Safety, Pharmacokinetics, and Pharmacodynamics of Etavopivat (FT‐4202), an Allosteric Activator of Pyruvate Kinase‐R, in Healthy Adults: A Randomized, Placebo‐Controlled, Double‐Blind, First‐in‐Human Phase 1 Trial
Abstract
Etavopivat (FT‐4202) is an orally administered, small‐molecule allosteric activator of erythrocyte pyruvate kinase‐R (PKR) in clinical development for the treatment of sickle cell disease and other hemoglobin disorders. This randomized, placebo‐controlled, double‐blind, first‐in‐human combination single‐ascending dose and multiple‐ascending dose phase 1 trial (NCT03815695) evaluated the safety and pharmacokinetics/pharmacodynamics of etavopivat in 90 healthy adult subjects. In 4 single‐ascending dose cohorts, 8 participants were randomized 3:1 to a single oral dose of either etavopivat (n = 6) or placebo (n = 2). In four 14‐day multiple‐ascending dose cohorts, 12 participants were randomized 3:1 to 14 days of etavopivat (n = 9) or placebo (n = 3). In these studies, most treatment‐emergent adverse events were of mild severity (grade 1) and none led to study discontinuation. Etavopivat exhibited a linear and time‐independent pharmacokinetic profile (at doses ≤400 mg) and elicited the expected pharmacodynamic effects of PKR activation (decreased 2,3‐diphosphoglycerate and increased adenosine triphosphate) and evidence of improved hemoglobin‐oxygen affinity. In addition, pharmacodynamic responses were durable with effects continuing for 48 to 72 hours after the last dose, thereby supporting once‐daily dosing. Food appeared to have no clinically meaningful effects on etavopivat exposure, thus facilitating administration with or without food. In conclusion, the evaluation of…
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Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design. Reported size: 90 participants or records.
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