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

Abstract

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.

Keywords: clinical trial; pharmacodynamics; pharmacokinetics; phase I; sickle cell disease; voxelotor.

Figure 1

Study design and dose‐escalation scheme. Stepwise dose‐escalation scheme for healthy volunteers and SCD patients. In each cohort, eight subjects were randomized to receive voxelotor (n = 6) or placebo (n = 2). Following the first dose, subsequent doses were escalated to reach 5%, 10% and 20% Hb modification. The first MAD cohort started after equivalent Hb modification was achieved in the single‐dose cohort. The maximum target for the MAD cohort was 40% Hb modification. Food effect was evaluated at 400 mg. Single dose in SCD subjects was initiated at 1000 mg, and the data were used to estimate MAD doses at targeted 20% and 30% Hb modification

Figure 2

Hb, reticulocyte count, and EPO levels following 900 mg voxelotor once daily for 15 days in healthy volunteers. Hb, reticulocyte count, and EPO values in healthy volunteers at predose, Day 15, and follow‐up (~45 days after the last dose). Data are shown as mean ± standard deviation

Figure 3

RBC and plasma voxelotor concentration–time profiles after single and multiple doses in healthy volunteers. Healthy volunteers (n = 6/cohort) received single dose of voxelotor at 100, 400, 1000, 2000 and 2800 mg. Concentration–time profiles in RBC (A) and plasma (B) show linear increase in exposure across these doses. Following daily dose at 300, 600 and 900 mg voxelotor for 15 days, RBC (C) and plasma (D) profiles on Day 15 also proportionally increase. Data are shown as mean ± standard deviation

Figure 4

RBC concentration–time profiles of voxelotor following 1000‐mg single dose in healthy volunteers and SCD patients. RBC concentration–time profiles in healthy volunteers (n = 6) and SCD patients (n = 6) receiving 1000 mg voxelotor single dose. Similar C _max was achieved but AUC_inf in healthy volunteers was higher than in SCD patients because of longer T _1/2. Data are shown as mean ± standard deviation

Figure 5

PD at steady state in healthy volunteers. A, Selected median OECs from subjects at C _min after 15 days of dosing. A summary of the p20 (B) and p50 (C) values observed in healthy volunteers at C _min after 15 days of dosing. A dose–dependent decrease in p20 and p50 was observed, showing that increasing levels of drug leads to increased Hb‐oxygen affinities. Sidak's multiple comparisons tests were used to measure statistical significance

Figure 6

Oxygen equilibrium curves from blood of a voxelotor‐treated SCD patient compared with a healthy volunteer. Representative predose and 24 h postdose OECs of SCD patients who achieved 23% Hb modification on a single 1000‐mg voxelotor dose, compared with the OEC of a healthy volunteer on placebo

Figure 7

PK/PD correlation in healthy volunteers. A, Linear correlation observed between percent Hb modification derived from OECs and percent Hb occupancy (derived from [voxelotor]_RBC) in healthy volunteers. B, Correlation observed between Δp20 and RBC voxelotor concentrations or percent Hb occupancy. C, Correlation observed between p20 and RBC voxelotor concentrations. D, Correlation observed between p50 and RBC voxelotor concentrations