Will Carrera, MD
Tufts Medical Center
Following recent advances in the treatment of wet age-related macular degeneration (AMD), the treatment of dry AMD has emerged as one of the greatest unmet needs in vitreoretinal disease, and the Dry AMD section of the Atlantic Coast Retina Club / Macula 2023 meeting certainly reflected the dynamism and energy that characterizes recent work in this field.
The section opened with a presentation by Eleanora Lad, MD, PhD of Duke University covering recent developments in “C3 Inhibition for Dry AMD.” Her discussion focused on pegcetacoplan (Apellis Pharmaceuticals), which inhibits C3 and C3b. She reviewed the 12-month and 24-month data from the DERBY (NCT03525600) and OAKS (NCT03525613) phase III clinical trials evaluating pegcetacoplan for the treatment of geographic atrophy (GA). The primary endpoint assessing change from baseline to month 12 in GA area as assessed by fundus autofluorescence (FAF) was met in OAKS, but was narrowly missed in DERBY. DERBY caught up with OAKS in the recent 24-month results, with the two trials showing a reduction in GA growth rate of 19% with monthly dosing and 16% with every other month (EOM) dosing and 22% with monthly dosing and 18% with EOM dosing, respectively. Dr. Lad highlighted a notable finding from the 24-month data, which demonstrated an acceleration in treatment effect over months 18-24. Perhaps most interestingly, post-hoc analysis of microperimetry data assessing the peri-lesional junctional zone suggested a possible functional benefit to pegcetacoplan treatment. Patients treated with pegcetacoplan monthly and EOM showed a 10% (p = 0.0650) and 12% (p = 0.0202) difference, respectively, in mean threshold sensitivity compared to sham, as well as a 10% (p = 0.1444) and 16% (p = 0.0140) reduction, respectively, in number of scotomatous points compared to sham.
In the second talk of the session, Carl Regillo, MD, FACS, FASRS of Wills Eye Hospital and Mid Atlantic Retina presented recent developments in “C5 Inhibition for Treatment of Dry AMD.” His presentation focused on avacincaptad pegol (Iveric bio), a pegylated RNA aptamer targeting C5, and recent results of the GATHER2 (NCT04435366) phase III clinical trial. He highlighted some differences between the design of GATHER2 and other clinical trials assessing complement inhibitors for GA treatment, such as DERBY or OAKS, particularly the exclusion of foveal-involving lesions and fellow eye choroidal neovascularization (CNV) in GATHER2. The study met its primary endpoint of slowing GA growth at 12 months as assessed by FAF, with a 14.3 to 17.7% reduction in lesion growth. Safety data showed good balance of treatment emergent adverse events (TEAE’s) between the treatment and sham arms, although the rate of total CNV was increased in the treatment arm (6.7%) versus sham (4.1%).
Allen Ho, MD, FACS, FASRS of Wills Eye Hospital and Mid Atlantic Retina then discussed “Surgical Delivery Strategies and Gene Therapy for Atrophic AMD” in the third talk of the session, focusing on results of the FOCUS (NCT03846193) Phase I/II clinical trial evaluating GT005 (Gyroscope Therapeutics). GT005 uses an AAV2 vector to deliver a gene expressing complement factor I (CFI), an inhibitor of the alternative complement pathway. He outlined the two methods of GT005 delivery currently under study: transvitreal, subretinal delivery via pars plana vitrectomy, and subretinal delivery via the Orbit SDS™ subretinal delivery system. Both methods of delivery were well-tolerated with no ocular serious adverse events. Treatment with GT005 resulted in increased concentrations of vitreous CFI, as well as decreased vitreous concentrations of C3, C3b/iC3b, and Ba.
In the next talk, Peter Kaiser, MD, of the Cleveland Clinic discussed “Other Approaches to Dry AMD Therapy.” His presentation emphasized 5 principle avenues of approach including reduction of oxidative stress, inhibition of beta amyloid, visual cycle modulation, stem cell therapy, and complement inhibition. A comprehensive overview was provided of the dozens of emerging therapies in these areas. Other treatment strategies on the horizon include photobiomodulation and optogenetics.
In the final talk of the session, Richard Spaide, MD, of Vitreous Retina Macula Consultants of New York presented a pointed and critical perspective on current strategies for dry AMD treatment with his talk “The Futility of Complement Inhibition in the Treatment of Geographic Atrophy.” He highlighted structural and clinical problems in many of the prominent trials in this space, including high rates of dropout and increased rates of CNV in patients treated with complement inhibitors. He also emphasized a significant challenge facing the study and treatment of geographic atrophy, which is the current lack of functional data to support complement inhibition in geographic atrophy. He argued that while a reduction in GA growth rate would seem to support an eventual benefit in visual function, the current data and length of clinical trials has not yet confirmed such a relationship, which remains conjectural at this time. Dr. Spaide also raised concerns about value and cost effectiveness in a treatment that may lack a demonstrated functional benefit.
Sonia Mehta, MD of Wills Eye Hospital and Mid Atlantic Retina then moderated a stimulating and at times heated panel discussion that ran nearly 30 minutes over its allotted time. There was a robust debate surrounding the discord between structural and functional assessments of GA in clinical trials for AMD. Dr. Spaide often took the role of the gadfly, again emphasizing a lack of functional data to support complement inhibition and stressing the importance of a data-driven approach that takes cost and value into consideration. Dr. Regillo and Dr. Lad underlined the importance of identifying the optimal patient population who would most benefit from treatment with complement inhibition, and the possibility of identifying a population that could support future trials with a functional, rather than anatomic, endpoint. Dr. Kaiser suggested that patients with non-foveal lesions could potentially provide the greatest opportunity for assessing preservation of visual function, while Dr. Ho suggested that studying and treating the disease earlier in its course may prove fruitful. The discussion returned to microperimetry, and the possibility that recent improvements in microperimetry technology and analytical models may provide an adequate functional test in the future.