Agios Pharmaceuticals (AGIO) Study Result summary

Disease background and unmet need

• Sickle cell disease is a hereditary, multisystem disorder with significant morbidity, early mortality, and median life expectancy in the late 30s in the U.S.

• Chronic hemolytic anemia and vasoocclusion are central to disease pathology, leading to organ damage and reduced quality of life.

• Treatment options are limited; hydroxyurea is the mainstay, while other agents like L-glutamine, crizanlizumab, and voxelotor have had limited uptake or were withdrawn.

• Gene therapies exist but are complex, costly, and have limited accessibility.

• There is a strong need for well-tolerated, physiologically anchored therapies that improve hemoglobin and reduce pain crises.

Study design and patient population

• The Phase 3 RISE UP trial randomized 207 patients 2:1 to mitapivat (100 mg BID) or placebo for 52 weeks, followed by an open-label extension.

• Patients were stratified by prior pain crises and hydroxyurea use; baseline characteristics were well balanced.

• Primary endpoints were hemoglobin response (≥1.0 g/dL increase) and annualized rate of sickle cell pain crises (SCPCs); key secondary endpoints included changes in hemoglobin, indirect bilirubin, PROMIS-Fatigue, hospitalizations, and reticulocyte percentage.

• 85% of patients completed the double-blind period, and most transitioned to the open-label extension.

• The trial targeted patients with 2–10 SCPCs in the prior year and hemoglobin 5.5–10.5 g/dL.

Efficacy results

• 40.6% of mitapivat-treated patients achieved a hemoglobin response (≥1 g/dL increase) vs 2.9% for placebo (p<0.0001), a highly statistically significant result.

• Mitapivat showed a 14% reduction in annualized pain crises (2.62 vs 3.05), but this did not reach statistical significance (p=0.12).

• Statistically significant improvements were seen in average hemoglobin concentration (+0.7 g/dL) and indirect bilirubin (–16.91 μmol/L), indicating reduced hemolysis.

• No significant difference in PROMIS-Fatigue scores between arms, though hemoglobin responders had clinically meaningful fatigue improvement.

• In hemoglobin responders, there was a 1.6 g/dL mean hemoglobin increase, 26% reduction in pain crises, 34% reduction in hospitalizations, and improved fatigue.