Aldeyra's reproxalap receives a third FDA rejection for dry eye disease as inconsistent trial results undermine efficacy case

The FDA on March 17, 2026 issued a third Complete Response Letter for reproxalap, Aldeyra Therapeutics' first-in-class RASP (reactive aldehyde species) inhibitor eye drop for dry eye disease. The agency cited a "lack of substantial evidence" of efficacy and stated that "inconsistency of study results raises serious concerns about the reliability and meaningfulness of the positive findings." As with both prior CRLs, no safety or manufacturing issues were identified.

The three-year regulatory saga began with a first CRL in November 2023, followed by a second in April 2025—both citing failure to demonstrate efficacy in treating dry eye symptoms. Between the second and third rejections, Aldeyra achieved the primary endpoint (p = 0.002) in a new Phase 3 dry eye chamber trial assessing ocular discomfort reduction, resubmitted the NDA in June 2025, and saw it accepted for review. However, in December 2025 the FDA requested the clinical study report from a separate field trial that had not met its primary endpoint, triggering a major amendment that extended the review to March 2026.

Reproxalap's mechanism differs fundamentally from existing dry eye treatments. While cyclosporine (Restasis) and lifitegrast (Xiidra) act downstream on immune cell activation, reproxalap targets reactive aldehyde species—pro-inflammatory molecules such as malondialdehyde and 4-hydroxynonenal that drive inflammation by activating NF-κB, scavenger receptors and inflammasomes. By acting at the top of the inflammatory cascade, the drug was expected to offer a broader anti-inflammatory effect with a rapid onset of action.

The TRANQUILITY clinical programme produced mixed results. The pivotal trial failed its primary endpoint of investigator-graded ocular redness but achieved statistical significance on the Schirmer test, a secondary endpoint measuring tear production. A subsequent chamber trial succeeded on its primary discomfort endpoint, but a parallel field trial did not. The FDA found this inconsistency insufficient to establish efficacy, noting that the totality of evidence across completed trials did not support effectiveness.

Dry eye disease affects an estimated 16 million diagnosed Americans, with the true prevalence thought to be significantly higher. The market for prescription dry eye therapies exceeded $5 billion globally in 2025, yet many patients remain dissatisfied with existing options due to slow onset, burning upon instillation or limited efficacy. A genuinely novel mechanism such as RASP inhibition would have represented a meaningful addition, but the clinical programme's inability to produce consistent results across trial settings has undermined the regulatory case.

The FDA did not recommend additional trials, instead suggesting the company explore why certain studies failed and identify patient populations where reproxalap may be effective.

Sources: Aldeyra Therapeutics; FDA; TRANQUILITY trial programme.