Creating a new generation of small molecule protease inhibitors


Diabetic macular edema (DME) is a leading cause of adult vision loss in developed countries and, despite current treatment options, there remains a substantial unmet medical need.

Diagram of eye
Image credit: National Eye Institute, National Institutes of Health

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 and vision loss. Although DME can occur at any stage of diabetic retinopathy, its prevalence increases in patients with advanced diabetic retinopathy, poor glycemic control, and hypertension.

KalVista’s intravitreal program

KalVista’s lead DME program is focused on the development of small molecule plasma kallikrein inhibitors for intravitreal (IVT) dosing. The Company’s most advanced compound, KVD001, has successfully completed its first-in-human study in patients with DME and is being prepared for Phase 2.

Intravitreal plasma kallikrein inhibitors may be efficacious in both improving symptoms of the disease, such as deteriorating visual acuity, and slowing disease progression. Direct injection into the eye delivers a high drug concentration at the desired site of action with a low systemic exposure resulting in the potential for a safe and effective treatment. Pre-clinical pharmacokinetic studies have shown that KVD001 is retained within the eye for a prolonged period.

KalVista’s oral program

Eye photo

KalVista has a number of highly potent and selective oral plasma kallikrein inhibitors with good bioavailability designed to treat DME. The lead candidates are being progressed through pre-clinical development.

An oral plasma kallikrein inhibitor may provide the opportunity to reduce treatment burden, treat patients earlier in disease development, and provide a convenient and readily accessible treatment option.

Current treatment options

Despite current treatment options to prevent or reverse DME there remains a major unmet clinical need.

Intravitreal injection

Although intravitreal VEGF inhibitors are often highly effective in reducing central macular thickness and increasing visual acuity, a substantial proportion of DME patients do not respond adequately to anti-VEGF therapy.

Plasma kallikrein represents an attractive drug target as it is believed to be central to the edematous and inflammatory processes occurring in the retina in advanced stages of diabetic retinopathy. In addition, recent evidence indicates that plasma kallikrein inhibition targets a separate pathway to VEGF and therefore may have the potential to add to the treatment options for DME.