The U.S. Food and Drug Administration (FDA) has issued a third rejection of Aldeyra Therapeutics’ experimental dry eye disease treatment, reproxalap, following a delayed review process. The decision was communicated through a complete response letter (CRL) that cited insufficient evidence of effectiveness.
According to a statement from the company, the FDA identified “a lack of substantial evidence consisting of adequate and well-controlled investigations” and concluded that the application failed to demonstrate efficacy. The agency also pointed to inconsistencies across clinical trial outcomes, raising concerns about the reliability and significance of positive findings.
Reproxalap, a reactive aldehyde species (RASP) modulator, has faced multiple regulatory setbacks. The FDA previously declined approval in November 2023 and again in April 2025, both times citing inadequate evidence supporting its effectiveness in treating dry eye symptoms. During the April 2025 review, the agency requested an additional trial to further assess the drug’s clinical benefit.
Subsequent studies produced mixed results. In one Phase 3 trial conducted in a controlled chamber designed to induce dry eye symptoms, reproxalap met its primary endpoint by significantly reducing ocular discomfort compared with placebo. However, a separate late-stage field trial failed to achieve its primary endpoint, although the company described the results as numerically supportive and consistent with earlier studies.
The FDA noted that these inconsistent outcomes contributed to its decision, stating that the overall body of evidence does not support the drug’s effectiveness under the proposed conditions of use. The agency also concluded that there is insufficient proof that reproxalap performs as described in its labeling.
Despite these concerns, the FDA did not request additional trials or new data submissions. Instead, it recommended that Aldeyra further investigate the reasons behind the unsuccessful trials and identify patient populations or conditions where the treatment may be effective.
Aldeyra stated that it plans to request a Type A meeting with the FDA to clarify the steps required for potential approval. These meetings are typically scheduled within 30 days of a request and are intended to address regulatory issues or disagreements.
The regulatory process for reproxalap has included multiple developments over the past year. The FDA had initially set a decision date of December 16, 2025, which was later extended to March 16, 2026, after the agency requested additional information. This included a report from a previously excluded trial, as noted by CEO Todd Brady during a December conference call.
The company also indicated that draft labeling documents were provided by the FDA in December and again more recently, although Aldeyra stated that label discussions were not finalized.
In response to the latest decision, CEO Todd Brady said, “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.”
Following the announcement, Aldeyra’s stock declined significantly, falling by nearly 70% from $4.23 per share to approximately $1.37 in early trading. As of December 31, the company reported $70 million in cash, cash equivalents, and marketable securities, which it expects will fund operations through 2028.
Reproxalap remains the most advanced candidate in Aldeyra’s pipeline of investigational RASP modulators. The company also continues to study the drug in allergic conjunctivitis and maintains an agreement with AbbVie, which includes a potential $100 million milestone payment contingent on FDA approval.
Background on Aldeyra’s Reproxalap
Aldeyra’s reproxalap is a late-stage investigational therapy designed to treat dry eye disease, a condition affecting millions globally. Despite multiple clinical trials and resubmissions, Aldeyra’s drug has struggled to meet FDA requirements, particularly around demonstrating consistent clinical efficacy.
Details of the Third FDA Rejection
The FDA issued a Complete Response Letter (CRL), stating that Aldeyra’s data did not sufficiently prove the drug’s effectiveness in treating dry eye symptoms. Importantly, the agency did not raise concerns about safety or manufacturing, focusing primarily on efficacy issues.
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