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Multicenter, phase 1 study of etavopivat (FT-4202) treatment for up to 12 weeks in patients with sickle cell disease.

Publication ,  Journal Article
Saraf, SL; Hagar, RW; Idowu, M; Osunkwo, I; Cruz, K; Kuypers, FA; Brown, RC; Geib, J; Ribadeneira, MD; Schroeder, P; Wu, E; Forsyth, S ...
Published in: Blood Adv
April 19, 2024

Etavopivat is an investigational, once-daily, oral, selective erythrocyte pyruvate kinase (PKR) activator. A multicenter, randomized, placebo-controlled, double-blind, 3-part, phase 1 study (https://clinicaltrials.gov/study/NCT03815695) was conducted to characterize the safety and clinical activity of etavopivat. Thirty-six patients with sickle cell disease (SCD) were enrolled into 4 cohorts: one single-dose; two multiple ascending doses; one open-label [OL]. In the OL cohort, 15 patients (median age 33.0 [range, 17‒55] years received 400-mg etavopivat once daily for 12 weeks; 14 completed treatment. Consistent with the mechanism of PKR activation, increases in ATP and decreases in 2,3 diphosphoglycerate were observed and sustained over 12 weeks' treatment. This translated clinically to an increase in hemoglobin (mean maximal increase 1.6 [range, 0.8‒2.8] g/dL), with >1 g/dL increase in 11 (73%) patients during treatment. Additionally, oxygen tension at which hemoglobin is 50% saturated was reduced (P=.0007) with concomitant shift in point-of-sickling (P=.0034) to lower oxygen tension in oxygen-gradient ektacytometry. Hemolysis markers (absolute reticulocyte count, indirect bilirubin, lactate dehydrogenase) decreased from baseline, along with matrix metalloproteinase-9 and erythropoietin. In the OL cohort, adverse events (AEs) were mostly grade 1/2, consistent with underlying SCD; 5 patients had serious AEs. Vaso-occlusive pain episode was the most common treatment-emergent AE (n=7) in the OL cohort. In this first study of etavopivat in SCD, 400 mg once daily for 12 weeks was well-tolerated, resulting in rapid and sustained increases in hemoglobin, improved RBC physiology, and decreased hemolysis.

Duke Scholars

Published In

Blood Adv

DOI

EISSN

2473-9537

Publication Date

April 19, 2024

Location

United States

Related Subject Headings

  • 3201 Cardiovascular medicine and haematology
 

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Saraf, S. L., Hagar, R. W., Idowu, M., Osunkwo, I., Cruz, K., Kuypers, F. A., … Telen, M. J. (2024). Multicenter, phase 1 study of etavopivat (FT-4202) treatment for up to 12 weeks in patients with sickle cell disease. Blood Adv. https://doi.org/10.1182/bloodadvances.2023012467
Saraf, Santosh L., Robert Ward Hagar, Modupe Idowu, Ifeyinwa Osunkwo, Kimberly Cruz, Frans A. Kuypers, R Clark Brown, et al. “Multicenter, phase 1 study of etavopivat (FT-4202) treatment for up to 12 weeks in patients with sickle cell disease.Blood Adv, April 19, 2024. https://doi.org/10.1182/bloodadvances.2023012467.
Saraf SL, Hagar RW, Idowu M, Osunkwo I, Cruz K, Kuypers FA, et al. Multicenter, phase 1 study of etavopivat (FT-4202) treatment for up to 12 weeks in patients with sickle cell disease. Blood Adv. 2024 Apr 19;
Saraf, Santosh L., et al. “Multicenter, phase 1 study of etavopivat (FT-4202) treatment for up to 12 weeks in patients with sickle cell disease.Blood Adv, Apr. 2024. Pubmed, doi:10.1182/bloodadvances.2023012467.
Saraf SL, Hagar RW, Idowu M, Osunkwo I, Cruz K, Kuypers FA, Brown RC, Geib J, Ribadeneira MD, Schroeder P, Wu E, Forsyth S, Kelly PF, Kalfa TA, Telen MJ. Multicenter, phase 1 study of etavopivat (FT-4202) treatment for up to 12 weeks in patients with sickle cell disease. Blood Adv. 2024 Apr 19;

Published In

Blood Adv

DOI

EISSN

2473-9537

Publication Date

April 19, 2024

Location

United States

Related Subject Headings

  • 3201 Cardiovascular medicine and haematology