Aldeyra Gets FDA SPA Agreement for ADX-2191 in Eye Cancer Treatment
Aldeyra Therapeutics, Inc. announced it has received a Special Protocol Assessment (SPA) Agreement Letter from the U.S. Food and Drug Administration (FDA) for its investigational drug, ADX-2191 (methotrexate injection, USP). The SPA covers a proposed clinical trial design for the treatment of primary vitreoretinal lymphoma (PVRL), a rare and life-threatening eye cancer for which no FDA-approved therapies currently exist.
The SPA is a formal agreement from the FDA that the planned trial design, clinical endpoints, and statistical analyses are acceptable to support a potential New Drug Application (NDA) submission, should the trial data prove positive. This regulatory milestone provides Aldeyra with a clearer path forward in its development of ADX-2191.
Addressing a Critical Unmet Need in Eye Oncology
Primary vitreoretinal lymphoma is a rare form of intraocular cancer that affects the retina and vitreous. It is often misdiagnosed as uveitis and typically progresses to central nervous system involvement, making timely and effective treatment essential. Currently, the standard of care involves off-label use of compounded intravitreal methotrexate injections—an approach that lacks FDA approval and comes with formulation and consistency challenges.
“Primary vitreoretinal lymphoma is treated today off label with intravitreal injections of compounded methotrexate,” said Todd C. Brady, M.D., Ph.D., President and CEO 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.”
By providing a standardized, FDA-reviewed methotrexate formulation specifically optimized for use in the eye, ADX-2191 could offer patients and physicians a more predictable and potentially safer alternative to compounded therapies.
Path to NDA: From Literature-Based Submission to Clinical Validation
In December 2022, Aldeyra held a pre-NDA meeting with the FDA, which led to the submission of a literature-based NDA for ADX-2191 in the treatment of PVRL. The application was accepted for Priority Review in March 2023, signaling the FDA’s recognition of the critical unmet need in this patient population.
However, in June 2023, the FDA issued a Complete Response Letter (CRL), stating that the existing literature alone was insufficient to establish the drug’s efficacy. The agency requested that Aldeyra conduct an adequate and well-controlled clinical trial to supplement the data. Following additional discussions, the FDA agreed that a single trial, in combination with supporting literature, would be adequate for NDA resubmission.
Details of the Proposed Clinical Trial
Under the terms of the SPA, Aldeyra will initiate a randomized clinical trial designed to evaluate cancer cell clearance following treatment with ADX-2191. The study will enroll up to 20 patients diagnosed with PVRL and will randomize them 1:1 into two treatment groups:
- One group will receive a single intravitreal injection of ADX-2191.
- The second group will receive eight intravitreal injections over a 30-day period.
The primary endpoint of the trial is cancer cell clearance from the vitreous fluid after 30 days of treatment. According to published data, the number of methotrexate injections has been correlated with the rate of cancer cell clearance in PVRL patients. On average, five injections are typically needed to achieve effective clearance of malignant cells from the eye.
The clinical trial is expected to begin in the second half of 2025, with completion anticipated in 2026.
Looking Ahead: Hope for a Rare Cancer Community
With no FDA-approved therapies currently available for PVRL, the advancement of ADX-2191 represents a critical development for patients, caregivers, and clinicians managing this rare cancer. If successful, the upcoming trial could pave the way for the first approved treatment specifically designed for intraocular use in PVRL patients.
Dr. Brady emphasized Aldeyra’s commitment to bringing a safe and effective option to market:
“Our goal is to deliver a formulation of methotrexate that is both convenient and clinically validated, providing oncologists and ophthalmologists with a tool they can trust in the fight against this devastating disease.”
As Aldeyra moves forward with trial preparations, the FDA’s SPA agreement ensures alignment on the clinical requirements necessary to resubmit the NDA and, potentially, secure the first-ever FDA-approved treatment for primary vitreoretinal lymphoma.
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.
About Aldeyra
Aldeyra Therapeutics is a biotechnology company devoted to discovering innovative therapies designed to treat immune-mediated and metabolic diseases. Our approach is to develop pharmaceuticals that modulate protein systems, instead of directly inhibiting or activating single protein targets, with the goal of optimizing multiple pathways at once while minimizing toxicity. Our product candidates include RASP (reactive aldehyde species) modulators ADX-629, ADX‑248, ADX-743, ADX-631, ADX-246, and chemically related molecules for the potential treatment of systemic and retinal immune-mediated and metabolic diseases. Our late-stage product candidates are reproxalap, a RASP modulator for the potential treatment of dry eye disease and allergic conjunctivitis, and ADX-2191, a novel formulation of intravitreal methotrexate for the potential treatment of primary vitreoretinal lymphoma and retinitis pigmentosa.
