A drop designed to stimulate tear production significantly improves dry eye disease (DED) symptoms, according to trial findings published in Ocular Surface. However, the medication failed to meet the co-primary endpoints of the phase 2b study, which included changes from baseline in ocular discomfort and anesthetized Schirmer score at day 28.
With a randomized, double-masked, vehicle-controlled trial (COMET-1, ClinicalTrials.gov Identifier: NCT04498182), researchers evaluated the safety and efficacy of AR-15512, an agonist of transient receptor potential melastatin 8 (TRPM8) receptors.
“Branches of the trigeminal nerve innervating the cornea and lids selectively express cold-sensitive thermoreceptors, called transient receptor potential melastatin 8 (TRPM8) receptors,” the study authors explain. “TRPM8 receptors are associated with the detection of ocular surface dryness and are activated by evaporative cooling and hyperosmolarity, leading to stimulation of tear production. TRPM8 knockout mice are characterized by dramatically reduced basal tearing and an abrogated cold responsiveness without any effect on nociceptor-mediated irritative tearing. In addition, agonists of TRPM8 promote a cooling sensation that may be beneficial for reducing ocular discomfort and pain. Thus, TRPM8 agonists, such as AR-15512, may have a dual role in the potential treatment of DED by both stimulating tear production and reducing ocular discomfort.”
The investigation was conducted across 15 US sites. Patients (N=369) received 14 days of vehicle run-in administered twice daily to both eyes. Following the run-in period, patients were randomly assigned in a 1:1:1 ratio to receive 0.0014% AR-15512 (n=121), 0.003% AR-15512 (n=122), or vehicle (n=126) for 12 weeks. The co-primary efficacy endpoints were change in ocular discomfort score visual analogue scale (ODS-VAS) and anesthetized Schirmer scores.
The study divided participants into 3 groups, those who were given a low-concentration (0.0014%; n=121; 67.8% women; mean age, 65.5%; ODS-VAS scores, 74.1), a high-concentration (0.003%; n=122; 75.4% women; mean age, 72.2; ODS-VAS scores, 72.2), and a vehicle (n=126; 73.0% women; mean age, 63.1%; ODS-VAS scores, 72.9). Anesthetized Schirmer scores for the 3 groups were 5.0, 4.6, and 5.2 mm, respectively.
At days 14 and 28, the researchers observed no significant change in ODS-VAS scores from baseline. At day 84, the 0.003% AR-15512 recipients had a significant change from baseline of -20.6 mm compared with -13.6 mm among vehicle recipients (P =.0281).
The change from baseline in unanesthetized Schirmer scores were 14.0 (P <.0001) and 15.7 (P <.0001) mm for the 0.0014% group, 20.1 (P <.0001) and 19.7 (P <.0001) mm for the 0.003% group, and 7.9 and 6.0 mm for the control group at days 1 and 14, respectively. No significant changes from baseline were observed at days 28 and 84 for anesthetized Schirmer scores.
In addition, significant improvements to Eye Dryness Score-VAS (P =.0302); Global Symptoms Assessment iN Dry Eye (SANDE) score (P =.0015); and DED impact on depression (P <.05), ability to drive (P <.05), reading books or magazines (P <.05), reading food labels (P <.05), watching television (P <.05), and using electronic devices (P <.05) were observed among 0.003% AR-15512 recipients compared with vehicle on day 84.
Any adverse events were reported by 47.1% of the low-concentration, 51.6% of the high-concentration, and 20.6% of the vehicle recipients. The discontinuation rates due to adverse events were 2.5% for the 0.0014% group, 1.6% for the 0.003% group, and 3.2% for the control group. The most common adverse event was instillation site burning or stinging, occurring more among AR-15512 recipients (37.2%-43.4%) than the vehicle recipients (3.2%).
This study was limited by not evaluating the duration of instillation site burning or stinging.
The researchers report that “0.003% AR-15512 demonstrated efficacy across multiple measures of DED signs, symptoms, and disease-related quality of life. In conjunction with a favorable tolerability profile, these results support further clinical development of 0.003% AR-15512 as a novel treatment for signs and symptoms of DED.”
Disclosure: Multiple study authors declared affiliations with the biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Wirta DL, Senchyna M, Lewis AE, et al. A randomized, vehicle-controlled, Phase 2b study of two concentrations of the TRPM8 receptor agonist AR-15512 in the treatment of dry eye disease (COMET-1). Ocul Surf. 2022;26:166-173. doi:10.1016/j.jtos.2022.08.003