Phase 1 Single- and Multiple-Ascending-Dose Randomized Studies of the Safety, Pharmacokinetics, and Pharmacodynamics of AG-348, a First-in-Class Allosteric Activator of Pyruvate Kinase R, in Healthy Volunteers.

Pyruvate kinase deficiency is a chronic hemolytic anemia caused by mutations in PK-R, a key glycolytic enzyme in erythrocytes. These 2 phase 1 randomized, placebo-controlled, double-blind healthy-volunteer studies assessed the safety, tolerability, and pharmacokinetics/pharmacodynamics of AG-348, a first-in-class allosteric PK-R activator. Twelve sequential cohorts were randomized 2:6 to receive oral placebo or AG-348, respectively, as a single dose (30-2500 mg) in the single-ascending-dose (SAD) study (ClinicalTrials.gov: NCT02108106) or 15-700 mg every 12 hours or 120 mg every 24 hours, for 14 days in the multiple-ascending-dose (MAD) study (ClinicalTrials.gov: NCT02149966). All 48 subjects completed the fasted SAD part; 44 of 48 completed the MAD (2 discontinued because of adverse events [AEs], 2 withdrew consent). The most common treatment-related AEs in AG-348-treated subjects were headache (16.7% [SAD] and 13.9% [MAD]) and nausea (13.9%, both studies). AE frequency increased at AG-348 doses ≥ 700 mg (SAD) and at 700 mg every 12 hours (MAD); 1 grade ≥ 3 AE occurred in the latter cohort. Pharmacokinetics were favorable with low variability. Dose-dependent changes in blood glycolytic intermediates consistent with glycolytic pathway activation were observed at all MAD doses, supporting future trials investigating the potential of AG-348 for treating PK deficiency or other anemias.