In a complete response letter, the FDA did not approve Aldeyra Therapeutics' new drug application (NDA) for dry eye disease candidate reproxalap. 

According to the company, no safety or manufacturing issues with reproxalap were identified. However, the FDA letter stated that the NDA 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.

Reproxalap is a small-molecule modulator of reactive aldehyde species—RASP, which are elevated in ocular and systemic inflammatory disease.

The company advised that the FDA draft guidance on dry eye disease states that efficacy in dry eye disease may be demonstrated with two symptom trials and two sign trials. Among other clinical trials, Aldeyra noted it 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 (the proposed trial) similar to the crossover chamber trial from which Aldeyra announced results on July 12, 2022. The SPA review cycle is anticipated to be 45 days, and Aldeyra expects FDA feedback from the SPA in December of 2023.

The company stated that the proposed trial is expected to cost less than $2 million, and topline results are anticipated in the first half of 2024, subject to FDA feedback on the SPA. The potential NDA resubmission is anticipated in the first half of 2024, pending FDA SPA feedback and positive results from the proposed trial.

In the potential NDA resubmission, Aldeyra intends to include a draft label describing chronic and acute symptomatic benefit, in addition to acute reduction in ocular redness of reproxalap. The review period for the potential NDA resubmission is expected to be 6 months.

“With $143 million in cash, cash equivalents, and marketable securities as of September 30, 2023, we are well positioned to conduct another symptom trial of reproxalap in patients with dry eye disease, with a potential NDA resubmission in the first half of 2024,” Aldeyra’s President and Chief Executive Officer Todd C. Brady, MD, said in a company news release. “If the SPA and proposed trial results are successful, and the potential resubmitted NDA is approved, the drug label may be the first label in dry eye disease to contain acute reduction in ocular redness, as well as a combination of chronic and acute symptomatic benefit, potentially highlighting the rapid activity of reproxalap on both signs and symptoms of dry eye disease.”

Reproxalap is also under development for the treatment of allergic conjunctivitis. Results from INVIGORATE-2, the third phase 3 clinical trial of reproxalap in allergic conjunctivitis, were announced on June 15, 2023. Aldeyra plans to conduct a Type C meeting with the FDA in the first half of 2024 to discuss the potential NDA submission of reproxalap for the treatment of allergic conjunctivitis.