Gastrointestinal (GI) Adverse Events (AEs) Observed With Berotralstat (BCX7353) Treatment for Hereditary Angioedema (HAE) are Primarily Mild, Self-limited, and Diminish with Time on Treatment

APeX-2, a randomized double-blind, placebo-controlled study, evaluated efficacy and safety of berotralstat, an oral kallikrein inhibitor, as once-daily prophylaxis in HAE Type 1/2 (NCT03485911). Subjects (n=121) were randomized into 3 arms (berotralstat 110mg, 150mg or placebo). All AEs were recorded over 24 weeks. AE incidence was analyzed overall and by onset month, defined as 4 weeks. AE incidence was similar in all 3 arms over the 24-week period, occurring in 82.9%, 85.0% and 76.9% of subjects receiving 110mg, 150mg, and placebo respectively. The greatest incidence of AEs was reported in the first month of study (51.2%, 42.5% and 59.0%) and afterwards declined. Gastrointestinal abdominal-associated AEs occurred primarily in the first month: 34.1%, 30% and 33.3% of 110mg, 150mg, and placebo subjects, respectively. In the 2nd and 3rd month, GI AEs were more common in subjects receiving 110mg (9.8% and 4.9%) and 150mg (17.5% and 8.1%) compared to placebo (2.6% and 2.6%). By the 4th month, GI AEs had a similarly low incidence in all 3 arms (2.4%, 2.7% and 2.7%), which was sustained. GI events were generally mild except for 2 subjects on 110mg experiencing brief, severe abdominal pain. One subject on 110mg discontinued due to moderate dyspepsia, nausea, and vomiting. 87.8%, 90.0% and 92.3% of GI AEs resolved without medication on 110mg, 150mg, and placebo. GI AEs were predominantly mild, self-limited, and most frequent in the first 3 months of treatment. The rate of GI events with berotralstat was similar to placebo in months 4 through 6.