HAE is a rare genetic disorder in which patients experience sudden onset of swelling in various locations of the body. Disease symptoms typically begin during childhood and become more pervasive during puberty and adulthood. Patients with HAE lack (type I) or have dysfunctional forms (type 2) of C1-inhibitor, a critical protein that controls the enzyme plasma kallikrein. Some number of patients, known as type 3, experience HAE attacks despite having normal levels of C1-inhibitor. In an HAE attack, lack of C1-inhibitor leads to excessive activation of plasma kallikrein that in turn generates the vasoactive peptide bradykinin, which is responsible for a sudden increase in vascular permeability and leakage of fluid into tissues. Swelling attacks can occur anywhere in the body, ranging from swelling of the abdomen which, if undetected, can lead to unnecessary surgery, to swelling of the airways, which can lead to asphyxiation and death. The disease occurs in approximately 1 in 10,000 to 1 in 50,000 people. Replacing C1-inhibitor or inhibiting activated plasma kallikrein or bradykinin has become the mainstay of therapy for HAE in the US since the early 2000s, although all the currently approved therapies are delivered by injection or infusion. An orally delivered, small molecule inhibitor of plasma kallikrein offers the opportunity to improve treatment for the disease by making it more convenient for patients to take therapies.
In a Phase 1 study, single ascending doses of KVD900 were tested in healthy volunteers and were shown to be generally well-tolerated at doses as high as 600 mg. Exposures increased in a dose proportional manner to and achieved concentrations well above 100-fold those we believe are required to demonstrate efficacy. Importantly for acute treatment, concentrations increased rapidly following dosing and reached what we consider will be effective concentrations within 30 minutes or less. Pharmacodynamic analysis showed that KVD900 inhibits plasma kallikrein from exerting its effect on bradykinin release for up to 10 hours following a single dose.
An ongoing Phase 2 clinical trial evaluating KVD900 as an on-demand treatment for HAE attacks will dose approximately 50 type 1 and type 2 patients, with data expected in the fourth quarter of 2020. Following the trial, we intend to interact with regulators to determine the requirements for future clinical trials to support filing of a New Drug Approval (NDA). We believe there is a well-defined regulatory pathway for an oral on-demand treatment of acute HAE.
KVD824 is in development for prophylactic treatment of HAE and is anticipated to enter a Phase 2 clinical trial in late 2020. The preclinical formulation work conducted showed evidence that KVD824 can achieve the properties we believe necessary for high efficacy as a twice-daily treatment for prevention of HAE attacks.