Clinical Trial, Phase I Journal Article Randomized Controlled Trial Research Support, Non-U.S. Gov't Ppublish 22 citations
PubMed: 35019238 DOI: 10.1002/cpdd.1058
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.
Clin Pharmacol Drug Dev 11(5):654-665
Authors: Sanjeev Forsyth, Patricia Schroeder, James Geib, Leela Vrishabhendra, Diamantis G Konstantinidis, Kari LaSalvia, Maria D Ribadeneira, Eric Wu, Patrick Kelly, Theodosia A Kalfa
Affiliations
- Forma Therapeutics, Inc. Watertown, Massachusetts, USA.
- Medpace Clinical Pharmacology Unit, Cincinnati, Ohio, USA.
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
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 etavopivat in healthy subjects demonstrated proof of mechanism (PKR activation) without significant adverse events. This study also allowed for the selection of dose levels, projected to have an acceptable safety profile and provide therapeutic benefit, for evaluation in future trials in patients with sickle cell disease.
MeSH
Cells, Hemoglobins, Safety, Anemia, Sickle Cell, Drug-Related Side Effects And Adverse Reactions, Therapeutics, Pyruvate Kinase, Pharmacokinetics
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