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.