Just over three months after Aldeyra Therapeutics’ new drug application (NDA) submission of ADX-2191 (intravitreal methotrexate 0.8%) for primary vitreoretinal lymphoma (PVRL) received priority review, the FDA has determined more clinical data evidence is needed.
Talk about ADX-2191.
ADX-2191 is a preservative-free intravitreal formulation of methotrexate that is being assessed for the potential prevention or treatment of specific rare retinal diseases such as PVRL, proliferative vitreoretinopathy (PVR), and retinitis pigmentosa (RP).
The therapeutic is the first sterile, non-compounded formulation of methotrexate designed for intravitreal administration for specific rare retinal diseases.
How has it performed in clinical trials?
The phase 3 GUARD trial compared ADX-2191 to standard-of-care for PVR patients over a 6-month period, during which the formulation was well-tolerated with no safety signals or serious adverse events reported.
That’s good, right?
Yes . . . however, ADX-2191 has not undergone clinical trials for PVRL, the disease that Aldeyra’s NDA submission targeted.
Give me a timeline of its FDA interactions.
- September 2019 → ADX-2191 Fast Track designation
- August 2021 → ADX-2191 Orphan Drug designation
- December 2022 → ADX-2191 NDA submission
- March 2023 → ADX-2191 NDA priority review acceptance
So what’s this FDA update about?
According to Aldeyra, the FDA determined that, although there were no safety or manufacturing issues with ADX-2191, there was a “‘lack of substantial evidence of effectiveness’ due to ‘a lack of adequate and well-controlled investigations’ in the literature-based NDA submission.”
Why wasn’t ADX-2191 studied for PVRL?
Per the company, no clinical trials were conducted based on prior discussions with the FDA.
How has the company responded?
Aldeyra’s President and CEO Todd C. Brady, MD, PhD, stated that randomized clinical trials of ADX-2191 in PVRL are not feasible.
Why not?
According to the FDA Drug Shortages database, there is currently a shortage of methotrexate, the compound formulated in ADX-2191.
“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 [EAP],” stated Brady.
Talk about this Expanded Access Program.
This type of program, also referred to as “compassionate use”, would enable access to treatment options for serious or immediately life-threatening diseases, such as PVRL, when other therapeutic treatments are unavailable.
How is this different from a clinical trial?
A clinical trial is conducted by a pharmaceutical company looking to have its drug approved and licensed for use, which means it has to prove to the FDA that it is safe for use and as good as, if not better than, current medications on the market.
With an EAP, a company is still able to gather safety and efficacy data from enrolled patients; however, its only purpose is to provide medication where there is an unmet need.
Gotcha. What’s next for Aldeyra?
The company expects to report topline data from its phase 2 data on ADX-2191 for RP later this month.
It is also planning a Type C meeting with the FDA in Q3 or Q4 2023 to go over clinical development completion plans for ADX-2191 for PVR.