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TRPM8 Agonist Eye Drop

AR-15512 (AVX-012) is an investigational eye drop currently in clinical development at Aerie as a potential treatment for dry eye that may improve both symptoms and signs of the 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 is a novel therapeutic target for dry eye.

How AR-15512 is Thought to Work

TRPM8 channels, located on the eyelid and cornea, are cold-sensitive thermoreceptors that play a central role in tear film homeostasis.1, 2

TRPM8 channels detect drops in corneal temperature associated with 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 development of dry eye.

Preclinical Evidence

In preclinical studies, including animal models of reduced tear secretion, AR-15512 has been shown to increase the activity of corneal cold thermoreceptor nerve fibers and tear production in a concentration-dependent manner.5

Clinical Studies

In a masked, Phase 1/ 2a study evaluating the safety and efficacy of AR-15512, more than 70% of all subjects receiving AR-15512 0.0014% twice daily (BID) 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. Continuous improvement in symptoms, and growing separation from the vehicle group, was observed at each visit over 28 days. Symptom improvement in patients with high-baseline SANDE scores, representing more severe disease, was even greater. At 4 weeks, the difference between AR-15512 and vehicle score improvement in this patient group was statistically significant.5

 

Sande score

Continued improvement in signs (tear production, as evaluated by Schirmer’s Test) was also observed at each visit over 28 days. Statistical significance was achieved for tear production (% subjects with > 3 mm improvement) with 0.0014% BID dosing.5

Schirmer’s Evaluation

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 has initiated a large Phase 2b study (powered as a Phase 3), COMET-1 (Cold-Thermoreceptor Modulation as an Effective Treatment for DED).

COMET-1 is a randomized, double-masked, vehicle-controlled trial evaluating the efficacy and safety of AR-15512 in patients with DED. Approximately 360 patients in total are expected to be enrolled. Patients will receive either AR-15512 0.0014%, AR-15512 0.003% or vehicle dosed as one drop BID in each eye over three months. The primary efficacy endpoints of the clinical trial are ocular discomfort (symptom) and tear production (sign). Patients will be evaluated on multiple efficacy assessments at days 14, 28 and 84; safety will be assessed at all visits.

We expect to report topline results from COMET-1 in Q3 2021.

  1. Eguchi et al. Biomed Res Int 2017 ​
  2. Yang et al. Pharmaceuticals 2018​
  3. Hirata and Meng. IOVS 2010​
  4. ​Belmonte and Gallar. IOVS 2011
  5. Data on file. Aerie Pharmaceuticals, Inc.​
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