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 required to demonstrate efficacy. Importantly for acute treatment, concentrations increased rapidly following dosing and reached what we believe 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.
We are currently planning to initiate a Phase 2 clinical trial for KVD900 in late 2018 that is anticipated to be completed in mid-2019. Following this trial, we intend to interact with regulators to determine the requirements for future clinical trials to support filing of a New Drug Approval (NDA) and also discuss Fast Track and Orphan Designation. We believe there is a well-defined regulatory pathway for an oral on-demand treatment of acute HAE attacks.
Future pipeline developments for HAE
KalVista will continue to both discover and develop additional oral candidates, as well as explore different formulations of KVD900 to potentially address the prophylactic segment of the HAE market. We anticipate that one additional candidate will enter the clinic in 2018 and potentially more molecules in 2019.