Voxelotor for Sickle Cell Disease: Initial Report from the Real-world PROSPECT Study
Authors: Shah Nirmish , Andemariam Biree , Billett Henny H , Ershler William B , Bergmann Shayla , Sakhalkar Vishwas S , Xu Michelle , Chang Alicia , Desai Payal C , Pennington Sharon , Miller Robin , De Castro Laura M , Hayward Brooke , Yu Ching-Ray , Liles Darla K K 
Published: June 2024

Abstract

Presentation Date: 6/8/2024
Presentation Start Time: 8:30:00 AM

Background
Sickle cell disease (SCD) is an inherited blood disorder in which sickle hemoglobin (HbS) polymerization results in red blood cell sickling, which in turn can lead to chronic hemolytic anemia, unpredictable pain episodes, and recurrent vaso-occlusive crises (VOCs). Hemolysis and low hemoglobin (Hb) are associated with 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. In the phase 3, randomized, controlled HOPE (NCT03036813) and the phase 2, open-label HOPE-KIDS 1 (NCT02850406) trials, patients treated with once-daily oral voxelotor had increased Hb levels and reductions in markers of hemolysis at Week 24 compared with baseline. Here we provide an interim report of efficacy and safety data from patients with SCD enrolled in the prospective PROSPECT registry who received voxelotor in a real-world setting.

Methods
PROSPECT (NCT04930445) is a post-marketing, open-label, observational, prospective patient registry of patients with SCD (aged ≥4 years) in the US. Eligible participants are being treated with voxelotor as prescribed by their physician as part of their usual care. Participants are treated and evaluated per standard of care and at the physician’s discretion. Treatment, including interruptions and restarting treatment, continues at the discretion of the treating physician. Patients receive any additional medications or transfusions as determined and prescribed by their physician. Follow-up duration is 5 years after the first dose of voxelotor therapy. Study data are collected from patient medical records and secondary data sources and entered in case report forms via an electronic data capture system. The study is ongoing, with estimated completion in 2029: for this analysis, the data cutoff was September 21, 2023. Data reflect those at time of data cutoff, have not undergone standard quality checks and may be subject to change.

Results
At data cutoff, 150 patients were enrolled at 17 sites. The mean (SD) age was 31.5 (14.1) years, 50.7% of patients were female, and most (89.3%) were Black or African American. Overall, 70.0% of patients were genotype HbSS, 60.7% were taking hydroxyurea concurrently, and mean (SD) Hb at baseline was 7.7 (1.49) g/dL. The mean (SD) duration of treatment, excluding interruptions, was 47.5 (11.60) weeks. At the data cutoff, 3 patients (2.0%) had discontinued voxelotor treatment; reasons for discontinuing were adverse events (n = 2) and moving location (n = 1). The initial prescribed daily doses of voxelotor were 1500 mg (80.0%), 1000 mg (6.7%), 900 mg (4.7%), 600 mg (1.3%), or 500 mg (6.7%). The most common reasons for prescribing voxelotor (multiple reasons could be selected) were to reduce either anemia (77.3%), frequency of VOCs (36.0%), pain (34.7%), or the frequency of blood transfusion (16.0%). In 109 patients with recorded baseline and posttreatment Hb values, the observed mean (SD) peak posttreatment Hb value was 9.2 (1.73) g/dL, representing a mean (SD) increase from baseline to peak of 1.5 (1.35) g/dL. The range of peak Hb change from baseline was −1.5 to 5.9 g/dL and 92/109 patients (84.4%) had a positive Hb response (Figure). Reductions in markers of hemolysis were also observed following voxelotor treatment, with nadir mean (SD) decreases from baseline of –5.2% (9.92%) in reticulocyte count (n = 92) and −1.7 (2.20) mg/dL in total bilirubin (n = 103). Approximately one-third of participants had treatment-emergent adverse events (TEAEs) that were not related to their underlying SCD (Table); most were of mild or moderate severity.

Conclusions
PROSPECT is the first prospective patient registry of voxelotor, with the potential to follow a large number of participants for up to 5 years. It enables robust and systematic data collection on voxelotor use in the real-world setting, and can provide insights on prescribing habits, care patterns, and analyses of clinical outcomes that require long-term follow-up and a large number of patients. In the cohort of participants enrolled by September 21, 2023, voxelotor treatment was associated with increased Hb levels and reductions in hemolytic markers, and safety data were consistent with the HOPE and HOPE-KIDS 1 trials. Overall, these findings provide support for the real-world safety, tolerability, and effectiveness of voxelotor treatment in individuals with SCD. Further evaluation is needed and while enrollment is ongoing, regular reports of updated data are planned.
© American Society of Hematology (2023). Reused with permission.