Background: Sickle cell disease (SCD) is a lifelong, inherited disorder characterized by sickle hemoglobin (HbS) polymerization that results in red blood cell (RBC) sickling and results in complications such as hemolytic anemia, vaso-occlusive crises (VOCs), endothelial dysfunction, and organ damage. Large and rapid increases in hemoglobin (Hb) concentration in response to RBC transfusions have raised concerns of hyperviscosity and associated increased risk of vaso-occlusive complications. Accordingly, current transfusion guidelines recommend raising Hb to no higher than 10 g/dL in adults.

Voxelotor (Oxbryta®) is an oral, once-daily HbS polymerization inhibitor indicated for treatment of SCD in adults and adolescents aged ≥12 years. Previous studies have demonstrated the ability of voxelotor to improve RBC rheology, as evidenced by improvement in RBC deformability, reduction in the percentage of irreversibly sickled cells, and reduction in viscosity.

In the 24-week analysis of the HOPE trial, treatment with voxelotor 1500 mg resulted in a significantly greater proportion of patients achieving a >1 g/dL Hb increase and numerically fewer VOCs compared with placebo. Post hoc analysis showed an inverse relationship between on-treatment Hb levels at week 24 and VOC incidence, with those achieving higher Hb levels experiencing numerically fewer VOCs. In this report, we extend this analysis by assessing the association between average on-treatment Hb and VOC incidence over the full 72-week period.

Methods: In the randomized, double-blinded, placebo-controlled, phase 3 HOPE trial, the efficacy and safety of 2 doses of voxelotor (1500 mg and 900 mg orally once daily) were compared with placebo. Included patients were aged 12 to 65 years, had a Hb level of 5.5 to 10.5 g/dL at enrollment, and experienced 1 to 10 VOCs in 12 months prior to screening. Concurrent hydroxyurea (HU) was allowed if the dose had been stable for ≥90 days. Average on-treatment Hb level achieved with voxelotor treatment was assessed. Annualized incidence rate of VOCs was evaluated by treatment group. Mean cumulative function of VOC incidence was estimated, stratified by average Hb level over the patients' duration of treatment.

Results: Patient demographics and baseline characteristics were generally balanced across subgroups defined by average on-treatment Hb level. For the overall study population, the annualized incidence rate of VOCs (events per person-year) was 2.4 in the voxelotor 1500 mg group, 2.4 in the voxelotor 900 mg group, and 2.8 in the placebo group, corresponding to an incidence rate ratio (IRR) of 0.85 (95% CI, 0.60-1.21) for the voxelotor 1500 mg group and 0.86 (95% CI, 0.61-1.22) for the voxelotor 900 mg group compared with placebo. Among patients with ≥2 VOCs in the 12 months prior to screening, the VOC IRR was 0.81 (95% CI, 0.52-1.28) for the voxelotor 1500 mg group and 0.98 (95% CI, 0.63-1.53) for the voxelotor 900 mg group compared with placebo. When the study population was stratified by on-treatment Hb pooled across both voxelotor doses, 60 study participants achieved average Hb levels ≥10 g/dL and 10 achieved average Hb ≥12 g/dL. The incidence rate of VOCs was lowest in patients who achieved the highest Hb levels (≥12 g/dL), compared with those who achieved lower Hb levels and those receiving placebo (Figure 1).

Conclusions: In this study, treatment with once-daily voxelotor resulted in increases in average Hb concentrations that reached or exceeded 10 g/dL in a substantial number of study participants. In contrast with the theoretical concern of higher VOC risk with higher Hb levels, patients who achieved the greatest average Hb levels over 72 weeks with voxelotor experienced the fewest VOCs, with a stepwise reduction in VOC rate with each increase in Hb stratum. These results suggest the mechanism of reducing hemolysis and raising Hb in individuals with SCD, such as via inhibition of polymerization, is important. The improvement in red cell health, including increased deformability and decreased viscosity, suggest higher Hb thresholds in patients on voxelotor may result in increased clinical benefit.

Disclosures

Vichinsky:Global Blood Therapeutics: Consultancy; Agios: Research Funding; Pfizer: Research Funding. Gordeuk:CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding; Novartis: Consultancy. Telfer:Bluebird Bio: Honoraria, Research Funding; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Terumo: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; ApoPharma: Membership on an entity's Board of Directors or advisory committees. Inati:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Cyclerion: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Research Funding; Octapharma: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees. Tonda:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gray:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Agodoa:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ataga:Novartis: Consultancy, Honoraria, Research Funding; Shire/Takeda: Research Funding; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Modus Therapeutics: Honoraria; Forma Therapeutics: Consultancy; Pfizer: Research Funding; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Editas Medicine: Honoraria; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Author notes

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Asterisk with author names denotes non-ASH members.