D3.391 - Results from the ALPHA-STAR Trial, a Phase 1b/2 Single and Multiple Dose Study to Assess the Safety, Tolerability, Clinical Activity, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Navenibart in Participants with Hereditary Angioedema (HAE)

HAE is a rare, disfiguring, painful and potentially life-threatening disease. Despite the advancement of on-demand and preventative therapies, there is an unmet need for therapies to reduce disease and treatment burden for people living with HAE. Navenibart is the first immunoglobulin G1 monoclonal antibody designed with an extended half-life, exhibiting rapid and sustained inhibition of plasma kallikrein that may support administration 2 or 4 times a year. The ALPHA-STAR (NCT05695248) trial is a Phase 1b/2, proof of concept, clinical trial which assessed the safety and clinical activity of navenibart in patients with HAE C1 esterase inhibitor deficiency (HAE-C1INH).

Adults with HAE-C1INH were sequentially enrolled in 3 cohorts (navenibart, subcutaneous: 450 mg on day 1; 600/300 mg on days 1/84; 600/600 mg on days 1/28) and followed for 6 months after the last dose. We are reporting full results from the targeted enrollment population.

16 (4/6/6) participants were enrolled in 3 cohorts (respectively). Mean age (SD) was 46 (20) years, 56% were female, and 88% had HAE-C1INH Type 1. Treatment-emergent adverse events (TEAEs) occurred in 15 (94%) participants; related TEAEs (injection site reactions, dizziness) occurred in 3 (19%) participants. No severe or serious TEAEs and no discontinuations occurred. Time-normalized monthly HAE attack rates decreased from a median (per cohort) of 2.9/1.9/1.7 to 0.2/0.0/0.0 by 6 months and to 0.2/0.2/0.0 by the end of the follow-up period; 67% of participants were attack-free in Cohort 3. Navenibart reduced the incidence of moderate/severe HAE attacks and the use of rescue medication. Pharmacokinetic (PK) and pharmacodynamic (PD) profiles were consistent with clinical outcomes. Treatment-emergent anti-drug antibodies were detected in 5/16 participants with no apparent impact on PK/PD. 

Navenibart demonstrated a favorable safety profile and rapid and sustained reductions in HAE attack rates after one or two doses through the 6–9-month follow-up periods. These results support progression to Phase 3 to investigate the potential for navenibart administration every 3 or 6 months in preventing HAE attacks.