Development of Anti-VEGF Therapies for Intraocular Use: A Guide for Clinicians (original) (raw)

Targeting VEGF in eye neovascularization: What's new?

Pharmacological Research, 2016

Roughly ten years ago the FDA approved most of the presently used anti-VEGF drugs for the treatment of neovascular AMD and other eye pathologies characterized by ocular neoangiogenesis. However, the recent findings on the physiologic activities of VEGF isoforms impose to reconsider the inhibitory effects of pan-VEGF antagonists and the concept that to face pathological alterations at ocular level is possible only through the full block of all VEGF isoforms. In fact, although pan-VEGF agents rapidly and effectively contrast ocular neovascularization, vascular leakage, and other pathological changes, in the long-term the inhibition of all VEGF isoforms likely may result in the loss of the physiologic effects exerted by VEGF 121 and the anti-angiogenic VEGF 165 b. Notably, selective inhibitors of VEGF 165 a, such as pegaptanib, spare these targets. Moreover, preclinical and clinical evidence suggests that also systemic side effects, secondary to intraocular treatment with non-selective anti-VEGF drugs, may be reinterpreted in light of these recent findings, which may be useful to clinicians for the choice of the most appropriate anti-VEGF agent. Another aspect that should be considered is the involvement of VEGF-independent pathways in ocular neovascularization, therefore a combined therapy can represent a more effective pharmacological approach that might help also to counteract tachyphylaxis, an important issue in anti-VEGF treatment. This complex picture and the recent findings on current anti-VEGF drugs should be therefore taken into account to guide the development of novel agents targeting VEGF and/or other key factors involved in the pathogenesis of neovascular ocular diseases along the signaling pathways stimulated by the various isoforms. Accordingly, this review also reports on novel pharmacological molecules targeting VEGF at ocular level and currently under development, with a special attention to oligonucleotide-based interventions.

A novel small molecule ameliorates ocular neovascularisation and synergises with anti-VEGF therapy

Ocular neovascularisation underlies blinding eye diseases such as retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. These diseases cause irreversible vision loss, and provide a significant health and economic burden. Biologics targeting vascular endothelial growth factor (VEGF) are the major approach for treatment. However, up to 30% of patients are non-responsive to these drugs and they are associated with ocular and systemic side effects. Therefore, there is a need for small molecule ocular angiogenesis inhibitors to complement existing therapies. We examined the safety and therapeutic potential of SH-11037, a synthetic derivative of the antiangiogenic homoisoflavonoid cremastranone, in models of ocular neovascularisation. SH-11037 dose-dependently suppressed angiogenesis in the choroidal sprouting assay ex vivo and inhibited ocular developmental angiogenesis in zebrafish larvae. Additionally, intravitreal SH-11037 (1 μM) significantly reduced choroidal neovascularisation (CNV) lesion volume in the laser-induced CNV mouse model, comparable to an anti-VEGF antibody. Moreover, SH-11037 synergised with anti-VEGF treatments in vitro and in vivo. Up to 100 μM SH-11037 was not associated with signs of ocular toxicity and did not interfere with retinal function or pre-existing retinal vasculature. SH-11037 is thus a safe and effective treatment for murine ocular neovascularisation, worthy of further mechanistic and pharmacokinetic evaluation. Neovascular eye diseases are a major cause of blindness throughout life. Between 6% and 18% of childhood blindness is attributable to retinopathy of prematurity (ROP) 1. The disease is estimated to cause vision loss in 1300 children a year in the USA, and severe visual impairment in a further 500 2. Meanwhile, proliferative diabetic retinopathy (PDR) affects an estimated 17 million adults of working age worldwide, or 7% of the growing diabetic population 3. Finally, almost 2 million elderly Americans are affected by " wet " age-related macular degeneration (AMD) 4. Wet AMD has an estimated loss of productivity burden of $5.4 billion annually in the United States 5. These diseases are characterised by the development of new blood vessels in the eye: either retinal (in ROP and PDR) or choroidal neovascularisation (CNV), where blood vessels grow into the sensory retina, causing hemorrhage and severe vision impairment 6. A standard treatment for these blinding diseases involves biologic drugs (bevacizumab, ranibizumab and aflibercept) that target vascular endothelial growth factor (VEGF), the most dominant angiogenic mediator in the eye 7–9. These biologics successfully slow or even reverse vision loss in about 70% of wet AMD patients 10 , and are now being used for ROP and PDR. However, repeated intravitreal injections of anti-VEGF drugs can be associated with ocular and systemic side effects such as ocular haemorrhage and stroke 9,11,12. Moreover, about 30% of wet AMD patients are non responsive to anti-VEGF treatments 13. Therefore, there is an unmet need to develop new antiangiogenic molecules to complement and combine with these existing approaches. Such novel therapies might also be useful for other neovascular diseases, including cancers.

VEGF and Intraocular Neovascularization: From Discovery to Therapy

Translational Vision Science & Technology, 2016

I am honored and humbled to be one of the awardees of the 2014 A. Champalimaud Vision Award. I offer my heartfelt thanks to the Champalimaud Foundation President, Leonor Beleza, and to the Award Committee Members for this wonderful recognition. I feel especially fortunate to have had the opportunity to witness my scientific discoveries move from the bench to the clinic. Scientific discovery is hugely exciting, but the ability to translate that work into potentially helping someone lead a better life is even more fulfilling. This Award is dedicated to the patients.

Corneal Neovascularization: An Anti-VEGF Therapy Review

Survey of Ophthalmology, 2012

Corneal neovascularization is a serious condition that can lead to a profound decline in vision. The abnormal vessels block light, cause corneal scarring, compromise visual acuity, and may lead to inflammation and edema. Corneal neovascularization occurs when the balance between angiogenic and antiangiogenic factors is tipped toward angiogenic molecules. Vascular endothelial growth factor (VEGF), one of the most important mediators of angiogenesis, is upregulated during neovascularization. In fact, anti-VEGF agents have efficacy in the treatment of neovascular agerelated macular degeneration, diabetic retinopathy, macular edema, neovascular glaucoma, and other neovascular diseases. These same agents have great potential for the treatment of corneal neovascularization. We review some of the most promising anti-VEGF therapies, including bevacizumab, VEGF trap, siRNA, and tyrosine kinase inhibitors.

Anti-VEGF for the management of diabetic macular edema

Journal of immunology research, 2014

Diabetic retinopathy (DR) is an important cause of vision loss around the world, being the leading cause in the population between 20 and 60 years old. Among patients with DR, diabetic macular edema (DME) is the most frequent cause of vision impairment and represents a significant public health issue. Macular photocoagulation has been the standard treatment for this condition reducing the risk of moderate visual loss by approximately 50%. The role of vascular endothelial growth factor (VEGF) in DR and DME pathogenesis has been demonstrated in recent studies. This review addresses and summarizes data from the clinical trials that investigated anti-VEGF for the management of DME and evaluates their impact on clinical practice. The literature searches were conducted between August and October 2013 in PubMed and Cochrane Library with no date restrictions and went through the most relevant studies on pegaptanib, ranibizumab, bevacizumab, and aflibercept for the management of DME. The eff...

Anti-VEGF in treatment of central retinal vein occlusion

Collegium antropologicum, 2010

Macular edema along with macular ischemia is responsible for decreased visual acuity in central retinal vein occlusion. Bevacizumab (Avastin, Genentech) blocks vascular endothelial growth factor (VEGF) induced hyperpermeability of blood vessels. In this prospective case series we investigated the efficacy of anti-VEGF treatment in reduction of central retinal thickness (CRT) and improvement in visual acuity (VA). 25 patients were followed up for 12 months and treated monthly with intravitreal bevacizumab. VA and CRT were measured at each visit. Treatment was discontinued as the peak improvement of either parameter was reached and reinstituted in case of deterioration/recurrence of edema. Study endpoints included: VA using ETDRS charts, CRT and number of injections at 12 months. Mean VA from all 25 patients increased by 3.1 logMAR lines (p < 0.05 compared to baseline). The improvement of VA after bevacizumab injection was in correlation with a decrease in CRT In subgroup analyses,...

Vascular endothelial growth factor and its inhibitor in age-related macular degeneration

Taiwan Journal of Ophthalmology, 2013

Intraocular angiogenesis is considered the leading cause for severe loss of vision, and contributes to many ocular diseases such as neovascular age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity, the main causes of blindness in developed countries. 1 An enormous body of work has demonstrated that vascular endothelial growth factor (VEGF) plays a prominent role as mediator in the procedure of pathological angiogenesis. This makes VEGF a potential target for the medical therapies of retinal angiogenesis and some clinical trials have proved the efficacy of anti-VEGF strategies. This review evaluates the role of VEGF in the pathogenesis of age-related macular degeneration and provides an overview of recent developments in therapeutic modalities.