Geographic atrophy is now a major research target.
Once there were none, but now there are many treatments for age-related macular degeneration (AMD). By far, more therapies are available for wet AMD, but research also is focused on dry AMD. The goal is to effectively reduce the treatment burden in addition to improving and preserving vision.
Dr Katherine Talcott highlighted the more recent therapeutic additions to the market. She is a staff surgeon at the Cleveland Clinic Cole Eye Institute and an assistant professor of ophthalmology at the Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, US.
Neovascular AMD therapies
Anti-vascular endothelial growth factor (VEGF) drugs are the first-line treatments for neovascular AMD, which have been effective in improving vision in randomised clinical trials.
However, Dr Talcott noted data from real-world studies illustrate that it is difficult to achieve good long-term outcomes. This can happen because of undertreatment resulting from the treatment burden on patients, caregivers and clinical practices.
The hope for the FDA-approved port delivery system (Susvimo implant, ranibizumab injection; Genentech), a permanent, refillable, surgically implanted device that continuously releases treatment, was to alleviate the treatment burden of patients with neovascular AMD. Susvimo is under a temporary recall because of dislodgement of the internal structures of the device.
Faricimab (Vabysmo; Genentech) is a bispecific antibody that is injected intravitreally and inhibits both VEGF-A and ANG2. In clinical trial results, the visual acuity gains with faricimab were equivalent to those achieved with aflibercept (Eylea; Regeneron Pharmaceuticals). One distinct advantage is that fewer injections are needed with faricimab compared with aflibercept, a finding that suggests the drug may be more durable.
The holy grail in the treatment of neovascular AMD is a one-and-done treatment for the disease and this is where gene therapy may play a role. RGX-314 (ReGenXBio) is a one-time surgically implanted subretinal gene therapy to encode for an anti-VEGF protein. The phase 1/2 trial results were promising, Dr Talcott reported, and the implant is being evaluated in two phase 3 trials, ATMOSPHERE (NCT04704921) and ASCENT (NCT05407636). “This is a promising option,” she said, and noted the importance of the availability of longer-acting options on the horizon.
Dry AMD therapies
Geographic atrophy (GA), the end stage of dry AMD, has become a major research target for which, until recently, no treatments were available. Most of the current therapies being evaluated are complement inhibitors of C3 and C5, which are important factors in development of inflammation in the eye and ultimately cell death.
Pegcetacoplan (Syfovre; Apellis), a complement C3 inhibitor, was approved in February 2023 by the US Food and Drug Administration to treat GA. A phase 2 study showed that the drug slowed progression of GA, which led to the DERBY (NCT03525600) and OAKS (NCT03525613)studies, the primary end point of which is the change in the total area of the GA lesions at 12 months. At the 18-month time point, data from both studies showed significant changes in the rate of growth of the GA in the patients receiving active treatment. There were no functional improvements in vision seen with the therapy.
Another drug under study is avacincaptad pegol (Zimura; Iveric Bio), a C5 inhibitor in the GATHER 1 and 2 studies. The end point of both studies was the rate of growth of GA, which was shown to slow with treatment.
With both investigational drugs, there is a higher rate of conversion to neovascular AMD compared with sham treatment.
Gene therapies also may have a role in controlling GA. Gyroscope Therapeutics is looking at a complement factor I, GT005, in the FOCUS study (NCT03846193), in which the gene therapy is delivered into a bleb created in the subretinal space.
“Neovascular AMD and GA both result in irreversible vision loss that require effective treatments to reduce individual and societal treatment burdens. Many studies are ongoing and investigating a number of therapeutic options. There also may be a role in the future for potential surgical innovations that may help address the treatment burden,” Dr Talcott concluded.