Researchers began exploring the genetic connection between age-related macular degeneration and COVID-19 after the emergence of new data showed patients with AMD had worse COVID-19 disease, morbidity and mortality outcomes than those who didn’t have AMD. Notably, the risk for severe infection was much higher in AMD compared with type-2 diabetes (21 percent) and obesity (13 percent).1 Neovascular AMD in particular was associated with a higher risk of severe infection compared with dry AMD.2
Considering these findings, study co-author Manju L. Subramanian, MD, FACS, an associate professor of ophthalmology at Boston University School of Medicine, says her group decided to conduct a genome-wide association study to see if they could find a potential genetic basis for AMD and COVID-19 that could explain why patients with AMD experienced such severe COVID-19 infections. They identified a novel association between the two diseases near the platelet-derived growth factor B (PDGFB) gene.
To investigate the two diseases’ shared genetic architecture, the researchers analyzed summary statistics from the AMD Genomics Consortium genome-wide association study, which included 16,144 AMD cases and a control cohort of European ancestry (n=17,832). They also used the COVID-19 Host Genetics Initiative website, round 5, for summary statistics on three European-population COVID-19-related outcomes: critical illness; hospitalization; and infection rates. Genetic correlations and pleiotropy (i.e., cross-phenotype meta-analysis) of AMD and COVID-19 were performed along with expression quantitative trait locus, differential gene expression and Mendelian randomization.
The researchers found a significant genetic correlation between AMD and COVID-19 infection as well as genome-wide-significant associations near the PDGFB gene. The rs130651 allele was significantly associated with increased PDGFB gene expression in multiple tissues and T-cells. PDGFB expression was highest in AMD cases vs. AMD controls, and during the peak COVID-19 symptom stage (days 11 to 20) vs. the early COVID-19 symptom stage (days 0-10) in infected patients over the age of 40.
“Platelet-derived growth factor is one of several factors, including vascular endothelial growth factor, that play a role in wound repair and angiogenesis,” Dr. Subramanian says. “The PDGFB gene encodes a version of this protein. This gene may also be involved in angiogenesis during retinal development and in pathological neovascularization.”
Blocking PDGF signaling may inhibit some neovascularization processes and may serve as a potential therapeutic target; however, combined anti-VEGF and PDGF signaling antagonist therapy hasn’t yet demonstrated better outcomes than anti-VEGF monotherapy. Both Ophthotech’s third Phase III trial for Fovista (pegpleranib) and Regeneron’s Phase II trial for rinucumab (anti-platelet-derived growth factor receptor beta antibody) failed to meet their primary endpoints of BCVA gains compared with intravitreal anti-VEGF injection alone.
Dr. Subramanian says her group’s findings confirm that both AMD and COVID-19 are complement-mediated disorders. “When patients have severe COVID-19 infection, they may experience an acute inflammatory response called a cytokine storm, which is a complement-mediated process,” she explains. “Previous studies have identified genetic variants in AMD associated with complement dysregulation, and because of this, complement-targeting therapeutics are being investigated, with one recently approved for dry AMD—Syfovre (pegcetacoplan; Apellis Pharmaceuticals) for geographic atrophy which targets C3, the main protein of the complement cascade.
“Because these two diseases share some genetic architecture, AMD patients are at an increased risk for severe COVID-19 infection and mortality,” she says. “Be sure to remind your AMD patients to get their vaccines and take precautions. Future studies will help us better understand the two diseases’ shared pathology and risk factors.”
Dr. Subramanian has no related financial disclosures.
1. Ramlall V, Thangaraj PM, Meydan C, et al. Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection. Nat Med 2020;26:1609–1615.
2. Yang J, Moon S, Lee J, et al. COVID-19 morbidity and severity in the patients with age-related macular degeneration: A Korean nationwide cohort study. Am J Ophthalmol 2021;239:159-169.
Vuity Approved by FDA for Twice-a-Day Dosing
U.S. presbyopes may be able to get more efficacy from Vuity eyedrops, thanks to a new labeling change. Originally approved for once-a-day dosing, the FDA recently approved Vuity’s dosage for twice-a-day, which will enhance its duration of use.
Vuity by Allergan, an AbbVie company, is a pilocarpine HCl ophthalmic solution that uses the eye’s ability to reduce pupil size to improve near and intermediate vision while maintaining some pupillary response to light. Results during the first two FDA clinical trials, GEMINI 1 and GEMINI 2, saw the effects of a single dose of Vuity lasting for approximately six hours. In a separate trial, the Phase III VIRGO trial, 230 participants aged 40 to 55 years old with presbyopia were randomized to take Vuity (n=114) or a placebo (vehicle alone, n=116). This trial lasted 14 days, with participants receiving one drop in each eye twice daily, with each dose administered six hours apart. The results of the trial proved that Vuity can be administered twice daily to improve a patient’s sight for nine hours, as opposed to six hours from a single dose.
“There’s a subset of patients who take Vuity that feel that it works, but doesn’t work long enough,” said Y. Ralph Chu, MD, CEO and chief medical officer at Chu Vision Institute. “Having this FDA approval showing that it’s safe, and it actually is effective and extends the duration of Vuity, is important and it’s going to expand the number of people that will be happy with Vuity.”
The recognition of Vuity’s safety by the FDA for twice-daily dosing is a step in the right direction, but adverse effects shouldn’t be overlooked. Clinical trials reported that greater than 5 percent of participants experienced headaches and eye irritation. Other reactions reported in 1 to 5 percent of participants during the trial were visual impairment, eye pain, blurred vision and vitreous floaters. Additionally, Vuity has been reported to cause temporary dim or dark vision, a caution for Vuity patients driving at night or operating heavy machinery.
“I do think that patients should have a full eye exam screening before any therapy, including pharmacological therapy,” says Dr. Chu. In his experience, he has found that it is best to educate patients about their presbyopia treatment options before prescribing Vuity. Patients he’s treated with Vuity, including himself, have reported positive outcomes with this therapy.
“It does what it’s supposed to do. It extends the duration of time, and we haven’t seen an increase in side effects,” says Dr. Chu. He notes that the second dose of Vuity wasn’t extending the number or duration of previously reported side effects. Dr. Chu describes Vuity as a lifestyle tool for his patients, potentially allowing them to be more active.
“I’m excited for the future of presbyopia treatment. More options will be available because everyone has a different response to different medications,” says Dr. Chu. Many observers consider Vuity, as the first approved presbyopia eye drop, to be paving the way for other presbyopia drops in the FDA approval pipeline. “I think it’s important to have as many choices as possible because everyone is a unique individual.”