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.

Pharmacokinetics and pharmacodynamics of voxelotor (GBT440) in healthy adults and patients with sickle cell disease

“…Here, we report results of single and multiple doses of voxelotor in healthy volunteers and a single dose in SCD patients. Results of multiple dosing in SCD patients are published elsewhere …”

Systematic Review of l‐glutamine for Prevention of Vaso‐occlusive Pain Crisis in Patients with Sickle Cell Disease

“…Results of these two trials were published in April 2019, finding that all patients receiving multiple doses of voxelotor for 28 days or longer experienced hematologic improvements including an increase in hemoglobin, a reduction in hemolysis, and reduction in the percentage of sickled RBCs. Voxelotor was well tolerated; patients had no treatment‐related serious adverse events …”

“…Voxelotor was well tolerated; patients had no treatment-related serious adverse events. [26][27][28] Global Blood Therapeutics published the results of a phase III trial (NCT03036813) known as the HOPE trial in 2019. 29 It reported on the efficacy and safety of voxelotor at two dose levels (1500 and 900 mg) for improvements in hemoglobin response from baseline over 24 weeks.…”

Voxelotor: A Ray of Hope for Sickle Disease

“…Howard and his colleagues published a phase 1/2 randomized, double-blind, placebocontrolled, single and multiple ascending dose study of voxelotor [12]. The study included both healthy volunteers and sickle cell disease patients.…”