Did Aldeyra's second chamber trial answer the FDA's 2025 objections?

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

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 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 8-K, filed May 6, 2025

For the prespecified primary endpoint of ocular discomfort, a symptom of dry eye disease, reproxalap (n=58) was statistically significantly superior to vehicle (n=58) on ocular discomfort symptom score (0-100) from 80 to 100 minutes after chamber entry (LS mean difference [95% confidence interval] -6.5 [-10.5, -2.5], P=0.002).

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

Consistent with a number of clinical trials that suggest the potential of reproxalap to rapidly improve the symptoms of dry eye disease, we believe the clinical trial results included in the resubmission announced today are robust,” stated Todd C. Brady, M.D., Ph.D., President and Chief Executive Officer of Aldeyra. “Based on the lack of notable baseline differences across treatment arms and the highly statistically significant achievement of the prespecified primary endpoint in favor of reproxalap over vehicle, in conjunction with recent FDA discussions, we believe that previous concerns raised by the FDA have been addressed.”

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

Trial Design Endpoint Reproxalap Improvement vs. Vehicle (%) 012 Field Symptoms 204% 012 Field Staining 21% 013 Field Symptoms 62% 019 Chamber Redness 0% 023 Chamber Schirmer Test 417% 023 Chamber Schirmer Response 113% 024 Chamber Redness 63% 024 Chamber Symptoms 11% 024 Chamber Schirmer Test 37% 027 Chamber Redness 34% 027 Chamber Schirmer Test 93% 030 Chamber Symptoms 66% 031 Field Symptoms 34% 032 Chamber Symptoms 102

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