FDA Issues Second Complete Response Letter for Reproxalap

The FDA has issued a complete response letter to Aldeyra Therapeutics for its investigational drug candidate, reproxlap, which could treat dry eye disease (DED).¹ The decision comes a year after Aldeyra Therapeutics received a complete response letter for a previous submission, with more evidence submitted to try to bolster the second application.²

The FDA stated that the reason for the rejection was 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.”¹ The FDA also stated that the study results were inconsistent and the reliability of the results was under question.

Reproxalap is a drug candidate being developed for use in patients with allergic conjunctivitis and DED. The treatment is a small-molecule modulator of reactive aldehyde species, which can be elevated in inflammatory diseases that affect the eye. Aldeyra stated that reproxalap had been studied in more than 2900 patients, with only mild and transient instillation site irritation being the most commonly reported adverse event.³

The new drug application was based on a phase 3 trial (NCT05424549) of the efficacy of 0.25% reproxalap ophthalmic solution when used by patients after they entered a dry eye chamber for 90 minutes.⁴ Patients were treated 4 times for 1 day and then treated with 1 dose before and after going into the dry eye chamber. There were 63 patients split into reproxalap and vehicle groups in the double-masked trial. Ocular redness during the chamber and results of the Schirmer test 10 minutes after the fourth dose on the prechamber day acted as the primary end points of the trial.

Reproxalap was found to significantly reduce ocular redness in patients as well as increase the Schirmer score, which evaluates whether the patient’s eyes are producing enough tears. Although patients had an increase in redness overall when using reproxalap in the dry eye chamber, the redness score remained lower in those using reproxalap throughout the trial vs those using the vehicle. The clinical relevance scores for symptoms, redness, and the Schirmer test were statistically significant for reproxalap over the vehicle, with an indication that 70% of patients were responders in favor of reproxalap.

Aldeyra Therapeutics resubmitted its new drug application after the first complete response letter, with the FDA accepting the new review on July 17, 2025.³

Aldeyra Therapeutics reaffirmed its commitment to getting the therapy on the market after the complete response letter came through.¹

“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…,” said Todd C. Brady, MD, PhD, president and CEO of Aldeyra.

References

1. Aldeyra Therapeutics receives complete response letter from the U.S. Food and Drug Administration for the reproxalap new drug application for the treatment of signs and symptoms of dry eye disease. News release. Aldeyra Therapeutics. March 17, 2026. Accessed March 17, 2026. https://ir.aldeyra.com/news-releases/news-release-details/aldeyra-therapeutics-receives-complete-response-letter-us-food-1
2. Bonavitacola J. Reproxalap receives complete response letter from FDA for use in dry eye disease. AJMC^®. April 3, 2025. Accessed March 10, 2026. https://www.ajmc.com/view/reproxalap-receives-crl-from-fda-for-use-in-dry-eye-disease
3. Aldeyra Therapeutics announces FDA acceptance for review of reproxalap new drug application for the treatment of dry eye disease. News release. Aldeyra. July 17, 2025. Accessed March 10, 2026. https://ir.aldeyra.com/news-releases/news-release-details/aldeyra-therapeutics-announces-fda-acceptance-review-0
4. Garg S, Donnenfeld E, Sheppard J, Epitropoulos A, Brade TC. Reproxalap improves ocular redness, tear production, and symptoms in a pivotal dry eye disease chamber trial. Ophthalmol Sci. 2026;6(1):100938. doi:10.1016/j.xops.2025.100938