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D. H. McGee, E. I. Goldenthal, D. Gauvin, R. Kubota; Nonclinical Profile of a Novel Visual Cycle Modulator for Oral Treatment of Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1460.
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The visual cycle involves a series complex sequence of reactions allowing a signal cascade from phototransduction to electrophysiological activity resulting in light perception and vision. The accumulation of toxic visual cycle by-products is associated with retinal degeneration, and inhibition of this process is hoped to retard or prevent this, and preserve vision. ACU-4429 is a small-molecule inhibitor of the enzymatic isomerization of all trans retinol to 11-cis retinol in the visual cycle, a step necessary in the replenishing of rhodopsin in the retinal. ACU-4429 inhibits recombinant human isomerohydrolase activity in vitro, with an IC50 of 4.4 + 1.3 nM and the isomerization reaction in mice following oral gavage administration, with an ED50 of 0.18 mg/kg.
A series of nonclinical toxicology studies was conducted with ACU-4429 to support early clinical development. These studies were conducted in multiple species and included single and repeated-dose studies (up to 28 days in duration), genotoxicity studies, safety pharmacology studies and assorted special studies.
ACU-4429 was not genotoxic in two in vitro assays, and did not cause significant inhibition of hERG channel activity (IKr IC50 = 13.6 µM). No significant effects on behavior, CNS and pulmonary function in rats (gavage) or cardiovascular function in conscious telemetered dogs (capsule) were see following oral doses of up to 30 mg/kg. Single dose toxicity studies in rats approximated an oral medial lethal dose of > 300 mg/kg in rats. A dog MTD study showed no significant toxicity at doses of up to 100 mg/kg, though dosing was limited by emesis. A 28 day studies in rats (oral gavage) showed no significant toxicity at doses of up to 100 mg/kg/day. Mortalities at the 300 mg/kg/day dose resulted in reduction to 200 mg/kg/day, with some mortalities occurring thereafter. Body weight and food consumption were significantly affected at the high dose (300/200 mg/kg/day), but not the mid (100 mg/kg/day) and low (30 mg/kg/day) doses. A 28 day studies in dogs (oral, capsule) showed no significant toxicity at up to and including 30 mg/kg/day, the highest dose employed.
Based on the results from the comprehensive nonclinical toxicology package, it was considered that ACU-4429 possesses a positive nonclinical safety profile, with significant margin of safety relative to anticipated clinical exposure, and the program was deemed adequate to support phase I trials.
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