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FDA Issues Complete Response Letter to Manufacturer of Reproxalap, Treatment for Dry Eye Disease, Allergic Conjunctivitis
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Key Takeaways
- The FDA's complete response letter highlighted reproxalap's failure to demonstrate efficacy in treating dry eye symptoms in controlled studies.
- Reproxalap, a first-in-class RASP modulator, showed no significant safety concerns in over 2500 patients, with mild instillation site irritation as the most common adverse event.
No manufacturing or safety issues were identified, but the FDA stated the new drug application did not demonstrate efficacy in adequate and well-controlled studies.
The FDA issued a complete response letter (CRL) to Aldeyra Therapeutics, the manufacturer of reproxalap, an investigational new drug candidate for the treatment of dry eye disease and allergic conjunctivitis. In the letter, the FDA noted that the new drug application (NDA) for reproxalap “failed to demonstrate efficacy in adequate and well-controlled studies in treating ocular symptoms associated with dry eyes.”1
Image credit: Evgeniya Primavera | stock.adobe.com
Reproxalap, which received an NDA in November 2024 and a prescription drug user fee act date of April 2, 2025, is a first-in-class small-molecule modulator of reactive aldehyde species (RASP), which are elevated in ocular and systemic inflammatory diseases. It has been studied in more than 2500 patients with no observed safety concerns, with the most common adverse event (AE) reported being mild and transient instillation site irritation. The mechanism of action of reproxalap was previously supported by the demonstration of statistically significant and clinically relevant activity in multiple physiologically distinct late-phase clinical indications, according to the manufacturer.1,2 In the CRL, the FDA requested that reproxalap must show a positive effect on the treatment of dry eye symptoms in at least 1 adequate and well-controlled study.1
To initially be considered for regulatory approval in the US, the manufacturer conducted 2 symptom trials and 2 sign trials to evaluate the efficacy of reproxalap in patients with dry eye disease. Additionally, 2 trials for ocular redness (a dry eye disease sign) in a dry eye chamber, and 2 dry eye disease symptom field (environmental exposure) trials were conducted, which were submitted as part of an initial NDA in November 2022. In November 2023, the FDA issued a CRL to the initial NDA stating that at least 1 additional symptom trial was required.1
Following this, the manufacturer initiated 3 clinical trials assessing dry eye disease symptoms: a dry eye chamber trial, a clinical trial in a different dry eye chamber, and a 6-week field trial. In August 2024, Aldeyra announced the achievement of the primary end point in the first dry eye chamber clinical trial of reproxalap.1,3
In this randomized, double-masked, vehicle-controlled phase 3 dry eye chamber trial, 132 patients were randomly assigned to receive either reproxalap (n = 66) or vehicle treatment (n = 66) before and during exposure to an additional dry eye chamber. In the trial, reproxalap demonstrated statistical superiority compared with the vehicle (P = .004) when improving ocular discomfort. The NDA that included results from this clinical trial was resubmitted in October 2024.1,2
“Pending positive results from the ongoing clinical trials and discussions with the FDA, we look forward to a potential NDA resubmission mid-year 2025,” Todd C. Brady, MD, PhD, president and CEO of Aldeyra Therapeutics, said in a news release. “Reproxalap remains the only late-stage topical ocular therapy suitable for chronic administration to have potentially demonstrated acute reduction in ocular redness, as well as reduction in ocular discomfort, highlighting rapid and broad activity for both the signs and symptoms of dry eye disease.”1
