BioCryst Pharmaceuticals, Inc. has announced that the randomized, placebo-controlled, Phase 1 clinical trial of orally-administered BCX7353 in healthy volunteers successfully 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.
Oral BCX7353 was generally safe and well tolerated at all doses up to 500 mg once-daily for 7 days and 350 mg once-daily for 14 days in healthy volunteers, and no dose-limiting toxicity was identified. There were no serious adverse events (AEs) and most AEs were mild. Two subjects discontinued the study due to moderate gastrointestinal AEs. One subject developed a delayed-type hypersensitivity rash after completing seven days of study drug; the rash resolved quickly with oral and topical steroids. No clinically significant laboratory abnormalities were seen at any dose or duration tested.
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 50-60 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 measured in a sensitive and specific bioassay. Daily dosing with BCX7353 strongly inhibited plasma kallikrein at all four dose levels; the degree of inhibition was dose-related (p < 0.0001) and inhibition was sustained throughout the 24 hour dosing interval. This pharmacodynamic effect correlated strongly to achieved drug concentration (r = 0.91, p < 0.0001).
“We are very pleased that our first-in-human trial of BCX7353 met all of its objectives. 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,” said Jon Stonehouse, CEO & President of BioCryst. “We are excited to now have the opportunity to test this promising drug in patients with HAE.”
A Phase 2, four week dose ranging trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of BCX7353 as a preventative treatment to reduce the frequency of attacks in HAE patients is expected to begin by late 2015 or early 2016.
Overall, 94 healthy volunteers were enrolled, and 92 completed the study. In the single dose part of the study, 34 subjects received a single dose of BCX7353 ranging from 30 mg up to 1000 mg, and 10 subjects received a single dose of placebo. In the daily dosing part of the study, 30 subjects received BCX7353 daily for seven days (10 each at 125 mg, 250 mg, and 500 mg per day), 10 subjects received 350 mg of BCX7353 daily for 14 days, and a total of 20 subjects received daily doses of placebo