Long-Term HOPE Data Supports Efficacy, Safety of Voxelotor for Sickle Cell

Jo Howard, MD

Complete data from the HOPE trial affirms the efficacy and safety of voxelotor (Oxbryta) in adolescents and adults with sickle cell disease (SCD). 

Follow-up data was initially presented at the American Society of Hematology (ASH) 2020 Annual Meeting.

In 2019, the US Food and Drug Administration (FDA) approved the sickle hemoglobin polymerization inhibitor in patients 12 years and older. This approval was based on results from the HOPE study, an international, randomized, placebo-controlled, phase 3 trial conducted at 60 clinical sites

Led by Jo Howard, MD, Department of Clinical Haematology, Guy's and St Thomas' NHS Foundation Trust, the investigative team evaluated the effects of treatment through weeks 72.

About the HOPE Trial

All patients (n = 274) included in the study presented with hemoglobin concentrations of 5.5–10.5 g/dL at the time of enrollment. Furthermore, these patients experienced 1-10 vaso-occlusive crises in the 12 months prior to enrollment.

“Patients receiving regularly scheduled transfusion therapy, who had received a transfusion in the previous 60 days, or who had been admitted to hospital for a vaso-occlusive crisis in the previous 14 days were excluded,” the investigators noted.

Those included were then randomly assigned 1:1:1 to receive once-daily oral voxelotor 1500 mg, voxelotor, 900 mg, and placebo for 72 weeks. Randomization was stratified by hydroxyurea use, age group and adulthood, and geographic region.

The primary endpoint sought by the investigators was the proportion of patients who achieved a hemoglobin response at week 24—results of which were previously reported in The New England Journal of Medicine.

Final Analysis: Week 72

The most up-to-date analysis of the trial results showed that the adjusted mean change in hemoglobin concentration from baseline was 1.0 g/dL (95% CI 0.7 to −1.3) in the voxelotor 1500 mg group, 0.5 g/dL (95% CI, 0·3 to −0·8) in the voxelotor 900 mg group, and 0.0 g/dL (95% CI, −0.3 to 0.3) in the placebo group.

The investigators stressed the significant differences between the voxelotor 1500 mg and placebo cohorts (P<.0001) as well as the voxelotor 900 mg and placebo cohorts (P<.014).

“Significant improvements in markers of hemolysis, as assessed by the difference in adjusted mean percentage change from baseline at week 72 versus placebo, were observed in the voxelotor 1500 mg group in indirect bilirubin concentrations (−26.6% [95% CI, −40.2 to −12.9]) and percentage of reticulocytes (−18·6% [−33.9 to −3.3]),” Howard and colleagues wrote.

They also noted that the proportion of patients rated as “moderately improved” and “very much improved” according to the Clinical Global Impression of Change (CGI-C) scale was significantly higher in the voxelotor 1500 mg group versus the placebo group (39 [74%] of 53 vs 24 [47%] of 51, respectively; P = .0057)

In terms of safety, 25 of 88 (28%) patients in the voxelotor 1500 mg group reported serious adverse advents unrelated to SCD—compared with 20 (22%) of 90 in the 900 mg group, and 23 (25%) of 91 patients in the placebo group.

The investigators reported that grade 3 or 4 adverse events occurred in <10% of patients, and anemia occurred in 2 voxelotor 1500 mg-treated patients, 7 voxelotor 900 mg-treated patients, and 3 placebo-treated patients.

Of the entire 274-person clinical population, 6 unrelated deaths occurred—2 in each treatment arm.

“Voxelotor 1500 mg resulted in rapid and durable improvements in haemoglobin concentrations maintained over 72 weeks and has potential to address the substantial morbidity associated with haemolytic anaemia in sickle cell disease,” Howard and team concluded.

The study, “Voxelotor in adolescents and adults with sickle cell disease (HOPE): long-term follow-up results of an international, randomised, double-blind, placebo-controlled, phase 3 trial,” was published online in The Lancet Haemtology.