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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.

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