First‐in‐Human Single and Multiple Ascending Dose Studies of Balinatunfib, a Small Molecule Inhibitor of <scp>TNFR1</scp> Signaling in Healthy Participants

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.