Long-term safety and efficacy of voxelotor in patients with sickle cell disease: results of an open-label extension study of the phase 3 HOPE trial

INTRODUCTION: Sickle cell disease is an inherited genetic disorder caused by hemoglobin polymerization and red blood cell sickling, leading to hemolysis, chronic anemia, and vaso-occlusive crises (VOCs). Voxelotor, an HbS polymerization inhibitor, was evaluated in the randomized, placebo-controlled, phase 3 HOPE trial. Results showed a significant increase in hemoglobin (Hb) > 1 g/dL and a reduction in hemolysis markers compared to placebo at 24 and 72 weeks in patients (12 to 65 years old) treated with voxelotor 1500 mg. To confirm the long-term safety and efficacy of voxelotor, we report an interim analysis of an ongoing extension study of the HOPE trial. PATIENTS AND METHODS: Patients who completed the HOPE trial were included in the open-label, multicenter extension study. All patients received voxelotor 1500 mg during this phase, including those who had received voxelotor 900 mg or placebo. Adverse events were collected from the date of informed consent until 28 days after voxelotor discontinuation. Hb and clinical marker measurements of hemolysis are ongoing and are reported here at 48 weeks of treatment in the extension phase based on interim data collection (December 31, 2020). RESULTS: Of the 199 patients who completed the HOPE trial, 178 were included and treated in the extension phase. The median age at enrollment was 25 years. At the cutoff date, the median duration of voxelotor exposure in the extension phase was 69.9 weeks (1.9–102.0 weeks), with 78 patients treated for ≥ 72 weeks, for a combined exposure duration of ≥ 144 weeks. Among those receiving placebo, the mean change (SD) in hemoglobin from baseline (start of the extension phase) to week 48 was 1.3 (1.51) g/dL, consistent with the HOPE results. Markers of hemolysis also improved from baseline to week 48 (indirect bilirubin level −39.5%; reticulocyte percentage −28.6%). Patients receiving voxelotor during the HOPE trial showed sustained long-term effect in the extension phase. The annualized incidence rate of vaso-occlusive crises (VOCs) was 1.3 (95% CI: 1.1–1.4) events per year in all patients. The most frequently reported non-sickle cell disease-related adverse events during treatment (AEDTs) were arthralgia, headache, pain, nausea, and pain in the extremities. No events suggestive of tissue oxygenation impairment were observed. CONCLUSION: In this open-label extension study, treatment with voxelotor 1500 mg resulted in improvements in hemoglobin and hemolysis markers at 48 weeks in placebo-receiving patients and demonstrated long-term maintenance of response in those already treated with voxelotor. No new safety signals were identified after a combined exposure of 144 weeks. In conclusion, these results confirm that long-term treatment with voxelotor is safe, well tolerated and effective for reducing anemia and hemolysis, and show a low rate of CVO, in patients with sickle cell disease.