P107: A PHASE 2/3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF MITAPIVAT IN PATIENTS WITH SICKLE CELL DISEASE

Abstract

Background: 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.1–3 Sickled RBCs are rigid, not deformable, and fragile, resulting in vaso-occlusion triggering pain and chronic hemolysis.4–6 SCD treatment options are limited, with an unmet need for safe and effective therapies to improve anemia and reduce pain. Mitapivat is an oral, activator of RBC pyruvate kinase (PKR), a key glycolytic enzyme. PKR activation decreases 2,3-DPG and increases ATP, which may reduce HbS polymerization, RBC sickling, and hemolysis in SCD.3,7–9 Data from the phase (ph) 1 National Institutes of Health multiple ascending dose study of up to 100 mg mitapivat twice daily (BID) in 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.8,10 Aims: To report the study design of RISE UP (NCT05031780, EudraCT: 2021-001674-34), a ph 2/3, double-blind, randomized, placebo-controlled, multicenter study evaluating the efficacy and safety of mitapivat in patients (pts) with SCD. Methods: Eligible: pts aged ≥16 yrs with documented SCD (HbSS, HbSC, HbSβ0/HbSβ+ thalassemia, other SCD variants), 2–10 sickle cell pain crises (SCPCs; acute pain needing medical contact, acute chest syndrome, priapism, hepatic or splenic sequestration) in the prior 12 months, and Hb 5.5–10.5 g/dL. If taking hydroxyurea (HU), the dose must be stable for ≥90 days before starting study drug. Ineligible: pts receiving regularly scheduled blood transfusions, with severe kidney disease or hepatobiliary disorders, currently receiving SCD therapies (excluding HU) or who have received 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 placebo BID for 12 weeks (wks). The primary objective of ph 2 is to determine the recommended ph 3 mitapivat dose by evaluating anemia and safety vs placebo via the following endpoints: Hb response (≥1.0 g/dL increase in average Hb concentration over Wks 10–12 vs baseline [BL]), and type, severity, and relationship of adverse events 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 placebo BID for 52 wks, stratified by number of SCPCs in the prior yr (<5, ≥5) and HU use. The primary objectives of ph 3 are to determine the effect of mitapivat vs placebo on anemia, measured by Hb response (≥1.0 g/dL increase in average Hb concentration over Wks 24–52 vs BL), and the effect of mitapivat vs placebo on SCPC, measured by annualized rate of SCPCs. Key secondary endpoints include average change from BL in Hb concentration, indirect bilirubin, percent reticulocyte, and Pt-Reported Outcomes Measurement Information System® Fatigue 13a Short Form score over Wks 24–52; and annualized frequency of hospitalizations for SCPC. Pts who complete the double-blind period will be eligible to receive mitapivat in the open-label extension period in each ph. Results: Not yet available. Conclusion: This ph 2/3 study will investigate the efficacy and safety of mitapivat in pts aged ≥16 yrs with SCD. Enrollment is currently ongoing.