FDA Issues Complete Response Letter to NDA for ADX-2191 in Primary Vitreoretinal Lymphoma

The FDA has issued a complete response letter (CRL) to the new drug application (NDA) seeking the approval of ADX-2191 (methotrexate for injection) for the treatment of patients with primary vitreoretinal lymphoma (PVRL), according to an announcement from Aldeyra Therapeutics.¹

The company said that the CRL cited a “lack of substantial evidence of effectiveness” due to “a lack of adequate and well-controlled investigations.” The announcement said that no clinical trials for ADX-2191 were conducted in patients with PVRL, based on prior discussions with the FDA. No safety or manufacturing issues were identified in the CRL.

“While we appreciate the FDA’s position with respect to providing evidence from adequate and controlled trials, we do not currently believe that randomized clinical trials of ADX-2191 in PVRL, a rare and fatal cancer with no approved therapy, are feasible,” Todd C. Brady, MD, PhD, president and chief executive officer of Aldeyra Therapeutics, stated in a news release. “Given the current shortage of methotrexate, the lack of approved therapy for PVRL, and the desire to avoid potential safety risks associated with ocular injection of compounded formulations, we look forward to discussing with the FDA the potential for making ADX-2191 available to PVRL patients under an Expanded Access Program.”

The company expects to further discuss ADX-2191 with the regulatory agency as a treatment option for patients with PVRL, including the potential to make the agent available to patients with PVRL under the Expanded Access Program. Methotrexate for injection is currently listed in shortage by the FDA due to an increase in demand for the agent, according to multiple manufacturers.²

PVRL is a rare, aggressive form of primary central nervous system (CNS) lymphoma that arises in the intraocular compartment without brain involvement. The malignancy could cause permanent vision loss and CNS relapse, which is attributed as a major cause of death within this patient population.³

Methotrexate or rituximab (Rituxan) as intravitreal injections, or local radiotherapy, are considered effective treatment options for clearing tumor cells in the eyes; however, these treatments do not prevent CNS relapse. Systemic treatment with high-dose methotrexate, with or without local treatment, could reduce the risk of CNS relapse.

Additionally, ADX-2191 is currently under evaluation as a potential therapeutic option for patients with proliferative vitreoretinopathy or retinitis pigmentosa—2 rare, sight-threatening retinal diseases. In June 2023, topline data from a phase 2 trial (NCT05392179) in retinitis pigmentosa are expected to read out.

Aldeyra plans to hold a Type C meeting with the FDA in the second half of 2023 to further discuss the clinical development of ADX-2191 for the prevention of proliferative vitreoretinopathy.¹

References

1. Aldeyra Therapeutics provides regulatory update on ADX-2191. News release. Aldeyra Therapeutics. June 21, 2023. Accessed June 22, 2023. https://ir.aldeyra.com/news-releases/news-release-details/aldeyra-therapeutics-provides-regulatory-update-adx-2191
2. Current and resolved drug shortages and discontinuations reported to FDA. FDA. Accessed June 22, 2023. https://www.accessdata.fda.gov/scripts/drugshortages/
3. Soussain C, Malaise D, Cassoux N. Primary vitreoretinal lymphoma: a diagnostic and management challenge. Blood. 2021;138(17):1519-1534. doi:10.1182/blood.2020008235