D3.390 - Rationale and Design for ALPHA-ORBIT: a phase 3 trial of navenibart, a monoclonal antibody inhibitor of plasma kallikrein for participants with hereditary angioedema (HAE)

Navenibart is an investigational monoclonal antibody inhibitor of plasma kallikrein with long-lasting activity enabled by a YTE-modified Fc domain. An interim analysis of a Phase 1b/2 trial demonstrated that navenibart was well-tolerated after 1 or 2 doses and reduced attack frequency, severity, and utilization of on-demand treatment for at least 6 months. Navenibart has the potential to become an effective and safe preventative treatment for HAE, with administration 2 or 4 times a year.

ALPHA-ORBIT is a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of navenibart in preventing HAE attacks in participants with HAE-C1INH Type 1 or Type 2. The trial will enroll approximately 135 adults and 10 adolescents from regions around the world. In adults, the trial will consist of a screening period that includes ≤ 90 days washout of long-term prophylaxis (if relevant), as well as ≥ 1-month and ≤ 2-month run-in period during which two attacks must occur, a treatment period (6 months), and a follow-up period (6 months); adolescent participants will not undergo washout as part of the screening period. The 4 treatment arms include: navenibart 600 mg initial dose and then 300 mg Q3M, 600 mg Q6M, 600 mg Q3M or placebo, subcutaneously. Adolescents will receive a navenibart 600 mg initial dose and then 300 mg Q3M. The primary efficacy endpoint is the number of time-normalized investigator-confirmed HAE attacks during the 6-month treatment period, and the primary efficacy analysis will compare each navenibart dosing regimen versus placebo for the adult participants. Secondary efficacy endpoints will evaluate the impact of navenibart on the burden of disease and the proportion of participants who are attack-free at 6 months. The primary safety endpoint is the incidence of treatment-emergent adverse events.

Navenibart has the potential to offer significant improvement in the clinical care of patients with HAE. The ALPHA-ORBIT trial design includes maximizing the sustained kallikrein inhibition with navenibart's long half-life by dosing every 3 or 6 months.

Navenibart's efficacy and safety in the long-term prevention of HAE attacks remain to be confirmed in the randomized, global Phase 3 trial, ALPHA-ORBIT.