Leg Ulcer Prevalence and Outcomes in a Real-World, Multicenter, Retrospective Study of Patients Treated with Voxelotor

Background: Sickle cell disease (SCD) is an inherited disorder driven by the polymerization of sickle hemoglobin in the deoxygenated state, leading to chronic hemolytic anemia. Leg ulcers are a severe, chronic, and often recurrent complication of SCD, occurring in about 14% to 18% of patients in the US and more commonly in men and those with severe SCD genotypes. Leg ulcers are painful and decrease physical function, increase pain interference, and cause psychosocial impacts. Symptoms and complications associated with leg ulcers include chronic hemolysis, edema, impaired endothelial function, and venous incompetence and vaso-occlusion. Leg ulcers in SCD are commonly treated with standard wound care, including mechanical/autolytic detersion and modern dressings. Studies on local and systemic treatments have been inconclusive. Voxelotor is a sickle hemoglobin polymerization inhibitor approved in the US for the treatment of SCD in patients aged ≥4 years and in the UK, EU, and UAE for patients aged ≥12 years. Phase 3 clinical trials have shown that voxelotor increases hemoglobin and reduces markers of hemolysis with an overall favorable safety profile. The Retrospective Real World Oxbryta Data Collection and Analysis Study (RETRO) aimed to characterize real-world safety and effectiveness of voxelotor in patients aged ≥12 years. RETRO expands upon our understanding of voxelotor, providing valuable insights and driving future studies that will investigate its descriptive results.

Objective: To examine leg ulcer prevalence and outcomes before and during voxelotor treatment in the RETRO study.

Methods: RETRO is a post-marketing study designed to collect and characterize real-world, retrospective laboratory and clinical data from patients aged ≥12 years with SCD (all genotypes) treated with voxelotor as part of their usual care. The study was conducted in 9 US sites. Data from patients treated with voxelotor for ≥2 consecutive weeks and with available medical records 1 year before and up to 1 year after their first voxelotor dose were included.

Results: A total of 216 patients with a mean (SD) age of 33.5 (14.21) years were included. Overall, 8.8% (19/216) of patients had an active or previous leg ulcer any time during the 1-year period before voxelotor initiation and up to 1-year post-treatment. Of these patients, 57.9% (11/19) reported 1 leg ulcer, and 42.1% (8/19) reported ≥2 leg ulcers; the mean (SD) age of these 19 patients was 40.5 (10.9) years, 36.8% (7/19) were female, and 79.0% (15/19) were Black or African American. Most patients (84.2% [16/19]) had the HbSS genotype, and 57.9% (11/19) were taking hydroxyurea.

Five leg ulcers in 4 patients resolved before voxelotor initiation. A total of 23 leg ulcers were ongoing at treatment initiation, meaning the ulcer either occurred before the first dose of voxelotor or occurred after treatment initiation. A total of 14/23 (60.9%) leg ulcers occurred before voxelotor initiation, with half of them (7/14) resolving after voxelotor initiation. The other 9 leg ulcers (39.1% [9/23]) occurred after voxelotor initiation; of these, 5 (55.6%) resolved during voxelotor treatment. Further descriptive analyses of leg ulcer events and resolutions are ongoing.

Conclusion: RETRO is the largest multicenter, retrospective study on voxelotor to date. Data reported here describe the prevalence and incidence of leg ulcers in this cohort and the reported outcomes before and during voxelotor treatment. The limitations of this retrospective study include small sample sizes, the reliance on data captured in medical records, and the lack of a control group. To address this gap in knowledge, the RESOLVE study to investigate the impact of voxelotor on leg ulcers is currently underway (PACTR202102669041711).

Funding: Global Blood Therapeutics.

Minniti:Sanguine Bio: Consultancy; Chiesi: Consultancy; Emmaus Life Sciences: Consultancy; Global Blood Therapeutics: Consultancy; Novartis: Consultancy; Novo Nordisk: Consultancy; Roche: Consultancy; Forma: Consultancy; Agios: Consultancy. Idowu:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Forma: Research Funding; Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Ironwood: Research Funding. Shah:Bluebird Bio: Consultancy; CSL Behring: Consultancy; Alexion: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau. Drachtman:Bluebird Bio: Consultancy; Agios: Consultancy; Global Blood Therapeutics: Consultancy, Other: Speaker. Glaros:Global Blood Therapeutics: Other: Advisory Board; Bausch: Membership on an entity's Board of Directors or advisory committees. Achebe:Fulcrum Therapeutics: Other: Advisory Board; Pharmacosmos: Other: Advisory Board; FORMA Therapeutics: Other: Advisory Board; GBT: Other: Advisory Board. Nero:Global Blood Therapeutics: Consultancy; Bluebird Bio: Consultancy; Novartis: Consultancy; Editas Medicine: Consultancy. Curtis:Novartis: Honoraria; Global Blood Therapeutics: Consultancy, Honoraria. Andemariam:Terumo BCT: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aruvant: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shenox: Consultancy, Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics AG: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk A/S: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Emmaus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hemanext: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.