Source: FDA, National Drug Code (US) Revision Year: 2025
Studies in animals suggest that acoltremon, the active substance in TRYPTYR, is an agonist of transient receptor potential melastatin 8 (TRPM8) thermoreceptors. TRPM8 thermoreceptor stimulation has been shown to activate trigeminal nerve signaling leading to increased basal tear production. The exact mechanism of action for TRYPTYR in dry eye disease is unknown.
PK was assessed in 25 patients with dry eye disease receiving TRYPTYR administration (1 drop twice daily) on Days 1, 14, and 90. A total of three (3) (12.0%) had plasma concentrations above 20 pg/mL (the lower limit of quantification), with the highest plasma concentration of 213 pg/mL.
Long term studies in animals have not been performed to evaluate the carcinogenic potential of acoltremon.
Acoltremon was not mutagenic or clastogenic in the standard battery of genotoxicity tests including a bacterial reverse mutation assay, an in vitro chromosomal aberration assay in human peripheral lymphocytes and micronucleus assay in rats.
Studies to evaluate the potential effects of acoltremon on male or female fertility in animals have not been performed.
The efficacy of TRYPTYR for the treatment of dry eye disease was supported by two randomized, multi-center, double-masked, vehicle-controlled studies (COMET-2 [NCT-05285644] and COMET-3 [NCT-05360966]) enrolling a total of 931 dry eye patients (462 of which received TRYPTYR).
Patients were randomized to TRYPTYR or vehicle (placebo) in a 1:1 ratio and dosed twice a day for 90 days. Use of artificial tears was not allowed during the studies. The mean age was 61 years (range, 30-93 years). The majority of patients were female (74.8%). Enrollment criteria included signs (i.e., corneal fluorescein staining score [2-15] and anesthetized Schirmer tear test [2-9 mm]) and symptoms (i.e., SANDE Score [≥50] and Ocular Discomfort Score [≥ 50]) of dry eye disease.
Tear film production was measured by unanesthetized Schirmer tear test assessed using a Schirmer strip (0-35 mm). The average baseline unanesthetized Schirmer scores for TRYPTYR and Vehicle treated patients was 6.2 mm and 5.9 mm in the COMET-2 study, and 6.8 mm and 6.4 mm in the COMET-3 study, respectively. Of the patients treated at Day 14 (primary endpoint) with TRYPTYR, 42.6% achieved ≥ 10 mm increase in Schirmer score from baseline in the COMET-2 study and 53.2% achieved ≥ 10 mm increase in Schirmer score from baseline at Day 14 in the COMET-3 study, compared to 8.2% and 14.4% of vehicle-treated patients in the COMET-2 study and the COMET-3 study, respectively. A statistically significant improvement in tear production favoring TRYPTYR (p<0.01) was observed in both studies (Table 1).
Table 1: Percent of Patients Achieving ≥ 10 mm Improvement from Baseline in Schirmer Score at Day 14 in Patients with Dry Eye Disease
| Tear Production | ||||
|---|---|---|---|---|
| COMET-2 | COMET-3 | |||
| TRYPTYR N=230 | Vehicle N=235 | TRYPTYR N=232 | Vehicle N=234 | |
| ≥10 mm increase in tear production at Day 14 | 42.6% | 8.2% | 53.2% | 14.4% |
| Difference (95% CI) | 34.4% (26.9, 42.0) | 38.8% (30.8, 46.8) | ||
| P-value versus vehicle | <0.01 | <0.01 | ||
Consistent results were observed at all timepoints through Day 90.
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