Long-term data finds acoltremon 0.003% increases tear production in DED

New phase 3 pivotal data on Alcon Inc.’s AR-15512 (acoltremon ophthalmic solution) 0.003% details a positive long-term impact in treating the signs and symptoms of dry eye disease (DED).

The findings are being presented during the 2025 annual meeting of the American Society for Cataract and Refractive Surgeons (ASCRS) this weekend.

Let’s start with this ophthalmic solution.

As a first-in-class investigational product candidate, acoltremon is a topical transient receptor potential melastatin 8 agonist (TRPM8) formulated to be administered via topical ocular instillation.

• Refresh: Located in the cornea and eyelid, TRPM8 is a cold-sensing receptor with the potential to relieve symptoms of DED.

Its intended indication: DED

• And keep in mind: The solution was originally developed by Aerie Pharmaceuticals, which Alcon acquired in 2022.

Got it. Now to the clinical research on it.

Acoltremon has undergone clinical investigation in the COMET clinical program, comprising of phase 2 and 3 clinical trials:

• COMET-1 (phase 2; NCT04498182)
• COMET-2 (phase 3; NCT05285644)
• COMET-3 (phase 3; NCT05360966)
• COMET-4 (phase 3; NCT05493111)

And its performance thus far?

We’ll start with COMET-1.

In the multicenter, vehicle-controlled, double-masked, randomized phase 2b COMET-1 trial, acoltremon was evaluated in two doses (low and high) versus a placebo administered to DED patients twice a day (BID) over a 12-week period.

The findings were a mixed bag:

• The bad: Both co-primary study endpoints failed to be met
• The good: Acoltremon demonstrated statistically significant improvements in DED signs, symptoms, and disease-related quality of life
  • The solution also had a favorable safety and tolerability profile with low rates of discontinuation
  • As for reported adverse events (AEs): These were mainly mild stinging and burning
  • And a notable limitation: Testing tear production without anesthesia only up to Day 14

Now to COMET-2 and COMET-3.

These randomized phase 3 trials evaluated acoltremon versus a placebo administered once a day in both eyes (BID) among over a combined 900 DED patients for 90 days.

• The outcome measures:
  • Primary: Unanesthetized Schirmer test (at Day 14), as measured by the number of participants with ≥ 10 mm increase in unanesthetized Schirmer score
  • Secondary: See here and here

And what were the initial findings?

Reported in January 2024, both trials met their primary endpoint and also “demonstrated the rapid onset and sustained tear production associated with acoltremon compared to vehicle, as early as Day 1 and persistent to Day 90.”

In other words: The study was also successful in meeting its secondary endpoints.

Sounds promising! Now to this COMET-4 study.

Take note: The trial focused on acoltremon-stimulated tear production over a 12-month period. Specifically: This multicenter, vehicle-controlled, double-masked, randomized phase 3 study was conducted with the following setup:

• The participants: 275 DED patients (aged 18+)
• The dosings: Patients randomized 2:1 to receive acoltremon (0.003%) or placebo administered BID in each eye
• The duration: 12 months (365 days)
• The outcome measures:
  • Primary: AEs; blood pressure; heart rate; endothelial cell counts; hematology, chemistry, and urinanalysis; LogMAR visual acuity (VA); Early Treatment Diabetic Retinopathy (ETDRS) VA; and biomicroscopy; intraocular pressure (IOP); and dilated fundus exam
    • See the other outcomes

So how was tear production assessed?

Investigators measured this as an exploratory efficacy via “unaesthetized Schirmer test in a subgroup of subjects at selected sites,” according to the ASCRS clinical poster.

Those details: They analyzed the percent of subjects with ≥10 mm increase in Schirmer test score and change from baseline (CFB) Schirmer test score at each visit with Fisher’s exact test and analysis of covariance (ANCOVA), respectively.

• Plus: Safety assessments were performed at all visits for the entire study cohort.

Now to these new results.

In an exploratory efficacy subgroup of 42 participants—with 28 administered acoltremon and 14 administered placebo—"tear production was consistently observed” throughout the 12-month period.

The response rate numbers:

• For acoltremon patients: 53.6% (Day 1) and 60% (Day 365)
• For placebo patients: 7.1% (Day 1) and 0% (Day 365)

The treatment differences between the two: 36.4% (Day 1; p = 0.0058) and 60% (Day 365; p = 0.0007)

What else?

The data also reported findings on the least squared (LS) mean change from baseline ± spherical equivalent (SE)

• At Day 1: 14.6 ± 1.90 (acoltremon) vs 3.4 ± 2.69 (vehicle)
• At Day 365: 14.8 ± 1.96 (acoltremon) vs 0.6 ± 2.95 (vehicle)

The treatment differences:

• Day 1: 11.3 ± 3.30 (p =0.0015)
• Day 365: 14.2 ± 3.54 (p =0.0003)

And what adverse events were reported?

As seen in the previous COMET trials, the most common ocular AE reported in the full safety cohort (as in: all 275 patients in the COMET-4 trial) was instillation site burning and stinging.

Notably: These were rated as “mild” by the majority of patients.

So what did investigators conclude based on these findings?

They concluded that acoltremon “demonstrated rapid onset and sustained improvement in tear production over 12 months, with a favorable safety profile.”

• Keep in mind: While the investigative candidate performed similarly in the COMET-2 and COMET-3 trials, those findings (as we noted) were only based on short-term data (just 14 days).

And all in all: This latest data supports the solution as “a promising novel treatment for the signs and symptoms of DED.”

Nice! Now, what if I want more details on these findings?

If you’re attending ASCRS 2025, check out the paper session presented by David L. Wirta, MD, on April 28.

The title: Sustained Tear Production with Acoltremon 0.003% over 12 Months: Results from Comet-4, a Phase 3 Long-Term Safety Study

And this the only new data on acoltremon?

Not at all. In fact, Alcon announced four other presentations highlighting new phase 3 findings from the COMET clinical program on the candidate’s efficacy in treating DED.

• See here, here, here, and here for specifics on each.

Lastly, what’s the end-game plan for the candidate moving forward?

Alcon has already submitted to the FDA a new drug application (NDA) for acoltremon—with a Prescription Drug User Fee Act (PDUFA) date set for May 30.