On June 26, 2025 Aldeyra Therapeutics, Inc. (Nasdaq: ALDX) (Aldeyra) reported receipt of a Special Protocol Assessment Agreement Letter from the U.S. Food and Drug Administration (FDA) for ADX-2191 (methotrexate injection, USP), an investigational drug candidate, for the treatment of primary vitreoretinal lymphoma (PVRL), a rare and potentially fatal cancer currently lacking FDA-approved therapy (Press release, Aldeyra Therapeutics, JUN 26, 2025, View Source [SID1234654131]).

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"Primary vitreoretinal lymphoma is treated today off label with intravitreal injections of compounded methotrexate," stated Todd C. Brady, M.D., Ph.D., President and Chief Executive Officer of Aldeyra. "ADX-2191, a novel, vitreous-compatible formulation of methotrexate that is specifically designed for intraocular injection, potentially allows for a reduced injection volume relative to compounding."

Based on a pre-New Drug Application (NDA) meeting with the FDA in December 2022, Aldeyra submitted a literature-based NDA of ADX-2191 for the treatment of PVRL, which was accepted for Priority Review in March 2023. In June 2023, Aldeyra received a Complete Response Letter that stated that the available literature was not sufficient to demonstrate efficacy and that adequate and well-controlled trials were required for approval. The FDA subsequently agreed that a single clinical trial in addition to literature references will be sufficient to support NDA resubmission.

The clinical trial proposed in the Special Protocol Assessment will compare cancer cell clearance after 30 days of therapy in up to 20 patients following 1:1 randomization to receive either a single intraocular injection or eight intraocular injections of ADX-2191. The frequency of methotrexate injections has been linked to cancer cell clearance in patients with PVRL,[1] and approximately five injections are required on average to achieve cancer cell clearance.[2] The clinical trial is expected to begin in the second half of 2025 and conclude in 2026.

About ADX-2191

ADX-2191 (methotrexate injection, USP) is a sterile, non-compounded intravitreal formulation of methotrexate for the potential treatment of specific rare retinal diseases, including primary vitreoretinal lymphoma and retinitis pigmentosa. The ADX-2191 intravitreal formulation is preservative-free, is designed to be vitreous-compatible, and is optimized for excipient composition, viscosity, density, tonicity, pH, concentration, and volume of administration. ADX-2191 has received FDA Orphan Drug Designation for the treatment of primary vitreoretinal lymphoma and retinitis pigmentosa.

About Primary Vitreoretinal Lymphoma

Primary vitreoretinal lymphoma is a rare, aggressive, and potentially fatal retinal cancer that is diagnosed in approximately 300 to 600 patients in the United States per year. The median survival for newly diagnosed patients is less than five years. No approved treatments are currently available, though intravitreal injection of compounded methotrexate represents the current standard of care.