Topical ocular TRPV1 antagonist SAF312 demonstrated safety, low systemic exposure, and no anesthetic effect in healthy volunteers

Abstract

Purpose : SAF312 is a potent inhibitor of the transient receptor potential cation channel subfamily V member 1 (TRPV1). This first-in-human study evaluated the safety, pharmacokinetics (PK), and cornea esthesiometry of topical ocular SAF312 in healthy volunteers.

Methods : This single-center, double-masked, randomized study comprised of three parts: single-ascending dose (SAD), multiple-ascending dose (MAD), and esthesiometry. Each dose cohort (SAF312 0.15%, 1.5%, 2.5%) included 8 healthy volunteers randomized 3:1 to either SAF312 or vehicle, 1 drop once (SAD), or 1 drop 4-times or 8-times (only for 2.5%) daily for 7 days (MAD). Safety and PK were the primary and secondary objectives. Exploratory objectives included tear production (Schirmer test without anesthesia), tear film break-up time (TFBUT), and blink rate in the MAD groups. Esthesiometry included 12 healthy volunteers randomized equally to 4 sequences consisting of a single drop of SAF312 2.5%, tetracaine 0.5% (anesthetic), diclofenac sodium 0.1% (nonsteroidal anti-inflammatory drug), or vehicle, in a Williams square design.

Results : SAF312 was safe and well tolerated at the maximum concentration 2.5%, 1 drop 8-times daily (7.4 mg/day, supratherapeutic dose) in one eye for 7 days. Most of the adverse events (AEs) were mild and similar between SAF312 and vehicle-treated healthy volunteers (54 healthy volunteers exposed to SAF312). No severe AEs, serious AEs, or deaths were reported. SAF312 was rapidly absorbed into systemic circulation with T_max ~0.5 h after single or multiple doses. After supratherapeutic dosing for 7 days, mean steady state exposures (C_max, 2 ng/mL and AUC_0–24h, 45 h*ng/mL) of SAF312 were low and afforded safety margins of >70-fold compared with systemic exposures in preclinical species at no-observed-adverse-event levels following oral dosing. No clinically relevant changes were observed with SAF312 in the blink rate, tear production, and TFBUT. SAF312 showed no anesthetic effect on the cornea, similar to diclofenac and vehicle as opposed to tetracaine (esthesiometry).

Conclusions : Topical ocular SAF312 was well tolerated with no ocular or systemic safety concerns up to a supratherapeutic (8x daily) dose of the maximum concentration (2.5%); it had no anesthetic effect on the cornea and demonstrated a rapid topical absorption with low systemic exposure in healthy volunteers.

This is a 2021 ARVO Annual Meeting abstract.