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Gene Signal has conducted a survey among members of the European Society of Ocular and Surface Disease Specialists (EUCORNEA) and of the European Eye Bank Association (EEBA). Topics included indications for keratoplasty, surgical techniques and management of patients with pre-graft corneal neovascularization.
Gene Signal has collected responses from 34 major European centres, corresponding to approximately 15 to 25% of the 20,000 keratoplasty procedures performed in the EU annually.
The outcome of this survey has provided a clear picture of the current medical practice in the EU, and will be instrumental in the design of the upcoming Phase III pivotal clinical trial with aganirsen 0.86 mg/mL eye drops. This survey also showed the continued interest of the EU cornea experts in aganirsen.
Ophthalmology 2014;-:1e10 2014 by the American Academy of Ophthalmology. Epub 2014 May 8 2014.
I-CAN is the first phase III RCT study of a topical inhibitor of corneal angiogenesis. The study showed that aganirsen eye drops significantly inhibited corneal neovascularization in patients with keratitis. The need for transplantation was significantly reduced in patients with viral keratitis and central neovascularization. Topical application of aganirsen was safe and well tolerated.
J Pharmacol Exp Ther. (JPET) 2014 Apr;349(1):107-17. doi: 10.1124/jpet.113.209346. Epub 2014 Feb 6.
The antiangiogenic insulin receptor substrate-1 antisense oligonucleotide aganirsen impairs AU-rich mRNA stability by reducing 14-3-3β-tristetraprolin protein complex, reducing inflammation and psoriatic lesion size in patients.
• Increased inflammation and aberrant angiogenesis underlie psoriasis. Here, we report that the inhibition of insulin receptor substrate-1 (IRS-1) expression with aganirsen resulted in a dose-dependent reduction (P < 0.0001) in IRS-1 protein in the cytoplasm, while IRS-1 protein remained quantitatively unchanged in the perinuclear environment.
• Aganirsen also inhibited (P < 0.001) in vitro the expression of interleukin-8 (IL-8), IL-12, IL-22, and tumor necrosis factor alpha (TNFα), four inflammatory mediators containing mRNA with AU-rich regions.
• To demonstrate the clinical relevance of this pathway, we tested the efficacy of aganirsen by topical application in a pilot, double-blind, randomized, dose-ranging study in 12 psoriatic human patients.
• After 6 weeks of treatment, least square mean differences with placebo were -38.9% (95% confidence interval, -75.8 to -2.0%) and -37.4% (-74.3 to -0.5%) at the doses of 0.86 and 1.72 mg/g, respectively.
• Lesion size reduction was associated with reduced expression of IRS-1 (P < 0.01), TNFα (P < 0.0001), and vascular endothelial growth factor (P < 0.01); reduced keratinocyte proliferation (P < 0.01); and the restoration (P < 0.02) of normal levels of infiltrating CD4(+) and CD3(+) lymphocytes in psoriatic skin lesions.
• These results suggest that aganirsen is a first-in-class of a new generation of antiangiogenic medicines combining anti-inflammatory activities. Aganirsen-induced downregulation of inflammatory mediators characterized by AU-rich mRNA likely underlies its beneficial clinical outcome in psoriasis. These results justify further large-scale clinical studies to establish the dose of aganirsen and its long-term efficacy in psoriasis..
“Anti-angiogenic activity of Aganirsen in non-human primate and rodent models of retinal neovascular disease following topical administration” Invest. Ophthalmol. Vis. Sci. (IOVS) February 9, 2012 iovs.11-9064"
The antiangiogenic activity of aganirsen was explored in animal models of retinal neovascularization - Nonhuman Primates after laser-induced choroidal neovascularization (CNV; model of wet age-related macular degeneration [AMD]) and in newborn rats after oxygen-induced retinopathy (OIR; model of ischemic retinopathy). Retinal aganirsen concentrations were also assessed in rabbits and monkeys after topical delivery (21.5, 43, or 86 μg). Clinical significance was further evaluated by determination of IRS-1 expression in monkey and human retinal biopsy specimens.
• CNV Model of AMD: Topical corneal application of aganirsen attenuated neovascular lesion development dose dependently in African green monkeys. The incidence of high-grade CNV lesions (grade IV) decreased from 20.5% in vehicle-treated animals to 1.7% (P < 0.05) at the 86-μg dose.
• OIR: Topical aganirsen inhibited retinal neovascularization after OIR in rats (P < 0.05); furthermore, a single intravitreal injection of aganirsen reduced OIR as effectively as ranibizumab, and their effects were additive. Significantly, topical applications of aganirsen did not interfere with physiological retinal vessel development in newborn rats.
“Consensus statement on indications for anti-angiogenic therapy in the management of corneal diseases associated with neovascularisation: outcome of an expert roundtable” http://www.ncbi.nlm.nih.gov/pubmed/21712359Br J Ophthalmol. 2012 Jan;96(1):3-9."
In this review, the authors formulate a consensus on the unmet medical needs in the management of corneal neovascularisation and outline a framework for the clinical research that is needed to identify suitable agents to meet these needs.
“Blockade of Insulin Receptor Substrate-1 inhibits corneal lymphangiogenesis“ Invest Ophthalmol Vis Sci (IOVS). 2011 Jun 10"
The study sought to analyze whether blockade of IRS-1 is involved in lymphatic vessel development and whether IRS-1 blockade can inhibit lymphangiogenesis in vivo. It was found that blockade of IRS-1 by Aganirsen inhibited lymphatic endothelial cell (LEC) proliferation dose dependently and decreased VEGF-A expression... In conclusion, blockade of IRS-1 inhibits not only hemangiogenesis but also lymphangiogenesis. To the authors' knowledge, this is the first evidence that IRS-1 is involved in the molecular pathway leading to lymphangiogenesis.
"Corneal Neovascularization as a Risk Factor for Graft Failure and Rejection after Keratoplasty: An Evidence-Based Meta-analysis" Ophthalmology 2010 Jul; 117(7):1300-5.e7
• Ophthalmology (July 1, 2010; 117(7)) | • Pub Med |
• English press release | • French press release |
The article highlights the results of topical administration of Aganirsen in nine patients for corneal neovascularisation associated with Penetrating Keratoplasty Graft Rejection.
• Access article |
Data published suggests Aganirsen (GS-101) provides safe & effective treatment for the management of corneal neovascularisation
“GS-101 antisense oligonucleotide eye drops inhibit corneal neovascularization: interim results of a randomized phase II trial”, Ophthalmology 2009; 116: 1630-1638"
“Aganirsen (GS-101) eye drops at the dose of 86µg /day (43 µg/drop) produced a highly significant regression of the corneal neovascularization (p=0.0047) together with a trend of an improvement of visual acuity. Compared to the placebo group with 100% ongoing progression of corneal neovascularisation over the 3-month period, the optimal treatment group achieved 86% regression and progression in only 14”, says Professor Claus Cursiefen at Friedrich-Alexander University in Erlangen-Nürnberg, Germany"
“Tolerability and safety of GS-101 eye drops, an Antisense Oligonucleotide to Insulin Receptor Substrate 1: a “first in man” phase I investigation”, British Journal of Clinical Pharmacology (BJCP) 2009, 68:2 (169–173)
The 14 healthy volunteers tolerated well 14 days’ continued use of escalating doses of GS-101 from 43 to 430 micrograms/day (5 times the therapeutic dose of 86 micrograms/day identified by Phase II Study). Other than itching experienced also in the control eye by one subject and determined to be unrelated to the study treatment, no signs of intolerance were observed. GS-101 is an antisense oligonucleotide that inhibits the expression of IRS-1 in pathological angiogenesis.
• Pub Med |
• Access manuscript |
Salvador Garcia-Delpech, MD, University Hospital of Valencia, Spain says:
”GS-101 acts on RNA regulating the production of VEGF, but unlike classical anti-VEGF agents, it does not completely suppress the VEGF”
"The reduction of VEGF is about 50%. This maintains the quantity of VEGF that is necessary to sustain limbal vasculature"
“Potent in vivo antiangiogenic effects of GS-101 (5'-TATCCGGAGGGCTCGCCATGCTGCT-3'), an antisense oligonucleotide preventing the expression of insulin receptor substrate-1”, J Pharmacol Exp Ther. (JPET) 2009 May;329(2):496-504
The study shows that GS-101’s anti-angiogenic effect is achieved by preventing the expression of Insulin Receptor Substrate-1 (IRS-1), demonstrating that IRS-1 is directly involved in the angiogenesis process. The study also shows that GS-101 combines a reduction in the activity of angiogenesis pathway (IRS-1 and VEGF) with an anti-inflammatory action (by suppressing IL-1β).
• Pub Med |
• View abstract |
• View full manuscript |
• 2009 Annual Meeting of ARVO (Association for Research in Vision and Ophthalmology), 3 -7 May 2009, Fort Lauderdale, USA |
• Poster |
• 2009 Annual Meeting of ARVO (Association for Research in Vision and Ophthalmology), 3 -7 May 2009, Fort Lauderdale, USA |
• Annual Meeting of the AAO and SOE, November, 8-11, 2008 in Atlanta, Georgia, USA |
• Congress of the German society of Ophthalmology, September 18-21, 2008 in Berlin, Germany • ESCRS 2008 , September, 13-17, 2008 in Berlin Germany |