Safety, Pharmacokinetics, and Pharmacodynamics of Osivelotor for Sickle Cell Disease: First‐in‐Human Studies in Healthy Participants and Patients

The investigational agent osivelotor, a small molecule hemoglobin (Hb) modifier in development for the treatment of sickle cell disease (SCD), acts by increasing Hb-oxygen affinity and inhibiting the polymerization of sickle Hb. We report safety, pharmacokinetic (PK), and pharmacodynamic (PD) data from the first two phase 1 clinical trials of osivelotor in healthy participants and participants with SCD. Healthy participants (N = 129) were randomized to receive either osivelotor or placebo in single-ascending doses (50-3,000 mg) or multiple-ascending doses (loading doses, then 15-100 mg once-daily maintenance doses through 14 days). A population PK-based adaptive design was used to inform loading- and maintenance-dose regimens from emerging data. Osivelotor was generally well tolerated, demonstrated dose-dependent PK exposure increase, and had a terminal elimination half-life of 19.9 to 30.7 days, with high partitioning into the red blood cell (RBC) compartment in healthy participants. In participants with SCD (N = 6), osivelotor treatment for up to 6 weeks was generally well tolerated; no participants discontinued due to treatment-emergent adverse events. Disease-dependent PK was observed in participants with SCD; notably, the terminal elimination half-life was shorter (~10 days) than in healthy participants. The percentage of Hb bound by osivelotor (%Hb occupancy) increased in a dose-dependent fashion, and improvements in Hb concentration and markers of hemolysis appeared related to osivelotor concentration. Furthermore, Hb-oxygen affinity and RBC deformability improved, whereas dense RBCs and circulating sickled cells decreased. In conclusion, once-daily osivelotor was generally well tolerated at exposures associated with meaningful PD activity, supporting the ongoing clinical investigation.