• Elliott Vichinsky, Carolyn C Hoppe, Kenneth I Ataga, Russell E Ware, Videlis Nduba, Amal El-Beshlawy, Hoda Hassab, Maureen M Achebe, Salam Alkindi, R Clark Brown, David L Diuguid, Paul Telfer, Dimitris A Tsitsikas, Ashraf Elghandour, Victor R Gordeuk, Julie Kanter, Miguel R Abboud, Joshua Lehrer-Graiwer, Margaret Tonda, Allison Intondi, Barbara Tong, Jo Howard, and HOPE Trial Investigators.
• From the University of California, San Francisco (UCSF) Benioff Children's Hospital Oakland, Oakland (E.V.), and Global Blood Therapeutics, South San Francisco (C.C.H., J.L.-G., M.T., A.I., B.T.) - both in California; the University of Tennessee Health Science Center at Memphis, Memphis (K.I.A.); Cincinnati Children's Hospital and University of Cincinnati, Cincinnati (R.E.W.); Kenya Medical Research Institute, Kisumu, Kenya (V.N.); Cairo University, Cairo (A.E.-B.), and the Pediatric Department and Clinical Research Center, Faculty of Medicine (H.H.), and the Faculty of Medicine (A.E.), Alexandria University, Alexandria - all in Egypt; Brigham and Women's Hospital and Harvard Medical School, Boston (M.M.A.); Sultan Qaboos University, Muscat, Oman (S.A.); Emory University and Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta (R.C.B.); New York-Presbyterian/Columbia University Medical Center, New York (D.L.D.); Barts Health NHS Trust (P.T.), Homerton University Hospital NHS Foundation Trust (D.A.T.), and Guy's and St. Thomas' NHS Foundation Trust and King's College (J.H.) - all in London; the University of Illinois at Chicago, Chicago (V.R.G.); the University of Alabama at Birmingham, Birmingham (J.K.); and the American University of Beirut Medical Center, Beirut, Lebanon (M.R.A.).
• N. Engl. J. Med. 2019 Aug 8; 381 (6): 509-519.

BackgroundDeoxygenated sickle hemoglobin (HbS) polymerization drives the pathophysiology of sickle cell disease. Therefore, direct inhibition of HbS polymerization has potential to favorably modify disease outcomes. Voxelotor is an HbS polymerization inhibitor.MethodsIn a multicenter, phase 3, double-blind, randomized, placebo-controlled trial, we compared the efficacy and safety of two dose levels of voxelotor (1500 mg and 900 mg, administered orally once daily) with placebo in persons with sickle cell disease. The primary end point was the percentage of participants who had a hemoglobin response, which was defined as an increase of more than 1.0 g per deciliter from baseline at week 24 in the intention-to-treat analysis.ResultsA total of 274 participants were randomly assigned in a 1:1:1 ratio to receive a once-daily oral dose of 1500 mg of voxelotor, 900 mg of voxelotor, or placebo. Most participants had sickle cell anemia (homozygous hemoglobin S or hemoglobin Sβ0-thalassemia), and approximately two thirds were receiving hydroxyurea at baseline. In the intention-to-treat analysis, a significantly higher percentage of participants had a hemoglobin response in the 1500-mg voxelotor group (51%; 95% confidence interval [CI], 41 to 61) than in the placebo group (7%; 95% CI, 1 to 12). Anemia worsened between baseline and week 24 in fewer participants in each voxelotor dose group than in those receiving placebo. At week 24, the 1500-mg voxelotor group had significantly greater reductions from baseline in the indirect bilirubin level and percentage of reticulocytes than the placebo group. The percentage of participants with an adverse event that occurred or worsened during the treatment period was similar across the trial groups. Adverse events of at least grade 3 occurred in 26% of the participants in the 1500-mg voxelotor group, 23% in the 900-mg voxelotor group, and 26% in the placebo group. Most adverse events were not related to the trial drug or placebo, as determined by the investigators.ConclusionsIn this phase 3 randomized, placebo-controlled trial involving participants with sickle cell disease, voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis. These findings are consistent with inhibition of HbS polymerization and indicate a disease-modifying potential. (Funded by Global Blood Therapeutics; HOPE ClinicalTrials.gov number, NCT03036813.).Copyright © 2019 Massachusetts Medical Society.

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