What did the FDA's 2025 letter say about Study 030, and how did Aldeyra describe it?

FDA Complete Response Letter, April 2, 2025 · page 2

Study 030 was similar in design to Study 024 from the original submission. When Study 030 is analyzed in a similar method to Study 024 from the initial submission (Visit 4 DEC score at each timepoint as the dependent variable), the study does not achieve statistical significance.

FDA Complete Response Letter, April 2, 2025 · page 2

You used Visit 2 and Visit 4 DEC results as the dependent variable and performed linear contrasts to obtain treatment differences between Visit 4 and Visit 2 results. The Agency finds the Study 030 primary efficacy endpoint analysis problematic, and we do not find the study results to be robust.

FDA Complete Response Letter, April 2, 2025 · page 2

It is not clear that the models proposed by you adequately account for the difference in baseline.

FDA Complete Response Letter, April 2, 2025 · page 2

The difference in the Visit 4 baseline of greater than 7 between raises concerns of whether these reflect similar populations. Ideally, baseline scores between groups should be similar.

Aldeyra Therapeutics Form 8-K, filed April 3, 2025

Although no manufacturing or safety issues with reproxalap were identified, the FDA stated in the letter that the NDA “failed to demonstrate efficacy in adequate and well controlled studies in treating ocular symptoms associated with dry eyes” and that “at least one additional adequate and well controlled study to demonstrate a positive effect on the treatment of ocular symptoms of dry eye” should be conducted. The letter identified concerns with the data from the trial submitted to the NDA that may have affected interpretation of the results, which the FDA stated may be related to methodological issues, including a difference in baseline scores across treatment arms.

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

Aldeyra believes that the dry eye chamber trial results, which included no notable differences in baseline scores across treatment arms, potentially address the U.S. Food and Drug Administration (FDA) feedback in a Complete Response Letter received in April 2025 in response to the prior New Drug Application (NDA). The Complete Response Letter identified concerns with a previously completed dry eye chamber trial that may have affected the interpretation of the results, including a baseline difference across treatment arms.

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

On April 3 2025, based primarily on a baseline imbalance in symptom scores across treatment arms and other statistical comments, Aldeyra announced that the FDA issued a CRL regarding the NDA resubmission, stating that the NDA did not demonstrate “efficacy in adequate and well controlled studies in treating ocular symptoms associated with dry eyes” and that “at least one additional adequate and well-controlled study to demonstrate a positive effect on the treatment of ocular symptoms of dry eye” should be conducted.

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

In July 2025, the FDA announced a policy shift toward public disclosure of complete response letters issued for drugs that had not been approved. Additionally, in September 2025, the FDA announced that it will release future complete response letters promptly after they are issued to sponsors and the agency released a number of unpublished complete response letters issued associated with pending or withdrawn applications, including the reproxalap Complete Response Letter.

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

The table presents the primary endpoints from all proposed commercial dosing regimen efficacy trials of reproxalap that were submitted to the dry eye disease NDA. FDA position is Aldeyra’s abbreviated interpretation of FDA review. Trials=ADX-102-DED-xxx where xxx is the trial number, Symptoms=patient-reported dryness (Trials 012 and 013) or discomfort (Trials 030, 031,and 032), Staining=nasal region fluorescein staining, Redness=investigator-assessed ocular redness, Schirmer Test=tear production score, Schirmer Response=≥10 mm response, FDA=US Food and Drug Administration, NDA=New Drug Application for reproxalap for the treatment of the signs and symptoms dry eye disease Five of the nine efficacy trials submitted in the NDA achieved all primary endpoints, and the P values for 9 of 14 endpoints were less than 0.05.

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