ADX-2191 Scores Orphan Designation in Europe for Primary LBCL of Immune-Privileged Sites

ADX-2191 (methotrexate for intravitreal injection) has received orphan designation from the European Medicines Agency (EMA) for the treatment of patients with large B-cell lymphoma (LBCL) of immune-privileged sites, including primary vitreoretinal lymphoma (PVRL).1

“Primary vitreoretinal lymphoma is a potentially fatal cancer that today is treated with off-label compounded formulations of methotrexate that are injected into the eye,” Todd C. Brady, MD, PhD, president and chief executive officer of Aldeyra Therapeutics—the developer of ADX-2191—stated in a news release. “The receipt of orphan designation from the EMA, in conjunction with the previously announced orphan drug designation from the United States FDA, is another important step forward for our retinal disease program, complementing our ongoing clinical development of ADX-2191, a novel, vitreous-compatible formulation of methotrexate that is specifically designed for intraocular injection.”

ADX-2191 is a sterile, non-compounded intravitreal methotrexate formulation that has been developed for the potential treatment of rare retinal diseases, such as retinitis pigmentosa and PVRL. This formulation is free of preservatives and designed to be compatible with vitreous administration. The agent is optimized for excipient composition, density, viscosity, pH, concentration, tonicity, and administration volume.

A proposed clinical trial investigating ADX-2191 received a Special Protocol Assessment agreement from the FDA. The trial is designed to compare cancer cell clearance following 30 days of therapy in a maximum of 20 patients, who will be randomly assigned 1:1 to receive ADX-2191 in a single intraocular injection or 8 intraocular injections. The trial is planned to begin in the second half of 2025 and end in 2026. Notably, methotrexate injection frequency has been correlated with cancer cell clearance in patients with PVRL, and cancer cell clearance has been achieved with an average of 5 injections.

PVRL is a retinal cancer that is rare, aggressive, and potentially fatal. Approximately 200 to 600 patients in the US and 100 to 200 patients in the European Union are diagnosed with this disease each year. The median overall survival for newly diagnosed patients with PVRL is under 5 years. No approved treatments are currently available for patients with PVRL; therefore, in this population, the current standard of care is compounded methotrexate administered via intravitreal injection.

Previously, on June 22, 2023, the FDA issued a complete response letter (CRL) to the new drug application seeking the approval of ADX-2191 for the treatment of patients with PVRL.2 According to an announcement from Aldeyra Therapeutics, the CRL cited a lack of substantial efficacy data stemming from a lack of well-controlled and adequate investigations. At the time the CRL was issued, no clinical trials had investigated the agent in patients with PVRL. The CRL did not cite manufacturing or safety issues related to ADX-2191.

ADX-2191 was previously granted FDA orphan drug designation for the treatment of patients with PVRL and retinitis pigmentosa. On July 24, 2025, the agent also received EMA orphan designation for the treatment of patients with inherited retinal dystrophies of the rod-dominant phenotype—including retinitis pigmentosa.3 This designation was supported by data from a phase 2 trial (NCT05392179), in which the agent generated improvements from baseline regarding retinal sensitivity. Notably, on August 19, 2025, ADX-2191 also received fast track designation from the FDA for the treatment of patients with retinitis pigmentosa based on these phase 2 trial data.4 A phase 2/3 clinical trial investigating ADX-2191 in patients with retinitis pigmentosa is planned to initiate in 2025.

References

1. Aldeyra Therapeutics receives orphan designation from the European Medicines Agency for ADX-2191 for the treatment of primary large b-cell lymphomas of immune-privileged sites, including primary vitreoretinal lymphoma. News release. Aldeyra Therapeutics, Inc. August 28, 2025. Accessed August 29, 2025. https://ir.aldeyra.com/news-releases/news-release-details/aldeyra-therapeutics-receives-orphan-designation-european-0
2. Aldeyra Therapeutics provides regulatory update on ADX-2191. News release. Aldeyra Therapeutics, Inc. June 21, 2023. Accessed August 29, 2025. https://ir.aldeyra.com/news-releases/news-release-details/aldeyra-therapeutics-provides-regulatory-update-adx-2191
3. Aldeyra Therapeutics receives orphan designation from the European Medicines Agency for ADX-2191 for the treatment of inherited retinal dystrophies including retinitis pigmentosa. News release. Aldeyra Therapeutics, Inc. July 24, 2025. Accessed August 29, 2025. https://ir.aldeyra.com/news-releases/news-release-details/aldeyra-therapeutics-receives-orphan-designation-european
4. Aldeyra Therapeutics receives fast track designation for ADX‑2191 for the treatment of retinitis pigmentosa. News release. Aldeyra Therapeutics, Inc. August 19, 2025. Accessed August 29, 2025. https://ir.aldeyra.com/news-releases/news-release-details/aldeyra-therapeutics-receives-fast-track-designation-adx-2191-0