TRPM8 Agonist Eye Drop
AR-15512 is an investigational eye drop currently in clinical development at Aerie as a potential treatment for the signs and symptoms of dry eye disease. It has not been approved by the U.S. Food and Drug Administration (FDA). The active ingredient in AR-15512 is a proprietary small-molecule selective agonist of the transient receptor potential melastatin 8 (TRPM8) cold thermoreceptor, which represents a novel therapeutic target for dry eye.
How AR-15512 is Thought to Work
TRPM8 channels, located on the cornea and eyelids, are cold-sensitive thermoreceptors that play a central role in tear film homeostasis.1, 2
TRPM8 channels detect drops in corneal temperature such as those associated with tear evaporation on the ocular surface. TRPM8 nerve terminals exhibit continuous (tonic) and spontaneous activity which rapidly increases with cooling.3, 4 Increased TRPM8 activity increases basal tear secretion and blink rate. Dysfunction in TRPM8 sensing of evaporation-induced temperature changes may play a role in the development of dry eye.
In preclinical studies, including animal models of reduced tear secretion, AR-15512 has been shown to increase both the activity of corneal cold thermoreceptor nerve fibers and tear production in a concentration-dependent manner.5
To date, two clinical studies with AR-15512 have been performed. Data from a Phase 1/2a study conducted by the previous sponsor, Avizorex demonstrated more than 70% of all subjects receiving AR-15512 0.0014% twice daily (BID) for 28 days reported at least a 20 point improvement in Global Symptom Assessment Questionnaire iN Dry Eye (SANDE) score, which quantifies both severity and frequency of dry eye symptoms. Continued improvement in signs (tear production) was also observed at each visit over 28 days. In this study, AR-15512 was safe and well-tolerated, with the majority of adverse events (AEs) rated as mild and none rated severe.5
Aerie then conducted a large (n= 369) multicenter, vehicle-controlled, double‑masked, randomized Phase 2b study COMET-1 (Cold-Thermoreceptor Modulation as an Effective Treatment for DED), to evaluate the safety and efficacy of two concentrations of AR‑15512 ophthalmic solution (0.0014% and 0.003%).
Statistically significant, dose-dependent improvements were observed across multiple validated pre-specified endpoints at multiple time points including signs (unanesthetized Schirmer Score, conjunctival redness and ocular surface staining), symptoms (SANDE, ocular discomfort, and eye dryness) and quality of life. Improvements were generally rapid in onset (within 14 days) with continued improvements over time, pointing to a potential sustained, meaningful treatment effect.
Sign: AR-15512 demonstrated a statistically significant & dose dependent increase in tear production, a validated endpoint
Symptoms: AR-15512 demonstrated statistically significant improvement at Day 14; continued improvement over time vs. a validated endpoint
There was a good tolerability profile with low discontinuations (< 4%, no difference across groups). A brief, mild sensation immediately after dosing occurred in ~40% of treated subjects. No systemic or serious adverse events were attributed to the study medication.
While the pre-specified co-primary endpoints in the Phase 2b study were not met, this study fully achieved its objectives of dose selection, comprehensive characterization of AR-15512 efficacy and safety and optimization of pivotal study designs for the Phase 3 program.
Aerie has now initiated two multicenter, vehicle-controlled, quadruple-masked, randomized trials: Phase 3 “COMET-2” and “COMET-3” studies. A long-term safety study (COMET-4) is planned to start in late 2022. Subjects in COMET-2 and COMET-3 will be dosed twice daily for 90 days with study visits planned at Days 1, 7, 14, 28 and 90. The primary study measure will be the unanesthetized Schirmer test at Day 14 and the key secondary assessment is SANDE at Day 28. Numerous other sign, symptom and Quality of Life measures are also planned as well as multiple pre-determined endpoints. Topline results are anticipated in the second half of 2023.
- Eguchi et al. Biomed Res Int 2017
- Yang et al. Pharmaceuticals 2018
- Hirata and Meng. IOVS 2010
- Belmonte and Gallar. IOVS 2011
- David L. Wirta, MD et al. Safety and Efficacy of a TRPM8 Agonist for the Treatment of Dry Eye Disease. Presented at the American Society of Cataract and Refractive Surgery Annual Meeting, April 22-26, 2022, Washington, D.C.