Efficacy and safety of mitapivat in patients with sickle cell disease (RISE UP): a phase 3, double-blind, global, randomised, placebo-controlled trial.

BACKGROUND

Persistent haemolytic anaemia and recurrent vaso-occlusion drive complications and accelerate mortality in sickle cell disease. Mitapivat, an oral allosteric activator of pyruvate kinase, increases ATP and decreases 2,3-DPG with the potential to improve haemolytic anaemia and reduce sickling. We aimed to evaluate the efficacy and safety of mitapivat in patients with sickle cell disease.

METHODS

We report results from RISE UP, a phase 3, double-blind, global, randomised, placebo-controlled trial from 69 sites across 15 countries. Patients older than 16 years with anaemia and recurrent sickle cell pain crises were randomly assigned (2:1) to either mitapivat 100 mg or placebo twice a day using permuted-block randomisation. Primary endpoints, assessed in all randomly assigned patients, were haemoglobin response (≥1·0 g/dL increase in average haemoglobin concentration from week 24 to week 52 compared with baseline) and annualised rate of sickle cell pain crises. This study is registered with ClinicalTrials.gov, NCT05031780, and the open-label extension is ongoing.

FINDINGS: A total of 207 patients were randomly assigned to mitapivat (138 [67%]) or placebo (69 [33%]). 56 (41%) of 138 patients in the mitapivat group had a haemoglobin response, compared with two (3%) of 69 patients on placebo (adjusted difference 38%, 95% CI 29-47; two-sided p<0·0001). The annualised rate (95% CI) of sickle cell pain crises was 2·6 (2·3-3·0) for mitapivat and 3·1 (2·6-3·6) for placebo (two-sided p=0·1213). Serious adverse events were reported in 28 (20%) patients on mitapivat and 20 (29%) patients on placebo; one (1%) patient and 0 patients, respectively, were deemed treatment related.

INTERPRETATION: Mitapivat, an oral pyruvate kinase activator, with a novel mechanism that ameliorates haemolytic anaemia, has the potential to be an effective and convenient disease-modifying treatment for people with sickle cell disease.

FUNDING: Agios Pharmaceuticals.