Sickle cell disease (SCD) results in the production of sickle hemoglobin (HbS), which polymerizes causing red blood cells (RBCs) to sickle. Voxelotor (vox), an HbS polymerization inhibitor, stabilizes oxygenated Hb, reducing RBC sickling. While the HOPE trial established that vox increases RBC survival, as evidenced by a 1 g/dL Hb increase, its impact on overall RBC health is not well established. This study aimed to assess the pharmacodynamic impact of vox on RBC health and ultimately on clinical outcomes.

Blood samples from 4 SCD clinical sites were collected from 2018-2024. Samples were shipped overnight to our central Detroit lab, in containers that maintained 2-8°C for up to 72 hours. Laboratory values were exported from the Ignite Medical Technologies system under an IRB-approved waiver, using de-identified patient information. Sample means were compared using a linear mixed model for repeated measures and a paired t-test for patient mean analysis; p-values <0.05 were considered statistically significant.

More than 5000 blood samples from 994 unique patients (551 females and 443 males) were analyzed. The age distribution of patients: 0-10 (n=269), 11-20 (n=340), 21-30 (n=178), 31-40 (n=102), 41-50 (n=64), 51-60 (n=26), 61-70 (n=7), 71-80 (n=5), and over 80 years (n=1).

We analyzed flow adhesion of whole blood to VCAM in samples from 994 patients, comparing those on vox (n=601, 337±249 cells/mm²) to those not on vox (n=4906, 360±276 cells/mm²,p=0.368). Though not statistically significant, the trend towards reduced adhesion on vox aligns with a phase 3 clinical trial showing a decrease in FA-WB-VCAM with a similar Hb-modifying therapy, Oxivelotor (Santosh et. al. ASH 2023).

We also evaluated the temporal response of patients pre and post vox therapy. Among 994 unique patients, we identified 32 patients on vox observed >90 days with 2 or more off-therapy and 2 or more on-therapy samples. 12 of 32 patients were identified with FA-WB-VCAM off-therapy values >400 cells/mm², the threshold above which steady state SCD patients are at higher risk of self-reported VOC events (White et. al. BCMD 2020). FA-WB-VCAM levels and pain scores trended lower on therapy (563±162 vs 487±185 cells/mm², p=0.148; 7.0±2.8 vs 6.0±3.9, p=0.271), although these reductions were not statistically significant. FA-WB-Psel is more specific for white blood cell adhesion in the context of whole blood and stratifies SCD patients according to their risk of developing self-reported VOC (Hines et. al. BJH 2021). FA-WB-Psel decreased significantly from 80±30 to 54±29 cells/mm² on-therapy (p=0.041), suggesting an improvement in systemic inflammation and lower risk for future self-reported VOC events. 20 of 32 patients with FA-WB-VCAM off-therapy values <400 cells/mm² showed no significant changes in FA-WB-VCAM, FA-WB-Psel levels, or self-reported pain scores after vox treatment.

This report represents the first multi-center real-world assessment of the impact of vox on clinical biomarkers of RBC health. We observed trends towards improved RBC adhesive properties in SCD patients on vox, consistent with previously reported results with other Hb-modifying therapies such as hydroxyurea (Bartolucci et. al. Blood 2010) and Oxivelotor. vox therapy demonstrated a significant reduction in P-selectin-mediated adhesion in patients with baseline VCAM adhesion phenotypes above established thresholds. These data support the need to establish baseline biological phenotypes in SCD patients, as this insight may help predict responses to Hb-modifying therapies and enable the use of blood-based surrogate endpoints to monitor treatment response and assess drug efficacy in SCD.

Disclosures

White:Functional Fluidics: Other: contractor and shareholder in privately held company. Campbell:Pfizer: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees.

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2024
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