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Discovery of orally-available, potent and selective plasma kallikrein inhibitors for the treatment of diabetic macular edema with KalVista Pharmaceuticals

Discovery of orally-available, potent and selective plasma kallikrein inhibitors for the treatment of diabetic macular edema with KalVista Pharmaceuticals

DME is the leading cause of adult visual loss in developed countries and, with limited treatment options, represents a large unmet medical need.  DME is caused by disruption of the blood–retinal barrier with increased permeability of the retinal vasculature leading to the accumulation of fluid in the macula, which causes photoreceptor disruption and ultimately visual loss. The incidence of DME and risk of visual loss increases with advancing disease severity and in the presence of other systemic co-morbidities, such as hypertension, dyslipidaemia and renal disease.

Plasma kallikrein is a serine protease that represents an attractive drug target in people with diabetic retinopathy as it is has been shown to contribute to blood vessel leakage and thickening of the retina through the collaborative work of KalVista with Drs. Edward P Feener and Lloyd Paul Aiello at the Joslin Diabetes Center (USA). The detrimental effects of plasma kallikrein on the retina in patients with diabetes are mediated by mechanisms that are independent of vascular endothelial growth factor (VEGF), which has been an area of intense recent interest as a target for treating DME.  However, while intra-vitreal VEGF inhibitors have shown clear benefit in clinical trials in many patients through reducing macular edema and increasing visual acuity, a substantial proportion of DME patients do not respond fully to anti-VEGF treatment.  KalVista’s approach, discovering and developing targeted and selective PKal inhibitors, has the potential to add to the treatment options for sufferers of DME including those that are non-responsive to VEGF inhibitors.

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