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Juergen Klar, Michael Karl Boettger, Julia Freundlieb, Joerg Keldenich, Pierre-Paul Elena, Georges von Degenfeld; Effects of the multi-kinase inhibitor regorafenib on ocular neovascularization. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):246.
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© ARVO (1962-2015); The Authors (2016-present)
Regorafenib is a multi-kinase inhibitor that potently blocks VEGF receptor signaling. Here, we investigated the efficacy of regorafenib on ocular neovascularization in two disease-relevant models of wet AMD in two species.
Different doses of regorafenib administered p.o. or topically in early and delayed treatment regimens were tested regarding the reduction of vascular leakage and/or neovascularization in the rat laser-induced choroidal neovascularization (CNV) model. As a second disease-relevant model, the oxygen induced mouse retinopathy (OIR) model was employed.
Regorafenib showed dose-dependent reduction of vascular leakage and neovascularization in the rat CNV model. The mean angiography score in the control group was 2.4±0.8 (all data presented as mean±SD; n=8) and was reduced to 2.4±0.7, 2.2±0.8 and 1.5±0.8 (n= 8) by Regorafenib at 1, 3 and 8 mg/kg, respectively. The volume of choroidal neovascularization was likewise reduced from 210209±52055 μm³ (n= 8) in the untreated rats to 192662±52055 μm³, 182360±97054 μm3 and 114256±37265 μm³ (n= 8) compared to the rats dosed with 1, 3 and 8 mg/kg Regorafenib PO, respectively. Regorafenib at 8mg/kg also significantly reduced vascular leakage and neovascular volume at day 21 when treatment start was delayed to 7 days after laser injury. In this delayed setup the mean score in the control group was 1.96±0.55 (n=6) and reduced to 1.1±0.28 by 8mg/kg Regorafenib (n=8; p=0.0012). The volume of choroidal neovascularization was 366729±76875 μm³ (n=6) in the vehicle group and reduced to 143234±114156 μm³ (n=8; p=0.0025) by 8 mg/kg Regorafenib.<br /> In addition, Regorafenib formulated as an eye drop suspension at 20 mg/mL, administered twice daily, reduced vascular leakage and neovascularization by 30.6% and 34.0% (p<0.0001), respectively, when compared to controls in the rat laser CNV model.<br /> In the OIR model the retinal vessel area was 45.3% ± 7.0% (mean±SD; n=19) for the control group and reduced by Regorafenib (2.5 mg/kg) or Regorafenib (10 mg/kg) administered IP once daily to 29.0% ± 11.1% (n=17; p<0.0001) or 17.9% ± 6.0% (n=17; p<0.0001), respectively.
Currently available treatment options require injection(s) into the eye by a physician. An eye drop formulation would be non-invasive and self-administered by patients. Regorafenib shows efficacy in two different rodent models of ocular neovascularisation.
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