statistically significant reduction in annualized sickle cell pain crises. The FDA is reviewing the data, with a decision on the drug’s potential sickle cell use expected by February 2027; liver-safety requirements remain under review.
Mitapivat improved hemoglobin response in a phase III sickle cell disease trial but did not significantly reduce pain crises compared with placebo, leaving the study with mixed results on its two primary goals. The findings from the RISE UP trial are under FDA review as the drugmaker seeks an expanded use for the oral treatment.
Among patients assigned to mitapivat, 41% met the trial’s hemoglobin-response definition, compared with 3% of those given placebo, a statistically significant difference (P<0.0001). A response meant an average hemoglobin increase of at least 1 g/dL from baseline over the period from weeks 24 to 52.
The second primary endpoint was the annualized rate of sickle cell pain crises. The rate was 2.6 with mitapivat and 3.1 with placebo, a difference that was not statistically significant (P=0.1213). The result does not establish that mitapivat reduces crisis frequency across the study population.
The trial enrolled 207 people older than 16 with anemia and recurrent crises at 69 sites in 15 countries. Participants were randomly assigned in a 2:1 ratio to twice-daily mitapivat at 100 mg or placebo. Researchers led by Biree Andemariam, MD, of the New England Sickle Cell Institute at University of Connecticut Health, reported the findings in The Lancet.
A Split Result for Sickle Cell Care
The results leave regulators and clinicians with two different signals: a clear improvement in hemoglobin response, but no statistically significant benefit on the trial’s measure of pain crises, a central complication of sickle cell disease. The distinction matters because a change in a blood measurement does not by itself show that patients experience fewer crises or related urgent-care needs.
The investigators also reported improved markers of hemolysis and reduced transfusion burden. They described additional clinical benefits among participants who achieved a hemoglobin response, but those subgroup findings do not replace the overall comparison on the pain-crisis endpoint. The study authors also found no improvement in patient-reported fatigue.
Mitapivat’s safety record will be part of the regulatory discussion. The drug already carries a boxed warning for liver injury in its approved uses for alpha- and beta-thalassemia. Although the trial did not show a liver-injury signal matching the pattern or severity seen in thalassemia trials, some participants stopped treatment after hepatic-related adverse events.
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From Thalassemia to Sickle Cell
Mitapivat, marketed as Aqvesme, is an oral pyruvate kinase activator approved by the FDA as a disease-modifying treatment for anemia in adults with alpha- or beta-thalassemia. Agios Pharmaceuticals is seeking a sickle cell disease indication, which would expand the drug’s use to another inherited blood disorder.
The RISE UP results arrive after setbacks for other sickle cell treatments. Crizanlizumab, approved in 2019, lost its marketing authorization in Europe after a randomized trial did not show it outperforming placebo on vaso-occlusive crises; it remains available in the United States. Voxelotor, which received accelerated approval in 2019, was later withdrawn globally after trial data showed an imbalance in deaths and acute vaso-occlusive crises among treated patients.
In an accompanying commentary, Jennifer Knight-Madden and Zachary Ramsay of the University of the West Indies said the findings should be interpreted cautiously. They pointed to post-hoc analyses suggesting that mitapivat recipients who achieved a hemoglobin response had fewer crises and related hospital visits, longer times to subsequent crises, and lower fatigue scores than nonresponders. Those comparisons were not the trial’s primary test of benefit.
“There could be clinical benefit”
— Jennifer Knight-Madden, MBBS, PhD, and Zachary Ramsay, MBBS, University of the West Indies
FDA Review and Safety Questions
The FDA is reviewing the trial data, but approval for sickle cell disease has not been announced. An FDA decision is expected by February 2027, according to the report. The agency has also requested an analysis of whether a risk evaluation and mitigation strategy, or REMS, would be needed for this use because of the existing liver-injury warning.
Agios said available data have not shown cases of liver injury matching the pattern or severity seen in the thalassemia trials. That company statement does not resolve the FDA’s assessment. In RISE UP, hepatic-related events led to discontinuation in some patients, although the trial report said there was no overall liver-injury signal of the cited type. One serious adverse event in the mitapivat group was considered treatment-related; deaths occurred in 2% of that group and 3% of the placebo group, and none was judged treatment-related.
It is also unclear whether researchers can identify in advance which patients are likely to achieve a hemoglobin response. The commentators said the trial was not designed to answer that question and noted that genetic, epigenetic and red-cell factors could contribute to differences in response.
The February FDA Decision
The next major milestone is the FDA’s expected decision by February 2027 on mitapivat’s potential use in sickle cell disease. The agency’s review will address the mixed primary-endpoint results as well as the drug’s safety information and whether a REMS is needed.
Until the review is complete, the trial supports a conclusion that mitapivat improved hemoglobin response in the studied population, but it does not show a statistically significant reduction in pain-crisis rates overall. Any regulatory decision and accompanying safety requirements will clarify whether the treatment becomes an option for people with sickle cell disease.
Key Questions
What did the RISE UP trial find?
Mitapivat met one of two primary endpoints. Hemoglobin response occurred in 41% of the mitapivat group and 3% of the placebo group, while the difference in annualized pain-crisis rates was not statistically significant.
Did mitapivat reduce sickle cell pain crises?
The reported annualized rates were 2.6 with mitapivat and 3.1 with placebo. The comparison did not reach statistical significance, so the trial did not establish an overall reduction in pain crises.
Is mitapivat approved for sickle cell disease?
No sickle cell approval has been announced. Mitapivat is approved for anemia in adults with alpha- or beta-thalassemia, and its proposed use in sickle cell disease is under FDA review.
What is the liver-safety concern?
Mitapivat carries a boxed warning for liver injury in its current approved uses. The FDA has requested an analysis of whether a REMS would be needed for sickle cell disease; the company has said trial data have not shown liver injury matching the pattern or severity seen in thalassemia trials.
When is the FDA expected to decide?
The report says an FDA decision on the proposed sickle cell use is expected by February 2027. The timing and any safety requirements will depend on the agency’s review.
Source: medpagetoday.com
