Oral mitapivat raised haemoglobin in sickle cell disease but did not significantly reduce pain crises

Design

Phase 3, double-blind, randomised, placebo-controlled trial

Population

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

Primary outcome

Haemoglobin response and annualised rate of pain crises

Effect

Haemoglobin 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 patients older than 16 with sickle cell disease, anaemia and recurrent pain crises, at 69 sites in 15 countries, to oral mitapivat 100 mg twice daily or placebo (2:1).

A haemoglobin rise of at least 1 g/dL, averaged over weeks 24–52, occurred in 41% on mitapivat versus 3% on placebo (adjusted difference 38%, 95% CI 29–47). The annual rate of pain crises was 2.6 versus 3.1, which was not statistically significant (P = 0.12). Serious adverse events were 20% versus 29%.

Mitapivat activates red-cell pyruvate kinase, which makes cells less prone to sickling and haemolysis. The haemoglobin response is real; whether it translates into fewer crises and less organ damage is not yet shown. It was industry funded.

Sickle cell disease is common in parts of central and western India, especially among tribal communities, where hydroxyurea remains the established disease-modifying treatment. Mitapivat's availability in India is unknown.

• Hydroxyurea remains the established disease-modifying treatment for sickle cell disease
• Mitapivat improved anaemia but did not significantly reduce pain crises in this trial
• A haemoglobin response is a surrogate; crisis and organ outcomes matter more
• Mitapivat's availability in India is unknown

Why it matters

A new oral mechanism for sickle cell disease, but the end point patients feel most has not yet moved.

Don't overread it

The pain-crisis reduction was not statistically significant; this trial does not show fewer crises.

The statistics, in plain English

A P value of 0.12 for pain crises means the difference between 2.6 and 3.1 crises a year could easily be chance. The haemoglobin result, with a confidence interval of 29–47 percentage points, is well clear of zero.

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