Topical Ocular TRPV1 Antagonist SAF312 (Libvatrep) Demonstrates Safety, Low Systemic Exposure, and No Anesthetic Effect in Healthy Participants

PURPOSE: This first-in-human (FIH) study evaluated the safety, tolerability, pharmacokinetics, and effect on corneal sensitivity of topical ocular SAF312 in healthy participants. METHODS: This double-masked, randomized study comprised single-ascending dose (SAD), multiple-ascending dose (MAD), and esthesiometry parts. In SAD and MAD, 8 participants in each dose cohort were randomized 3:1 to receive SAF312 or vehicle, 1 drop once (SAD), or 1 drop 4 or 8 times daily for 7 days (MAD). Safety and pharmacokinetics were the primary and secondary objectives. Blink rate, tear production, tear film break-up time (TFBUT), and corneal sensitivity were also explored. RESULTS: SAF312 was tolerated in single and multiple doses, including the maximum concentration of 2.5% dosed up to 1 drop 8 times daily for 7 days. Most adverse events (AEs) were mild and similar between SAF312 and vehicle-treated groups. No serious AEs were reported. SAF312 was rapidly absorbed, and had low systemic exposure. After supratherapeutic dosing for 7 days, mean steady-state exposures of SAF312 were low and afforded safety margins of >70-fold compared with no-observed-AE levels following oral dosing in preclinical studies. No clinically relevant changes were observed in blink rate, tear production, and TFBUT. SAF312 showed no undesired anesthetic effect on the cornea. CONCLUSIONS: SAF312 was well tolerated, with no ocular or systemic safety concerns; had no anesthetic effect, and demonstrated rapid topical absorption with low systemic exposure. TRANSLATIONAL RELEVANCE: This work bridges the gap between basic research and clinical care by providing FIH data of SAF312, supporting the further investigation as a potential treatment for ocular surface pain.