source: The American Society of Pediatric Hematology/Oncology Conference

year: 2018

authors: Carolyn C. Hoppe, Adlette C. Inati, Clark Brown, Winfred Wang, Lewis Hsu, Victor Gordeuk, Robert I. Liem, Gerald Woods, Connie M. Piccone, Erica Fong, Ganesh Balaratnam, Sandra Dixon, Margaret Tonda, Carla Washington, Yifah Yaron, Josh Lehrer

Background:

Sickle cell disease (SCD), a genetic disorder characterized by defective sickle hemoglobin (HbS), triggers red blood cell sickling, hemolysis, vaso-occlusion, and inflammation. Ischemic injury from SCD starts in infancy and accumulates over a lifetime, causing pain, fatigue, and progressive end-organ damage that culminates in early mortality. Voxelotor (GBT440) is an oral, once-daily therapy that modulates hemoglobin’s oxygen affinity, thereby inhibiting hemoglobin polymerization.

Objectives:

To assess the safety, pharmacokinetics, and efficacy of voxelotor in pediatric patients with SCD.

Design/Method:

This ongoing study is being conducted in 2 parts: Part A: a single dose of voxelotor 600 mg in pediatric and adolescent patients; Part B: multiple doses of voxelotor 900 mg/d or 1500 mg/d for 24 weeks in adolescents. Part B’s primary objective is to assess the effect of voxelotor on modifying anemia. Secondary objectives include measuring other markers of disease modification, such as hemolysis; daily SCD symptoms, using a patient-reported outcome (PRO) measure; and safety.

Results:

As of November 6, 2017, 24 patients (10 females) had received voxelotor 900 mg and 12 patients (6 females) had received voxelotor for >=16 weeks. The median age for the 12 patients was 13 years, 92% were receiving hydroxyurea (HU), and 41% had >=1 painful crises in the past year. Data for hemolysis measures are available for 11 patients who received voxelotor for 16 weeks. Six of the 11 patients achieved a hemoglobin (Hb) response of >1 g/dL increase. Laboratory markers of hemolysis improved concordantly; the median reductions in reticulocytes and indirect bilirubin were 11% and 40%, respectively. Ten of 12 patients showed reduction in total symptom scores (TSS) at week 16, with a 94% median reduction in TSS from baseline. There were no treatment-related serious adverse events (AEs) or drug discontinuations due to AEs.

Conclusion:

Voxelotor 900 mg for 16 weeks in adolescents with SCD, the majority receiving HU, demonstrated consistent, sustained efficacy on Hb levels and measures of hemolysis; >50% of patients showed a >1 g/dL improvement in Hb. Improvement in TSS in mildly symptomatic patients suggests that the PRO is sensitive to treatment effect and supports use in the ongoing HOPE phase 3 study. Voxelotor’s reassuring safety profile is consistent with results in adults. These interim results support ongoing clinical evaluation of voxelotor as a potential disease-modifying therapy for adults and children with SCD.

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