D1.253 - Probiotic Co-administration to Improve Gastrointestinal Tolerability of Berotralstat in Hereditary Angioedema: a multicenter case series from the ITACA network

Early gastrointestinal (GI) adverse events remain a limitation of berotralstat, the first oral plasma kallikrein inhibitor approved for long-term prophylaxis of hereditary angioedema (HAE) and may lead to early discontinuation. No preventive strategies have been formally evaluated. Given emerging evidence of microbiome alterations in HAE and the established role of probiotics in mitigating drug-related GI disturbances, we investigated whether probiotic co-administration during berotralstat initiation could improve tolerability without affecting efficacy.

This multicenter, longitudinal, real-world case series included adolescents (≥12 years) and adults with HAE due to C1-inhibitor deficiency who initiated berotralstat between December 2023 and November 2025 in 6 Italian ITACA network centers and received probiotics during the initiation phase. GI adverse events were graded using CTCAE. Monthly HAE attack rates before and during treatment were collected. Analyses were descriptive.

Twenty-five patients were included (60% female; mean age 45 years, range 12–82). Median exposure to berotralstat was 111 days (range 13–512), while median duration of probiotic co-administration was 16 days (range 3–261), predominantly limited to the early treatment phase. Probiotic formulations were heterogeneous, most commonly containing Lactobacillus species or Saccharomyces boulardii. GI adverse events occurred in 5/25 patients (20%). Only 3/25 (12%) experienced GI symptoms during concomitant berotralstat–probiotic use, whereas 2/25 (8%) developed symptoms after probiotic discontinuation. All events were mild to moderate, and no serious adverse events were observed. Berotralstat discontinuation occurred in 3/25 patients (12%), including one due to GI intolerance. Mean monthly HAE attack rate decreased from 2.6 at baseline to 0.8 during treatment (≈70% reduction); 28% of patients were attack-free and 72% experienced ≤1 attack/month.

In this real-world multicenter experience, probiotic co-administration during berotralstat initiation was associated with a low incidence of GI adverse events and high treatment persistence, while preserving prophylactic efficacy. These findings support prospective controlled studies to evaluate probiotics as a simple, low-burden strategy to improve early tolerability of oral prophylaxis in HAE.