Pharmacokinetics and Pharmacodynamics of Voxelotor (GBT440) in Healthy Adults and Patients With Sickle Cell Disease.

Aims Voxelotor (previously GBT440) is a haemoglobin (Hb) modulator that increases Hb-oxygen affinity, thereby reducing Hb polymerization and sickling of red blood cells (RBCs), being developed as a once-daily oral drug to treat sickle cell disease (SCD). This first-in-human study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of voxelotor in healthy volunteers and SCD patients. Methods A total of 40 healthy volunteers (100, 400, 1000, 2000 or 2800 mg) and 8 SCD patients (1000 mg) were randomly assigned to a single dose of voxelotor once daily (n = 6 per group) or placebo (n = 2 per group). Twenty-four healthy volunteers received multiple doses of voxelotor once daily for 15 days (300, 600 or 900 mg, n = 6 per group) or placebo (n = 2 per group). Results Voxelotor was well tolerated and exhibited a linear pharmacokinetic profile and a half-life ranging from 61 +/- 7 h to 85 +/- 7 h. High partitioning into the RBC compartment provides evidence of highly specific binding to Hb. Voxelotor exhibited a concentration-dependent left-shift of oxygen equilibrium curves. Percent Hb modification following 900 mg voxelotor for 15 days was 38 +/- 9%. Terminal half-life of voxelotor in SCD patients (50 +/- 3 h) was shorter than in healthy volunteers. Evaluation of erythropoietin, exercise testing, and haematologic parameters were consistent with normal oxygen delivery during both rest and exercise. Conclusion This first-in-human study demonstrates voxelotor was well tolerated in SCD patients and healthy volunteers and established proof of mechanism on increasing Hb-oxygen affinity.