Plasma kallikrein is an enzyme (a serine protease) that has been identified as a potential therapeutic target in people with diabetic retinopathy. Research has shown that it contributes to increases in blood vessel leakage and thickening of the retina. Previous JDRF-funded studies led by one of KalVista’s co-founders, Edward Feener, Ph.D., Associate Professor of Medicine at Harvard Medical School and Joslin Diabetes Center, demonstrated that plasma kallikrein is increased and activated in the vitreous fluid of people with DME . This data suggests that chronic activation of plasma kallikrein increases blood vessel inflammation and permeability by generating the production of a hormone called bradykinin, which causes blood vessels to dilate or enlarge. Plasma kallikrein inhibitors are believed to reduce retinal vessel leakage by suppressing the chronic and excessive production of bradykinin.
“Diabetic eye disease is a high priority research area for JDRF. Our support of Dr. Feener’s academic research over the years at the Joslin Diabetes Center on validating plasma kallikrein as a potential therapeutic target for diabetic macular edema underscores JDRF’s commitment to developing innovative approaches to prevent and treat this condition to save vision before it deteriorates,” said Aaron Kowalski, Ph.D., assistant vice president of Treatment Therapies for JDRF.
KalVista’s candidate will be selected from a series of novel small molecule plasma kallikrein inhibitors, which are advancing through pre-clinical development for the treatment of DME by delivery via intravitreal (IVT) injection into the eye. The pre-clinical studies being co-funded by JDRF will test whether administration of plasma kallikrein inhibitors by injection are likely to be safe and effective in improving symptoms of DME as well as in preserving visual acuity and slowing disease progression.
“JDRF is the leading global organization focused on research into diabetes and its complications and we are delighted it has recognized the potential of our novel approach to treating diabetic macular edema based on plasma kallikrein inhibitors,“ said Andrew Crockett, KalVista’s CEO. “This is an exciting collaboration and we look forward to the added expertise they will contribute to the development of our lead programme.”
“JDRF’s goal is to have the greatest and fastest positive impact on individuals with type 1 diabetes, which is why we are working to accelerate the translation of novel discoveries in the lab, through clinical evaluation of safety and efficacy, and into commercial development,” added Kowalski. “What makes our collaboration with KalVista so exciting is that we are gradually seeing this novel therapy, which could represent a whole new approach to treating DME, move from basic research discovery into a potential commercially viable drug with the help of JDRF funding.”
About diabetic eye disease and current available treatments
Diabetic retinopathy is the most common and most serious eye-related complication of diabetes, and is the leading cause of new cases of legal blindness among adults aged 20 to 74 years in the United States. It is a progressive disease that causes retinal swelling and destroys small blood vessels in the retina, eventually leading to vision problems. In its most advanced forms, known as diabetic macular edema and proliferative retinopathy, it can cause moderate to severe vision loss and blindness. According to the National Eye Institute, 40-45 percent of Americans diagnosed with diabetes have some stage of diabetic retinopathy.
DME, which involves swelling in the retina that transiently or permanently impairs vision, can occur at any stage of diabetic retinopathy. Treatment to prevent or reverse this condition remains a major unmet clinical need.
The detrimental effects of plasma kallikrein on the retina occur independently of vascular endothelial growth factor (VEGF), which is produced in excessive amounts in people with diabetes and also contributes to the development of diabetic eye disease. VEGF causes leakage in the small blood vessels of the eye that can lead to vision loss and, eventually, blindness. Therapies targeting VEGF are approved for the treatment of DME in Europe and are currently being submitted to the U.S. FDA for approval. However, while intravitreal VEGF inhibitors have shown clear benefit in clinical trials through reducing macular edema and increasing visual acuity, a significant proportion of DME patients do not respond fully to VEGF treatment. KalVista’s approach offers the potential to add to the treatment options for sufferers of DME including those that are non-responsive to VEGF inhibitors.
About KalVista Pharmaceuticals
KalVista is a new ophthalmology company with a focus on diabetic macular edema (DME). KalVista is developing novel plasma kallikrein inhibitors, which represents a new approach to the treatment of DME, a leading cause of adult visual loss in developed countries. KalVista has an advanced pre-clinical product pipeline and is targeting both intravitreal injection and oral administration. Although VEGF inhibitors clearly can benefit DME, a significant number of patients do not respond fully to these agents and have limited treatment options. Plasma kallikrein inhibitors target a distinct molecular pathway and as such have the potential to offer those patients an effective treatment option.
KalVista’s founders include world-leading experts in diabetic retinopathy, Dr Lloyd Paul Aiello, Professor of Ophthalmology at Harvard Medical School and Director of the Joslin’s Beetham Eye Institute, and Dr Edward Feener, Associate Professor of Medicine at Harvard Medical School and Joslin Diabetes Center. In addition to this therapeutic expertise, KalVista has a management team with proven experience in bringing small molecules through the clinic to commercialisation and as a result has attracted significant financial backing from leading life science investors, SV Life Sciences and Novo Ventures. www.kalvista.com
 Klein R, Klein B. Vision disorders in diabetes. In: National Diabetes Data Group, ed. Diabetes in America.2nd ed. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 1995:293-337.