ADX-2191
A Novel Therapy for the Treatment of Rare Retinal Diseases
Methotrexate, the active drug substance of ADX-2191, has long been utilized as both a chemotherapeutic agent and an immunomodulator. Intraocular methotrexate injections are the established standard of care for primary vitreoretinal lymphoma, a cancer affecting the back of the eye. Additionally, off-label use of methotrexate has become increasingly common in the management of proliferative vitreoretinopathy, posterior uveitis, and other retinal diseases.
The off-label intraocular injection of methotrexate for retinal diseases is an example of a practice known as compounding. The disadvantages of compounding are significant, and include a risk of microbial contamination that can lead to severe ocular infection, resulting in vision loss or surgical removal of the eye. In contrast to compounded methotrexate, ADX‑2191 is specifically formulated for intraocular injection such that pH, viscosity, and solute concentration have been designed to be compatible with the vitreous humor, the fluid in the back of the eye. Further, ADX-2191 is a concentrated formulation of methotrexate that requires only a small injection volume, thereby mitigating injection site reflux and reducing the risk of corneal damage associated with off-label ocular methotrexate injections. Unlike compounded methotrexate, ADX‑2191 possesses a higher density than the vitreous humor, enabling a localized and sustained concentration of methotrexate in close proximity to the retina.
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. Although no approved treatments are currently available, intraocular injection of compounded methotrexate represents the current standard of care. The frequency of methotrexate injections has been linked to cancer cell clearance in patients with primary vitreoretinal lymphoma,1 and approximately five injections are required on average to achieve cancer cell clearance.2
Retinitis pigmentosa comprises a group of rare genetic diseases characterized by progressive photoreceptor degeneration and vision loss. All but one rare form of retinitis pigmentosa lacks a targeted drug treatment. In vivo preclinical research has identified the activity of methotrexate in inducing misfolded rhodopsin (a visual cycle protein) clearance, suggesting the potential of ADX-2191 as a disease-modifying therapy for retinitis pigmentosa subtypes associated with rhodopsin misfolding. In a Phase 2 clinical trial in eight patients with retinitis pigmentosa, treatment with ADX-2191 was associated with improvement from baseline in visual acuity, sensitivity to light, and retinal function. Retinitis pigmentosa affects more than one million people worldwide and remains a significant cause of inherited blindness. Mutations leading to rhodopsin misfolding account for approximately one-third of retinitis pigmentosa cases.
The U.S. Food and Drug Administration has granted ADX-2191 Orphan Drug Designation for the treatment of primary vitreoretinal lymphoma and retinitis pigmentosa. Orphan Drug Designation facilitates the development of therapies for rare diseases by providing regulatory incentives, such as extended market exclusivity and financial support for clinical research.
1 Am J Ophthalmol 251: 189–196, 2023
2 Br J Haematol, 194, 92–100, 2021; Cancer Sci. 107:1458-1464, 2016