The key pathology in sickle cell disease (SCD), a life-threatening, hereditary hemoglobin (Hb) disorder, is red blood cell (RBC) sickling due to polymerization of deoxygenated sickle Hb (HbS), which can be exacerbated by increased levels of the glycolytic metabolite 2,3-diphosphoglycerate (2,3-DPG) and decreased ATP. Sickled RBCs are rigid, non-deformable, and fragile, resulting in vaso-occlusive pain and chronic hemolysis. Current SCD treatment options are limited; therefore, there is an unmet need for safe, effective therapies that alleviate both anemia and pain. Activation of the key RBC glycolytic enzyme pyruvate kinase (PKR) by oral mitapivat decreases 2,3-DPG and increases ATP, which may reduce HbS polymerization, RBC sickling, and hemolysis in SCD. Data from the phase (ph) 1 National Institutes of Health multiple ascending dose study of up to 100 mg mitapivat twice daily (BID) in patients with SCD (NCT04000165) showed that mitapivat was safe and tolerable, increased ATP and decreased 2,3-DPG in a dose-dependent manner, and improved anemia and hemolysis. Here we report the study design of RISE UP (NCT05031780, EudraCT: 2021-001674-34), a ph 2/3, double-blind, randomized, placebo (PBO)-controlled, multicenter study evaluating the efficacy and safety of mitapivat in patients (pts) with SCD.

Eligible: pts aged ≥16 yrs (≥18 yrs [France and Germany]) with documented SCD (HbSS, HbSC, HbSβ0/HbSβ+ thalassemia, other variants), 2–10 sickle cell pain crises (SCPCs; acute pain requiring intervention, acute chest syndrome, priapism, hepatic or splenic sequestration) in the prior 12 months, and Hb 5.5–10.5 g/dL. If on hydroxyurea (HU), the dose must be stable for ≥ 90 days before starting study drug. Ineligible: pts receiving regular blood transfusions, with severe kidney or hepatobiliary disease, current SCD therapies except HU, or prior gene therapy, bone marrow or stem cell transplantation. In the double-blind ph 2 part, 69 pts will be randomized (1:1:1) to 50 mg or 100 mg mitapivat, or PBO BID for 12 weeks (wk). The primary objective is to determine the recommended ph 3 mitapivat dose by evaluating anemia and safety vs PBO via the following endpoints: Hb response (≥ 1.0 g/dL increase in average (avg) Hb concentration over Wk 10–12 vs baseline [BL]), and type, severity, and relationship of adverse events (AEs) and serious AEs. In the double-blind ph 3 part, 198 pts who did not participate in ph 2 will be randomized (2:1) to the selected ph 3 mitapivat dose or PBO BID for 52 wk. The primary objectives are to determine the effect of mitapivat vs PBO on anemia, measured by Hb response (≥ 1.0 g/dL increase in avg Hb concentration over Wk 24–52 vs BL), and the effect of mitapivat vs PBO on SCPC, measured by annualized rate of SCPCs. Key secondary endpoints: avg change from BL in Hb concentration, indirect bilirubin, percent reticulocyte, and Pt-Reported Outcomes Measurement Information System® Fatigue 13a Short Form score over Wk 24–52; and annualized frequency of SCPC admissions. Pts who complete the double-blind period will be eligible to receive mitapivat in the open-label extension period in each ph.

Pending.

N/A.

This ph 2/3 study will investigate the efficacy and safety of mitapivat in pts with SCD. Enrollment is currently ongoing.