Safety and Pharmacokinetics of Long-Acting Plasma Kallikrein Inhibitor Navenibart (STAR-0215) in Healthy Adults.

Abstract

Background: Hereditary angioedema (HAE) is a rare, autosomal dominant disorder characterized by bradykinin-mediated episodic, localized swelling that can be fatal. Currently approved long-term prophylactic therapies for HAE attacks incur substantial treatment burden through frequent dosing. Navenibart (STAR-0215) is a monoclonal antibody inhibitor of plasma kallikrein modified to extend circulating half-life and is under investigation for HAE prophylaxis.

Objective: The aim of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of a single dose of navenibart in healthy adults and to assess feasibility of every 3- and 6-month dosing.

Methods: In this phase 1a study, participants were randomized 3:1 to receive placebo or navenibart in escalating (100 mg to 1200 mg) dosing cohorts. Safety outcomes, including treatment-emergent adverse events (TEAEs) and serious AEs, were monitored through end of study (Day 224). Additional endpoints included PK parameters and inhibition of plasma kallikrein activity.

Results: In total, 31 participants received navenibart and 10 received placebo. The median age of participants was 36 years; 53.7% were male; 51.2% were Black or African American. Rates of TEAEs were similar between navenibart and placebo, and no serious AEs were reported. Navenibart-related TEAEs included injection-site reactions, inclusive of erythema, pruritic, and swelling, that resolved without intervention. For all doses ≥300 mg, navenibart mean half-life ranged from 82 to 105 days and inhibition of factor XIIa-induced plasma kallikrein activity versus placebo was statistically significant (P<0.05) Statistically significant inhibition of factor XIIa-induced plasma kallikrein activity versus placebo (P<0.05) was observed with all doses of navenibart.

Conclusion: In this first-in-human study, up to 1200 mg of navenibart was well tolerated and demonstrated an extended half-life with durable plasma kallikrein inhibition.