Sebetralstat for On‐Demand Treatment of Mucosal Hereditary Angioedema Attacks in KONFIDENT‐S

Background Hereditary angioedema (HAE‐C1INH) attacks involving mucosal tissue may progress rapidly and often lead to substantial morbidity. Severe laryngeal attacks can be fatal without prompt administration of on‐demand treatment. This prespecified interim analysis evaluated the safety and effectiveness of sebetralstat in laryngeal and abdominal attacks in the ongoing, 2‐year, open‐label extension KONFIDENT‐S study (NCT05505916). Methods Eligible participants ≥ 12 years with HAE‐C1INH self‐administered sebetralstat 600 mg film‐coated tablets with an optional second dose after 3 h, if warranted. Primary outcome: incidence of treatment‐emergent adverse events (TEAEs). Secondary outcomes: times to beginning of symptom relief, reduction in severity, and complete resolution. Results At data cutoff (Sep 14, 2024), 32 laryngeal (16 participants) and 533 abdominal only attacks (102 participants) were treated with sebetralstat. Seven (43.8%) participants with laryngeal attacks experienced 14 TEAEs whereas 36 (35.3%) participants with abdominal attacks experienced 91 TEAEs. No difficulty swallowing sebetralstat was reported. Median (IQR) time to treatment: 11.5 min (1.0–34.0) and 20.0 min (1.0–61.0) for laryngeal and abdominal attacks, respectively; time to beginning of symptom relief: 1.29 h (0.76–3.02) and 1.27 h (0.76–3.54); reduction in attack severity: 4.25 h (1.22 to > 12) and 3.52 h (1.26 to > 12); complete attack resolution: 12.69 h (5.11 to > 24) and 15.17 h (4.46 to > 24). Most mucosal attacks that achieved beginning of symptom relief within 12 h did so with a single dose of sebetralstat (laryngeal: 96.0%; abdominal: 95.8%). Conventional on‐demand treatment was administered within 12 h for 3 (9.4%) laryngeal and 43 (8.1%) abdominal attacks. Conclusion Oral sebetralstat enabled rapid treatment of laryngeal and abdominal attacks of all severities, was well tolerated, and provided early symptom relief.