RESULTS FROM THE RANDOMIZED PLACEBO-CONTROLLED PHASE 3 HOPE TRIAL OF VOXELOTOR IN ADULTS AND ADOLESCENTS WITH SICKLE CELL DISEASE
Author(s): ,
Elliott Vichinsky
Affiliations:
UCSF Benioff Children's Hospital,Oakland,United States
,
Carolyn C. Hoppe
Affiliations:
Global Blood Therapeutics,South San Francisco,United States
,
Kenneth I. Ataga
Affiliations:
University of Tennessee Health Science Center at Memphis,Memphis,United States
,
Russell E. Ware
Affiliations:
Cincinnati Children’s Hospital,Cincinnati,United States
,
Videlis Nduba
Affiliations:
Kenya Medical Research Institute,Kisumu,Kenya
,
Amal El Beshlawy
Affiliations:
Cairo University,Cairo,Egypt
,
Hoda Hassab
Affiliations:
Pediatric Department and Clinical Research Center Faculty of Medicine,Alexandria University,Alexandria,Egypt
,
Maureen M. Achebe
Affiliations:
Brigham and Women’s Hospital,Boston,United States
,
Salam Al-Kindi
Affiliations:
Sultan Qaboos University,Muscat,Oman
,
Clark Brown
Affiliations:
Emory University, Aflac Cancer and Blood Disorders Center Children's Healthcare of Atlanta,Atlanta,United States
,
David L. Diuguid
Affiliations:
New York Presbyterian Hospital, Columbia University Medical Center,New York,United States
,
Paul Telfer
Affiliations:
Barts Health NHS Trust,London,United Kingdom
,
Dimitris A. Tsitsikas
Affiliations:
Homerton University Hospital NHS Foundation Trust,London,United Kingdom
,
Ashraf El Ghandour
Affiliations:
Alexandria University Hospital,Alexandria,Egypt
,
Victor R. Gordeuk
Affiliations:
University of Illinois at Chicago,Chicago,United States
,
Julie Kanter
Affiliations:
University of Alabama at Birmingham,Birmingham,United States
,
Miguel R. Abboud
Affiliations:
American University of Beirut Medical Center,Beruit,Lebanon
,
Joshua Lehrer-Graiwer
Affiliations:
Global Blood Therapeutics,South San Francisco,United States
,
Margaret Tonda
Affiliations:
Global Blood Therapeutics,South San Francisco,United States
,
Allison Intondi
Affiliations:
Global Blood Therapeutics,South San Francisco,United States
,
Barbara Tong
Affiliations:
Global Blood Therapeutics,South San Francisco,United States
Jo Howard
Affiliations:
Guy’s and St Thomas’ NHS Foundation Trust and King’s College,London,United Kingdom
EHA Library. Howard J. Jun 14, 2019; 267348; S147
J Howard
J Howard
Contributions
Abstract
This abstract is embargoed until Friday, June 14, 08:30 local time.

Abstract: S147

Type: Presidential Symposium

Presentation during EHA24: On Friday, June 14, 2019 from 16:15 - 16:30

Location: Hall 5

Background
Sickle cell disease (SCD) is an inherited disorder caused by a single amino acid substitution in the β-chain of hemoglobin (Hb) resulting in the production of sickle hemoglobin (HbS). When deoxygenated, HbS polymerizes, leading to red blood cell sickling and damage. This results in a triad of clinical features (anemia, hemolysis, and vaso-occlusion), which contribute to the acute and chronic manifestations of SCD. These long-term complications contribute to the decreased quality of life and reduced life expectancy observed in patients with SCD. Voxelotor is an oral, once-daily hemoglobin-oxygen affinity modulator designed to inhibit HbS polymerization, thus improving anemia and reducing hemolysis. The randomized phase 3 HOPE trial (NCT03036813) evaluates the efficacy and safety of voxelotor in patients with SCD aged 12 to 65 years. 

Aims
To present the results of the pre-specified Part A analysis of the first approximately 150 randomized patients in the HOPE trial.

Methods
Patients with SCD (HbSS, HbSC, HbSβ0 thalassemia, or other variants), Hb ≥5.5 and ≤10.5 g/dL, and between 1 and 10 vaso-occlusive crises in the prior 12 months were eligible. Concurrent hydroxyurea was allowed if the dose had been stable for ≥90 days. Patients were randomly assigned to receive voxelotor 1500 mg/day, 900 mg/day, or placebo for at least 24 weeks. The primary endpoint was the proportion of patients with a >1.0-g/dL increase in Hb from baseline at week 24. Secondary endpoints included change from baseline to week 24 in measures of hemolysis (absolute and percent reticulocyte counts, indirect bilirubin levels, and lactate dehydrogenase levels) and safety.

Results
154 patients were included in the preliminary Part A analysis; median age was 25 years (range, 12–59), and 42% were male. Most patients were HbSS/HbSβ0: 92% (1500 mg), 94% (900 mg), and 90% (placebo). Hydroxyurea use at study entry was 62% (1500 mg), 67% (900 mg), and 64% (placebo), and median baseline Hb was 8.6 g/dL (1500 mg; range, 5.9–10.8), 8.3 g/dL (900 mg; range, 6.3–10.8), and 8.5 g/dL (placebo; range, 6.1–10.4). At week 24, the proportion of patients with a >1.0-g/dL increase in Hb from baseline was significantly higher for both voxelotor 1500 mg (65%; P<0.0001) and 900 mg (33%; P=0.0159) compared with placebo (10%) (Figure). The mean change in Hb from baseline to week 24 was 1.5 g/dL with 1500 mg, 0.6 g/dL with 900 mg, and 0 g/dL with placebo. Consistent with improvement in Hb, voxelotor also resulted in concordant improvements in measures of hemolysis (Table). Overall, the treatment-emergent adverse events (TEAEs) were similar across all treatment arms except for diarrhea, which was higher with voxelotor (1500 mg, 21%; 900 mg, 19%) compared with placebo (10%). The majority of TEAEs were grade 1 or 2 in severity. The efficacy and safety data from the full patient population of the phase 3 HOPE trial (N=274) will be presented.

Conclusion
Voxelotor treatment demonstrated a dose-dependent increase in Hb, with the majority of patients on voxelotor 1500 mg achieving a >1.0-g/dL improvement in Hb from baseline to week 24. In addition, there was a dose-dependent decrease in measures of hemolysis with voxelotor. Furthermore, voxelotor was generally well tolerated. These results suggest that voxelotor has the potential to be disease-modifying by improving anemia and reducing hemolysis and their associated morbidity and mortality. 

Session topic: 26. Sickle cell disease

Keyword(s): Anemia, Hemoglobin, Hemolysis, Sickle cell disease

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