The FDA has issued a Complete Response Letter to Aldeyra Therapeutics for reproxalap, citing insufficient evidence of efficacy for dry eye disease despite multiple clinical trials, including the Phase 3 TRANQUILITY study.
Written By: Pharmacally Medical News Desk
Aldeyra Therapeutics has received a Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA) for its New Drug Application (NDA) seeking approval of reproxalap for the treatment of dry eye disease, with regulators concluding that the application failed to demonstrate sufficient evidence of effectiveness.
This CRL marks the third regulatory setback for reproxalap, following previous Complete Response Letters issued by the FDA in 2023 and 2025.
According to the company, the FDA determined that the NDA lacked “substantial evidence consisting of adequate and well-controlled investigations” to support the drug’s proposed clinical benefits. The agency stated that the application did not adequately demonstrate improvement in both the signs and symptoms of dry eye disease and raised concerns about the reliability of positive findings due to inconsistent results across studies. The FDA further noted that the totality of evidence from completed clinical trials did not support the product’s effectiveness.
The NDA was supported by data from multiple trials, including the Phase 3 TRANQUILITY study (NCT04674358) and related dry eye chamber trials, which showed rapid symptom relief in controlled environments but produced inconsistent results in broader field studies, including a failure to meet the primary endpoint in TRANQUILITY.
The agency did not identify safety or manufacturing issues during its review, consistent with previous regulatory assessments of reproxalap.
During the review process, the FDA provided draft labeling in December 2025 and again in March 2026. However, Aldeyra said label negotiations were not finalized before the CRL was issued.
The FDA recommended that Aldeyra further investigate the reasons behind trial failures and explore whether specific patient populations or clinical conditions might demonstrate clearer therapeutic benefit. The agency did not request additional confirmatory trials or new clinical evidence.
Based on this guidance, Aldeyra stated that it does not currently plan to initiate new clinical trials. Instead, the company intends to request a Type A meeting with the FDA to clarify the steps needed to move the NDA toward potential approval. Under Prescription Drug User Fee Act (PDUFA) timelines, such meetings are typically scheduled within 30 days of the request.
Todd C. Brady, M.D., Ph.D., President and Chief Executive Officer of Aldeyra Therapeutics, said the company remains committed to working with regulators to advance the therapy. He emphasized that reproxalap may offer rapid relief for dry eye symptoms, noting that the investigational treatment has shown clinical activity within minutes of administration in some patients, compared with currently available medications that may take weeks or months to produce modest improvements.
As of December 31, 2025, Aldeyra reported approximately $70 million in cash, cash equivalents, and marketable securities, which the company expects will support operations through 2028.
Reproxalap is a reactive aldehyde species (RASP) modulator designed to reduce inflammation by targeting aldehyde-mediated signaling pathways implicated in immune-mediated diseases. Beyond dry eye disease, Aldeyra is also evaluating the candidate for allergic conjunctivitis.
The company’s broader pipeline includes RASP modulators such as ADX-248 and ADX-246 for systemic and retinal immune-mediated disorders, as well as ADX-2191, a novel intravitreal formulation of methotrexate being investigated for primary vitreoretinal lymphoma and retinitis pigmentosa.
References
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, 17 March 2026, https://ir.aldeyra.com/news-releases/news-release-details/aldeyra-therapeutics-receives-complete-response-letter-us-food-1
The TRANQUILITY Trial: Clinical Trial to Assess the Efficacy and Safety in Subjects With Dry Eye Disease, ClinicalTrials.gov ID NCT04674358, https://clinicaltrials.gov/study/NCT04674358