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Wenhu Huang, Mark Zorbas; A 49-Week Chronic Study of PF-04523655 Given by Intravitreal Injection to Cynomolgus Monkeys with a 13-Week Interim Evaluation. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5365.
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PF-04523655, a synthetic and chemically-modified 19 base-pair siRNA designed to temporarily inhibit expression of the RTP801 gene, is currently in Phase II trials for the treatment of wet AMD and DME. Preclinical studies have shown a dose-related suppression of RTP801 expression in rat CNV and DME models. A GLP chronic toxicity study was conducted to evaluate the safety profile of PF-04523655 following intravitreal administration in the monkey to support Phase II repeat dose clinical studies.
Male and female cynomolgus monkeys (Macaca fascicularis) received monthly bilateral intravitreal injections of vehicle control (phosphate buffered saline; PBS), or 0.3, 1, or 3 mg/eye of PF-04523655 in a dose volume of 50 µL for 13 or 49 weeks (4 or 13 doses given at monthly intervals). The main study groups were sacrificed 4 days after the last dose. Recovery animals sacrificed 4 weeks following the last dose were included in the vehicle control and high-dose (3 mg/eye) groups. Assessment of toxicity was based on mortality, clinical signs, electrocardiography, ophthalmic examinations, ocular photography, intraocular pressure measurements, electroretinography, clinical and anatomic pathology, and immunogenicity/ antigenicity evaluations.
PF-04523655 was well tolerated based on clinical signs. Intravitreal administration of both the vehicle control (PBS) or PF-04523655 test material typically resulted in mild and reversible mid anterior segment and vitreal inflammatory response, the severity of which was comparable between the control group and PF-04523655 treatment groups, whereas the incidence of these findings was greater in eyes receiving 3 mg/eye (high-dose group). Posterior lens capsular haze was noted in three males given 3 mg/eye started on week 16 and was transient in two animals and progressed to an incipient posterior capsular cataract in one animal. As for the neural retina, there was no test article related finding in histopathology, electroretinogram, or ophthalmic examinations. In addition, no changes were noted on body weight or electrocardiographic parameters that were attributable to test article treatment.
The test article, PF-04523655, when administered monthly via bilateral intravitreal injection to cynomolgus monkeys, was well tolerated following 49 weeks of treatment. Procedure-related mild and transient ocular inflammation was noticed in all treatment groups. The cataract in one high dose animal was considered adverse. There was no clinical, histomorphologic or electroretinographic evidence of a test article-related effect on the retina.
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