The decision follows promising data from two clinical trials, in which KVD824 was well tolerated and reached therapeutically relevant levels in healthy participants. The company plans to seek regulatory permission to launch the trial in the first quarter of 2021.
Meanwhile, KalVista also announced a new program for HAE, in which the company will develop an oral preventive treatment that blocks Factor XIIa, a key protein that initiates the cascade of events leading to swelling attacks. Preclinical studies supporting clinical development are expected in 2021.
“Our ongoing work to optimize the exposure profile of KVD824 has yielded a formulation that maintains the concentrations we believe are required to compete with approved injectable therapies, while showing an encouraging safety and tolerability profile in up to 14 days of dosing,” Andrew Crockett, KalVista’s CEO, said in a press release.
“Looking to the future, we are also excited to share early data on our oral Factor XIIa inhibitor program as an additional HAE therapy,” he added.
In HAE, a deficiency in the functional C1-inhibitor protein, known as C1-INH, results in the increased activity of an enzyme called plasma kallikrein. The excess activity of kallikrein increases the levels of the inflammatory mediator bradykinin, causing blood vessels to dilate and tissue to swell.
KVD824 is an oral inhibitor of plasma kallikrein, designed for the prevention of swelling attacks in people with HAE.
A first-in-human trial involving 84 participants has investigated the medication, either as a single dose up to 1,280 mg or in multiple doses up to 640 mg. It also assessed whether food impacted KVD824’s metabolism in the body.
A formulation study — in which a drugmaker seeks a preparation of its medicine that is both stable and acceptable to patients — also is being conducted among 16 healthy participants in the U.K. Select formulations, ranging from 600 to 900 mg, are being tested as a twice-daily treatment for two weeks.
To date, 98 people have received KVD824 in both trials, and no safety or tolerability issues have been reported. There were no serious adverse events (harmful side effects), and no participants have discontinued treatment or withdrawn from the trials.
In addition, researchers have noted that a twice-daily 600 mg dose in the formulation trial was enough to maintain levels of KVD824 above those required for a therapeutic effect. A twice-daily 900 mg dose appeared to increase these levels even further.
Adverse events in this trial have so far been mild. KalVista plans to fully release safety data upon the study’s completion.
“We intend to submit an Investigational New Drug application for a Phase 2 study to evaluate KVD824 in prevention of HAE attacks in the first quarter of 2021,” Crockett said. An investigational new drug, or IND, application is needed for the initiation of clinical studies of new drugs; if granted, it will allow KalVista to test KVD824 in HAE patients.
In addition to kallikrein inhibitors — KVD824 as a preventive treatment and KVD900 as an on-demand therapy — KalVista is now developing a new class of HAE therapies that inhibit the Factor XIIa protein.
Factor XIIa is an enzyme that activates kallikrein, initiating the cascade of events leading to elevated bradykinin in the bloodstream. Injectable antibodies targeting Factor XIIa are the focus of ongoing clinical studies, which have so far shown no safety concerns.
Developing oral formulations of Factor XIIa inhibitors has proven challenging. KalVista reports having discovered several potent and highly selective inhibitors that effectively enter circulation when taken orally. This, the company says, “represents a major breakthrough.”
KalVista is currently working to secure intellectual property rights for this program and anticipates beginning studies to support an IND application in 2021.
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