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Jason S. Slakter, Michael J. Tolentino, Brian B. Berger, Joel Pearlman, Robert Noble, Li Ye, Chun-Fang Xu, Ronald P. Danis, Megan McLaughlin, Robert Kim; A Phase I/II Study of Oral Pazopanib, a Receptor Tyrosine Kinase Inhibitor, in Neovascular Age Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2038.
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Pazopanib is an anti-angiogenic agent inhibiting the VEGF receptors -1, 2, and 3, PDGF receptors -α and -β, and the stem cell factor receptor (c-kit). It has been approved for the treatment of advanced renal cell carcinoma, and is under clinical investigation for the treatment of neovascular AMD and several cancers. Pazopanib has demonstrated activity in preclinical models of ocular neovascularization and in a Phase IIa clinical study, following eye drop administration. The purpose of the study was to evaluate the safety, tolerability, efficacy, pharmacokinetics and exploratory pharmacogenetics and response of oral pazopanib, administered to neovascular AMD patients.
A multicenter, open-label Phase I/II study of patients with occult and minimally classic subfoveal choroidal neovascularization (CNV) secondary to AMD was conducted. CNV inclusion criteria were determined by central reading center determination of fluorescein angiography and spectral domain OCT. 15 mg oral pazopanib was administered once daily for 28 days. Safety, change from baseline to Day 29 for best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were the main endpoints.
There were no SAEs, withdrawals due to AEs, or clinically significant systemic safety findings. Ocular AEs were consistent with disease progression or rescue therapy. Prior to the Day 29 assessments, six of 15 patients received intravitreal anti-VEGF rescue therapy at the discretion of the investigator. Statistically significant mean increase in BCVA 8.0 (95% CI 0.1, 15.9) ETDRS letters and mean decrease in CRT -50.3 (95% CI= -100.1 , -0.4) microns were observed in the per protocol population on Day 29 (N=9). There was a trend for an association between CFH Y402H genotype and response to oral pazopanib, although a formal statistical analysis was not performed due to limited sample size.
15 mg oral pazopanib eye drops administered to neovascular AMD patients was well tolerated and resulted in mean improvements in vision and retinal edema. An exploratory subgroup analysis suggested patients carrying a T allele of CFH Y402H had improved outcomes, similar to previous findings with anti-VEGF agents and pazopanib.
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