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    Pipeline for dry AMD features diverse compounds

    Investigational agents represent several strategies; complement inhibition shows most promise to date

     

    Blocking pathways

    Dr. Rosenfeld noted that lampalizumab blocks only one of the three pathways of complement activation. In contrast, the investigational agent APL-2 (Apellis Pharmaceuticals) inhibits C3 activation and blocks all three pathways of complement activation.

    APL-2 is a reformulated version of POT-4 (Potentia), which was shown to be safe and well-tolerated as an intravitreal injection in initial clinical testing.

    However, POT-4 formed a gel-like deposit in the vitreous that did not fully dissolve, Dr. Rosenfeld explained.

    APL-2 is now being investigated in a randomized phase II study where it is being given monthly or every other month for 12 months. Follow-up will continue to 18 months.

    LFG316 (Alcon), a monoclonal antibody against C5 in the complement pathway, is also being investigated as an intravitreal injection in two studies—one in which it is being administered as monotherapy and the other where it is being given in combination with CLG561, a drug that inhibits another complement pathway protein known as properdin.

    At the Angiogenesis, Exudation, and Degeneration 2016 meeting in February, Novartis reported that CLG561 did not slow the enlargement of GA in the phase II study. The combination trial with CLG561 and LFG316 is ongoing.

    Alternative approaches

    Visual cycle modulation is another strategy being looked at as a treatment for GA, and is represented by emixustat (Acucela). By inhibiting RPE65, emixustat prevents isomerization of 11-trans-retinal to 11-cis-retinal and thereby suppresses rod photoreceptor function.

    Emixustat is being evaluated as a once daily oral medication at three different doses in a Phase 2/3 study.

    Two other investigational modalities for GA related to AMD are being developed as neuroprotective agents. One is an anti-amyloid ß antibody (GSK933776, GlaxoSmithKline) being studied as a monthly intravenous infusion at three different doses.

    “Amyloid accumulates in the back of the eye and activates complement,” Dr. Rosenfeld said. “The goal of this treatment is to leach ß -amyloid out of the tissue of concern.”

    In addition, brimonidine (Allergan) is being pursued as an intravitreal treatment. It is currently in a phase II study in which patients are being randomly assigned to receive a 0.40 mg brimonidine implant or sham every 3 months.

    Stem cell therapy for GA is also under investigation in phase II trials. One company (Ocata Therapeutics) is developing a subretinal injection of fully differentiated human embryonic stem cells that are differentiated to RPE cells.

    “The phase I study with the Ocata stem cells had good safety outcomes and some encouraging visual acuity data,” Dr. Rosenfeld said.

    StemCells Inc. also reported encouraging phase I data, but its phase II study has been suspended pending additional funding. Additional phase 1 studies are under way in the United States, Europe, and Asia.

     

     

     

    Philip J. Rosenfeld, MD, PhD

    E: [email protected]

    This article is based on Dr. Rosenfeld’ presentation at the 2015 meeting of the American Academy of Ophthalmolgoy. Dr. Rosenfeld receives research grants and/or consults for several companies that are developing treatments for geographic atrophy related to age-related macular degeneration.

     

     

     

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