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David G. Birch, John W. Chandler, Al Reaves, John Koester, Ryo Kubota; Prolonged Rod Visual Cycle Suppression with ACU-4429 in Patients with Geographic Atrophy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2044.
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ACU-4429 is an oral drug in clinical development for the treatment of atrophic age-related macular degeneration (AMD). ACU-4429 has been shown to inhibit isomerase (RPE65) activity in pre-clinical studies and, as a visual cycle modulator, may decrease levels of toxic by-products such as A2E linked to the progression of dry AMD. In this interim analysis, electroretinograms (ERGs) were assessed to determine whether the degree of visual cycle inhibition, as measured by rod ERG recovery following bleaching light exposure, is dose dependent in patients with geographic atrophy.
In this 90-day dose-escalation study, subjects with the advanced form of dry AMD (geographic atrophy) received ACU-4429 (2, 5, 7, or 10 mg) or placebo orally once a day. Pupils were dilated and after 30 minutes of dark adaptation ISCEV standard computer-averaged full-field ERGs were recorded from both eyes. Subjects then received 3 minutes exposure to a bright, bleaching light and ERGs were recorded immediately and at 10, 20, and 30 minutes. Rod b-wave amplitudes in each eye were expressed as the percentage of the prebleach dark-adapted rod amplitude from the baseline visit. The degree (%) of suppression of the rod response was then quantified from the slopes of the recovery functions.
Forty-two subjects received ACU-4429 and 14 received placebo. The slopes and corresponding percentages of rod ERG suppression vs placebo were dose dependent. Results for Day 14 are presented in the table. Times between Day 14 and 90 had similar results. ERGs returned to baseline by 2 weeks after the final dose.
Administration of ACU-4429 to subjects with dry AMD resulted in a dose-dependent suppression of ERG b-wave recovery. It remains to be determined whether suppression of the visual cycle will also modulate processes that produce A2E and slow the progression of geographic atrophy.
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