FDA Issues Complete Response Letter to Reproxalap for Dry Eye Disease

The US Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) for the resubmission of the New Drug Application (NDA) for reproxalap, a topical ocular treatment for dry eye disease (DED).1

Announced by Aldeyra Therapeutics on April 3, 2025, the FDA determined the trials had "failed to demonstrate efficacy in adequate and well-controlled studies in treating ocular symptoms associated with dry eyes." According to the release, the regulatory agency also expressed concern that certain data from the recent trial may have affected interpretation of the final results.1

"Pending positive results from the ongoing clinical trials and discussions with the FDA, we look forward to a potential NDA resubmission mid-year 2025," said Todd C. Brady, MD, PhD, CEO of Aldeyra Therapeutics. "Reproxalap remains the only late-stage topical ocular therapy suitable for chronic administration to have potentially demonstrated acute reduction in ocular redness, as well as reduction in ocular discomfort, highlighting rapid and broad activity for both the signs and symptoms of DED."1

Reproxalap is a novel small-molecule modulator and inhibitor of reactive aldehyde species (RASP), a pre-cytokine mediator of inflammation typically elevated in systemic inflammatory and ocular diseases. Reproxalap was developed specifically for the treatment of DED and allergic conjunctivitis.2

Aldeyra first submitted the NDA for reproxalap in early 2023; they received a CRL on November 16, 2023, which stated that the NDA did not exhibit “efficacy in treating ocular symptoms associated with dry eyes” as defined by the FDA. Aldeyra announced the resubmission of the NDA on October 3, 2024.3,4

The FDA's dry eye disease guidance requires efficacy in DED to be demonstrated with two symptom trials and two sign trials to be considered for regulatory approval.

The resubmitted NDA was based on the results from the recent ALLEVIATE trial, a Phase 3 randomized, double-masked, vehicle-controlled clinical trial which achieved its primary endpoint in August 2024. According to Aldeyra, the ALLEVIATE trial indicated the superiority of reproxalap over vehicle in treating ocular discomfort (P = .004), which is an FDA-accepted symptom of DED.5

During the trial, participants were administered vehicle – the drug product sans active ingredient – before and during exposure to a dry eye chamber. The 132 qualifying patients were then randomized to another dose of vehicle or reproxalap before and during exposure to another dry eye chamber. 66 patients received vehicle and 66 received reproxalap. The trial's primary endpoint was ocular discomfort from 80-100 minutes of exposure to the chamber.5

Investigators reported no safety signals observed during the trial, and reproxalap was well tolerated by the participants. Aldeyra indicated the most reported adverse event was mild and transient instillation site discomfort, which was consistent with prior trials.5

According to the press release, Aldeyra plans to announce topline results from its ongoing DED field trial and chamber clinical trial in the second quarter of 2025. The company expects a Type A meeting to be held within approximately 30 days to discuss the CRL for the resubmitted NDA and these ongoing trials.

Pending discussions with the FDA, the company intends to resubmit the NDA for reproxalap by mid-2025, with an expected 6-month review period.1

References

1. Aldeyra Therapeutics, Inc. Aldeyra Therapeutics Receives Complete Response Letter from the U.S. Food and Drug Administration for the Reproxalap New Drug Application for the Treatment of Signs and Symptoms of Dry Eye Disease. Aldeyra Therapeutics, Inc. April 3, 2025. Accessed April 3, 2025. https://ir.aldeyra.com/news-releases/news-release-details/aldeyra-therapeutics-receives-complete-response-letter-us-food-0

2. Clark D, Cavanagh B, Shields AL, Karpecki P, Sheppard J, Brady TC. Clinically Relevant Activity of the Novel RASP Inhibitor Reproxalap in Allergic Conjunctivitis: The Phase 3 ALLEVIATE Trial. Am J Ophthalmol. 2021;230:60-67. doi:10.1016/j.ajo.2021.04.023

3. Aldeyra Therapeutics, Inc. Aldeyra Therapeutics Receives Complete Response Letter from the U.S. Food and Drug Administration for the Reproxalap New Drug Application for the Treatment of Dry Eye Disease. Aldeyra Therapeutics, Inc. November 27, 2023. Accessed April 1, 2025. https://ir.aldeyra.com/news-releases/news-release-details/aldeyra-therapeutics-receives-complete-response-letter-us-food 

4. Aldeyra Therapeutics, Inc. Aldeyra Therapeutics Resubmits Reproxalap New Drug Application for the Treatment of Dry Eye Disease. Aldeyra Therapeutics, Inc. October 3, 2024. Accessed April 1, 2025. https://ir.aldeyra.com/news-releases/news-release-details/aldeyra-therapeutics-resubmits-reproxalap-new-drug-application

5. Aldeyra Therapeutics, Inc. Aldeyra Therapeutics Achieves Primary Endpoint in Phase 3 Dry Eye Disease Clinical Trial of Reproxalap. Aldeyra Therapeutics, Inc. August 8, 2024. Accessed April 1, 2025. https://ir.aldeyra.com/news-releases/news-release-details/aldeyra-therapeutics-achieves-primary-endpoint-phase-3-dry-eye