Article

Plasma Kallikrein Inhibition Targets Chronic DME

KalVista advances clinical studies to phase 2.

After more than a decade of preclinical research, initiated and primarily conducted at the Joslin Diabetes Center and Harvard Medical School, a potentially transformative therapy for DME not responsive to anti-VEGF has advanced into human clinical trials. Researchers at Joslin identified high levels of the enzyme plasma kallikrein (PKal) in the vitreous from DME patients and performed preclinical studies demonstrating that PKal increases retinal vascular permeability and edema. In a 14-patient, open-label phase 1b study undertaken by KalVista Pharmaceuticals, the effects of intravitreal injection of the company’s small-molecule PKal inhibitor KVD001 in DME patients were investigated. This first-in-human study showed that KVD001 was generally well tolerated. Although this was not an efficacy study, most subjects showed improvement in visual acuity and reduced subfield thickness.

KalVista (in collaboration with partner Merck) has since advanced its PKal program to a 123-patient phase 2 study, which is anticipated to complete in the second half of 2019. The phase 2 trial consists of patients in the United States who have discontinued treatment with anti-VEGF therapy, and who still have significant edema and reduced visual acuity. This sham-controlled, double-masked clinical trial will evaluate 2 dose levels of KVD001. Four intravitreal injections, or sham, will be administered over 3 months with a 3-month follow-up period. Efficacy endpoints include best corrected visual acuity, retinal central subfield thickness, and the diabetic retinopathy severity scale. The safety and tolerability of monthly dosing of KVD001 will also be assessed.

KalVista Chief Scientific Officer Edward Feener, PhD, formerly a senior investigator at Joslin, says that preclinical studies show that PKal inhibition blocks both VEGF-dependent and VEGF-independent retinal edema, suggesting that this approach might be useful in treating a range of retinal diseases. He leaves the door open for potential combination therapies that include a PKal inhibitor and another drug. KalVista is also developing oral PKal inhibitors for DME and hereditary angioedema.

While KalVista has the most advanced clinical program in PKal inhibition, two other companies are now pursuing the same target. ThromboGenics NV (now Oxurion) has enrolled the first patient in a phase 1 open-label, multicenter, dose-escalation study evaluating the safety of the plasma kallikrein inhibitor THR-149 in the treatment of DME. THR-149 is a novel PKal inhibitor generated using Bicycle Therapeutics’ Bicycle technology platform. Preclinical studies have demonstrated the potency and efficacy of bicyclic peptide inhibitors of PKal, such as THR-149, supporting its progression into clinical trials for the potential treatment of DME. The phase 1 study will primarily assess the safety of a single intravitreal injection of escalating dose levels of THR-149 in patients with DME. Approximately 18 patients will be enrolled. Another company, Rezolute (formerly AntriaBio) is planning an initial human trial of an oral form of PKal inhibitor called AB402.