DRIVE PK: A Phase 2 Trial of AG-348 in Patients with Pyruvate Kinase Deficiency (2015)

Abstract INTRODUCTION: Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by deficient function of the PK enzyme. This condition is currently managed with supportive care, including transfusions, folate supplementation, splenectomy, and reducing iron overload, but there are no treatments specifically targeting the underlying metabolic defect. AG-348 is a novel, orally available, small molecule activator of wild-type and mutant red blood cell PK. METHODS: Results of single-ascending dose (SAD) and multiple-ascending dose (MAD) studies in healthy adult volunteers (Yang H et al. Blood 2014;124[21]:4007; Yang H et al. Haematologica 2015;100[s1]:Abs S138) indicated good safety and tolerability and predictable pharmacokinetics at doses that demonstrated significant pharmacodynamic responses of increased whole blood adenosine triphosphate (ATP) and decreased 2,3-diphosphoglycerate (2,3-DPG) levels. In pre-clinical studies AG-348 inhibited the enzyme aromatase, and sex hormone profiles in the MAD study showed signs of aromatase inhibition. RESULTS: DRIVE PK is a multicenter, international, randomized, open-label, two-arm dose ranging trial of AG-348 in adults with PK deficiency. DRIVE PK is currently open for enrollment. Eligible patients are randomized to either low dose (50 mg BID) or high dose (300 mg BID) arms and receive treatment for 6 months, with the option of extended treatment. Patients are stratified by genotype to allow for genotype-phenotype correlations. A third dose may be added based on the observations made in the two original arms. The primary objective is to evaluate the safety and tolerability of AG-348. Secondary objectives include evaluation of pharmacokinetics and pharmacodynamics, as measured by AG-348, ATP and 2,3-DPG levels. A range of biochemical markers of clinical benefit will be assessed, including hemoglobin levels, reticulocyte count, bilirubin, erythropoietin, ferritin, transferrin saturation, and haptoglobin. PK activity, glycolytic flux assay and PK protein levels in blood will be analyzed as exploratory endpoints. The trial population consists of adult patients with PK deficiency with hemoglobin levels at screening of ≤12.0 g/dL (men) or ≤11.0 g/dL (women), who have received no more than three units of red blood cells in the 12 months preceding the first dose of AG-348, and no transfusion within 4 months. Full inclusion/exclusion criteria can be found on www.clinicaltrials.gov, NCT02476916. CONCLUSION: DRIVE PK, an ongoing phase 2 trial of the PK activator, AG-348, is the first interventional trial to target the underlying metabolic defect in patients with PK deficiency. This flexible trial with two dose arms, and potential for a third dose arm, is designed to evaluate safety and tolerability, pharmacokinetic and pharmacodynamic responses, as well as hematological markers of red blood cell metabolism. Disclosures Barbier: Agios: Employment, Equity Ownership. Silver:Agios: Consultancy. Merica:Agios Pharmaceuticals: Employment, Equity Ownership. Cohen:Agios: Consultancy. Kung:Agios: Employment, Equity Ownership. Yang:Agios Pharmaceuticals: Employment, Equity Ownership. Grace:Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Agresta:Agios: Employment, Equity Ownership.