Safety and pharmacokinetics of long-acting plasma kallikrein inhibitor navenibart (STAR-0215) in healthy adults.

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

To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of a single dose of navenibart in healthy adults and to assess the 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 (100-1200 mg) dosing cohorts. Safety outcomes, including treatment-emergent adverse events (TEAEs) and serious AEs, were monitored until the end of the study (day 224). Additional end points included pharmacokinetic parameters and inhibition of plasma kallikrein activity.

RESULTS

In total, 31 participants received navenibart and 10 received placebo. The median age of the 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, pruritus, and swelling, which resolved without intervention. For all doses more than or equal to 300 mg, navenibart mean half-life ranged from 82 to 105 days and inhibition of factor XIIa-induced plasma kallikrein activity vs placebo was statistically significant (P < .05). Statistically significant inhibition of factor XIIa-induced plasma kallikrein activity vs placebo (P < .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.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05477160.