RESEARCH TRIANGLE PARK, N.C.—Hereditary angioedema (HAE) is a rare, severely debilitating and potentially fatal genetic condition occurring in about one in 50,000 people, involving recurrent episodes of edema in the hands, feet, face, genitalia and airways. Patients may have bouts of excruciating abdominal pain, nausea and vomiting caused by swelling in the intestinal walls. Airway swelling can lead to death by asphyxiation.
With treatment of this condition in mind, BioCryst Pharmaceuticals Inc. has conducted a randomized, placebo-controlled, Phase 1 clinical trial of orally administered BCX7353 in healthy volunteers that met all of its objectives. The safety, tolerability, drug exposure and on-target plasma kallikrein inhibition results strongly support advancing the development program into a Phase 2 study in HAE patients, according to the company, which expects to begin a Phase 2, four-week, dose-ranging trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of BCX7353 as a preventive treatment to reduce the frequency of attacks in HAE patients by late 2015 or early 2016.
CEO Jon Stonehouse said that BioCryst is “very pleased that our first-in-human trial of BCX7353 met all of its objectives.” He added that “The results show 7353 to be generally safe and well tolerated, and the observed drug exposure and kallikrein inhibition reaffirms our expectation that 7353 has the potential to be a once-daily treatment to wipe out HAE attacks.”
BioCryst is “passionate about advancing novel therapeutics for patients with rare and serious diseases and experienced in drug discovery, clinical development and regulatory affairs,” according to Stonehouse. Founded in 1986, the company has 60 employees in Research Triangle Park, N.C., and Birmingham, Ala.
Generating new compounds from its own discovery engine, BioCryst performs structure-guided drug design, in which “scientists use detailed knowledge of the active sites of protein targets associated with particular diseases to design synthetic compounds that fight the disease,” according to the company’s website. A chemical or biological molecule fits into the active site of an enzyme to trigger a biochemical reaction. The molecule is designed to bind to the active site of a targeted enzyme, preventing the normal chemical reaction and eventually halting the progression of the disease.
As Stonehouse explains, BioCryst’s structure-guided drug design integrates traditional biology and medicinal chemistry, using advanced technologies—among them X-ray crystallography, computer modeling of molecular structures, virtual screening and protein biophysical chemistry—to focus on the three-dimensional structure of the active site of the target enzyme. By identifying the target protein in advance, and by determining molecular structure of the protein, BioCryst’s scientists design a more optimal drug to interact with the protein, Stonehouse says.
BCX7353, which was discovered by BioCryst, is a novel, once-daily, selective inhibitor for plasma kallikrein the company is developing to prevent HAE attacks. BCX7353 inhibits plasma kallikrein to suppress the production of bradykinin, the mediator of acute swelling attacks in HAE patients.
The study determined that oral BCX7353 was generally safe and well tolerated at all doses up to 500 mg once daily for seven days and 350 mg once daily for 14 days in healthy volunteers. No dose-limiting toxicity was identified. There were no serious adverse events and most adverse events were mild. BCX7353 plasma levels increased in approximate proportion to dose, and drug exposure was not affected by dosing with food. The half-life of BCX7353 was estimated at 50 to 60 hours. After daily dosing, blood levels met or exceeded a predicted target therapeutic range throughout the 24-hour dosing interval. Inhibition of the target enzyme, plasma kallikrein, was achieved throughout the dosing interval at generally safe and well tolerated dosing regimens.
Piper Jaffray analyst Charles Duncan wrote that the results could facilitate once- or twice-daily dosing and confirm the potential value of the HAE franchise. As he explained, “BioCryst’s positive Phase 1 data on second-gen kallikrein inhibitor 7353 and enrollment completion for its OPuS-2 study, together demonstrate significant progress toward development of the first oral prophylaxis drug in HAE and the first HAE drug with QD dosing.”