Mitapivat sNDA Seeks FDA Accelerated Approval in Sickle Cell Disease

Key Takeaways

• Agios aligned with FDA on a 52-week, randomized, double-blind confirmatory trial (n≈159; age ≥12 years) using transfusion-free status from weeks 4–52 as the primary endpoint.
• RISE UP phase 3 (NCT05031780) randomized 207 patients (≥16 years) 2:1 to mitapivat 100 mg BID vs placebo for 52 weeks with dual primaries: hemoglobin response and pain-crisis rate.
• Hemoglobin response met statistical criteria, whereas annualized sickle cell pain crises decreased numerically but missed significance, complicating reliance on surrogate endpoints for accelerated approval.
• Public materials lack effect sizes, confidence intervals, and detailed safety tables, limiting assessment of magnitude, subgroup consistency, and toxicity until the planned June 2026 EHA presentation.
• Mitapivat’s RBC pyruvate kinase activation increases ATP and lowers 2,3-DPG, with prior FDA approvals in PK deficiency and thalassemia informing regulatory familiarity but not sickle cell benefit-risk.