Sebetralstat for on-demand treatment of hereditary angioedema: A pooled analysis of placebo-controlled clinical trials

Background Clinical trial designs evaluating on-demand therapies for hereditary angioedema attacks have evolved in response to changes in treatment guidelines. Sebetralstat, an oral plasma kallikrein inhibitor, was evaluated in 2 randomized, placebo-controlled clinical trials, which instructed early treatment of attacks with no minimum severity requirement. Objective Characterize the efficacy and safety of sebetralstat by pooling data from phase 2 and 3 trials. Methods This pooled analysis included participants (phase 2, aged ≥18 years; phase 3, aged ≥12 years) who received ≥1 dose of study drug (phase 2, sebetralstat 600 mg or placebo; phase 3, sebetralstat 300 mg or 600 mg, or placebo). Efficacy outcomes included times to beginning of symptom relief within 12 h, reduction in severity within 12 h, and complete attack resolution within 24 h. P values were not adjusted for multiplicity. Results 377 attacks were treated: 87 with sebetralstat 300 mg; 151 with sebetralstat 600 mg; 139 with placebo. Median (interquartile range) time to treatment was 32.5 min (8.0–94.0). Baseline severity was rated as "Mild" (46.2%), "Moderate" (40.6%), or "Severe"/"Very Severe" (12.7%). Compared with placebo, time to beginning of symptom relief was faster with sebetralstat (300 mg; 600 mg [ P = 0.0001; P < 0.0001]), as was reduction in severity ( P = 0.0038; P < 0.0001) and complete attack resolution ( P = 0.0021; P < 0.0001). Median time to beginning of symptom relief was 1.6 h (0.8–7.0) and 1.8 h (1.0–4.3) with sebetralstat 300 mg and 600 mg, respectively, and 8.3 h (1.5 to >12) with placebo. Sebetralstat had a safety profile comparable to placebo. Conclusion Across phase 2 and 3 clinical trials, sebetralstat enabled early treatment, provided effective symptom relief versus placebo, and was well tolerated, regardless of attack location or baseline severity. Clinical trial registration ClinicalTrials.gov Identifier NCT04208412, registered on 2019-07-02; ClinicalTrials.gov Identifier NCT05259917 (KONFIDENT), registered on 2022-02-22.