The investigational drug reproxalap led to significantly diminished ocular discomfort among patients with dry eye disease, according to results of a phase 3 trial presented at the American Society of Cataract and Refractive Surgery (ASCRS) 2026 Annual Meeting.

In the study, patients given reproxalap reported a nearly 17-point drop in eye dryness on a visual analog scale, compared with about 10 points for those receiving placebo, after sitting in a specialized room. However, the data were not enough to convince the FDA. The agency in mid-March declined to approve a new drug application for the indication from reproxalap’s manufacturer, Aldeyra Therapeutics, marking the third such rejection.

In the single-center, double-masked trial of 116 patients with dry eye disease, participants were randomized to receive one drop of either reproxalap (n = 58) or placebo (n = 58) four times a day in one day in a medical office. The next day, they received one drop of either reproxalap or placebo 5 minutes before and 50 minutes into sitting in a dry eye chamber for 100 minutes.

The chamber has low humidity and high airflow, said Eric Donnenfeld, MD, a cornea, laser cataract, and refractive surgeon with OCLI Vision in Fairfield, Connecticut, and in Garden City, New York, who presented the findings. Patients were required to keep their eyes open and look at a screen during the study and asked to assess their level of eye dryness every 5 minutes from 10 to 100 minutes.

Roughly one third of patients (mean age, roughly 64 years; 93% White) had cataract. Mean ocular discomfort score on a 0 to 100 visual analog scale was about 39 for all participants at baseline. One patient in the treatment arm discontinued due to a scheduling conflict; no patients discontinued the trial due to adverse events.

The primary endpoint was ocular discomfort experienced in the chamber from 80 to 100 minutes after entry. Overall change in the ocular discomfort symptom score was -16.9 (95% CI, -19.7 to -14.0) in the patients who received reproxalap and -10.4 (95% CI, -13.2 to -7.5) in the placebo group (P = .0015).

The trial “showed that this drug significantly reduces the feeling of dryness, which is the most important symptom patients have with dry eye,” Donnenfeld said. Some patients had a “menthol-type” feeling in their eyes upon receiving the drop, which lasted for a minute or two. “Other than that, there were really very few adverse events,” he said. “For a dry eye treatment that is comfortable and works quickly, this is a novel medication and something that I think is certainly worth further investigation.”

Ocular adverse events related to treatment occurred in 40 (69%) of those who received reproxalap and two (3.4%) of those who received placebo. All were mild in severity, with the most common in both groups being instillation site irritation generally lasting less than a minute, Donnenfeld reported.

Reproxalap works by inhibiting reactive aldehyde species that contribute to ocular inflammation. “It has a very novel mechanism of action,” Donnenfeld said.

Sezen Karakus, MD, MPH, an assistant professor of ophthalmology at the Wilmer Eye Institute, Johns Hopkins Medicine, and an associate director of the Johns Hopkins Jerome L. Greene Sjögren’s Disease Center, both in Baltimore, said she was excited to see different mechanisms being addressed for dry eye. The condition can result from varying causes including oxidative stress and T cell-mediated inflammation. As a result, it can be difficult for researchers to know if they are including the right patients or measuring the correct endpoints, she said.

“That is the biggest problem in the clinical trials, and probably one of the reasons some trials fail,” Karakus said.

Karakus said she would have liked to know more details about the patients included in this trial and their responses to the medication beyond the visual analog scale. “From this abstract alone, I cannot get too excited because I actually don’t know exactly which patients would benefit from this,” she said. Still, she said, if a patient had symptomatic dry eye and the drug could provide quick relief in the same day, she would consider prescribing it.

Finding the correct medication for patients “is definitely like an art,” Karakus said. “We just use all of the knowledge and experience we’ve had from prior cases, and what’s available at the moment, based on what we think is most prominent in that specific patient.”

Details from this trial and one other were submitted by Aldeyra Therapeutics to the FDA in June 2025 as part of its latest application for reproxalap, Todd Brady, MD, PhD, the company’s CEO, told Medscape Medical News. On March 17, the FDA issued a third complete response letter, saying the company failed to demonstrate efficacy in adequate and well-controlled studies in the treatment of signs and symptoms of dry eye disease, according to a company news release.

The study was funded by Aldeyra Therapeutics, which participated in the trial design, research, data collection, analysis, interpretation of data, and review and approval of the publication. AbbVie participated in the interpretation of data and review and approval of the publication. Donnenfeld and Karakus reported having no relevant financial conflicts of interest.

Karen Blum is a freelance medical/science writer in the Baltimore area.