After delaying its review, the FDA has rejected Aldeyra Therapeutics’ experimental dry eye disease treatment for the third time.
The agency’s complete response letter (CRL) cited “a lack of substantial evidence consisting of adequate and well-controlled investigations” and a failure “to demonstrate efficacy,” according to a March 17 release from the Massachusetts biotech.
Aldeyra’s candidate, a RASP modulator known as reproxalap, has already been rejected twice by the FDA, with the most recent rebuff occurring in April 2025. At the time, the agency said there wasn’t enough data demonstrating the small molecule’s ability to address the symptoms of dry eye disease and requested that Aldeyra conduct another trial.
In May, Aldeyra appeared to meet the mark, with reproxalap hitting the primary endpoint of a phase 3 trial by significantly improving eye discomfort compared with placebo. In that study, patients were tested in a chamber designed to induce symptoms.
At the same time, however, the biotech announced that a separate late-stage field trial had failed to meet its primary endpoint but was “numerically supportive of reproxalap and consistent with prior field trials.”
Now, the FDA has 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,” according to Aldeyra’s release.
The agency added that there isn’t enough evidence showing that reproxalap “has the effect it purports or is represented to have under the conditions of use prescribed, recommended or suggested in its proposed labeling.”
Moving forward, the FDA suggested that the biotech explore the reasoning behind the failure in certain trials and identify specific populations or conditions in which reproxalap may be effective.
Related
The agency didn’t recommend running any new trials or ask for additional data, according to Aldeyra. The biotech said it plans to “expeditiously” ask for a Type A meeting—a format designed to resolve disagreements or address deficiencies and understand what would be required to secure FDA approval. The meetings are supposed to be held within 30 days of when the agency receives the requests.
The biotech also said that the FDA had provided label drafts in both December and again this month as part of the review process. The company “does not believe that label negotiations were completed,” according to today’s release.
As of publication, the Department of Health and Human Services has not responded to Fierce’s request for comment about the claim.
Despite the FDA’s plan to publicly release CRLs promptly after they are issued to sponsoring companies, the Aldeyra letter is not yet included in the agency’s public database.
Related
Aldeyra was initially supposed to receive an FDA approval decision by Dec. 16, 2025, a date that was pushed back to March 16 of this year after the agency requested in December that new information be included in the application.
The FDA had asked Aldeyra to submit a report for the failed trial that the regulator had previously told the company not to include in reproxalap’s new drug application, Aldeyra CEO Todd Brady, M.D., Ph.D., said during a Dec. 16 conference call.
“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,” Brady said in a March 16 statement after the rejection.
Since market close yesterday, Aldeyra’s stock has plummeted nearly 70% from $4.23 per share to $1.37 as of 10:30 a.m. ET today.
Related
As of Dec. 31, Aldeyra had $70 million in cash, cash equivalents and marketable securities—a runway the company believes will stretch into 2028.
The biotech has a pipeline of investigational RASP modulators, with reproxalap being the most advanced clinical candidate. Big Pharma AbbVie has an exclusive option agreement for reproxalap, with Aldeyra in line to receive a $100 million milestone payment if the FDA approves the drug in dry eye disease. The biotech is also studying the program in allergic conjunctivitis.
