TRPM8

Alcon says dry eye affects an estimated 38 million people in the U.S. Alcon’s $770 million takeover of Aerie Pharmaceuticals has delivered an early win. The lead candidate in the acquired pipeline met the primary endpoint in a pair of phase 3 dry eye trials, positioning Alcon to file for FDA approval in the middle of the year. The studies randomized around 930 people with dry eye to receive AR-15512, a topical transient TRPM8 agonist, or vehicle control. After 14 days, a higher proportion of patients on AR-15512 had a 10 mm or greater increase in tear production, causing the program to meet its primary endpoint with a p value of less than 0.0001. Alcon saw improvements in tear production as early as day one. The effects persisted through to day 90, although the former Novartis unit is yet to share data from the trial. Alcon is also yet to comment on the phase 3 trial’s other secondary endpoints such as ocular discomfort, which was once a focus of AR-15512 development. AR-15512 failed to improve tear production or ocular discomfort on day 28 in an earlier study, causing that trial to miss its co-primary endpoints. Aerie looked past the setback, focused on successes against secondary goals—including tear production at day 14—designed a phase 3 program around the lessons of the earlier trial and was rewarded with a buyout bid from Alcon, plus positive top-line phase 3 data. Alcon plans to use the data, which is free from serious ocular adverse events, to file for FDA approval in the middle of 2024. Talking to investors on a quarterly results conference call in November, Alcon CEO David Endicott said it would “probably take four months, five months to get [the data] into a submission format.” The eye care specialist is also working to wrap up a long-term safety study by April. Approval will position Alcon to start selling a first-in-class treatment for dry eye disease, a condition that the company says affects an estimated 38 million people in the U.S. Around 20 million of those people are undiagnosed, according to Alcon, and fewer than 10% of people with a diagnosis take a prescription drug.  Most patients initially try artificial tears, and most pharmacologic topical therapies, including Bausch + Lomb’s Xiidra, target inflammation. AR-15512 has a different mechanism, as researchers have tied TRPM8 to the detection of ocular surface dryness.

Top-line results from two Phase III efficacy trials suggest Alcon's experimental dry-eye therapy AR-15512 could grab a significant chunk of the US market from mainstay treatments Xiidra (lifitegrast) and Restasis (ciclosporin). Based on findings from the COMET-2 and COMET-3 trials, the Novartis spinout said it plans to file its topical dry-eye candidate with the FDA in mid-2024.Novartis offloaded Xiidra and its other "front of eye" assets to Bausch + Lomb in a deal worth up to $2.5 billion last year. Xiidra, which was approved by the FDA for dry-eye disease in 2016, generated sales of $185 million in the first half of 2023. Restasis, which is marketed by AbbVie, brought in $308 million in the first nine months of last year.Alcon acquired AR-15512 through its $770-million purchase of Aerie Pharmaceuticals. The TRPM8 agonist acts as a thermoreceptor modulator to stimulate the cold sensing receptors found on nerve endings that supply the cornea and eyelids. The company said that both the COMET-2 and COMET-3 studies, which enrolled a total of more than 930 participants, achieved the primary endpoint of ≥10mm increase in unanaesthetised Schirmer's score, a measure of tear production, after two weeks.Addressing the rapid onset gapAccording to Alcon, secondary endpoints also demonstrated the drug's rapid onset compared to vehicle, beginning as early as the first day and persisting through to day 90. UBS analysts view this as an even more encouraging sign, noting "this could be an important commercial factor given it looks to deliver an onset of action well ahead of marketed drugs." Meanwhile, there were no serious ocular safety events reported in either study, although the COMET-4 safety trial in 275 patients is ongoing.Alcon suggested there is a large untapped market for dry-eye disease treatments. While the condition is estimated to affect 38 million people in the US, the company said only about 18 million are diagnosed and <10% of those are treated with a prescription product. "A key gap in dry-eye medications is rapid speed of onset," said Edward Holland, a key advisor on COMET-2 and COMET-3, as well as a senior scientific advisor at Alcon. He added that AR-15512 represents a first-in-class candidate for chronic dry eye.UBS estimates AR-15512 could post sales of just over $1 billion annually at its peak by 2030. "Even if there are competitive challenges, we still think – assuming the detailed data supports the headline conclusions – the drug can generate sales comparable to Xiidra" of about $600 million, they added.

Pictured: Woman using eye drops/iStock, eternalcreative Alcon on Tuesday posted promising top-line results from two pivotal Phase III clinical trials—COMET-2 and COMET-3—demonstrating that its investigational eye drops AR-15512 improved tear production in patients with dry eye disease. The Swiss eye disease specialist did not reveal specific data in its news release, but said that in both studies, AR-15512 treatment led to a higher proportion of patients achieving at least a 10-mm improvement in unanesthetized Schirmer’s score, a validated measure of tear production. At day 14, this effect reached statistical significance, with a p-value less than 0.0001, according to Alcon’s announcement. As for safety, Alcon also reported that AR-15512 was well-tolerated. There were no serious ocular adverse events documented in COMET-2 or COMET-3. In a statement, Alcon CEO David Endicott said that Tuesday’s readouts underscore AR-15512’s “potential to address the limitations of current dry eye prescription options,” providing both doctors and patients with a new approach to treat the chronic condition. Data from both studies also showed that AR-15512 met its secondary endpoints, eliciting rapid-onset and durable tear production as compared with vehicle controls. This benefit was apparent as early as day 1 and persisted through 90 days of observation. “A key gap in dry eye medications is rapid speed of onset,” Edward Holland, professor of ophthalmology at the University of Cincinnati, said in Alcon’s announcement. “AR-15512 demonstrated this important achievement in both pivotal efficacy and safety studies and it represents a first-in-class candidate for chronic dry eye.” Holland is a scientific advisor at Alcon and is a key advisor on COMET-2 and COMET-3. Armed with these data, Alcon expects to submit a New Drug Application to the FDA by mid-2024, according to its news release. AR-15512 is a topical, first-in-class agonist of the TRPM8 receptor, which is a cold-sensing channel found in the dorsal root and trigeminal ganglia. AR-15512 stimulates cold-sensing receptors in nerves that innervate the cornea and eyelids, thereby inducing a cooling sensation across the eye and stimulating natural tear production. The candidate was first discovered and developed by Aerie Pharmaceuticals, which Alcon bought for $770 million in August 2022. Tuesday’s positive readout from COMET-2 and COMET-3 comes after a high-pro in the dry eye disease space. In November 2023, the FDA denied approval for Aldeyra Therapeutics’ investigational reactive aldehyde species modulator reproxalap, which the company was hoping to position as a treatment for dry eye disease. In the Complete Response Letter, the agency pointed to a lack of data to establish the candidate’s efficacy in treating dry eye symptoms and asked for at least one more well-controlled trial. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.