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    Multiple strategies pursue treatment of dry AMD

    Reviewed by David S. Boyer, MD

    There are a number of ongoing clinical trials investigating treatments for dry age-related macular degeneration (AMD). These modalities include medications that are already in use for other indications and investigational agents representing various novel mechanisms of action.

    “There were also several agents being developed for dry AMD that failed in clinical trials,” said David S. Boyer, MD, clinical professor of ophthalmology, University of Southern California Keck School of Medicine, Los Angeles. “One of the major problems faced by researchers in this area is the absence of a good animal model for testing candidate drugs.”

    Neuroprotection to prevent loss of photoreceptors and retinal pigment epithelial (RPE) cells is one area of interest and a realm in which there have been several agents that failed to meet their endpoints in clinical trials. Intravitreal brimonidine (Allergan) is one treatment that is still being pursued.

    In preclinical studies, intravitreal brimonidine protected retinal ganglion cells, bipolar cells, and photoreceptors from insults that included ischemia, ocular hypertension, phototoxicity, and partial optic nerve crush. The drug is being evaluated in a phase II study, and there are some encouraging results showing it has biological activity as measured by reduction in geographic atrophy (GA) progression rates.

    Glatiramer acetate (Copaxone, Teva) is another existing drug in development as a treatment for dry AMD. It is an immunomodulatory agent that reduces accumulation of harmful byproducts. When given by subcutaneous injection, glatiramer acetate has shown to reduce drusen.

    “We do know, however, that drusen can diminish spontaneously,” Dr. Boyer said.

    Topical agent

    MC-1101 (MacuCLEAR) is a topically administered agent that aims to increase ocular blood flow in the choroidal vessels and prevent Bruch membrane rupture. A phase Ib proof-of-concept study was successfully completed. Its results showed MC-1101 reached the posterior segment when applied topically and increased choroidal blood flow.

    “If ischemia is involved in the etiology of dry AMD, hopefully MC-1101 will be helpful,” Dr. Boyer said. “A phase II/III vehicle-controlled, double-masked, single center study is currently underway,”

    Oral doxycycline (Oracea, Galderma Laboratories) is also being investigated in a phase II/III study of patients with GA secondary to dry AMD. Interest in using the tetracycline derives from its potential to affect multiple molecular pathways suspected as important in the pathogenesis of GA in AMD.

    “At low, subantimicrobial doses, tetracyclines have shown activity against reactive oxygen species, matrix metalloproteinases, caspase activation, complement activation, and various inflammatory cytokines,” Dr. Boyer explained. “In addition, there is evidence from preclinical studies that tetracyclines can protect human RPE cells against oxidative damage, attenuate photoreceptor degeneration in a murine model of hemorrhagic neovascular AMD, and reduce neovascularization and lesion volume in a murine laser model of choroidal neovascularization.”

    The ongoing phase II/III multicenter, placebo-controlled trial investigating doxycycline as a treatment for dry AMD (TOGA study) enrolled almost 300 patients.

    Focus on inflammation

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