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Pravin U Dugel, Derek Kunimoto, Edward Quinlan, Karim Jamal, David Goldenberg, Sachin Mehta, Matthew Witmer, Mark Barakat, Milad Hakimbashi; Anti-VEGF resistance in neovascular AMD: Role of PDGF antagonism. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2826.
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Dual inhibition of VEGF/PDGF has been shown to enhance visual outcome in NVAMD patients compared to monotherapy anti-VEGF in a phase 2b controlled study. Anti-VEGF therapy is associated up-regulation of PDGF, a survival factor for pericytes. Pericyte coverage of neovascular endothelial cells is implicated as a potential mechanism for anti-VEGF resistance in pathologic neovascularization (NV). Anti-VEGF therapy is also known to up-regulate PDGF. Monotherapy anti-PDGF administration prior to dual PDGF/VEGF combination therapy may strip the pericyte component of NV thereby increasing the subsequent anti-VEGF sensitivity of NV endothelial cells and counter the expected PDGF up-regulation. We investigated this potential effect in a subgroup of NVAMD patients with sub-optimal anti-VEGF monotherapy response.
30 patients (n=3 treatment naïve, n=27 with prior anti-VEGF therapy) with NVAMD are enrolled in an ongoing open label sub-foveal fibrosis study (24 months). This study assessed the role of monotherapy IVT FovistaTM 1.5mg (anti-PDGF-B) administered ~24 hours prior (“with pre-treatment”) to combination therapy with FovistaTM 1.5mg and anti-VEGF (Lucentis®, Avastin® or Eylea®). In the subgroup of patients with prior anti-VEGF monotherapy (average of 25 prior IVT treatments/pt.), judged to be “suboptimal anti-VEGF responders” (n=27), visual outcome was evaluated following three monthly loading doses of combination therapy (n=10 “with pre-treatment”, n=17 “without pre-treatment”). Baseline VA was 52.3 and 56.8 ETDRS letters in patients with and without FovistaTM “pre-treatment” respectively.
At 3 months following three FovistaTM combination therapy loading doses, visual acuity improved by +17.6-ETDRS letters in the treatment naïve group (n=3) and +7.1 ETDRS letters in the “suboptimal anti-VEGF responder” group (n=27). “Suboptimal anti-VEGF responder” patient sub-group “with pre-treatment” (n=10) gained an average of +11.1 ETDRS letters versus +4.7 ETDRS letters in those “without pre-treatment” (n=17) at three months.
PDGF inhibition prior to dual antagonism of PDGF/VEGF may augment the sensitivity of endothelial cells to anti-VEGF effects by enhancing the pericyte stripping of NV tissue and may optimize blockade of anti-VEGF induced PDGF up-regulation in treatment resistant NVAMD patients.
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