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Q. D. Nguyen, T. Ong, S. M. Shah, the B0451008 Study Group; Interim Results of the Phase 1, Open-Label, Dose-Escalation Study of Intravitreal siRNA PF-04523655 in Patients With Choroidal Neovascularization Secondary to Exudative Age-Related Macular Degeneration: Safety, Tolerability, and Bioactivity. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3092.
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PF-04523655 is a small interfering RNA (siRNA) of 19 nucleotides in length which acts via RNA interference to inhibit the expression of the hypoxia-inducible gene RTP801. RTP801 is a stress-response gene mediating the shut down of the mammalian target of rapamycin (m-TOR) pathway. The primary objective of the study is to determine the safety and tolerability of intravitreal (ITV) injection of PF-04523655 in subjects with neovascular AMD, while exploring the potential bioactivity of siRNA in the treatment of patients with choroidal neovascularization.
In this phase 1, single ITV injection, open-label, dose-escalating study, patients with neovascular AMD who were treatment naïve or had received prior therapy, including pegaptanib, ranibizumab, and others, and whose visual acuity (VA) was ≤ 20/100 were eligible. After the initial single injection with PF-04523655, VA and retinal thickness were measured at 1, 7, and 14 days after the initial ITV injection through to day 28. Subjects were eligible for rescue therapy if they did not show a VA improvement of at least 5 letters and/or a reduction in retinal thickness of at least 50 µm at day 14.
No drug-associated ocular or systemic adverse events were noted. Among the 13 subjects enrolled in the study, nine were treatment-naïve (mean disease duration of 15 months, range 2 days to 5 years); four had one to 13 treatments prior to study entry. Eight subjects did not meet eligibility for rescue at day 14. Visual acuity and optical coherence tomography measurements in the 8 subjects not eligible for rescue at Day 14 were evaluated again at Day 28. At this time point, these subjects showed a mean improvement in VA of +8 letters (standard deviation: +12.25; range: -3 to +28 letters; n = 6 as 2 subjects were rescued despite not being eligible for rescue). One subject was also treatment naïve and showed a VA improvement of 40 letters at day 14. Three other subjects who have had refractory responses to other therapy demonstrated a visual gain of 7.6 letters.
Interim results have supported the safety of intravitreal PF-04523655 in patients with neovascular AMD. Approximately 80% of subjects showed stable or improved vision two weeks after a single injection of the siRNA. Additional studies are being conducted to investigate the role of PF-04523655 in the management of neovascular AMD.
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