January 23, 2024
Dr. Ben Gaddie wrote back in April about the anticipated FDA approval for Aldeyra’s Reproxalap. The PDUFA date was November 23, 2023, upon which Aldeyra would learn of the final review for Reproxalap. The company received a Complete Response Letter from the FDA on November 27, 2023, indicating that an additional trial is required to demonstrate a positive effect on the treatment of ocular symptoms associated with dry eye disease.
Reproxalap is a new first-in-class small molecule modulator of reactive aldehyde species (RASP) inhibitor. RASP molecules modulate inflammation at the top of the cascade and serve as gatekeepers of inflammation. RASP are pro-inflammatory molecules that covalently bind to thiol and amino groups expressed on various receptors and kinases. This binding activates the pro-inflammatory signaling cascade, which involves the activation of inflammatory cytokines leading to inflammation and pro-histaminic factors leading to an allergic response.1 Patients with dry eye disease have been found to have elevated RASP levels. The FDA officially named RASP as an objective sign of dry eye disease in June 2020.2 RASP inhibitors are believed to block several pro-inflammatory substrates, which in turn block cytokine release. This blockage of inflammation reduces pro-inflammatory cytokine and histamine levels.1
The Complete Response Letter did not indicate any safety or manufacturing issues with Reproxalap. The FDA stated that the NDA (new drug application) did not demonstrate “efficacy 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.
FDA dry eye disease guidance requires efficacy in dry eye disease, which may be demonstrated with two symptom trials and two sign trials. Among other clinical trials, Aldeyra previously conducted two trials for ocular redness (a dry eye disease sign) as well as a dry eye disease symptom trial. On November 16, 2023, Aldeyra submitted to the FDA a Special Protocol Assessment (SPA) for a dry eye disease chamber crossover clinical trial like the crossover chamber trial from which Aldeyra announced results on July 12, 2022. The proposed trial is expected to cost less than $2 million, and top-line results are anticipated in the first half of 2024, subject to FDA feedback on the SPA.
1 Labib BA, Chigbu DI. Therapeutic targets in allergic conjunctivitis. Pharmaceuticals (Basel). 2022;15:547. DOI: 10.3390/ph15050547
2 Verlato G, Corsico A, Villani S, et al. Is the prevalence of adult asthma and allergic rhinitis still increasing? Results of an Italian study. J Allergy Clin Immunol. 2003;111:1232–38. DOI: 10.1067/mai.2003.1484