Effects of AG-348, a Pyruvate Kinase Activator, on Anemia and Hemolysis in Patients with Pyruvate Kinase Deficiency: Data from the DRIVE PK Study

Abstract BACKGROUND Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by deficiency of the glycolytic enzyme red cell PK (PK-R). AG-348 is an orally available, small molecule, allosteric activator of PK-R that activates wild-type and a range of mutated PK-R enzymes in vitro, and increases PK-R activity and restores adenosine triphosphate (ATP) levels in red blood cells from patients with PK deficiency ex vivo. AIMS To describe data from the ongoing DRIVE PK study (NCT02476916), an open-label, dose-ranging trial of AG-348 in transfusion-independent adults with PK deficiency. Early data from this study have been reported (Grace et al. EHA 2016, S466). METHODS After providing informed consent, patients are randomized to AG-348 50 mg or 300 mg orally twice daily (BID) for 6 months. Transfusion independence is defined as no more than 3 units of red blood cells transfused in the 12 months preceding first dose and no transfusions in the 4 months preceding first dose. Patients are followed weekly for Weeks 1-3, then every 3 weeks until Week 12, and then monthly until Week 24. Sex hormone levels and iron status are evaluated at Baseline, Week 12 and End of Study. RESULTS As of the data cutoff date of June 20, 2016, 25 patients have been enrolled and treated for ≥3 weeks. Adverse events (AEs) were mild to moderate. The most frequent AEs were nausea (n=11/25), headache, and insomnia (each n=8/25). One serious AE (Grade 2 osteoporosis) has been reported. Grade 3 AEs were hypertension (n=1), hypertriglyceridemia (n=1), insomnia (n=2), and anemia (n=1). One patient was discontinued from treatment because anemia worsened. There were no Grade 4 AEs and no deaths. Three patients had dose reductions because of headache, nausea, or insomnia. Serum levels of sex steroids were measured at baseline, 12 and 24 weeks; increases in free and total testosterone, and decreases in estradiol and estrone, indicate aromatase inhibition by AG-348, consistent with previously reported results. In 25 patients with ≥3 weeks on treatment, 13 patients (52%) showed a hemoglobin (Hgb) increase >1.0 g/dL (range: 1.2-4.9 g/dL; median: 3.40 g/dL). Three patients had dose reductions because of Hgb values exceeding the protocol-mandated maximum. Hgb responses were typically observed within 2 weeks of treatment and were stable with continued treatment. Two patients had dose increases because of insufficient response to 50 mg. Maximal change in Hgb from baseline according to genotype is shown in Figure 1. Of the 25 enrolled patients with ≥3 weeks on treatment, 6 (24%) had two non-missense mutations and none of these had an Hgb response >1.0 g/dL. Of the 19 patients with at least one missense mutation, 13 (68%) had an Hgb increase exceeding 1.0 g/dL. CONCLUSION AG-348 is a novel, first-in-class, PK-R activator in clinical testing as a disease-altering therapy to improve anemia in patients with PK deficiency. The ongoing DRIVE PK study has now enrolled over 25 patients, and data from additional patients will be available at the time of presentation. Daily dosing with AG-348 is well tolerated and has demonstrated clinically relevant durable increases in Hgb in the majority of the patients with at least 1 missense mutation. Out of the 19 patients with at least one missense mutation, 13 had an Hgb increase of >1.0 g/dL. These data highlight the potential of AG-348 as the first disease-altering treatment for patients with PK deficiency. Figure 1 Maximum hemoglobin (Hgb) increase by genotype Figure 1. Maximum hemoglobin (Hgb) increase by genotype Disclosures Grace: Agios Pharmaceuticals: Other: Scientific Advisor, Research Funding. Rose:Novartis: Honoraria; Celgene: Honoraria; Genzyme: Honoraria. Layton:Novartis: Other: Advisory board meeting; Alexion: Other: Advisory board meeting; GSK: Other: Advisory board meeting; Agios: Speakers Bureau. Yaish:Baxalta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer Healthcare: Consultancy; Octapharma: Consultancy. Barcellini:Agios: Consultancy. Kuo:Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apotex: Other: Unrestricted education grant; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Silver:Agios Pharmaceuticals, Inc.: Consultancy. Merica:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Kung:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Cohen:Agios Pharmaceuticals, Inc.: Consultancy. Yang:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Hixon:Agios Pharmaceuticals, Inc.: Equity Ownership, Other: Employment (former); KSQ Therapeutics: Employment, Equity Ownership. Kosinski:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Silverman:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Dang:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yuan:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Barbier:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Glader:Agios Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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