Dry AMD pipeline

While there is currently no approved treatment for dry age-related macular degeneration (AMD), hope remains that the multiple trials presently under way will ultimately yield an effective drug in terms of prevention and progression of the disease, Francesco Bandello MD told delegates attending the 17th EURETINA Congress in Barcelona. “The failure of the phase III trial of lampalizumab for geographic atrophy that was just announced at this meeting is a big disappointment for all of us and for our patients. However, there are still a number of treatments for dry AMD under investigation with some promising results in preliminary studies. We need evidence-based data that will allow us to use some new approaches for this devastating disease,” said Prof Francesco Bandello, Professor and Chairman at the Department of Ophthalmology, Vita-Salute University, San Raffaele Scientific Institute, Milano, Italy. Although anti-VEGF agents have transformed the treatment of wet-AMD, almost 80% of people diagnosed with AMD have the non-neovascular (dry) or atrophic subtypes. AMD has a complex pathogenesis, with oxidative stress, deposits of lipofuscin, chronic inflammation, choroidal blood flow insufficiency, environmental and predisposing genetic factors all potentially playing important roles in the development of the disease, said Prof Bandello. He noted that evidence from the Age-Related Eye Disease Study (AREDS) suggests that antioxidant vitamin and mineral supplementation may be beneficial to patients with dry AMD. “It is one of the areas where we have more evidence, but unfortunately that evidence is not very strong and it related to patients who were at an advanced stage and intermediate stage of the disease. It is perhaps the case that treatment earlier in the disease course might be beneficial, although we need more studies on that,” he said. In terms of anti-inflammatory therapy, Prof Bandello said that Iluvien (Alimera Sciences), a sustained-release formulation of fluocinolone acetonide, already approved for the treatment of diabetic macular oedema (DME), may have potential to slow the progression of geographic atrophy (GA). A phase II study of 40 patients affected bilaterally by GA has been completed, but the results are not yet available. Some complement system inhibitors are also currently under investigation, said Prof Bandello. The rationale behind these agents is that undesirable activation of the complement system, which forms a vital part of the innate immune system, occurs in connection with a number of diseases. While phase I clinical trials of the C3 inhibitor POT-4 (Potentia Pharmaceuticals) and the anti-C5 aptamer ARC1905 (Ophthotech Corp) have been completed, no phase II clinical trial has yet proven the safety and efficacy of either of these drugs in dry AMD, said Prof Bandello. While hopes had been high for lampalizumab (Genentech/Roche) after phase II trials showed a positive effect in slowing growth of GA through complement inhibition, the phase III trial results failed to meet the primary endpoint of reducing mean change in lesion area. “Unfortunately, we know the results of the lampalizumab phase III trials were not good, and the company has decided to stop its trials in dry AMD. This is disappointing, as we are likely to see less interest around this field as a result of its failure,” he said. Another anti-inflammatory therapy, Sirolimus (MacuSight/Santen), has been shown to be well tolerated in patients with GA, but demonstrated no positive anatomic or functional effects in an open-label phase II trial of 11 patients. A phase I study of another compound, glatiramer acetate (Reva Pharmaceuticals), demonstrated reduction of the drusen area in patients with drusen after weekly subcutaneous injections over 12 weeks. A phase II/III study is currently under way. Neuroprotection is another interesting area of research in dry AMD, said Prof Bandello, with promising early results of two neuroprotective therapies: ciliary neurotrophic factor-501 (CNFT) and brimonidine. Using a sustained release implant in a phase II trial of GA patients, CNFT showed a dose-dependent stabilisation of visual acuity, which was related to a retinal thickness increase at structural OCT. A phase II study of brimonidine, administered by an intravitreal biodegradable implant (Allergan), to evaluate the changes of GA area and best-corrected visual acuity in 119 patients with bilateral GA, did not show reliable data. A second multi-centre trial is ongoing and is expected to be completed in March 2019. Another novel approach to dry AMD treatment comes in the form of lipofuscin and visual cycle inhibitors, said Prof Bandello. Emixustat (Acucela), which works by reducing the accumulation of lipofuscin in the retinal pigment epithelium, has completed a phase II/III study but results are not yet available. Choroidal blood flow restoration agents are also being trialled in dry AMD, with compounds such as Alprostadil (UCB Pharma) and the vasodilator MC-1101 (MacuClear Inc) needing further studies to demonstrate their safety and efficacy, he said. A variety of stem cell therapies using human pluripotent stem cells, embryonic (hESC) or induced (iPSC) are also currently being investigated in clinical trials for AMD, and definitely merit further investigation, concluded Prof Bandello.