Retinal Physician

JAN-FEB 2017

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22 R E T I N A L P H Y S I C I A N . C O M | M A Y 2 0 1 3 22 R E T I N A L P H Y S I C I A N | J A N U A R Y / F E B R U A R Y 2 0 1 7 reducing the treatment burden. CLG561 and LFG316 (Alcon, Fort Worth, TX) are also aimed at the complement pathway in GA, but with different targets. CLG561 inhibits a complement path- way protein called properdin, while LFG316 is a mono- clonal antibody designed as a complement C5 inhibitor. In a proof-of-concept 114-patient study, Alcon is look- ing at CLG561 as both a monotherapy and in combina- tion with LFG316. APL-2 is a conjugate of a synthetic cyclic peptide that broadly targets the complement cascade at the C3 level, where three complement pathways converge. Apellis believes its approach can block all effects of the complement cascade regardless of which pathway exces- sively or uncontrollably activated the complement. APL-2 is now in a phase 2 trial. Apellis was spun off from its former parent company, Potentia, in 2010; Apellis acquired all the intellectual property relating to APL-2 from Potentia in 2014. NEUROPROTECTION Almost a decade ago, Allergan (Dublin) began to study its glaucoma drug brimonidine (now known as Alphagan) as a potential treatment for GA because it had demonstrated neuroprotective qualities in the com- pany's animal studies. In addition, the specific receptor target of brimonidine is in the retina, which is important in achieving optic neuroprotection. In a 119-patient study begun in 2008, the drug, an alpha-2 adrenergic receptor agonist, was delivered via an intravitreal implant at higher concentration than its usual use as a topical glaucoma treatment. At one year, results were equivocal and a second clinical trial was indicated to obtain stronger data. This second study, called BEACON, has 311 patients. This study is ongoing, with each patient receiv- ing 400 microns of brimonidine via intravitreal implant every three months for 21 months. Primary endpoint is change in the GA lesion area at two years. Secondary endpoints are change in BCVA and change in low-lumi- nance BCVA. BLOCKING THE FAS PATHWAY David N. Zacks, MD, PhD, of the Kellogg Eye Center, University of Michigan, has spent more than 15 years studying photoreceptor cell death and its impact on vision loss. His conclusion: Inhibiting the FAS-pathway through medical intervention is key to stopping unwanted photoreceptor cell death (apoptosis) in retinal detachment, wet and dry AMD, geographic atrophy, and diabetic retinopathy. Though blocking the FAS pathway is a specific therapeutic goal, it could well come under the broader category of neuroprotection. The first human clinical trials of the neuroprotec- tive ONL1204 peptide drug that Dr. Zacks' spin-off company ONL Therapeutics (Ann Arbor, MI) will be conducting are still at least one year away. The 25,000 annual US cases of "macula-off " retinal detachment are the initial targets. This is an area of treatment for which surgical results have been excellent, but visual outcomes almost uniformly poor, with average BCVA at one year after surgery at 20/70 — with many patients' visual out- comes much worse than that. "The photoreceptor cell death that takes place between the time the retinal detachment occurs and the reattachment surgery is significant," says Dr. Zacks. "That lost vision is not being regained. Our goal is to get our ONL1204 drug [an analogue of the small-molecule peptide Met12] injected into the patient's eye as quickly as possible to shut off the FAS pathway and stop the cell death, which should allow much better visual outcomes in retinal detachment surgery." Dr. Zacks says ONL1204 should also be able to pro- vide neuroprotection in geographic atrophy, treating the root cause of vision loss in GA, which is photoreceptor cell death. CELL THERAPY e Janssen (Beerse, Belgium) drug development division of Johnson & Johnson has for several years been pursuing an initiative using cell therapy in an attempt to reverse the vision loss associated with geographic atrophy. GEOGRAPHIC ATROPHY NOW IN RESEARCHERS' SIGHTS The most common targets for investigational GA therapies are the complement factors and complement factor pathways that have been shown to play a role in the development of retinal diseases.

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