Lancet: oral mitapivat raises haemoglobin in sickle cell disease but does not significantly cut pain crises

The Lancet has published full results of RISE UP, a phase 3, double-blind, randomised, placebo-controlled trial of mitapivat, an oral drug from Agios, in sickle cell disease. Mitapivat activates the enzyme pyruvate kinase in red blood cells, which is meant to ease haemolytic anaemia and reduce sickling.

The trial

• 207 patients older than 16 with anaemia and recurrent pain crises at 69 sites in 15 countries were randomised 2:1 to mitapivat 100 mg twice daily (138) or placebo (69).
• Haemoglobin: 41% (56 of 138) on mitapivat had a haemoglobin response (an average rise of at least 1.0 g/dL between weeks 24 and 52) versus 3% (2 of 69) on placebo — a statistically significant difference.
• Pain crises: the annual rate was 2.6 with mitapivat and 3.1 with placebo, but the difference was not statistically significant (p=0.12), so this co-primary goal was not met.
• Safety: serious adverse events occurred in 20% on mitapivat and 29% on placebo; one serious event was judged treatment-related.

Limitations and next steps

Higher haemoglobin is a lab marker; the trial did not show a significant reduction in the painful crises that matter most to patients. Follow-up was about one year, the open-label extension is still running. Agios says it is seeking a path to US accelerated approval, which would require a confirmatory trial. Mitapivat is not approved for sickle cell disease; patients should discuss options with their haematologist.