A Phase 3 randomized trial of voxelotor in sickle cell disease

Elliott Vichinsky, Carolyn C. Hoppe, Kenneth 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 & 2 others Barbara Tong, Jo Howard

Research output: Contribution to journalArticle

Abstract

BACKGROUND Deoxygenated 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. METHODS In 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. RESULTS A 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 Sß0-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. CONCLUSIONS In 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.

Original languageEnglish (US)
Pages (from-to)509-519
Number of pages11
JournalNew England Journal of Medicine
Volume381
Issue number6
DOIs
StatePublished - Aug 8 2019

Fingerprint

Sickle Cell Anemia
Placebos
Polymerization
Hemoglobins
Sickle Hemoglobin
Intention to Treat Analysis
Randomized Controlled Trials
Confidence Intervals
Thalassemia
Hydroxyurea
Reticulocytes
Hemolysis
Bilirubin
Anemia
Research Personnel
Safety

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Vichinsky, E., Hoppe, C. C., Ataga, K., Ware, R. E., Nduba, V., El-Beshlawy, A., ... Howard, J. (2019). A Phase 3 randomized trial of voxelotor in sickle cell disease. New England Journal of Medicine, 381(6), 509-519. https://doi.org/10.1056/NEJMoa1903212

A Phase 3 randomized trial of voxelotor in sickle cell disease. / Vichinsky, Elliott; Hoppe, Carolyn C.; Ataga, Kenneth; Ware, Russell E.; Nduba, Videlis; El-Beshlawy, Amal; Hassab, Hoda; Achebe, Maureen M.; Alkindi, Salam; Brown, R. Clark; Diuguid, David L.; Telfer, Paul; Tsitsikas, Dimitris A.; Elghandour, Ashraf; Gordeuk, Victor R.; Kanter, Julie; Abboud, Miguel R.; Lehrer-Graiwer, Joshua; Tonda, Margaret; Intondi, Allison; Tong, Barbara; Howard, Jo.

In: New England Journal of Medicine, Vol. 381, No. 6, 08.08.2019, p. 509-519.

Research output: Contribution to journalArticle

Vichinsky, E, Hoppe, CC, Ataga, K, Ware, RE, Nduba, V, El-Beshlawy, A, Hassab, H, Achebe, MM, Alkindi, S, Brown, RC, Diuguid, DL, Telfer, P, Tsitsikas, DA, Elghandour, A, Gordeuk, VR, Kanter, J, Abboud, MR, Lehrer-Graiwer, J, Tonda, M, Intondi, A, Tong, B & Howard, J 2019, 'A Phase 3 randomized trial of voxelotor in sickle cell disease', New England Journal of Medicine, vol. 381, no. 6, pp. 509-519. https://doi.org/10.1056/NEJMoa1903212
Vichinsky E, Hoppe CC, Ataga K, Ware RE, Nduba V, El-Beshlawy A et al. A Phase 3 randomized trial of voxelotor in sickle cell disease. New England Journal of Medicine. 2019 Aug 8;381(6):509-519. https://doi.org/10.1056/NEJMoa1903212
Vichinsky, Elliott ; Hoppe, Carolyn C. ; Ataga, Kenneth ; Ware, Russell E. ; Nduba, Videlis ; El-Beshlawy, Amal ; Hassab, Hoda ; Achebe, Maureen M. ; Alkindi, Salam ; Brown, R. Clark ; Diuguid, David L. ; Telfer, Paul ; Tsitsikas, Dimitris A. ; Elghandour, Ashraf ; Gordeuk, Victor R. ; Kanter, Julie ; Abboud, Miguel R. ; Lehrer-Graiwer, Joshua ; Tonda, Margaret ; Intondi, Allison ; Tong, Barbara ; Howard, Jo. / A Phase 3 randomized trial of voxelotor in sickle cell disease. In: New England Journal of Medicine. 2019 ; Vol. 381, No. 6. pp. 509-519.
@article{92222d21f56b4a54805a241306355a1b,
title = "A Phase 3 randomized trial of voxelotor in sickle cell disease",
abstract = "BACKGROUND Deoxygenated 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. METHODS In 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. RESULTS A 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 S{\ss}0-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. CONCLUSIONS In 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.",
author = "Elliott Vichinsky and Hoppe, {Carolyn C.} and Kenneth Ataga and Ware, {Russell E.} and Videlis Nduba and Amal El-Beshlawy and Hoda Hassab and Achebe, {Maureen M.} and Salam Alkindi and Brown, {R. Clark} and Diuguid, {David L.} and Paul Telfer and Tsitsikas, {Dimitris A.} and Ashraf Elghandour and Gordeuk, {Victor R.} and Julie Kanter and Abboud, {Miguel R.} and Joshua Lehrer-Graiwer and Margaret Tonda and Allison Intondi and Barbara Tong and Jo Howard",
year = "2019",
month = "8",
day = "8",
doi = "10.1056/NEJMoa1903212",
language = "English (US)",
volume = "381",
pages = "509--519",
journal = "New England Journal of Medicine",
issn = "0028-4793",
publisher = "Massachussetts Medical Society",
number = "6",

}

TY - JOUR

T1 - A Phase 3 randomized trial of voxelotor in sickle cell disease

AU - Vichinsky, Elliott

AU - Hoppe, Carolyn C.

AU - Ataga, Kenneth

AU - Ware, Russell E.

AU - Nduba, Videlis

AU - El-Beshlawy, Amal

AU - Hassab, Hoda

AU - Achebe, Maureen M.

AU - Alkindi, Salam

AU - Brown, R. Clark

AU - Diuguid, David L.

AU - Telfer, Paul

AU - Tsitsikas, Dimitris A.

AU - Elghandour, Ashraf

AU - Gordeuk, Victor R.

AU - Kanter, Julie

AU - Abboud, Miguel R.

AU - Lehrer-Graiwer, Joshua

AU - Tonda, Margaret

AU - Intondi, Allison

AU - Tong, Barbara

AU - Howard, Jo

PY - 2019/8/8

Y1 - 2019/8/8

N2 - BACKGROUND Deoxygenated 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. METHODS In 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. RESULTS A 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 Sß0-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. CONCLUSIONS In 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.

AB - BACKGROUND Deoxygenated 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. METHODS In 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. RESULTS A 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 Sß0-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. CONCLUSIONS In 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.

UR - http://www.scopus.com/inward/record.url?scp=85070589589&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070589589&partnerID=8YFLogxK

U2 - 10.1056/NEJMoa1903212

DO - 10.1056/NEJMoa1903212

M3 - Article

VL - 381

SP - 509

EP - 519

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 6

ER -