Open-label phase 1b/2 trial of navenibart, a long-acting plasma kallikrein inhibitor for hereditary angioedema

BACKGROUND: Hereditary angioedema (HAE), characterized by unpredictable, painful, recurrent swelling events (HAE attacks), poses a significant health care burden. OBJECTIVE: This phase 1b/2 trial (ALPHA-STAR) assessed the safety, efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity of navenibart, a novel long-acting monoclonal antibody targeting plasma kallikrein. METHODS: This global, dose-ranging, proof-of-concept trial assigned adults with HAE due to C1 inhibitor deficiency (HAE-C1INH) sequentially to 3 cohorts: 450 mg as a single dose on day 1 (cohort 1); 600 mg on day 1 and 300 mg on day 84 (cohort 2); or 600 mg on days 1 and 28 (cohort 3). Study assessments lasted up to 9 months (6 months after final dose). Primary end points included safety, secondary end points included clinical outcomes, and exploratory end points included quality of life. RESULTS: Twenty-nine participants received navenibart and completed the trial. There were no severe or serious treatment-emergent adverse events, and no treatment-emergent adverse events led to discontinuation. The most common treatment-emergent adverse events were headache, nasopharyngitis, and urinary tract infection. Rapid reductions in HAE attack rates (including moderate and severe attacks) versus baseline were observed in all cohorts. Overall, the mean (standard deviation) time-normalized monthly attack rate was reduced from 2.23 (1.46) at baseline to 0.31 (0.48) after treatment with navenibart. The overall mean (median) reduction in time-normalized monthly attack rate was 86.3% (95.4%) compared with baseline. Participants had improved Angioedema Quality of Life total scores, with a mean decrease ranging 21.0 to 30.3 points. CONCLUSIONS: Navenibart was well tolerated and substantially reduced HAE attacks, providing support for every-3-month and every-6-month administration of navenibart to prevent HAE attacks.