Recently US FDA granted orphan drug designation of ADX-2191(methotrexate for intravitreal injection) by Aldeyra Therapeutics, Inc for the treatment of retinitis pigmentosa (RP) . RP is a serious genetic condition that leads to retinal cell death and vision loss. It is a rare condition, which is defined as affecting fewer than 200,000 people in the United States. It has no cure, and limited treatment options, and is one of those eye conditions that doctors cannot do much about. So it is great to hear that now a drug is being developed to improve RP.
What is also surprising is that methotrexate is not a new drug. In fact, it has been around for quite some time now, and primarily used to treat cancer of the blood, bone, lung, breast, head, and neck. It can also treat rheumatoid arthritis and psoriasis. It works by inhibiting cancer cells and certain immune cells to replicate, thereby can be used to treat cancer and certain autoimmune conditions. Now that it is injected into the eyeball for RP, does it mean it inhibits cells to grow and divide in the retina? In RP, retinal cells die, so it does not appear to be helpful to have a drug that further reduces cell duplication. Plus, the retinal cells are already terminally differentiated and do not divide anyways. So how does methotrexate work to help RP?
I am very curious now about this and looked into literature. It turns out it is a brand new mechanism of action of this old drug that renders it effective against RP. Scientists from University of Pittsburgh, University of Cincinnati and National Institute of Health discovered that methotrexate can reduce the misfolding of a protein called rhodopsin that is frequently mutated in RP, without affecting the healthy version of this protein. Rhodopsin is THE molecule to mediate vision in the retina. When it is mutated such as in RP, it folds in the wrong shape, leading to loss of function and death of retinal cells. Methotrexate could help the body’s natural garbage disposal system to work better to clear these wrongly formed proteins, and improved vision in a mouse model of RP .
Note this study using mice was published in 2020, and the FDA designation of orphan drug in 2021. The company moved fast!
Of course, orphan drug designation does not mean it’s already approved or will be approved by the FDA eventually for the treatment of RP. Phase 1 clinical trial was being planned and investigated at Mass Eye and Ear/ Harvard Medical School . Hopefully data in humans will give some hope to those with this condition.
 Aldeyra Therapeutics receives Orphan Drug designation from the U.S. Food and Drug Administration for ADX-2191 to treat retinitis pigmentosa. News release. Aldeyra Therapeutics, Inc. Accessed August 4, 2021. https://www.businesswire.com/news/home/20210804005122/en/Aldeyra-Therapeutics-Receives-Orphan-Drug-Designation-from-the-U.S.-Food-and-Drug-Administration-for-ADX-2191-to-Treat-Retinitis-Pigmentosa.
 Liu X, Feng B, Vats A, Tang H, Seibel W, Swaroop M, Tawa G, Zheng W, Byrne L, Schurdak M, Chen Y. Pharmacological clearance of misfolded rhodopsin for the treatment of RHO-associated retinitis pigmentosa. FASEB J. 2020 Aug;34(8):10146-10167. doi: 10.1096/fj.202000282R. Epub 2020 Jun 14. PMID: 32536017; PMCID: PMC7688577.