Mitapivat (AG-348) in Adults with Pyruvate Kinase Deficiency Who Are Not Regularly Transfused: A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled Study (ACTIVATE) in Progress

Background: Pyruvate kinase (PK) deficiency is an under-recognized hereditary disease that causes lifelong hemolytic anemia. Mutations in the PKLR gene lead to reduced red cell PK (PK-R) enzyme activity, resulting in defective glycolysis and decreased lifespan of red blood cells. Mitapivat (AG-348) is a novel, first-in-class, oral, small-molecule allosteric activator of PK-R under clinical testing as the first targeted, disease-altering therapy for PK deficiency. The DRIVE PK study (NCT02476916; a phase 2, open-label, dose-ranging trial in adults with PK deficiency who are not regularly transfused) demonstrated that twice-daily (BID) dosing with mitapivat for >6 months was well tolerated and induced rapid, substantial, and durable responses (Grace et al. ASH 2017). Of 52 enrolled subjects, 26 (50%) had a maximum hemoglobin (Hb) increase of >1 g/dL in the 6-month treatment period. Among these 26 subjects, the mean maximum Hb increase was 3.4 g/dL, and 25 (96%) had ≥1 missense PKLR mutation. Based on these findings, mitapivat has entered phase 3 development in PK deficiency. The design of the ongoing phase 3 ACTIVATE study and its extension study are reported here, with an update on country/site activation. Methods: ACTIVATE is a phase 3, multicenter, randomized, double-blind, placebo-controlled study (NCT03548220) evaluating the efficacy and safety of mitapivat. Adults with PK deficiency who are not regularly transfused (≤4 transfusion episodes in the previous year and no transfusions in the prior 3 months) will be randomized in a 1:1 ratio to mitapivat (administered orally, BID) or matched placebo. Additional criteria include baseline Hb ≤10.0 g/dL and adequate organ function. Subjects who are homozygous for the R479H mutation or have 2 non-missense mutations (without the presence of another missense mutation) in PKLR will be excluded. The study consists of a screening period of up to 42 days, a 12-week dose optimization period, and a 12-week fixed-dose period (Figure). During the dose optimization period, mitapivat or matched placebo are titrated up to each subject's individually optimized dose, with an initial dose of 5 mg BID for all subjects and potentially 2 sequential dose increases (from 5 to 20 mg BID and from 20 to 50 mg BID), depending on safety and Hb change. The primary endpoint is the Hb response, defined as the proportion of subjects who achieve an increase of ≥1.5 g/dL in Hb sustained over at least 2 of the last 3 visits in the fixed-dose period. The average change in Hb during the fixed-dose period is considered a key secondary endpoint to further evaluate the magnitude of the treatment effect. Other secondary efficacy endpoints, such as markers of hemolysis and hematopoietic activity, will be evaluated to support the efficacy evaluation and confirm the mechanism of action, and safety is included as a secondary objective and endpoint. Two questionnaires, one specifically designed to measure the signs and symptoms of PK deficiency and the other designed to evaluate their impact on patients' lives, are also included for their validation and to further evaluate the efficacy of the treatment. All subjects who complete the study have the opportunity to enroll in an open-label extension study (NCT03853798) in which all participants will receive mitapivat for up to 192 weeks. An independent data monitoring committee will review the study data periodically and provide safety oversight. The ACTIVATE study is currently ongoing. Disclosures van Beers: Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding; Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Judge:Agios: Employment, Equity Ownership. Hua:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Mix:Agios: Employment, Equity Ownership.