New pill mitapivat successfully raises hemoglobin in SCD trial
Developer plans FDA filing after study meets primary goal, shows strong safety
A new oral treatment, mitapivat, for sickle cell disease (SCD) significantly boosted hemoglobin levels in patients over a year, achieving one of the primary goals of a Phase 3 clinical trial.
In the RISE UP trial (NCT05031780), the medication helped patients 16 and older experience a key increase in the oxygen-carrying protein in red blood cells, which can help counter the anemia and red blood cell destruction (hemolysis) that characterize the disorder.
While the therapy showed a positive trend in reducing the rate of painful crises, this reduction did not reach statistical significance. However, mitapivat was also effective at significantly dropping indirect bilirubin, a marker of red blood cell destruction, and the developer, Agios Pharmaceuticals, plans to use these results to file for U.S. regulatory approval.
Mitapivat boosts hemoglobin, reduces hemolysis
“The data from RISE UP demonstrate that treatment with mitapivat significantly improved hemoglobin concentration and reduced hemolysis,” Biree Andemariam, MD, professor of medicine at the University of Connecticut Health and a RISE UP trial investigator, said in a press release. “Patients who achieved the threshold of hemoglobin response also experienced clinically meaningful benefits in the rate of sickle cell pain crises and hospital visits for those events, as well as in fatigue.”
Agios plans to present detailed data at a medical congress and file for mitapivat’s approval for SCD in the U.S. after a meeting with the Food and Drug Administration early next year.
In SCD, an abnormal form of hemoglobin causes red blood cells to assume a sickle shape, making them prone to premature hemolysis, leading to symptoms of anemia. Mitapivat is designed to activate pyruvate kinase, an enzyme in red blood cells that helps with energy generation, supporting cell integrity and survival. By activating pyruvate kinase, the oral therapy also lowers levels of 2,3-DPG, a molecule elevated in SCD patients and known to promote red blood cell sickling.
Sold as Pyrukynd, mitapivat is already approved for adults with pyruvate kinase deficiency, a genetic disorder that causes red blood cells to break down too quickly. It’s also under review in the U.S. for thalassemia, another bleeding disorder.
RISE UP trial design
Launched in 2022, the Phase 2/3 RISE UP study included 286 SCD patients, 16 years or older, who had hemoglobin levels between 5.5 and 10.5 gram per deciliter (g/dL) and experienced two to 10 pain crises in the previous year.
In its Phase 2 portion, 79 participants were randomly assigned to receive either one of two mitapivat doses (50 mg and 100 mg) or a placebo twice daily for about three months. Data showed mitapivat increased hemoglobin levels and reduced the annual rate of pain crises compared with the placebo.
The Phase 3 part, which completed enrollment last year, included 207 SCD patients, who received mitapivat or a placebo twice daily for 52 weeks.
Top-line data showed significantly more mitapivat-treated patients achieved a hemoglobin response — defined as a hemoglobin increase by at least 1 g/dL — from week 24 through week 52 compared with the placebo (40.6% vs. 2.9%), meeting one of the trial’s main goals.
Although the annualized rate of pain crises was lower in the mitapivat group (2.62 vs. 3.05), the difference didn’t reach statistical significance, failing to meet the trial’s second main goal.
In secondary measures, the average hemoglobin increase from week 24 through week 52 was significantly higher with mitapivat versus the placebo (7.69 vs. 0.26 g/dL), as was the reduction in indirect bilirubin levels (16.03 vs. 0.88 micromole/L).
Mitapivat-treated patients also showed trends of less fatigue, as indicated by lower PROMIS Fatigue scores, and of lower annualized frequency of hospitalizations for pain crises. Immature red blood cells, a hemolysis marker, significantly decreased with mitapivat.
Additional analyses showed that those who achieved a mitapivat-induced hemoglobin response had a 26% lower annualized rate of pain crises and a 34% lower annualized rate of hospitalizations for pain crises than non-responders. Responders also showed an average reduction in fatigue considered clinically meaningful, while non-responders did not reach such reductions.
Safety profile remains favorable
Rates of adverse events were similar between the mitapivat and placebo groups. Less than 3% of patients in each group died; no death was considered therapy-related. Mitapivat’s safety profile was consistent with previous SCD trials.
All but two participants completing the study’s one-year placebo-controlled part chose to enter an open-label extension period, where all will receive the therapy for up to four years.
“The RISE UP Phase 3 results further support mitapivat’s strong anti-hemolytic profile, as demonstrated in other rare blood disease trials,” said Sarah Gheuens, MD, PhD, chief medical officer and head of research and development at Agios.
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