Acoltremon (TRYPTYR®)

Key Points at a Glance

Key Points of This Drug

• Acortremon (TRYPTYR®) is the first-in-class TRPM8 receptor agonist, approved by the FDA in 2025 for the treatment of dry eye disease.
• It is an eye drop that stimulates cold receptors on the cornea, promoting basal tear secretion via the trigeminal nerve through a neurosensory approach.
• The COMET-2 and COMET-3 trials demonstrated significant improvement in Schirmer test scores (p < 0.0001).
• The most common side effect is a burning sensation upon instillation (approximately 50%), but discontinuation occurs in less than 1% of cases.
• As of March 2026, it is not approved in Japan.

1. What is Acortremon (TRYPTYR®)?

TRYPTYR® (acortremon ophthalmic solution 0.003%) is a prescription eye drop developed by Alcon®. The development code is AR-15512, and it was approved by the U.S. Food and Drug Administration (FDA) in May 2025 for the treatment of signs and symptoms of dry eye disease ¹⁾.

This agent is the first-in-class TRPM8 receptor agonist, employing a neurosensory approach distinct from conventional dry eye treatments. While cyclosporine and lifitegrast suppress ocular surface inflammation, acortremon stimulates cold receptors on the cornea to directly promote tear secretion.

Approval Status in Japan

As of March 2026, acortremon is not approved in Japan. The following information is based on the U.S. approval.

2. Mechanism of Action

Acortremon is a potent and selective agonist of the transient receptor potential melastatin 8 (TRPM8) ion channel ¹⁾.

Characteristics of the TRPM8 Channel

TRPM8 is a cold-sensitive non-selective cation channel highly expressed on corneal sensory neurons, including C-fibers and Aδ-fibers ¹⁾. It is activated by temperature decrease, evaporative cooling, and compounds such as menthol and icilin. Expressed on temperature-sensing neurons innervating the cornea and upper eyelid, it is involved in the regulation of tear secretion.

Pathway of Tear Secretion Promotion

When acortremon activates the TRPM8 channel, the influx of sodium and calcium ions depolarizes the neuron and generates action potentials. This signal is transmitted via the ophthalmic branch of the trigeminal nerve to central nervous system pathways that regulate lacrimal gland activity. As a result, reflex basal tear secretion increases independently of inflammatory cascades ¹⁾.

Because it targets the afferent arm of the lacrimal functional unit (LFU), rapid effects are expected. Clinical trials have reported measurable increases in tear volume from the first day of administration. However, the FDA-approved prescribing information states that the exact mechanism for therapeutic effect remains unknown.

Q Why is acortremon considered to have a different mechanism of action from existing drugs?

A

Existing cyclosporine and lifitegrast improve the tear film environment indirectly by suppressing ocular surface inflammation. Acortremon directly stimulates the afferent pathway of the lacrimal functional unit (TRPM8 channel → trigeminal nerve) to promote tear secretion. This neurosensory mechanism enables a rapid increase in tear volume independent of inflammation.

3. Clinical Trial Results

COMET-2 and COMET-3 Trials

The efficacy and safety of acortremon 0.003% ophthalmic solution were evaluated in two pivotal trials. The primary endpoint was the proportion of patients with an increase of at least 10 mm in Schirmer test score at day 14.

Endpoint	COMET-2	COMET-3
Drug group	42.6%	53.2%
Vehicle group	8.2%	14.4%

Both trials showed a statistically significant difference with p < 0.0001. The effect was maintained for at least 90 days. In addition to objective improvement in Schirmer test scores, patients also reported relief of subjective symptoms.

Q Is the effect of the COMET trials long-lasting?

A

In the COMET-2 and COMET-3 trials, the effect was confirmed to persist up to day 90. Long-term data beyond this are currently limited, and further data accumulation is needed to confirm sustained efficacy with long-term use.

4. Dosage and Administration and Precautions

Dosage and Administration

Instill one drop into each eye twice daily, approximately 12 hours apart. Use a preservative-free, sterile, single-use LDPE vial (0.4 mL). Discard any remaining solution after opening.

Supply Form

Packaged in aluminum pouches containing 5 vials each. One box contains 60 vials (12 pouches).

Storage

Store refrigerated at 2–8°C. After opening the outer carton, it can be stored at room temperature (up to 25°C) for a maximum of 30 days. After opening the aluminum pouch, use the vials within 7 days.

Precautions for Use

• Do not let the tip of the dropper touch any surface, including the eye.
• Remove contact lenses before instillation and wait at least 15 minutes before reinserting them.
• If using with other topical ophthalmic medications, allow at least 5 minutes between instillations.

5. Side Effects and Safety

Main Side Effects

The most common side effect is a burning or stinging sensation at the instillation site. This has been reported in approximately 50% of patients, but less than 1% discontinued treatment due to discomfort. No cases of overdose have been reported, and the risk of systemic toxicity is low due to negligible systemic absorption.

Special Patient Populations

Pregnant Women

Adequate studies: No studies have been conducted in pregnant women.

Animal studies: No teratogenicity has been observed.

Systemic absorption: Negligible, and fetal exposure is expected to be minimal.

Nursing Mothers

Breast milk transfer: It is unknown whether this drug is excreted in human milk.

Decision criteria: The benefit to the mother and the risk to the infant should be evaluated individually.

Pediatric Patients

Safety and efficacy: Not established in pediatric populations.

Use: Not recommended for use in children at this time.

Nonclinical Safety

In animal studies, no evidence of carcinogenicity, mutagenicity, or impairment of fertility was observed at doses significantly exceeding human exposure. No known drug interactions.

Q Burning sensation is about 50%, but does it interfere with treatment continuation?

A

The burning sensation is transient, and discontinuation due to discomfort is extremely rare (<1%). No serious adverse events have been reported in clinical trials, and the impact on treatment compliance is considered limited.

6. Position in Dry Eye Treatment

Dry eye is a disease in which the stability of the tear film is reduced due to various factors, accompanied by ocular discomfort and visual dysfunction. Treatment options include tear replacement therapy (artificial tears), anti-inflammatory therapy (cyclosporine, lifitegrast), and punctal plugs, among others.

Acortremon is a novel therapeutic agent that targets the neural regulatory pathway of tear secretion. In the TFOS DEWS III treatment guidelines, it is positioned as a new neuromodulation approach classified under the category of tear restoration or stimulation ¹⁾. For dry eye primarily characterized by reduced tear volume, it may expand treatment options as a different approach from existing anti-inflammatory therapies.

Q Are there any TRPM8 agonists available in Japan?

A

As of March 2026, no TRPM8 receptor agonists have been approved in Japan. In Japanese dry eye treatment, drugs with different mechanisms of action that promote secretion of tear components, such as diquafosol sodium (Diquas®) and rebamipide (Mucosta® ophthalmic solution), are used.

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7. References

1. Craig JP, Alves M, Wolffsohn JS, et al. TFOS DEWS III: Management and Therapy of Dry Eye Disease. Am J Ophthalmol. 2025;269:1-35.
2. Zhou Y, Zhang W, Sun F. Acoltremon: The first TRPM8 agonist approved for the treatment of dry eye disease. Drug Discov Ther. 2025;19(3):210-211. PMID: 40571589.
3. Pattar GR, Wirta D, Jerkins G, Paauw J, McLaurin EB, Liu A, et al. Acoltremon Ophthalmic Solution 0.003% for Signs and Symptoms of Dry Eye Disease: Results of Phase 3 Pivotal COMET-2 and COMET-3 Studies. Ophthalmology. 2026;133(5):563-574. PMID: 41038456.