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

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 (Hb) for oxygen, thus inhibiting HbS polymerization and 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, followed by a single-arm, open-label extension study. This report describes results of voxelotor (500-1000 mg per day) in patients with sickle cell anemia. 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 per day or placebo; 16 patients received 90 days of voxelotor 700 or 900 mg per day or placebo. Four patients from the 90-day cohort were subsequently enrolled in an extension study and treated with voxelotor 900 mg per day for 6 months. All patients who received multiple doses of voxelotor for ≥28 days experienced hematologic improvements including increased Hb and reduction in hemolysis and percentage 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. These trials were registered at www.clinicaltrials.gov as #NCT02285088 and #NCT03041909.

Graphical abstract

Figure 1.

Study flowchart for the SCD cohort of the GBT440-001 study.

Figure 2.

Time-dependent change in hemoglobin from baseline to day ≥90.

Figure 3.

Hb change from baseline to last observation (≥90 days): responder analysis for ≥1 g/dL. *Day 15 presented due to a protocol-specified dose reduction on day 17 (because of a 2.7 g/dL increase in Hb). †Day 150 presented because this is the last time point collected for Hb while the patient was receiving study drug. ‡Concurrent hydroxyurea. §Documented nonadherence with study drug regimen.

Figure 4.

Sickled red cells. Change from (A) baseline (Wright-Giemsa stain) to (B) day 90 (Wright-Giemsa stain) in SCD patients. (C) Percentage of sickled red cells. Relative change from baseline, median, and 25th and 75th percentile; baseline irreversibly sickled cell (ISC) counts ranged from 3.1% to 17.2%. †Represents 5 of 6 subjects at day 90 (D90).

Figure 5.

A summary of the p20 and p50 values observed in SCD patients after 28 days of dosing. (A) p20 values; (B) p50 values. *Sidak multiple comparisons tests were used to measure statistical significance. ns, not significant.

Figure 6.

Linear correlation. Linear correlation observed between the percentage of Hb modification (derived from OECs) and the percentage of Hb occupancy (derived from voxelotor RBC concentrations) in time-matched samples from SCD patients.