Diabetic Macular Edema (DME), is the main cause of vision loss in working-age adults in the U.S. and worldwide. It develops when breakdown of the blood-retinal barrier allows fluid and other plasma components, to leak from blood vessels into the retina. Blood-retinal barrier breakdown, detected as increased retinal vascular permeability, is observed very early in the diabetic retina before any other retinopathic changes. The greater the amount of retinal vascular permeability, the greater the chance of progression to DME and vision loss. Current clinical thinking identifies increased retinal vascular permeability as critical to the pathophysiology of DME.
An estimated 750,000 individuals in the U.S. have DME, and another 6 to 9 million worldwide, numbers that are expected to grow as the incidence of diabetes increases globally. In the United States, current treatment approaches are dominated by monthly/bimonthly intravitreal injections of anti-VEGF agents such as ranibizumab, bevacizumab and aflibercept. Frequency of injection correlates directly with therapeutic benefit for these agents, resulting in high treatment burden for both patients and their healthcare providers. However, even with monthly injections of ranibizumab maintained over 36 months, less than 50% of treated DME patients showed clinically significant vision gain, underscoring the need to develop alternative therapies for this catastrophic complication of diabetes.
Hereditary Angioedema (HAE) is an orphan indication, affecting >6,500 individuals in the U.S., caused by an inherited lack of the protein C1-Inhibitor, the physiological inhibitor of the protease plasma kallikrein. The disease is characterized by recurrent episodes of severe, painful edema affecting the face, hands, feet, abdomen and the larynx, owing to excessive production of the vasodilatory peptide bradykinin, mediated by plasma kallikrein. Treatment of ongoing attacks is achieved by parenteral plasma kallikrein inhibitors such as ecallantide and C1-Inhibitor and the bradykinin-receptor antagonist icatibant. Current prophylaxis is achieved via twice-weekly intravenous infusion of plasma-derived C1-Inhibitor.
ActiveSite's Approach to DME & HAE ActiveSite’s lead product candidate is an orally-administered small molecule plasma kallikrein inhibitor, which has demonstrated high efficacy in clinically validated animal models of DME, on par with that exhibited by the benchmark clinical anti-VEGF agent aflibercept. The lead compound normalizes diabetes-induced excess vascular permeability, the root cause of DME, by blocking the activity as well as the activation of plasma kallikrein and therefore blocking the formation of bradykinin.
For HAE, plasma levels of the lead compound readily achieved via once-daily dosing inhibit bradykinin formation more effectively than physiological levels of C1-Inhibitor, providing empirical confirmation of its prophylactic potential.