Voxelotor, is a first-in-class modifying therapy approved to treat patients with sickle cell disease (SCD), a once-daily, oral treatment that reversibly binds to the a-chain of hemoglobin (Hb) and modulates its affinity for oxygen, inhibits Hb S polymerazation, preventing HbS sickling and reducing hemolysis in patients with SCD. Therapeutic approach can be as single agent or in combination with hydroxyurea (HU). Voxelotor was approved by the FDA in 2019 for children over 12 years and from 2021, for children over 4 years. While voxelotor is not yet approved in Brazil, several centers in the country are involved in clinical trials for the drug under the Early Access Program approved by ANVISA. In the present study, we report the results of the early access program in Brazil.

To describe the mean Hb change from baseline, reduction of hemolytic parameters and safety profile and tolerability in SCD patients treated with Voxelotor.

Eligible participants with aged ≥12 years, confirmed SCD and Hb level between 5.5 and 10.5 g/dL were enrolled in 5 research centers in Brazil. During the initial evaluation visit, demographic characteristics, comorbidities, concomitant medications, parameters of hemolysis, history of vaso-occlusive crises (VOCs) requiring treatment and/or hospitalization according to institutional guidelines were collected. Each qualified study participant was oriented to take a daily dose of voxeletor 1,500 mg and evaluated every three months. During each visit laboratory analyses were performed according to institutional guidelines.

A total of 64 patients were enrolled. Of these, 68% (44/64) were able to complete the second and third visits. Fifty three percent (34/64) and 45% (29/64) of the patients completed 4 and 5 visits, respectively, and 15% (10/64) patients have completed 6 visits. At the time of data cutoff (June 30, 2023), the median duration of follow-up was 270 days (range, 90 to 450 days). The mean age was 37.7 years (17-65); 73.5% (45/64) were female; 93.7% (60/64) were HbSS genotype, 65.6% (42/64) on HU and 48.4% on an opioid-based pain medication on a need-to-basis. Descriptive analysis of the mean Hb level showed an increase from 7.4 ± 1.1 g/dL at baseline to 8.3 ±1.4 g/dL by visit 6 (Hb mean diference of 1.4 g/dL). The mean levels of LDH (U/L) and indirect bilirubin (mg/dL) were 557.7 ± 266.0 and 2.1 ± 1.5 to 1.9 ± 1.2 at baseline and 629.8 ±239.5 and 1.9 ± 1.2 at visit 6, respectively. The mean absolute reticulocyte counts showed a decrease from 236.6 x 103 ± 170 x 103 cells/mm3 at baseline to 125.0 x 103 ± 82.0 x 103 cells/mm3 by visit 6 (Reticulocyte mean diference of -120.0 x 103 cells/mm3). The most common adverse events (AEs), with an incidence of at least 20%, were headache and diarrhea, and the majority were grade 1 or 2. Five (7.8%) participants had an AEs of at least grade 3 and 6 (9.3%) of treatment discontinuatio because of na AE. Two participants had fatal AEs (pulmonary sepsis, acute chest syndrome) unrelated to the trial drug by the investigators.

Our data indicate that there is a trend to Hb levels to increase while the reticulocyte showed a gradual decrease. These results are consistent with those previously published by the phase 3 HOPE trial.