source: American Society of Pediatric Hematology/Oncology

year: N/A

Background:
Sickle cell disease (SCD) is an inherited disorder caused by a single amino acid substitution producing sickle hemoglobin (HbS). Deoxygenation of HbS causes polymer formation and red blood cell sickling, which lead to anemia, hemolysis, and vaso-occlusion. These clinical features contribute to the chronic and acute manifestations of SCD. Voxelotor is a once-daily oral therapy designed to modify HbS, interfere with hemoglobin (Hb) polymerization, and improve anemia and hemolysis. The randomized phase 3 HOPE study (NCT03036813) evaluates the efficacy and safety of voxelotor in patients with SCD aged 12 to 65 years.

Objectives:
To present the results of the pre-specified Part A of the HOPE study (first ≈150 randomized patients).

Design/Method:
Eligible patients were randomly assigned to receive voxelotor 900 mg/day, 1500 mg/day, or placebo for >=24 weeks. The primary endpoint was the proportion of patients with a >1-g/dL increase in Hb from baseline at week 24. Secondary endpoints included change from baseline in measures of hemolysis (eg, reticulocyte counts and unconjugated bilirubin level) and safety.

Results:
154 patients were included in Part A; median age was 25 years (range, 12–59), 14% were adolescents, and 42% were male. Most were HbSS/HbSβ0: 94% (900 mg), 92% (1500 mg), and 90% (placebo). Hydroxyurea use at study entry was 67% (900 mg), 62% (1500 mg), and 64% (placebo), and median baseline Hb was 8.3 g/dL (900 mg; range, 6.3–10.8), 8.6 g/dL (1500 mg; range, 5.9–10.8), and 8.5 g/dL (placebo; range, 6.1–10.4). At week 24, the proportion of patients with a >1-g/dL increase in Hb from baseline was significantly larger for both voxelotor 900 mg (33%; P=0.0159) and 1500 mg (65%; P<0.0001) compared with placebo (10%). Consistent with improvement in Hb, voxelotor also resulted in concordant improvements in measures of hemolysis. Overall, the treatment-emergent adverse events (TEAEs) were similar across all treatment arms except for diarrhea, which was higher in the voxelotor treatment arms (900 mg, 19%; 1500 mg, 21%; compared to placebo, 10%). The majority of these TEAEs were grade 1 or 2 in severity.

Conclusion:
Voxelotor treatment demonstrated a dose-dependent increase in Hb, with a large proportion of patients achieving a >1-g/dL improvement in Hb, and decreases in measures of hemolysis. Voxelotor was generally well tolerated. Voxelotor has the potential to modify the morbidity of chronic organ damage associated with SCD by improving anemia and hemolysis. Supported by Global Blood Therapeutics.

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