Long-term Safety and Effectiveness of Sebetralstat: Interim Analysis of KONFIDENT-S Open-label Extension.

Abstract

Background: Poor compliance with hereditary angioedema guidelines for on-demand treatment is common due to challenges with parenteral administration. Sebetralstat, an oral plasma kallikrein inhibitor, demonstrated faster times to beginning of symptom relief, reduction in attack severity, and complete resolution than placebo in the phase 3 KONFIDENT trial (NCT05259917).

Objective: This analysis evaluated long-term safety and effectiveness of sebetralstat in KONFIDENT-S (NCT05505916), an ongoing, 2-year, open-label extension study.

Methods: Enrolled participants ≥12 years with hereditary angioedema with C1-inhibitor deficiency administered sebetralstat 600mg for each attack as early as possible, regardless of severity or location.

Primary outcome: incidence of treatment-emergent adverse events (TEAE).

Secondary outcomes: times to beginning of symptom relief, reduction in severity, and complete resolution.

Results: At data cutoff (Jan 31, 2024), 84 participants (mean age: 35.9 years; 14.3% <18 years; 64.3% female) treated 640 attacks with sebetralstat (84% of total attacks); median (interquartile range, IQR) 5 (2-8) attacks per participant. Median time from attack onset to treatment: 9 minutes (1-69). Baseline severity: 30.0% mild, 43.3% moderate, 25.0% severe or very severe. Treatment-related TEAEs occurred in 8 participants (9.5%); none were serious. Median times to beginning of symptom relief (allowing for missing data entries between consecutive time points): 1.68h (0.76-5.05), reduction in severity: 6.57h (1.61->12), and complete attack resolution: 21.02h (7.22->24). No evidence of a diminished response over repeated treatments of attacks was observed.

Conclusion: Oral sebetralstat enabled compliance with treatment guidelines. No new safety signals were observed, and effectiveness for repeated attacks was consistent with the KONFIDENT trial results.