THE RANDOMIZED, DOUBLE-BLIND, MULTICENTER, PLACEBO-CONTROLLED PHASE 3 RESOLVE TRIAL INVESTIGATING THE EFFICACY OF VOXELOTOR WITH STANDARD OF CARE IN THE RESOLUTION OF LEG ULCERS IN PATIENTS WITH SICKLE CELL DISEASE

Abstract

In sickle cell disease (SCD), polymerization of deoxygenated sickle hemoglobin (HbS) is the major pathological process that leads to red blood cell sickling and hemolysis. In addition to the major complications of SCD, including hemolytic anemia, inflammation, and vascular occlusion, patients often experience secondary complications such as stroke, organ damage, shortened lifespan, and painful and debilitating skin ulcers. Given the lack of registries and large prospective studies examining leg ulcers, their prevalence among individuals with SCD is likely underestimated but varies widely by geographic region: 43% in Brazil, 30% in Jamaica, 27% in Nigeria, 19% in Ghana, 13% in Sierra Leone, 8% in Saudi Arabia, and 1% to 5% in the US. Voxelotor, a HbS polymerization inhibitor that targets the underlying SCD pathology, is approved in the US for treatment of SCD in patients aged ≥4 years and in the UK, EU, and UAE for patients aged ≥12 years. In a post hoc analysis of voxelotor-treated patients from the pivotal HOPE trial (NCT03036813), leg ulcers resolved within 24 weeks in 10 out of 14 patients and improved or resolved by week 72 in 13 out of 14 patients. RESOLVE is an ongoing phase 3, randomized, double-blind, placebo-controlled, multicenter trial investigating the efficacy of voxelotor with standard of care (SOC) in the resolution of leg ulcers in patients with SCD. The study will be conducted at sites in Brazil (9), Nigeria (7), and Kenya (5). Target study enrollment is 80 patients aged ≥ 12 years with a confirmed diagnosis of SCD (HbSS or HbSβ 0 genotype) and ≥1 cutaneous ulcer on the lower extremity (leg, ankle, or dorsum of foot) that meets the following criteria: ≥ 2 weeks’ and < 6 months’ duration at screening and >2 cm 2 in area before randomization. After a 2-week run-in period, participants are randomized 1:1 to receive once-daily oral voxelotor 1500 mg or placebo in addition to SOC for 12 weeks. After the randomized treatment period, all participants enter an open-label treatment period and receive voxelotor 1500 mg plus SOC for an additional 12 weeks. Participants will have the option to enroll in a separate open-label extension study after completing the 24-week treatment period. All study sites in Brazil will be activated by the end of 2022, with the first patient evaluation in Brazil anticipated to occur in the first week of December 2022. The primary objective of this study—to assess the efficacy of voxelotor plus SOC compared with placebo plus SOC in healing leg ulcers—is measured by the proportion of patients with resolution of target ulcer(s) in each treatment group by week 12. Key secondary endpoints include days to resolution of target ulcer(s) up to week 12, change from baseline in total surface area of target ulcer(s) at week 12, and incidence of new ulcers by week 12. Exploratory analyses include correlation of target ulcer(s) healing with change in hemoglobin and hemolytic parameters. The study will also assess patient-reported outcome measures, including health-related quality of life and pain. Findings from a post hoc analysis of participants with leg ulcers in the HOPE trial suggest that voxelotor may be an effective treatment for leg ulcers in patients with SCD. Voxelotor directly targets the underlying mechanism of disease (namely HbS polymerization) and may have a therapeutic effect on the clinical complications of SCD associated with anemia and hemolysis, including leg ulcers. Results from this study will advance our understanding of the potential effects of voxelotor on leg ulcers in patients with SCD in global populations.