Over 4 Years of Safety and Efficacy with Voxelotor Treatment for Patients with Sickle Cell Disease: Updated Results from an Open-Label Extension of the Phase 3 HOPE Trial

Introduction: Sickle cell disease (SCD) is an inherited blood disorder caused by a homozygous or compound heterozygous mutation in the hemoglobin (Hb) subunit β gene, leading to sickle hemoglobin (HbS). Polymerization of HbS results in red blood cell sickling/damage and leads to hemolysis, chronic anemia, and vaso-occlusive crises (VOCs). Hemolysis and low Hb put patients with SCD at risk of end-organ damage, increased morbidity, and early mortality. Voxelotor, a first-in-class HbS polymerization inhibitor, is approved in the US for the treatment of patients with SCD aged ≥4 years and in Europe for the treatment of hemolytic anemia due to SCD in patients aged ≥12 years. In the phase 3, randomized, placebo-controlled HOPE trial (NCT03036813), significantly more patients (aged ≥12 years) treated with voxelotor 1500 mg achieved a >1 g/dL Hb increase vs placebo (89% vs 25%, respectively) at any time up to Week 72. Hb increases were associated with reductions in markers of hemolysis (indirect bilirubin, reticulocyte percentage, and lactate dehydrogenase). To assess the safety and efficacy of long-term voxelotor use, we report an updated interim analysis of an open-label extension (OLE) of the HOPE trial. Methods: Patients who completed the HOPE trial were eligible to enroll in the multicenter, global OLE study (NCT03573882) and receive ongoing treatment with once daily voxelotor 1500 mg if they continued to derive clinical benefit and/or until voxelotor was available via an alternative source. Adverse event (AE) data were collected through 28 days after voxelotor discontinuation, and measurements of Hb and clinical markers of hemolysis were summarized through 168 weeks of treatment in the OLE. Central laboratory assessments were used for the US and Europe through Week 48; local laboratory assessments were used for the rest of the world throughout the study. The annualized rate of VOCs was calculated from events reported as sickle cell anemia with crisis or acute chest syndrome. Data presented are based on an interim data cut (Dec 31, 2022). Results: Of 199 patients who completed the HOPE trial, 178 (89.4%) were enrolled and dosed in the OLE. Median age at enrollment was 25 years (15.7% adolescents, 84.3% adults). At data cutoff, the median (range) duration of voxelotor exposure the OLE was 124.0 (1.9-205.9) weeks, and 81 patients were treated for ≥168 weeks. Of these 81 patients, 52 had previously received voxelotor in the randomized part of the study, for a co