ADX-2191 will not be granted approval by the FDA due to the results of the phase 3 GUARD trial.
The FDA issued a complete response letter regarding the new drug application (NDA) of ADX-2191 (methotrexate for injection, USP), for the treatment of primary vitreoretinal lymphoma (PVRL).1
Despite no safety or manufacturing issues with ADX-2191 being identified, the FDA denied the NDA based on the “lack of substantial evidence of effectiveness” due to insufficient and a lack of well-controlled investigations derived from the literature-based NDA submission. Aligning with prior discussions with the FDA, no trials of ADX-2191 in PVRL were conducted by Aldeyra.
“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,” said Todd C. Brady, MD, PhD, president and chief executive officer of Aldeyra Therapeutics, in a press 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.”
ADX-2191 is a sterile, non-compounded intravitreal formulation of methotrexate being examined for the potential prevention and treatment of specific rare retinal diseases, including primary vitreoretinal lymphoma, proliferative vitreoretinopathy, and retinitis pigmentosa.2 ADX-2191 is preservative-free is designed as a vitreous-compatible that is optimized for excipient composition, viscosity, density, tonicity, pH, concentration, and volume of administration.
The previous submission of the NDA was supported by a combination of over 3 decades of published literature on the safety and efficacy of methotrexate, which is the active ingredient of ADX‑2191.2 Research looked at the intravitreal formulation for the treatment of primary vitreoretinal lymphoma. Additionally, safety data from the recently completed phase 3 GUARD Trial (NCT04136366) which evaluated ADX-2191 in patients with proliferative vitreoretinopathy supported the NDA.
In the GUARD Trial, no safety signals were observed, and ADX-2191 was well tolerated with no observed treatment-emergent serious adverse events (AE). Punctate keratitis, a frequently observed AE of intravitreal methotrexate, was the most common AE associated with ADX‑2191, and it was most commonly mild in severity.
ADX-2191 is also being developed for the treatment of patients with proliferative vitreoretinopathy and retinitis pigmentosa, and top-line results from a phase 2 clinical trial of ADX-2191 in retinitis pigmentosa (NCT05392179) are expected to be announced in June of 2023.
A Type C meeting is also anticipated to be conducted with the FDA in the second half of 2023 to discuss the completion of clinical development of ADX-2191 for the prevention of proliferative vitreoretinopathy.