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BACKGROUND: Hereditary angioedema is a life-threatening illness caused by mutations in the gene encoding C1 inhibitor (also called C1 esterase inhibitor) that lead to over- activation of the kallikrein–bradykinin cascade. BCX7353 is a potent oral small- molecule inhibitor of plasma kallikrein with a pharmacokinetic and pharmaco- dynamic profile that may help prevent angioedema attacks.

METHODS: In this international, three-part, dose-ranging, placebo-controlled trial, we evalu- ated four doses of BCX7353 (62.5 mg, 125 mg, 250 mg, and 350 mg once daily) for the prevention of angioedema attacks over a 28-day period. Patients with type I or II hereditary angioedema with a history of at least two angioedema attacks per month were randomly assigned to BCX7353 or placebo. The primary efficacy end point was the number of confirmed angioedema attacks. Key secondary end points included angioedema attacks according to anatomical location and quality of life.

RESULTS: A total of 77 patients underwent randomization, 75 received BCX7353 or placebo, and 72 completed the trial. The rate of confirmed angioedema attacks was signifi- cantly lower among patients who received BCX7353 at daily doses of 125 mg or more than among those who received placebo, with a 73.8% difference at 125 mg (P<0.001). Significant benefits with respect to quality-of-life scores were observed in the 125-mg and 250-mg dose groups (P<0.05). Gastrointestinal adverse events, predominantly of grade 1, were the most commonly reported adverse events, par- ticularly in the two highest BCX7353 dose groups.

CONCLUSIONS: Once-daily oral administration of BCX7353 at a dose of 125 mg or more resulted in a significantly lower rate of attacks of hereditary angioedema than placebo. Mild gastrointestinal symptoms were the principal side effect. (Funded by BioCryst Pharmaceuticals; APeX-1 ClinicalTrials.gov number, NCT02870972.)