Mitapivat raised haemoglobin in sickle cell disease but not pain crises

Design

Phase 3, randomised (2:1), double-blind, placebo-controlled, 52 weeks

Population

207 patients over 16 with sickle cell disease, anaemia and recurrent pain crises

Primary outcome

Haemoglobin response (≥1 g/dL rise) and annualised pain crisis rate

Effect

Response 41% vs 3% (difference 38%, 95% CI 29-47); crises 2.6 vs 3.1 per year (p=0.12)

RISE UP randomised 207 people over 16 with sickle cell disease, anaemia and recurrent pain crises, 2:1, to mitapivat 100 mg twice daily or placebo, at 69 sites in 15 countries. Mitapivat is an oral activator of red cell pyruvate kinase, which raises ATP and lowers 2,3-DPG and so may reduce sickling. Published in The Lancet on 24 October 2026.

A haemoglobin rise of at least 1 g/dL between weeks 24 and 52 occurred in 41% on mitapivat and 3% on placebo, an adjusted difference of 38 percentage points (95% CI 29 to 47). The co-primary endpoint, annual pain crises, was 2.6 versus 3.1 and not significantly different. Serious adverse events were fewer on mitapivat (20% vs 29%).

Anaemia drives much of the long-term organ damage in sickle cell disease, so a convenient oral drug that improves it is useful. But patients feel the crises, and on those the trial did not show a clear benefit.

India carries a large share of the world's sickle cell disease, concentrated in tribal populations of central and western India. Mitapivat's status with CDSCO for this indication is not known, and hydroxyurea remains the established disease-modifying treatment.

• Continue hydroxyurea as the standard disease-modifying treatment for sickle cell disease
• Expect mitapivat to improve haemoglobin in about two in five patients, based on this trial
• Tell patients this trial did not show a significant reduction in pain crises
• Mitapivat is not established for sickle cell disease in India; its regulatory status here is unknown
• Refer adults with frequent crises or worsening anaemia to a haematology service with trial access

Why it matters

An oral drug that targets the red cell's energy supply improved anaemia, but the endpoint patients feel did not move.

Don't overread it

A haemoglobin response is a surrogate; the pain crisis endpoint was not met.

The statistics, in plain English

The 38-point haemoglobin response difference has a confidence interval well clear of zero, so it is real. For pain crises, p=0.12 means a difference of the size seen could easily have arisen by chance; the trial cannot claim a reduction.

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