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.