RISE UP Study Highlights Efficacy, Safety of Mitapivat in SCD

Mitapivat is a safe and effective treatment for patients with sickle cell disease (SCD), according to results from the phase II, double-blind portion of the RISE UP trial published in The Lancet Haematology.

The researchers evaluated the efficacy and safety of mitapivat, a first-in-class, oral, allosteric pyruvate kinase activator. Seventy-nine patients aged 16 years and older from 32 clinical sites across 13 countries were randomly assigned 1:1:1 to receive mitapivat at 50 mg (n=26), mitapivat at 100 mg (n=26), or placebo (n=27) twice daily. Patients had baseline hemoglobin levels of 5.5 to 10.5 g/dL and two to ten sickle cell pain crises within 12 months.

The primary efficacy endpoint was hemoglobin response (defined as a ≥1.0 g/dL increase from baseline in average hemoglobin concentration from week 10 through week 12). The primary safety endpoints were type and severity of adverse events (AEs) and the relationship between AEs and mitapivat.

Both treatment groups showed a statistically significant hemoglobin response rate compared with placebo, the authors noted. Specifically, 12 of 26 (46%) patients in the 50-mg group, 13 of 26 (50%) patients in the 100 mg group, and 1 of 27 (4%) patients in the placebo group achieved a statistically significant hemoglobin response rate (2-sided P=.0003 and P=.0001, respectively).

As for safety, 2 of 26 (8%) patients in the 50-mg group, 4 of 26 (15%) patients in the 100-mg group, and 3 of 27 (11%) patients in the placebo group reported AEs. The rates of grade 3 or higher AEs were 12% for the 50-mg group, 19% for the 100-mg group, and 7% for the placebo group.

The most common grade 3 or higher AEs were infections and infestations. This included one patient with meningitis and one with pelvic inflammatory disease in the 50-mg group; one patient each with malaria, pneumonia, and tonsillitis in the 100-mg group; and one patient with an infected skin ulcer in the placebo group. There were no serious AEs, grade 3 or higher AEs, or deaths that were considered treatment related.

“Mitapivat, through its dual effect of increasing ATP and decreasing 2,3-diphosphoglycerate, could provide clinical benefit to patients with sickle cell disease,” the researchers concluded. “These results support continued evaluation of mitapivat in the phase 3 portion of the study.”

Reference

Idowu M, Otieno L, Dumitriu B, et al. Safety and efficacy of mitapivat in sickle cell disease (RISE UP): results from the phase 2 portion of a global, double-blind, randomised, placebo-controlled trial. Lancet Haematol. 2025;12(1):e35-e44. doi:10.1016/S2352-3026(24)00319-3