Acoltremon Ophthalmic Solution 0.003% for Signs and Symptoms of Dry Eye Disease: Results of Phase 3 Pivotal Studies COMET-2 and COMET-3.

Purpose: Evaluate safety and efficacy of the novel transient receptor potential melastatin 8 agonist acoltremon on signs and symptoms of dry eye disease (DED).

Design: Two identical randomized, multicenter, double-masked, vehicle-controlled, phase 3 studies.

Subjects: Adults aged ≥ 30 years with a DED diagnosis within 6 months, at least 1 eye with both total corneal fluorescein staining (tCFS) score ≥ 2 and ≤ 15 (no region > 3) and anesthetized Schirmer test score ≥ 2 and < 10 mm/5 min, and both ocular discomfort (visual analog scale) and Symptom Assessment iN Dry Eye (SANDE) scores ≥ 50.

Methods: Subjects were randomized 1:1 to acoltremon 0.003% (ACO; TRYPTYR®) or vehicle (VEH) twice daily for 90 days (ClinicalTrials.gov identifiers: COMET-2, NCT05285644; COMET-3, NCT05360966).

Main outcome measures: Primary endpoint was proportion of subjects achieving ≥ 10-mm increase in unanesthetized Schirmer test (UST) score on day 14. Key secondary endpoint was change from baseline (CFB) in global SANDE score on day 28. Additional secondary endpoints included CFB in UST on days 1, 14, and 90. Exploratory endpoints included CFB in tCFS and total conjunctival staining.

Results: 465 (COMET-2) and 466 (COMET-3) subjects were randomized. Primary endpoint was met in both studies, with higher proportions of subjects achieving ≥ 10-mm increase in UST on day 14 with ACO versus VEH (COMET-2: 42.6% versus 8.2%, respectively; COMET-3: 53.2% versus 14.4%, respectively; both P < 0.0001). Reduction from baseline in global SANDE score on day 28 (key secondary endpoint) was in favor of ACO in both studies, with statistical significance achieved in COMET-2. Evidence of tear production in favor of ACO versus VEH was observed as early as day 1 through day 90 in both studies (P < 0.0001). Numerically greater reductions with ACO were also observed in tCFS on days 28 and 90 and in total conjunctival staining at all time points in both studies. Mild instillation-site burning/stinging was the only ocular adverse event reported with > 2.5% incidence.

Conclusions: In both phase 3 studies, ACO compared with VEH led to consistent, clinically meaningful tear production as well as reductions in other DED signs and symptoms.