Real-world experience of voxelotor treatment in patients with sickle cell disease

Abstract Introduction: Sickle cell disease (SCD) is an inherited blood disorder marked by hemolysis and frequent vaso-occlusion, leading to complications that may cause significant morbidity and early mortality. In November 2019, the FDA approved voxelotor for treating SCD in adolescents and adults. Voxelotor binds reversibly to the alpha-globin chain of hemoglobin, increasing its oxygen affinity, preventing polymerization, improving red blood cell (RBC) function, and decreasing hemolysis. In 2021, approval was expanded to include children as young as four. However, in September 2024, voxelotor was removed from the market due to safety concerns, prompting urgent evaluation of its real-world use and impact. We aim to assess toxicity, efficacy, and adherence patterns in patients before, during, and after voxelotor use in a real-world setting. Methods: This retrospective and prospective observational study was approved by the Wake Forest University IRB. Patients diagnosed with SCD who were prescribed voxelotor at pediatric or adult SCD clinics at Levine Cancer Institute (LCI) or Levine Children's Hospital (LCH) between November 2019 and November 2024 were included. Those who received voxelotor in a clinical trial setting were excluded. Data collected included demographics, SCD genotype, adherence, initial and maximum tolerated dosages, incidence of gastrointestinal (GI) and dermatologic adverse events (AE), and reason for discontinuation. Laboratory values - hemoglobin, absolute reticulocyte count (ARC), total bilirubin, and lactate dehydrogenase (LDH) - were collected at baseline (pre-voxelotor) and at best on-treatment value. Data was verified by manual chart review. Categorical outcomes were summarized with frequencies and proportions; continuous outcomes with medians and ranges. Baseline and best values were compared via Wilcoxon signed rank tests. Results: A total of 148 patients met inclusion criteria, of whom 142 (96%) filled their voxelotor prescription. The median age was 26 years (range, 4-73); 64.2% were female; 91.9% identified as not Hispanic/Latino, 92.6% as African American; and 90.5% had SS genotype. Of those who did not fill their initial voxelotor prescription, 50% cited insurance issues. The median time from prescription to first fill was 3 days (range, 0-137), and median time on voxelotor was 20.1 months (range, 0.4-58.7). Adherence was documented in 90 patients (63.4%). Starting doses were 500mg (9.2%), 600mg (1.4%), 900mg (6.3%), 1000mg (8.5%), and 1500mg (74.7%). The maximum tolerated dose was 1500 mg in adults (62.7%), 900 mg in pediatrics (6.3%), or unknown (3.5%). Among patients who filled voxelotor (n=142), lab parameters improved significantly. Hemoglobin (n=135) rose from a baseline median of 7.8 g/dL (4.7-12.8) to 10.0 g/dL (6.3-13.9), a median increase of 2.0 g/dL (p<0.001). ARC (n=106) decreased from a median of 193.1x103/uL (33-619.4) to 90.6x103/uL (3.7-364.2), a median reduction of 93.9x103/uL (p<0.001). Total bilirubin (n=130) decreased from a median of 2.8 mg/dL (0.6-12.8) to 1.2 mg/dL (0.0-13.6), a median decrease of 1.0 (p<0.001). LDH (n=90) decreased from a median of 406 U/L (119-2082) to 310 U/L (135-955), a median decrease of 99.5 U/L (p<0.001). In the adherent subgroup (n=90), improvements were consistent. Hemoglobin (n=88) increased by a median of 2.2 g/dL, from a baseline median of 7.9 g/dL (4.7-12.8) to 10.0 g/dL (6.3-13.9) (p<0.001). ARC decreased from a median baseline of 184.1 x103/uL (33.4-619.4) to 83.7 x103/uL (3.7-364.2) (p<0.001). Total bilirubin decreased from a median baseline of 2.6mg/dL (0.6-12.8) to 1.2mg/dL (0.0-13.6), a median reduction of 1.0mg/dL (p<0.001). LDH levels declined from a baseline median of 409.5 U/L (119-2082) to 324 U/L (135-955) (p<0.001). Conclusions:Our data show that most patients were able to obtain voxelotor. Despite about one-third reporting GI toxicity, the majority who filled their prescription reported adherence, suggesting that perceived clinical benefit outweighed side effects. Most adult and pediatric patients were able to tolerate maximum dosing. Across both total and adherent populations, voxelotor was associated with statistically significant improvements in hemoglobin and reductions in markers of hemolysis. These findings underscore voxelotor's real-world benefits in improving anemia and reducing hemolysis. We hope this data will guide future clinical use if voxelotor is reintroduced. Next steps include assessing AEs at market withdrawal.