First-in-Human Single and Multiple Ascending Dose Studies of Balinatunfib, a Small Molecule Inhibitor of TNFR1 Signaling in Healthy Participants.

Abstract

Oral small molecule inhibitors of tumor necrosis factor alpha (TNFα) are emerging as attractive therapeutic agents for the treatment of various autoimmune diseases. Balinatunfib (SAR441566), a novel oral inhibitor of tumor necrosis factor receptor 1 (TNFR1) signaling, changes the configuration of the soluble TNFα (sTNFα) trimer and prevents its heterotrimerization with TNFR1 but not TNFR2, thereby blocking TNFR1 signaling. Herein, we report the results from a first-in-human (FIH) study that evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) following single ascending doses (SAD) and multiple ascending doses (MAD) of balinatunfib in healthy male participants. Single (5-600 mg) and multiple (100-600 mg total daily dose for up to 14 days) oral doses of balinatunfib were well-tolerated in all participants. Consistent PK data were obtained across the studies, with a median t_max of 2.5-5 hours, a mean terminal half-life of 22-30 hours, and a time to steady state of 5-6 days. A supra-proportional exposure increase was observed in both SAD and MAD studies, which was less pronounced at doses ≥ 180 mg. Food had no relevant effects on the PK characteristics of balinatunfib. As the main PD read-out, complete TNFα occupancy was shown at all tested time points after the treatment started. Balinatunfib, as the first clinically tested oral TNFR1 signal inhibitor, demonstrated a good safety profile along with favorable PK/PD characteristics that allowed both once and twice daily dosing, confirming a successful preclinical-to-clinical translation and guiding dose selection for further clinical efficacy studies.