ACTIVATE-Kids: Mitapivat in Children with Pyruvate Kinase Deficiency Who Are Not Regularly Transfused

Background: Pyruvate kinase (PK) deficiency is a rare, inherited disorder caused by PKLR gene mutations; the disease is associated with chronic hemolytic anemia and lifelong complications. Clinical management includes red blood cell (RBC) transfusions and splenectomy, which only partially improve anemia. No pharmacotherapies are approved for use in children, and therapies targeting the underlying cause of hemolysis are needed. Mitapivat (AG-348), a first-in-class, oral, allosteric activator of the RBC PK enzyme, demonstrated significant and durable improvements in hemoglobin (Hb) and markers of hemolysis and hematopoiesis in adults with PK deficiency who were not regularly transfused (ACTIVATE NCT03548220; long-term extension study NCT03853798). Mitapivat has been approved by the US Food and Drug Administration for the treatment of hemolytic anemia in adults with PK deficiency. Safety and efficacy data support the evaluation of mitapivat in children with PK deficiency who are not regularly transfused. Here, we report the design of ACTIVATE-Kids (NCT05175105), a phase 3 study, which will evaluate the efficacy and safety of mitapivat in children with PK deficiency who are not regularly transfused.

Methods: ACTIVATE-Kids, a phase 3, global, multicenter, double-blind, placebo-controlled study, will stratify 30 children by age (1-<6, 6-<12, and 12-<18 years); a minimum of 6 patients in each age group will be randomized (2:1) to mitapivat or placebo (Figure). The double-blind period comprises an 8-week (wk) dose-titration period and a 12-wk fixed-dose period. A 5-year open-label extension (OLE) period will follow the double-blind period. The study drug will be administered orally (as granules taken with food or tablets swallowed whole) at a dose of 1-50 mg twice daily, depending on age and weight. Pediatric dosing is based on pharmacokinetic modeling and simulation such that, within each age and weight category, the proposed dose provides exposure similar to that in adults at the same dose level. Key inclusion criteria include: ≥2 PKLR mutant alleles with ≥1 missense mutation, ≤5 RBC transfusions in the past year, Hb concentrations of ≤10 g/dL (12 to <18 years) or ≤9 g/dL (1 to <12 years). Key exclusion criteria include: R479H homozygosity, 2 non-missense mutations without a missense mutation in PKLR, or prior stem cell transplantation. The primary endpoint is Hb response, defined as a ≥1.5 g/dL increase in Hb concentration from baseline that is sustained at ≥2 scheduled assessments at Wks 12, 16, and 20 in the double-blind period. Secondary endpoints will evaluate the effect of mitapivat on Hb, hemolysis, erythropoiesis, iron metabolism and overload, safety, quality of life, and pharmacokinetics. With a planned sample size of 30 randomized patients (mitapivat, N=20; placebo, N=10), and assuming an Hb response rate of 35% for mitapivat and 5% for placebo, there will be >80% probability that the lower bound of the 95% credible interval for the odds ratio of Hb response (mitapivat vs placebo), based on the Bayesian logistic regression model with weight ≥0.35, of a robust prior, will be >1. The primary endpoint of Hb response will be analyzed using a Bayesian logistic regression model, including Hb response status (yes, no), as the dependent variable and treatment as the independent variable. Patients completing the double-blind period will be eligible to receive mitapivat for up to 5 years in an OLE. During the OLE, all patients will receive mitapivat.

Results: Global site recruitment is in progress, with a total of 20 sites planned in Canada, France, Germany, Israel, Italy, Netherlands, Spain, Switzerland, United Kingdom, and United States. Patient enrollment has also begun, with the first patient enrolled in July 2022.

Conclusions: The phase 3 ACTIVATE-Kids study of children with PK deficiency who are not regularly transfused will evaluate treatment with mitapivat, a potential disease-modifying pharmacotherapy.

Grace:Sobi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy; Novartis: Research Funding; Agios Pharmaceuticals: Consultancy, Research Funding. Tyler:Agios: Current Employment, Other: Stockholder. Larcom:Agios: Current Employment, Other: Stockholder. Kosinski:Agios: Consultancy, Other: Shareholder. Beynon:Agios: Current Employment, Other: Stockholder.