Parkinson’s Disease Drug Stabilizes Age-Related Macular Degeneration and Improves Vision

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The results of an open-label pilot study have found that treating patients with an advanced form of age-related macular degeneration (AMD) using the Parkinson’s disease drug, levodopa, stabilized their disease and improved vision. The study, reported in The American Journal of Medicine by researchers at the University of Arizona, Tuscon, Retina Associates, and Snyder Biomedical, demonstrated that oral levodopa therapy was safe and well-tolerated, and reduced the need for patients with neovascular AMD (nAMD) to receive anti-VEGF injections.

The research team, headed by Snyder Biomedical co-founder Robert Snyder, MD, PhD, said the findings suggest that levodopa may be effective as an adjunct to anti-VEGF injection therapy for nAMD. “Using levodopa as an adjuvant therapy for nAMD could well alter the course of disease progression and save billions of dollars without sacrificing vision,” the investigators concluded in their published paper, which is titled, “Levodopa Positively Affects Neovascular Age-Related Macular Degeneration.”

AMD is characterized by degeneration of the central part of the retina, the macula, which is responsible for high-acuity vision, the authors wrote. More than 15% of the U.S. population over the age of 70 years has AMD, which represents a common cause of blindness in developed nations. Neovascular AMD is characterized by the abnormal growth of new blood vessels, triggered by vascular endothelial growth factor (VEGF), which can cause fluid and blood to leak in the subretinal space of the eye. While nAMD represents only 10–15% of all AMD cases, it is responsible for 90% of vision loss attributed to the disease, the investigators continued.

Standard therapy for nAMD requires frequent injections of agents to block VEGF. But while the injections are effective, they are also painful, and expensive. The investigators cited Centers for Medicare and Medicaid Services figures indicating that total cost of such drugs—aflibercept, ranibizumab, and bevacizumab—in the U.S. in 2017 was $4.8 billion, and the total payments for the injection procedure amounted to $3.9 billion, totaling $8.7 billion.

Race is one of the strongest risk factors for AMD, with vision loss from the disease being most prevalent in white populations. The researchers interpreted this racial bias to suggest that ocular pigmentation protects from AMD, because people with the least pigmentation are particularly susceptible. The retinal pigment epithelium is the most likely initial tissue affected in AMD, they further explained. It has a G protein-coupled receptor, GPR143, which is activated by levodopa. “GPR143 is a component of the pigmentation pathway,” they wrote, “such that the retinal pigment epithelium both synthesizes and responds to levodopa.”

Earlier research had found that patients being treated with levodopa for movement disorders such as Parkinson’s disease were significantly less likely to develop any type of AMD. “Levodopa has a receptor (GPR143) selectively expressed on pigmented cells,” continued Snyder, an ophthalmologist and cell biologist, at the department of biomedical engineering, University of Arizona, Tucson. “This receptor can be supportive of retinal health and survival, which led to the development of our hypothesis that it may prevent or treat AMD.”

To test this in AMD patients the investigators developed two proof-of-concept studies to evaluate whether levodopa could improve visual acuity and impact on anatomical changes caused by nAMD. They also evaluated the safety and tolerability of the drug in treating nAMD, and assessed whether treatment reduced or delayed the need for anti-VEGF therapy.

In the first study, 20 patients newly diagnosed with nAMD, who had never received anti-VEGF treatment, were given a small daily dose of levodopa for one month, and were evaluated weekly by their referring retina specialist, who determined whether anti-VEGF treatment was needed. In the second part of the study, the patients who completed the first study, and a second group of 14 patients who had received anti-VEGF treatment for at least three months prior to the study, received escalating doses of levodopa to test the tolerance and efficacy of the drug. The patients continued to be evaluated monthly by their referring retina specialist.

Spectral domain optical coherence tomography images of the same macular segmentation line at baseline and monthly follow-up visits in a patient naïve to intravitreal anti-vascular endothelial growth factor (VEGF) therapy. There was a 59% reduction in retinal fluid at one month; retinal fluid completely resolved at the same macular segmentation line at month 2, and fluid remained stable up to month 3 without anti-VEGF injections. Collectively, all macular segmentation lines revealed a 92% total retinal fluid decrease at 3 months. [The American Journal of Medicine]

This trial demonstrated for the first time that levodopa is safe, well-tolerated, and delayed anti-VEGF injection therapy while improving visual outcomes. In the first month, retinal fluid decreased by 29% without anti-VEGF treatment. “The observed early visual acuity improvements with levodopa are comparable with the early visual acuity improvements reported with ranibizumab and bevacizumab,” the team noted. After six months the decrease in retinal fluid was sustained and mean visual acuity improved, enabling patients in the first and second groups to read an additional line on the eye chart. This is the equivalent of improvement from 20/40 to 20/32.

There was also a 52% reduction in the frequency of anti-VEGF injections in the second patient group, with three patients requiring no anti-VEGF injections during the six months. Side-effects were also limited. “Both studies demonstrated an acceptable safety profile in 28 patients treated with levodopa for six months,” the team noted.

The investigators acknowledged that it is unlikely that levodopa could be used as a standalone treatment in patients with newly diagnosed nAMD, given that 11 of the 15 newly diagnosed nAMD patients did still require anti-VEGF injections. However, the patients required less frequent injections than the standard monthly treatment. “… levodopa did result in fewer required anti-VEGF injections (0.38 injections/month) to improve visual function and stabilize nAMD retinal changes, compared with a monthly injection regimen,” the scientists reported. “The improvement in our study is particularly impressive because the patients were already receiving anti-VEGF injections, which had almost certainly already improved visual acuity and anatomical features prior to enrollment.”

Snyder maintains that while the reported proof-of-concept study included only a small sample size and limited patient diversity, the findings still suggest efficacy and support targeting of the GPR13 receptor with levodopa for the treatment of nAMD in future studies. “Collectively, our observations indicate that this oral, systemic medication with a well-established safety history has the potential to stabilize and improve vision while reducing the pain, risks, and financial burden of frequent anti-VEGF injections,” the investigators concluded.

The reasoning behind the study has its origins 20 years ago, when Snyder began working with co-investigator Brian S. McKay, PhD, who had developed techniques to culture and examine retinal endothelial pigment cells. “We had a strong desire to make an impact in AMD, and I had a strong hunch that Dr. McKay could make a significant contribution,” Snyder said. “Although this is nowhere near completed, I am happy to say, 20 years later, we have all persevered, and I believe the GPR143/levodopa story will make a significant impact on our treatment and prevention of AMD.”

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