FDA Issues Third Reproxalap CRL for Dry Eye Disease

The US Food and Drug Administration has issued a Complete Response Letter (CRL) to Aldeyra Therapeutics’ New Drug Application (NDA) of reproxalap, an investigational drug candidate, for the treatment of dry eye disease. 

As described in a March 17, 2026, release from the Company, the CRL stated that there is “a lack of substantial evidence consisting of adequate and well-controlled investigations … that the drug product will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in its proposed labeling” and that “the application has failed to demonstrate efficacy in adequate and well controlled studies in the treatment of signs and symptoms of dry eye disease.” The letter also stated that the “inconsistency of study results raises serious concerns about the reliability and meaningfulness of the positive findings” and that the “totality of evidence from the completed clinical trials does not support the effectiveness of the product.” Consistent with prior NDA reviews of reproxalap, no safety or manufacturing concerns were identified.

“To the thousands of American and Canadian patients who participated in our clinical trials and to the tens of millions of patients with dry eye disease worldwide, I want to assure you that we will work with urgency to support the FDA in enabling market access to what is, to our knowledge, the only drug with clinical activity within minutes of administration in patients with dry eye disease, a condition that is today treated with medications that require weeks or months of treatment to achieve even modest improvement,” stated Todd Brady, MD, PhD, President and Chief Executive Officer of Aldeyra.

Aldeyra first submitted an 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. After another CRL in April of 2025, Aldeyra conducted an additional dry eye chamber trial, supplementing the NDA with these data in June of 2025.3,4,6

The latest NDA was supported by results from both the ALLEVIATE trial, a Phase 3 randomized, double-masked, vehicle-controlled clinical trial which achieved its primary endpoint in August of 2024, and the more recent dry eye chamber trial, requested after the FDA administered another CRL in April of 2025. 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 dry eye disease.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 either another dose of vehicle or reproxalap before and during exposure to another dry eye chamber. 66 patients received vehicle and 66 received reproxalap. The primary endpoint of the trial 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. The most reported adverse event was, according to Aldeyra, mild and transient instillation site discomfort, which was consistent with prior trials.5

In May of 2025, Aldeyra announced the completion of the dry eye chamber trial, which demonstrated reproxalap’s capacity to reduce ocular discomfort. No notable differences in baseline scores were noted across treatment arms during this trial, and no safety concerns were identified. As with prior trials, the most common adverse event was mild and transient installation site discomfort, rarely lasting longer than 1 minute.6

In the latest CRL, the FDA recommended that the reasons for failure in certain trials be explored, and that populations or certain conditions in which reproxalap may be effective be identified. The Agency did not recommend conducting additional trials or request submission of additional confirmatory evidence.

In the press release, Aldeyra indicated it does not currently expect to pursue additional clinical trials and intends to expeditiously request a Type A meeting to understand the actions needed for NDA approval. Per Prescription Drug User Fee Act (PDUFA) goals, the target Type A meeting date is within 30 days of receipt of the meeting request.

References

1. Aldeyra Therapeutics. 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. March 17, 2026. Accessed March 17, 2026. https://ir.aldeyra.com/news-releases/news-release-details/aldeyra-therapeutics-receives-complete-response-letter-us-food-1

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. 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. 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. 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

6. Aldeyra Therapeutics, Inc. Aldeyra Therapeutics Resubmits Reproxalap New Drug Application for the Treatment of Dry Eye Disease. June 17, 2025. Accessed March 13, 2026. https://ir.aldeyra.com/news-releases/news-release-details/aldeyra-therapeutics-resubmits-reproxalap-new-drug-application-0