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

Sanjeev Forsyth, Patricia Schroeder, James Geib, Leela Vrishabhendra, Diamantis G Konstantinidis, Kari LaSalvia, Maria D Ribadeneira, Eric Wu, Patrick Kelly, Theodosia A Kalfa, Sanjeev Forsyth, Patricia Schroeder, James Geib, Leela Vrishabhendra, Diamantis G Konstantinidis, Kari LaSalvia, Maria D Ribadeneira, Eric Wu, Patrick Kelly, Theodosia A Kalfa

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.

Trial registration: ClinicalTrials.gov NCT04624659 NCT03815695.

Keywords: clinical trial; etavopivat; first-in-human study; pharmacodynamics; pharmacokinetics; safety; sickle cell disease.

Conflict of interest statement

This study was funded by Forma Therapeutics, Inc., Watertown, Massachusetts, the manufacturer of etavopivat. S.F., P.S., J.G., M.D.R., E.W., and P.K. are employees of Forma Therapeutics. L.V. and K.L. are employees of Medpace Clinical Pharmacology, which was contracted by Forma Therapeutics for the clinical studies reported here. D.G.K. reports no conflicts of interest. T.A.K. reports consultancy for Agios Pharmaceuticals, and research funding from Agios Pharmaceuticals, Forma Therapeutics, and National Institutes of Health National Heart, Lung, and Blood Institute. All authors had full access to the study data and were involved in the analysis, interpretation, and preparation of this report. All authors were responsible for the decision to submit the manuscript for publication.

© 2022 Forma Therapeutics Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
Trial design schematic. aSentinel dosing: n = 3, randomized 2:1 to etavopivat or placebo, with the remaining subjects randomized ≥48 hours later. BID, twice daily (every 12 hours); MAD, multiple‐ascending dose; PK, pharmacokinetics; QD, once daily; SAD, single‐ascending dose.
Figure 2
Figure 2
Etavopivat plasma concentrations following single doses (200–1000 mg) in healthy subjects. Data points are offset for clarity. Inset shows the interval from 0 to 8 hours on an extended time scale. Concentrations below the LLOQ were set to zero. LLOQ, lower limit of quantitation; SD, standard deviation.
Figure 3
Figure 3
Etavopivat plasma concentrations on (A) day 1 and (B) day 14 following multiple doses in healthy subjects. Data points are offset for clarity. Concentrations below the LLOQ were set to zero. BID, twice daily; LLOQ, lower limit of quantitation; QD, once daily; SD, standard deviation.
Figure 4
Figure 4
Change from baseline in (A) 2,3‐DPG and (B) ATP in healthy subjects receiving multiple doses of etavopivat for 14 days. 2,3‐DPG, 2,3‐diphosphoglycerate; ATP, adenosine triphosphate; BID, twice daily; QD, once daily; SE, standard error.
Figure 5
Figure 5
Changes in hemoglobin‐oxygen affinity in RBCs of healthy subjects with etavopivat (A) single dose and (B) multiple doses. *All P < .05. P values based on Wilcoxon matched‐pairs signed‐rank test. Horizontal lines show the median values, the boxes the 25th to 75th percentiles, and the whiskers show the minimum to maximum values. BID, twice daily; NS, not significant; P50, partial pressure of oxygen at which hemoglobin‐oxygen saturation of 50% is achieved; QD, once daily; RBC, red blood cell.
Figure 6
Figure 6
Correlation between 2,3‐DPG concentrations and hemoglobin‐oxygen affinity. Linear regression: r2 is the coefficient of determination and the shaded regions show the 90% prediction band. 2,3‐DPG, 2,3‐diphosphoglycerate; P50, partial pressure of oxygen at which hemoglobin‐oxygen saturation of 50% is achieved.

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