Efficacy and safety of mitapivat in patients with sickle cell disease (RISE UP): a phase 3, double-blind, global, randomised, placebo-controlled trial.
Biree Andemariam, Kevin H M Kuo, Farjah H Algahtani et al.
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In 30 seconds
RISE UP was a phase 3, double-blind, global, randomised, placebo-controlled trial conducted at 69 sites in 15 countries. It evaluated twice-daily mitapivat in patients older than 16 years with sickle cell disease, anaemia and recurrent pain crises. Among 207 participants, haemoglobin response occurred in 56 (41%) of 138 assigned mitapivat and two (3%) of 69 assigned placebo (adjusted difference 38%, 95% CI 29-47; p<0·0001). The annualised pain-crisis rate was numerically lower with mitapivat, but the difference was not statistically significant.
Key findings
- Haemoglobin response occurred in 56 (41%) of 138 mitapivat recipients versus two (3%) of 69 placebo recipients.
- The adjusted difference in haemoglobin response was 38% (95% CI 29-47; two-sided p<0·0001).
- Annualised pain-crisis rates were 2·6 (2·3-3·0) with mitapivat and 3·1 (2·6-3·6) with placebo (two-sided p=0·1213).
- Serious adverse events occurred in 28 (20%) patients receiving mitapivat and 20 (29%) receiving placebo; treatment-related events were deemed in one and zero patients, respectively.
Why it matters
The trial found a substantial improvement in the prespecified haemoglobin response with mitapivat, supporting its potential to address haemolytic anaemia in sickle cell disease. However, the observed difference in pain-crisis rates was not statistically significant, so the results do not establish a reduction in recurrent vaso-occlusive events. Both outcomes are relevant to assessing the potential role of a disease-modifying approach.
What to keep in mind
The trial enrolled patients older than 16 years with anaemia and recurrent pain crises, so findings may not apply to other sickle cell disease populations. The open-label extension is ongoing.