Eyeworld

EW RETINA 72 by Stefanie Petrou Binder, MD, EyeWorld Contributing Writer Retina specialists take a realistic look at their options at the German Ophthalmic Surgeons (DOC) Congress in Nuremberg, Germany G eographic atrophy (GA) is a devastating late-stage manifestation of age-relat- ed macular degeneration (AMD). While some pre- ventive measures are well in place for persons with early and interme- diate AMD, an effective treatment for delaying progression in those who have developed advanced dry AMD with atrophy seems more chal- lenging. The increasing prevalence of blindness in today's ever-aging population lends urgency to finding effective therapeutic approaches. EyeWorld spoke with retinal special- ists Frank Holz, MD, Department of Ophthalmology, Bonn University Eye Clinic, Bonn, Germany, and Sylvia Bopp, MD, Augenklinik Universitätsallee, Bremen, Germany, for an updated perspective on the disease and current research efforts. Terminology Current AMD classification distin- guishes early and intermediate AMD on the one hand, in which central vision is usually maintained, and late stage AMD, which is either asso- ciated with neovascularization (wet) or GA with areas of central vision loss, on the other. According to Dr. Holz, who spoke about treating GA at the German Ophthalmic Surgeons (DOC) Congress in Nuremberg, Germany, "Dry AMD is a term we are now trying to modify because it causes a lot of confusion. Dry AMD can be everything from a single little drusen associated with aging but with no functional deficit whatsoev- er, to geographic atrophy, which can lead to complete disability with loss of central vision. Geographic atro- phy is late-stage disease, which was formerly labeled late dry AMD." Slow it down Retinal specialists think that slow- ing down the unrelenting forward progression of AMD is the physician's best chance to preserve patients' eyesight. However, unlike antivascu- lar endothelial growth factor (anti- VEGF) therapy, which has shown high efficacy in halting progression of exudative AMD, there are no approved treatments for GA, as yet. Dr. Holz discussed the results and expectations of two current trials that take two very different approaches to the problem. The S.E.A.T.T.L.E. study imple- mented an investigational visual cycle modulator emixustat hydro- chloride to reduce A2E, a vitamin A-based toxin thought to have del- eterious effects on RPE cells, to slow progression in GA patients. The ran- domized study enrolled 508 patients with GA to receive oral emixustat for 24 months. The study failed to meet its primary endpoint with none of the treatment groups demonstrating a significant difference in lesion growth rates. The lesion growth rates over 24 months for the 10 mg, 5 mg, 2.5 mg, and placebo groups were 1.84 mm 2 /year, 1.83 mm 2 /year, 1.69 mm 2 /year, and 1.69 mm 2 /year, respectively. "There are several lines of evi- dence to indicate that toxic byprod- ucts of the visual cycle play a role in aging of the retina, the retinal pigment epithelium, and in AMD. The hope was that by slowing down the visual cycle and having lower amounts of these toxic byproducts that it would help to slow disease progression. Following the study outcomes, emixustat will not be pursued for this phenotype of AMD, as the drug unfortunately did not influence the course of the disease," Dr. Holz said. On a far more promising front, investigators in the dual CHROMA and SPECTRI studies are focusing on intervening in the complement pathway responsible for inflamma- tion and cell death in GA through the use of lampalizumab. This humanized mouse anti-factor D monoclonal antibody is designed to limit the rate-limiting step in the alternative complement pathway, by binding to factor D, a protein in the complement cascade. In a Phase 2 trial that investigated the role of lampalizumab in GA (MAHALO), a 20% reduction in GA growth rate was achieved at 18 months, with monthly intravitreal lampalizumab injections. In a subgroup analysis of patients with the complement factor I biomarker, a 44% reduction in GA growth rate was observed. These results sparked the currently recruiting Phase 3 October 2016 Slowing down dry AMD progression Geographic atrophy due to AMD with soft and crystalline drusen; color fundus photograph (left) and corresponding fundus autofluorescence image (right) Source: Frank Holz, MD

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