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A phase 1/2 ascending dose study and open-label extension study of voxelotor in patients with sickle cell disease

Jo Howard, Claire Jane Hemmaway, Paul Telfer, D. Mark Layton, John Porter, Moji Awogbade, Timothy Mant, Daniel D. Gretler, Kobina Dufu, Athiwat Hutchaleelaha, Mira Patel, Vincent Siu, Sandra Dixon, Noel Landsman, Margaret Tonda and Joshua Lehrer-Graiwer

Key points

  • In a randomized, placebo-controlled, phase 1/2 study in patients with SCD, voxelotor (500-1000 mg/day) was well tolerated.

  • All patients receiving voxelotor for ≥28 days demonstrated hematologic improvements, suggesting disease-modifying activity in SCD.

Abstract

New treatments directly targeting polymerization of sickle hemoglobin (HbS), the proximate event in the pathophysiology of sickle cell disease (SCD), are needed to address the severe morbidity and early mortality associated with the disease. Voxelotor (GBT440) is a first-in-class, oral therapy specifically developed to treat SCD by modulating the affinity of hemoglobin for oxygen, thus inhibiting HbS polymerization and the downstream adverse effects of hemolytic anemia and vaso-occlusion. GBT440-001 was a phase 1/2 randomized, double-blind, placebo-controlled, single and multiple ascending dose study of voxelotor in adult healthy volunteers and patients with SCD which was followed by a single-arm, open-label extension study. This report describes results of voxelotor (500-1000 mg/day) in patients with sickle cell anemia (HbSS). The study evaluated the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of voxelotor and established proof-of-concept by improving clinical measures of anemia, hemolysis, and sickling. Thirty-eight patients with SCD received 28 days of voxelotor 500, 700, or 1000 mg/day, or placebo; 16 patients received 90 days of voxelotor 700 or 900 mg/day, or placebo. Four patients from the 90-day cohort were subsequently enrolled in an extension study and treated with voxelotor 900 mg/day for 6 months. All patients who received multiple doses of voxelotor for ≥28 days experienced hematologic improvements including increased hemoglobin and reduction in hemolysis and percent of sickled red cells, supporting the potential of voxelotor to serve as a disease-modifying therapy for SCD. Voxelotor was well tolerated with no treatment-related serious adverse events and no evidence of tissue hypoxia. ClinicalTrials.gov identification: #NCT02285088 and #NCT03041909.

  • Submitted August 14, 2018.
  • Accepted December 21, 2018.