Beyond anti-VEGF

As it becomes clear that anti-vascular endothelial growth factor (anti-VEGF) agents are not sufficient by themselves to provide long-term treatment of neovascular age-related macular degeneration (AMD), researchers are looking for effective additive treatments. “We have more or less reached the ceiling of anti-VEGF efficacy. Aflibercept, bevacizumab and ranibizumab have similar efficacy, and increasing the dosage or regimen does not substantially enhance visual outcome for most patients,” said Marco Zarbin, of the New Jersey Medical School, Rutgers University, New Jersey, USA. Dr Zarbin made these comments at a symposium, entitled 'Neovascular AMD: Novel Insights & Lessons Learned', which featured a series of presentations that provided both a coherent overview of the current state-of-the-art in neovascular AMD and a detailed examination of what has been learned to date. Dr Zarbin led attendees through the current state of the so-called 'pathway-based' therapy of AMD-related choroidal neovascularisation. “Every step of the angiogenesis sequence is being examined for potentially clinically relevant targets. The anti-VEGF molecules bind the angiogenic factors that have been released, but researchers have investigated molecules, such as sirolimus, bevasiranib and everolimus, intended to decrease the factors’ production in the first place,” he reported. Once the angiogenic factors have been produced, and if they make it past the anti-VEGF treatment, they bind to specific receptors on the vascular endothelial cells in order to initiate intracellular signalling. Squalamine, pazopanib, and vatalanib are intended to target this step, he said. CELL MEMBRANES Squalamine, an angiostatic steroid derived from the dogfish shark (Squalus acanthias) binds to cell membranes and interferes with signals initiated by the binding of growth factors to the cell. “A phase 2b trial by Ohr Pharmaceutical of 128 patients studied combination therapy of squalamine eye drops plus ranibizumab,” said Dr Zarbin. This study showed potentially beneficial results in terms of both letters gained and subsequent ranibizumab injection frequency. The phase 3 study is under way, with data expected in December 2017. Other steps being targeted include endothelial cell activation and proliferation, directional migration, extracellular matrix remodelling, vascular formation and, finally, vascular stabilisation. “At this relatively late point in the cascade, pericytes are protecting the endothelium, leading to one mechanism of resistance to anti-VEGF treatment,” said Dr Zarbin. A study in 1998 identified a 'plasticity window' for blood vessel remodelling, defined by pericyte coverage of the preformed endothelial network and is regulated by platelet-derived growth factor B (PDGF B). Once pericytes have intimate interactions with vascular endothelial cells, the pericytes become a source of VEGF that allows tumour vasculature to sidestep VEGF blockade mediated by exogenous anti-VEGF agents. Research into oncologic treatments outlined the benefits of targeting both pericytes (via PDGF B blockade) and endothelial cells (via anti-VEGF agents) in tumour vasculature. COMBINATION THERAPY “That’s where Fovista® comes into the equation,” he said. Fovista (pegpleranib) is an aptamer directed at PDGF B that is undergoing trials by Ophthotech. The goal is to antagonise both endothelial cell activation and vascular stabilisation using combination therapy. In a large phase 2 trial, among patients treated with 1.5mg Fovista plus 0.5mg Lucentis, the mean visual acuity of patients at week 24, a pre-specified primary endpoint, showed 62% additional benefit when compared to Lucentis monotherapy. A recently completed phase 3 trial compared combination of Fovista plus anti-VEGF versus anti-VEGF monotherapy using ranibizumab. In contrast to the phase 2 results, there was no significant difference in visual outcome among patients treated with combination therapy versus ranibizumab monotherapy. The phase 2 trial was of six months duration, whereas the phase 3 trial was of one year duration. Additional phase 3 trials involving combination therapy of Fovista with aflibercept or bevacizumab are in progress. VEGF has a potent enhancer, angiopoietin 2 (Ang2). This molecule increases the responsiveness of retinal vessels to VEGF and promotes vascular leakage and neovascularisation. With this in mind, both Genentech/Roche and Regeneron are targeting Ang2, he said. Now that new molecules are in the pipeline, further questions will arise as to how they should be used. “Should we try to block several molecules simultaneously, as RG7716 does with VEGF-A and Ang2? Or should treatment focus on sequential targeting, as suggested by Dr Pravin Dugel and colleagues based on a study using Fovista and ranibizumab?” asked Dr Zarbin. In any case, combination therapy should be both pathway-specific and synergistic, allowing us to break through the ceiling of efficacy that we currently encounter, he concluded. Marco Zarbin: zarbin@rutgers.edu

Tags: retina