Therapeutics
Figure 1: The kallikrein-kinin system
One of the first pharmacological approaches for treating diabetic retinopathy targets the vascular endothelial growth factor (VEGF). Anti-VEGF therapies are meanwhile important therapies for the management of several cancer types and other diseases that include wet age-related macular oede- ma (AMD). The latter is caused by the abnormal growth of blood vessels behind the retina under the macula. Currently, ranibizumab, pegaptanib, beva- cizumab and VEGF Trap-Eye are in clinical trials to investigate local (ocular) agents for the manage- ment of diabetic retinopathy7.
Ranibizumab is a recombinant humanised mon- oclonal antibody fragment that is directed against all isoforms of human VEGF-A. The US Food and Drug Administration (FDA) approved ranibizum- ab for wet AMD in June 2006, and studies are under way to investigate ranibizumab in DME. Pegaptanib is a PEGylated (conjugated to poly- ethylene glycol) neutralising RNA aptamer that specifically targets the VEGF-A165 isoform. Intravitreal Pegaptinib showed some efficacy in DME, and the subset analysis of the Phase II clini- cal trial also demonstrated a regression of retinal neovascularisation in patients with PDR. Pegaptanib was approved by the FDA for the treat- ment of exudative AMD in December 2004.
Drug Discovery World Summer 2010
Bevacizumab, approved by the FDA in February 2004 for the treatment of metastatic colorectal cancer, has been used as intravitreal bevacizumab for DME and PDR. Randomised clinical trials have shown that bevacizumab demonstrated favourable short-term anatomic and visual outcomes in patients with DME and short-term efficacy as an adjunct to photocoagu- lation in patients with PDR. It is noteworthy that some patients with PDR suffered from tractional retinal detachment after intravitreal treatment with bevacizumab8. VEGF-Trap-Eye is a recombinant fusion protein that binds all forms of VEGF-A along with the related placental growth factor (PlGF). VEGF- Trap-Eye is currently in a Phase II study of a patient population with DME.
Hyperglycaemia is known to increase the forma- tion of diacylglycerol and subsequently activates protein Kinase C (PKC), an upregulator of VEGF. First studies of ruboxistaurin, an orally adminis- tered inhibitor targeting protein kinase C (PKC)-, showed that the drug was associated with a reduc- tion of the progression of DME and a reduction of vision loss in patients with DME. The occurrence of visual improvement in patients with non-prolif- erative retinopathy also increased9.
References 1World Health Organization, G., Diabetes Fact Sheet 321. 2009. 2 Delcourt, C, Massin, P and Rosilio, M. Epidemiology of diabetic retinopathy: expected vs reported prevalence of cases in the French population. Diabetes Metab, 2009. 35(6): p. 431-8. 3 The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med, 1993. 329(14): p. 977-86. 4 Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet, 1998. 352(9131): p. 837-53. 5 Fioretto, P et al. Residual microvascular risk in diabetes: unmet needs and future directions. Nat Rev Endocrinol, 2010. 6(1): p. 19-25. 6 Frank, RN. Diabetic retinopathy. N Engl J Med, 2004. 350(1): p. 48-58. 7 Schwartz, SG, Flynn, HW Jr and Scott, IU. Pharmacotherapy for diabetic retinopathy. Expert Opin Pharmacother, 2009. 10(7): p. 1123-31. 8 Arevalo, JF et al. Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy. Br J Ophthalmol, 2008. 92(2): p. 213-6. 9 Aiello, LP et al. Effect of ruboxistaurin on visual loss in patients with diabetic retinopathy. Ophthalmology, 2006. 113(12): p. 2221-30. 10 Bressler, NM et al. Exploratory analysis of diabetic retinopathy progression through 3 years in a randomized clinical trial that compares intravitreal triamcinolone acetonide with focal/grid photocoagulation. Arch Ophthalmol, 2009. 127(12): p. 1566-71.
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