How did a field trial left out of the June 2025 resubmission end up in the FDA's review?

Aldeyra Therapeutics Form 8-K, filed June 13, 2024

A Phase 3 clinical trial of reproxalap at a different dry eye chamber, in addition to a traditional six-week field clinical trial, are being conducted in parallel as part of a comprehensive strategy designed to account for disease heterogeneity and potential differences in clinical sites and environment.

Aldeyra Therapeutics Form 8-K, filed May 6, 2025

Pending a Type A meeting with the FDA, NDA resubmission is anticipated mid-2025, and the review period is expected to be six months. A recently completed dry eye disease field trial, which was numerically supportive of reproxalap and consistent with prior field trials, did not reach statistical significance, and is expected to be submitted to the planned NDA resubmission as supportive.

Aldeyra Therapeutics Form 8-K, filed May 6, 2025

Following the CRL, Aldeyra requested and received feedback from the FDA on two ongoing clinical trials designed to assess the effect of reproxalap on the symptoms of dry eye disease: a dry eye chamber trial and a field trial. The dry eye chamber trial, which was substantially similar to the dry eye chamber trial previously submitted, achieved statistical significance in favor of reproxalap over vehicle (P=0.002). There were no notable differences in baseline scores observed across treatment arms. While reproxalap was numerically superior to that of vehicle in the field trial, the effect was not statistically significant.

Aldeyra Therapeutics Form 8-K, filed June 17, 2025

Per FDA agreement, the only new clinical data included in the resubmitted NDA were from the recently completed dry eye chamber trial, which achieved the primary endpoint.

Aldeyra Therapeutics Form 8-K, filed July 17, 2025

Based on the FDA’s requirement for an additional clinical trial demonstrating the efficacy of reproxalap in treating the symptoms of dry eye disease, and per agreement with the FDA, the NDA resubmission contained a single clinical trial that achieved the primary endpoint of reducing ocular discomfort relative to the vehicle control

Aldeyra Therapeutics Form 8-K, filed December 16, 2025

On December 12, 2025, the FDA met with Aldeyra to request submission to the NDA of the Clinical Study Report (CSR) for the dry eye disease field trial of reproxalap, for which top-line results were announced on May 5, 2025. The field trial, which was supportive of the activity of reproxalap relative to vehicle, did not meet the primary endpoint of improvement in dry eye symptoms relative to the vehicle control.

Aldeyra Therapeutics Form 8-K, filed December 16, 2025

Prior to submitting the NDA in June, the field trial was discussed with the FDA. At the December 12 meeting, the FDA made no other requests and did not identify any other specific issues with the NDA review.

Aldeyra Therapeutics Form 8-K, filed December 16, 2025

The extended PDUFA target action date is March 16, 2026.

Aldeyra Therapeutics Form 8-K, filed December 16, 2025

The CSR, which had been previously submitted to the Investigational New Drug (IND) file for reproxalap, was submitted to the NDA the same day of the meeting and was considered a major amendment to the NDA by the FDA. Per the FDA’s earlier request during the NDA review, the safety data from the field trial was submitted to the NDA on August 21, 2025. The CSR has been reviewed by the FDA under the IND.

Aldeyra Therapeutics Form 10-K, filed February 27, 2026

In early December 2025, a draft label was received from the FDA. On December 15, 2025, the day before the target action PDUFA date for the second NDA resubmission, we announced that the FDA requested that the field trial be submitted to the NDA, triggering a three-month extension of the PDUFA target action date to March 16, 2026.

Aldeyra Therapeutics Form 10-K, filed February 27, 2026

Subsequent to the SPA Type A meeting, two chamber trials were initiated, in addition to one field trial, in which patients administered reproxalap or vehicle (placebo) over six weeks and reported ocular discomfort weekly.

Aldeyra Therapeutics Form 10-K, filed February 27, 2026

During a meeting with the FDA, we informed the FDA of the results of the second chamber and field trials and subsequently received written confirmation from the FDA that, for NDA resubmission, only the second chamber trial need be included in the NDA.

Aldeyra Therapeutics Form 8-K, filed March 17, 2026

The CRL stated that there is “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 that “the application has failed to demonstrate efficacy in adequate and well controlled studies in the treatment of signs and symptoms of dry eye disease.” The letter also 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.”

Aldeyra Therapeutics Form 8-K, filed September 29, 2026

Trials 012, 013, and 031 were field trials; other trials were single-day exposures (Day 1, Schirmer Test) followed by a dry eye chamber (Day 2, redness and symptoms).

Aldeyra Therapeutics Form 8-K, filed September 29, 2026

TRIAL PRIMARY ENDPOINT(S) P<0.05 FDA POSITION ALDEYRA POSITION 012 Symptoms Staining ✓ Co-primary not met Supportive for symptoms 013 Symptoms ✓ Endpoint met Endpoint met 019 Redness Endpoint not met Supportive for Schirmer Test (secondary P<0.0001), Schirmer Response (post-hoc P<0.0001) 023 Schirmer Test Schirmer Response ✓ ✓ Methodological issues Endpoints met, methodological sensitivity testing supportive of outcome 024 Redness Symptoms Schirmer Test ✓ Redness endpoint met Redness endpoint met; Symptoms and Schirmer Test numerically supportive 027 Redness Schirmer Test ✓ ✓ Redness met, Schirmer Test methodological issues Both endpoints met, methodological sensitivity testing supportive of outcome for Schirmer Test 030 Symptoms ✓ Methodological issues Endpoint met, methodological sensitivity testing supportive of outcome 031 Symptoms Not statistically significant Results numerically favored reproxalap 032 Symptoms ✓ Endpoint met Endpoint met