SUMMARY OF RESULTS:
Participant Disposition

A total of 162 participants were enrolled and treated with voxelotor in this study: 54 participants had received placebo in parent study GBT440-032 (Treatment Naïve group) and 108 participants had received voxelotor from parent studies GBT440-007, GBT440-032, and GBT440-042 (Voxelotor group).

A total of 25 (15.4%) participants completed the study and the majority of participants discontinued from the treatment due to sponsor decision (78.4%; 127/162).

Of the 76 participants in the MD DT subset, 1 participant completed the study and the rest of the participants discontinued the study due to sponsor decision (98.7%; 75/76).

Demographic and Other Baseline Characteristics:
Demographic and baseline characteristics for participants in this study are as follows:

- The mean age (standard deviation [SD]) was 9.2 years (5.68), ranging from 2 to 35 years old. The majority of participants were between 4 years to <12 years (71.6%; 116/162), followed by 12 to <18 years (13.6%; 22/162), 2 to <4 years (8.6%; 14/162), and the remaining participants were 18 years old or older (6.2%; 10/162).

- There were slightly more males (53.7%; 87/162) than females (46.3%; 75/162).

- The majority of participants were African (58.0%; 94/162).

- The mean (SD) weight was 25.0 kg (10.98), ranging from 11 kg to 75 kg.

- The mean (SD) body mass index (BMI) was 15.5 kg/m2 (2.37), ranging from 11 kg/m2 to 27 kg/m2.

- The majority of participants were diagnosed with the hemoglobin SS (HbSS) SCD genotype (93.2%; 151/162) and just under half were on hydroxyurea (HU) (46.9%; 76/162).

Key demographic and baseline characteristics in the MD DT subset:

- The mean (SD) age was 6.7 years (2.71), ranging from 2 to 11 years old.

- The mean (SD) weight was 19.6 kg (5.06), ranging from 11 kg to 31 kg.

- The mean (SD) BMI was 14.7 kg/m2 (1.60), ranging from 12 kg/m2 to 20 kg/m2.

- The majority of participants were diagnosed with the HbSS SCD genotype (93.4%; 71/76) and 35.5% (27/76) were on HU.

Exposure:

The mean (SD) exposure time for all study participants was 48.0 (46.76) weeks. Similarly, the actual exposure time (determined by excluding the days with missed dose) was 46.7 (45.07) weeks. For participants in the MD DT subset, the mean (SD) exposure time was 10.2 (10.84) weeks. The actual exposure time was less (10.1 [10.75] weeks).

CONCLUSIONS:

Voxelotor, in this population, was generally well tolerated and no new non-SCD or SCD related safety signals were identified in this study. Sickle cell anaemia with crisis was the most frequently reported SCD-related TEAE, which is consistent with what was observed in the respective parent studies. Dose reductions, interruptions, and permanent discontinuations due to TEAEs were infrequent, affecting fewer than 3% of participants. There was one death in this study that was considered not related to voxelotor.

Dosing in GBT440-038 was paused in May 2024 for participants who entered from parent studies GBT440-032 and GBT440-042, and the study was voluntarily terminated early in September 2024 due to concerns of an imbalance in vaso-occlusive crisis (VOCs) and fatalities among voxelotor-treated participants observed in the parent studies. Thus, treatment duration was limited, thereby constraining interpretation of long-term efficacy and safety outcomes

Sickle cell disease (SCD) is a rare, devastating, and debilitating disease marked by the pathophysiologic features of hemolytic anemia, vaso-occlusion, and progressive end-organ damage, with a clinical course characterized by life-long disability and early death.As current treatment options are limited, there remains a significant unmet medical need for novel therapies and for the early treatment of pediatric patients with SCD to mitigate the consequences of the disease.

Voxelotor (formerly known as GBT440) is an orally administered small molecule that inhibits HbS polymerization by allosterically modifying hemoglobin-oxygen (Hb-O2) affinity. It is approved in the United States for the treatment of SCD in adults and pediatric patients 4 years of age and older. By inhibiting HbS polymerization, voxelotor has been shown to improve RBC deformability and reduce blood viscosity. Treatment with voxelotor has also led to significant reductions in sickle cell counts in the peripheral blood, which supports the potential for voxelotor to serve as a disease-modifying therapy for SCD.

The objective of this OLE is to assess the safety of, and SCD-related complications with, long-term treatment with voxelotor in participants who have completed treatment in a GBT-sponsored voxelotor clinical study, based on the following parameters: 1. Adverse events (AEs), clinical laboratory tests, physical examinations (PEs), and other clinical measures 2.Frequency of SCD-related complications

This multicenter, nonrandomized OLE will be conducted globally and will be available to eligible participants from GBT-sponsored voxelotor clinical studies. Participants must have completed participation in their originating clinical study and must meet the entry criteria for this study to be eligible for enrollment. The study will be conducted at up to approximately 70 global clinical sites, and up to approximately 600 participants will be enrolled. All participants will receive voxelotor QD, administered orally as tablets, dispersible tablets, or a powder for oral suspension dosage form (packaged as stick packs). Participants aged ≥ 12 years will receive a voxelotor dose of 1500 mg QD. Participants aged < 12 years will receive a voxelotor dose based on their body weight, to provide exposure corresponding to the adult dose of 1500 mg QD. Participants may receive the study drug as long as receive clinical benefit that outweighs risk as determined by the Investigator for a minimum of 96 weeks and/or until they have access to voxelotor from an alternative source (e.g., through commercialization or a managed access program) and will end when the last participant’s last visit occurs.

Statistical programming and analyses will be performed using established statistical methods. Study data will be reported using summary tables, figures, and select data listings. Continuous variables will be summarized using mean, standard deviation, median, minimum, and maximum. Categorical variables will be summarized by presenting the number (frequency) and percentage in each category. All statistical analyses conducted will be descriptive and no formal statistical tests are planned. As appropriate, study data may be summarized separately based on the antecedent study.