FDA Gives Reproxalap the Red Light For Dry Eye Disease

The US Food and Drug Administration has sent a second detailed reaction letter to Aldeyra Therapeutics about its new drug application (NDA) for reproxalap. A pioneering small-molecule modulator of reactive aldehyde species (RASP), the medication is now undergoing evaluation for the treatment of dry eye disease.

The FDA endorsed Aldeyra’s updated NDA in November 2024, after the issuance of a comprehensive response letter requiring more evidence to substantiate effectiveness, particularly concerning ocular symptoms. This time around, the FDA said that the amended NDA did not prove effectiveness and requested at least one more controlled research, as reported by Aldeyra. The company’s press statement dated April 3 said that no production or safety concerns were detected.

Dry eye disease (DED), a prevalent cause for seeking ophthalmic treatment, is a complicated, multifactorial illness marked by tear film instability and persistent ocular surface irritation.

The primary objective of managing dry eye disease is to restore tear film equilibrium, which involves disrupting the cycle of inflammation. Although artificial tears are the cornerstone of treatment and provide symptomatic relief for DED, they fail to target the underlying disease processes. Current immunomodulators, such as cyclosporine and lifitegrast, often exhibit delayed onset and restricted tolerability, resulting in insufficient management of many patients’ DED.

Reproxalap targets RASP, namely malondialdehyde (MDA), which serve as upstream catalysts of inflammation by chemically altering cellular receptors and kinases.

The NDA for Reproxalap was substantiated by data from several studies, including the first Phase 3 TRANQUILITY study and the subsequent Dry Eye Chamber research after the initial NDA rejection. Collectively, these assessments examined both the immediate and long-term effectiveness of the medication in relieving ocular inflammation and patient-reported complaints.

The TRANQUILITY trial was a randomized, double-blind, vehicle-controlled Phase 2b/3 research study that included individuals with moderate to severe DED. Patients were subjected to a clinical setting intended to intensify dry eye symptoms and received either reproxalap 0.25% ophthalmic solution or a placebo.

The results indicated statistically significant reductions in ocular redness within hours after delivery, along with positive trends in ocular pain and tear stability. Nonetheless, while the sign goals were achieved, the FDA said that the symptom data were inadequate to warrant approval.

The agency demanded an extra carefully controlled experiment that specifically demonstrated effectiveness for ocular symptoms, resulting in the Dry Eye Chamber experiment. This Phase 3 experiment was developed in accordance with FDA instructions to directly evaluate symptom management during acute dry eye stress.

In both studies, including over 2,500 participants, reproxalap displayed a reliable safety profile. The predominant adverse event was moderate, temporary pain at the instillation site, with no discontinuations linked to therapy. No systemic safety concerns or novel signals were detected, confirming the drug’s appropriateness for long-term usage.

Aldeyra intends to disclose top-line findings from its current field study and chamber investigation in the second quarter of the year The firm announced its intention to resubmit its NDA soon this year.