Highlights
- Tryptyr (acoltremon ophthalmic solution 0.003%) is the first TRPM8 receptor agonist approved for dry eye disease, showing a rapid increase in natural tear production from day 1.
- FDA approval was based on positive phase 3 COMET-2 and COMET-3 trials demonstrating statistically significant efficacy.
- Alcon’s launch includes broad access initiatives and educational campaigns for both clinicians and patients.
Clinical Background and Disease Burden
Dry eye disease (DED) is a chronic, multifactorial condition characterized by tear film instability and ocular surface inflammation, leading to discomfort, visual disturbance, and potential damage to the ocular surface. Prevalence estimates range from 5% to 30% in adults, increasing with age and comorbidities. DED significantly impacts quality of life, work productivity, and healthcare costs. Current therapies—including lubricating drops, anti-inflammatories, and secretagogues—often provide incomplete or delayed relief, underscoring the need for innovative, rapid-acting treatments.
Research Methodology
The FDA approval of Tryptyr was underpinned by results from two pivotal phase 3 clinical trials: COMET-2 and COMET-3. Both were multicenter, randomized, double-masked, placebo-controlled studies enrolling adults diagnosed with moderate to severe dry eye disease. Participants were randomized to receive either Tryptyr (acoltremon ophthalmic solution 0.003%) or placebo, with primary endpoints focused on objective measures of tear production (Schirmer test) and patient-reported symptom improvement. Key secondary endpoints included onset of action, safety, and tolerability.
Key Findings
In both COMET-2 and COMET-3, Tryptyr demonstrated a statistically significant improvement in natural tear production compared to placebo, with effects evident as early as day 1 post-administration. The Schirmer test, a standard measure of aqueous tear production, showed rapid and sustained increases in treated subjects. While detailed effect sizes and confidence intervals are pending full peer-reviewed publication, the available data indicate a clinically meaningful benefit. Additionally, patients reported symptomatic relief, including reductions in dryness, grittiness, and ocular discomfort. Tryptyr was generally well-tolerated, with adverse events comparable to placebo and primarily limited to mild, transient ocular sensations.
Mechanistic Insights and Biological Plausibility
Tryptyr’s active ingredient, acolteremon, is a selective agonist of the transient receptor potential melastatin 8 (TRPM8) channel, a cold-sensing ion channel expressed on sensory neurons of the ocular surface. Activation of TRPM8 is believed to stimulate basal tear secretion via sensory-neural pathways, bypassing the inflammatory cascades targeted by conventional therapies. This neuromodulatory mechanism offers a novel therapeutic angle for DED, particularly for patients with insufficient tear production and incomplete response to anti-inflammatory treatments.
Expert Commentary
Lisa Praeger, Vice President and General Manager of U.S. Ocular Health Pharmaceuticals at Alcon, emphasized Tryptyr’s anticipated impact as the first neuromodulator eye drop to rapidly boost natural tear production. The product’s swift onset and novel mechanism are expected to fill a significant gap in current DED management. Early commentary from ophthalmology experts highlights the potential for Tryptyr to be integrated as an adjunct or alternative to existing therapies, especially in patients with aqueous-deficient dry eye.
Controversies or Limitations
While initial results are promising, several limitations warrant attention. First, the full peer-reviewed data from COMET-2 and COMET-3 have not yet been published, limiting independent assessment of effect sizes and subgroup analyses. Long-term safety and efficacy beyond the trial duration remain to be established, as does the comparative effectiveness relative to other DED therapies. Additionally, the symptomatic diversity of dry eye disease and multifactorial etiology may mean that not all patients will respond equally to TRPM8 agonism. Cost, access, and insurance coverage (despite Alcon’s support initiatives) could also influence real-world uptake.
Conclusion
Tryptyr represents a significant advance in the pharmacological management of dry eye disease, introducing neuromodulation as a rapid, effective, and well-tolerated option for enhancing natural tear production. While broader clinical experience and published data are awaited, the FDA approval and initial launch strategy signal a promising new era for patients and clinicians confronting the challenges of dry eye. Future research should focus on long-term outcomes, head-to-head comparisons, and patient selection criteria to optimize therapeutic benefit.
References
1. Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II Definition and Classification Report. Ocul Surf. 2017;15(3):276-283.
2. Stapleton F, Alves M, Bunya VY, et al. TFOS DEWS II Epidemiology Report. Ocul Surf. 2017;15(3):334-365.
3. Alcon press release. Alcon launches Tryptyr for dry eye disease. May 2024.
4. FDA approves Tryptyr for dry eye disease. U.S. Food and Drug Administration. May 2024.
5. Belmonte C, Nichols JJ, Cox SM, et al. TRPM8 channel activation and dry eye. Invest Ophthalmol Vis Sci. 2021;62(8):35.