Aldeyra receives third complete response letter for reproxalap

The US Food and Drug Administration (FDA) has issued a Complete Response Letter to Aldeyra Therapeutics for its New Drug Application of reproxalap for the treatment of dry eye disease. This marks the third CRL from the FDA to Aldeyra over reproxalap.¹

Previously, the company had received CRLs from the FDA in April 2025² and November 2023³.

In the CRL at the end of 2023³, the FDA identified no safety or manufacturing issues with reproxalap but noted the NDA did not demonstrate “efficacy in treating ocular symptoms associated with dry eyes” and that “at least one additional adequate and well-controlled study to demonstrate a positive effect on the treatment of ocular symptoms of dry eye” should be conducted.

In the NDA issued in April 2025², again the FDA found no manufacturing or safety issues with reproxalap but noted that the NDA “failed to demonstrate efficacy in adequate and well-controlled studies in treating ocular symptoms associated with dry eyes” and that “at least one additional adequate and well-controlled study to demonstrate a positive effect on the treatment of ocular symptoms of dry eye” should be conducted, mirroring the prior CRL.

In the most recent CRL¹, the FDA stated “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 “the application has failed to demonstrate efficacy in adequate and well-controlled studies in the treatment of signs and symptoms of dry eye disease.” Additionally, the FDA noted 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.”

The most recent NDA was submitted to the FDA in June 2025⁴ and accepted for review in July of the same year.⁵ It included new clinical data from a completed dry eye chamber trial, which achieved the primary end point.⁶ The dry eye chamber trial was statistically superior to the vehicle in terms of ocular discomfort, and although the field trial missed statistical significance for the primary endpoint, the company noted it was consistent with previous field trials.

The FDA did not recommend additional trials or request submission of additional confirmatory evidence after the recent CRL.

Aldeyra stated in a press release¹ that during the most recent NDA review, label drafts were provided by the FDA in December 2025 and again in March 2026. However, the company noted it does not believe that label negotiations were completed.

Todd C Brady, MD, PhD, president and CEO of Aldeyra, commented on the CRL in a press release from the company, saying, “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.”

The company noted it intends to request a Type A meeting with the FDA to understand the actions needed for NDA approval. Aldeyra stated it currently has no intention to pursue additional clinical trials.

References:

1. 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. Published 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. Harp MD. FDA issues complete response letter to Aldeyra Therapeutics for resubmitted new drug application of reproxalap. April 3, 2025. Accessed March 17, 2026. https://www.ophthalmologytimes.com/view/fda-issues-complete-response-letter-to-aldeyra-therapeutics-for-resubmitted-new-drug-application-of-reproxalap

3. Hutton D. Aldeyra Therapeutics receives complete response letter from FDA for reproxalap NDA. Published November 29, 2023. Accessed March 17, 2026. https://www.ophthalmologytimes.com/view/aldeyra-therapeutics-receives-complete-response-letter-from-fda-for-reproxalap-nda

4. Harp MD. Aldeyra submits third new drug application for reproxalap for the treatment of dry eye disease. Published June 17, 2025. Accessed March 17, 2026. https://www.ophthalmologytimes.com/view/aldeyra-submits-third-reproxalap-new-drug-application-for-the-treatment-of-dry-eye-disease

5. Harp MD. FDA accepts for review Aldeyra Therapeutics’ resubmitted New Drug Application for reproxalap. Published July 17, 2025. Accessed March 17, 2026. https://www.ophthalmologytimes.com/view/fda-accepts-for-review-aldeyra-therapeutics-resubmitted-new-drug-application-for-reproxalap

6. Maharjan EK. Aldeyra Therapeutics hits primary end point in 1 of 2 phase 3 trials for reproxalap. May 7, 2025. Accessed March 17, 2026. https://www.ophthalmologytimes.com/view/aldeyra-therapeutics-hits-primary-end-point-in-1-of-2-phase-3-trials-for-reproxalap