A Phase 1 Microtracer Study Evaluating the Mass Balance, Excretion, and Pharmacokinetics of Osivelotor in Healthy Participants.

Osivelotor (GBT021601) is an orally bioavailable, small molecule hemoglobin polymerization inhibitor in clinical development for the treatment of sickle cell disease (SCD). In this Phase 1 study, the disposition of osivelotor was assessed using accelerator mass spectrometry (AMS) after a single oral 200-mg dose containing a microtracer amount of [14C]-labeled osivelotor (~74 kBq [~2 μCi]) was received by nine healthy volunteers. Due to a long half-life (27-30 days), continuous and non-continuous sample collection was needed over a nearly 7-month study. The results indicate an average 87.6% (47.2% in urine; 40.4% in feces) recovery of the dose in excreta. Comparison of osivelotor and total radioactivity (TRA) systemic concentration versus time profiles in whole blood and plasma suggests the absence of a long-lived metabolite. Osivelotor was the main circulating drug-related material in plasma (68.1% of [14C]). Also observed in plasma was a glucuronide metabolite (19.7% of [14C]). In whole blood, the effect compartment, only osivelotor (98.3% of [14C]) was present and no metabolites were observed. The single oral 200-mg dose of osivelotor was well tolerated. The results of this unique study design provide insights into the absorption, metabolism, and excretion (ADME) of osivelotor and support its continued development for SCD. Trial Registration: ClinicalTrials.gov NCT05718687.