Tryptyr Increases Tear Production in Dry Eye Disease

Introduction

On May 28, 2025, the FDA granted approval to acoltremon ophthalmic solution 0.003% (Tryptyr) for the treatment of signs and symptoms of dry eye disease (DED).¹ Tryptyr is an agonist of the TRPM8 cold-sensing receptor. Activation of TRPM8 thermoreceptors stimulates trigeminal nerve signaling, which has been shown to increase basal tear production.²

Efficacy

The efficacy of acoltremon for DED was demonstrated in 2 randomized, multicenter, double-masked, vehicle-controlled phase 3 studies (COMET-2 [NCT05285644] and COMET-3 [NCT05360966]).³ Participants were randomly assigned 1:1 to acoltremon 0.003% or vehicle, administered twice daily for 90 days. The primary end point of both studies was the proportion of participants who achieved an increase of 10 mm or more in unanesthetized Schirmer test (UST) score on day 14, a measure used to capture increases in both basic and reflex tear production. Acoltremon met the primary end point in both studies, producing improvements in tear production compared with the vehicle (COMET-2: 42.6% vs 8.2%, respectively; COMET-3: 53.2% vs 14.1%; both P < .0001). The treatment difference in responders favoring acoltremon was 34.4% (95% CI, 26.9%-42.0%; P < .0001) in COMET-2 and 38.8% (95% CI, 30.8%-46.8%; P < .0001) in COMET-3. These results demonstrated consistent and clinically meaningful increases in tear production with acoltremon.³

COMET-4 (NCT05493111), a randomized, multicenter, double-masked, vehicle-controlled phase 3 extension study, evaluated tear production over 12 months. Patients were randomly assigned 2:1 to acoltremon 0.003% or vehicle administered twice daily.⁴ The percentage of participants achieving an increase of 10 mm or more in UST score was analyzed. Tear production benefits improved with acoltremon and were sustained throughout the study, with significantly higher response rates compared with vehicle on day 1 (53.6% vs 7.1%, respectively; P = .0058) and day 365 (60.0% vs 0%; P = .0007).⁵

Safety

In both COMET-2 and COMET-3, the only ocular treatment emergent adverse event (TEAE) reported in more than 2.5% of participants was instillation-site pain (burning or stinging). In COMET-2, this occurred in 53.0% of participants receiving acoltremon compared with 3.8% receiving the vehicle; in COMET-3, it occurred in 50.0% vs 2.6% of participants, respectively. Despite its frequency, this TEAE was reported as mild in most cases (98.4% in COMET-2 and 97.5% in COMET-3), supporting a favorable overall safety profile.³

Instillation site burning or stinging remained the most reported ocular adverse event in COMET-4 and was similarly rated as mild by most participants.^4,5

Across all studies, visual acuity reduction and blurred vision were each reported in approximately 1% of participants. The most common nonocular adverse reaction was a urinary tract infection, occurring in 2.1% of participants.⁶

There are no current contraindications for acoltremon. To minimize the risk of contamination or eye injury, patients should be instructed to not touch the vial tip to the eye or any other surface.²

Dosing and Duration

The recommended dose is 1 drop instilled in each eye twice daily, approximately 12 hours apart. There is no defined treatment duration or discontinuation point for this medication; however, DED is a chronic condition, and continued use may be expected to maintain tear production and symptom control. Before using, the patient must wash their hands and remove contact lenses; lenses may be reinserted 15 minutes following administration. Acoltremon 0.003% ophthalmic solution is supplied in a single-dose vial. Each vial is intended for immediate use after opening and contains enough solution to dose both eyes. The vial, including any remaining contents, should be discarded immediately after use.²

References

1. Drug trials snapshot: Tryptyr. FDA. Updated August 15, 2025. Accessed November 22, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshot-tryptyr

2. Tryptyr. Prescribing information. Alcon Laboratories Inc; 2025. Accessed November 22, 2025. https://alcon.widen.net/s/vmnmcnwkfq/tryptyr-pi

3. Pattar GR, Wirta D, Jerkins G, et al; COMET-2 and COMET-3 Study Groups. Acoltremon ophthalmic solution 0.003% for signs and symptoms of dry eye disease: results of phase 3 pivotal studies COMET-2 and COMET-3. Ophthalmology. Published online September 30, 2025. doi:10.1016/j.ophtha.2025.09.018

4. Delaney-Gesing A. Long-term data finds acoltremon 0.003% increases tear production in DED. Eyes On Eyecare. April 25, 2025. Accessed November 22, 2025. https://glance.eyesoneyecare.com/stories/2025-04-25/long-term-data-finds-acoltremon-0-003-increases-tear-production-in-ded/

5. Wirta DL, Senchyna M, Garcia Santana S, et al. Sustained tear production with acoltremon 0.003% over 12 months: results from COMET‑4, a phase 3 long-term safety study. Poster presented at: 2025 American Society of Cataract and Refractive Surgery Annual Meeting; April 25-28, 2025; Los Angeles, CA.

6. Center for Drug Evaluation and Research. Application number: 217370Orig1s000. Integrated Review. May 27, 2025. Accessed November 22, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2025/217370Orig1s000IntegratedR.pdf