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Pravin Dugel, Roger Novack, Karl Csaky, Preston Richmond, David Birch, Ryo Kubota; A Phase 2 Double-masked, Placebo-controlled, Dose Ranging Study of Emixustat Hydrochloride (ACU-4429) in Subjects with GA Associated with Dry AMD. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4506.
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Emixustat HCl is a novel orally administered agent in clinical development for the treatment of geographic atrophy (GA) associated with dry age-related macular degeneration (AMD). Emixustat HCl acts as a rod visual cycle modulator by inhibiting isomerase (RPE65) activity and reducing retinal toxins (eg, A2E) that damage the RPE and overlying photoreceptors. The purpose of the study was to assess the biologic activity and safety of emixustat in subjects with GA compared with placebo. Four dose levels (2, 5, 7, and 10 mg) and 2 dose regimens (AM and PM dosing) were evaluated.
: Subjects (n=72) were randomly assigned to emixustat HCl (2, 5, 7 or 10 mg AM, or 5 mg PM) or placebo orally daily for up to 90 days in a 3:1 ratio. Adverse events and other safety parameters were collected. After 30 min of dark adaptation, ERGs were recorded, then eyes were photo bleached and ERGs were recorded immediately and at 10, 20, and 30 min. Rod b-wave amplitudes were expressed as a percentage of the prebleach dark-adapted rod amplitude from baseline. The rate of rod recovery (slope) for each emixustat HCl group was compared to the placebo group.
Emixustat HCl suppressed ERG b-wave rod recovery after light exposure in a dose-related manner. Suppression plateaued by Day 14 of dosing, and reversed within 7-14 days after cessation. No systemic adverse events (AEs) of concern were noted. Chromatopsia and delayed dark adaptation were the most common ocular AEs. There were 2 subjects with a treatment-related serious AE (both were moderate chromatopsia; at 5 mg). All ocular AEs resolved upon drug cessation; most events were mild and no severe events were observed.
This proof of concept study demonstrated a dose-dependent biologic effect and emixustat’s ability to modulate the visual cycle. Despite oral dosing, systemic adverse events were minimal. The common ocular AEs are explainable based on the understood mechanism of action. Results suggest that emixustat HCl has the potential to be a useful agent in the treatment of geographic atrophy associated with dry AMD. A long-term Phase 2b/3 study is underway to evaluate emixustat HCl in GA subjects.
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