Efficacy and Safety Evaluation of Navenibart in Hereditary Angioedema: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Multicenter Trial

The primary objective of this study is to evaluate the **superiority** of navenibart compared to placebo in preventing attacks of **Hereditary Angioedema** (HAE) in adult participants. This is clinically relevant as it aims to establish navenibart as a more effective preventive treatment option for HAE, potentially reducing the frequency and severity of attacks, thereby improving patient outcomes.

Secondary objectives include: - For adults and adolescents, assessing the clinical efficacy of navenibart as a preventive treatment for HAE. - Evaluating the quality of life associated with the use of navenibart in participants with HAE. - For adults only, assessing the safety and tolerability of navenibart relative to placebo as a preventive treatment. These objectives are crucial for understanding the broader impact of navenibart on patient well-being and its safety profile, which are essential for its potential adoption in clinical practice.

The clinical trial involves a total of **93 participants** diagnosed with **Hereditary Angioedema** (HAE), including both Type 1 and Type 2. The study population comprises both male and female subjects, spanning an age range that includes children, adolescents, and adults. Participants were selected based on a documented diagnosis of HAE, with a clinical history and laboratory findings consistent with the condition. Additionally, participants must have experienced at least two HAE attacks during the Run-In period. The trial includes a vulnerable population, indicating special considerations for the participants' safety and well-being. The study does not specify particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that the trial population is representative of individuals affected by HAE, providing a comprehensive assessment of the investigational treatment's efficacy and safety across different age groups.

The clinical trial is a **Phase 3**, multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of **Navenibart** in participants with **Hereditary Angioedema** (HAE). The trial aims to assess the superiority of Navenibart compared to placebo in preventing HAE attacks in adults and to evaluate its efficacy, safety, and tolerability in adolescents. The study is expected to commence recruitment on August 30, 2025, and conclude by March 31, 2027, with a total duration of approximately 19 months.

Participants will be involved in the study for a maximum of 6 months during the treatment period, following a run-in period where at least two HAE attacks must be documented. The trial will include several key visits: an initial screening visit to confirm eligibility based on documented diagnosis and clinical history of HAE, followed by regular follow-up visits to monitor the frequency and severity of HAE attacks, and an end-of-study visit to assess overall outcomes and any adverse events. The primary endpoint is the number of time-normalized investigator-confirmed HAE attacks during the treatment period, with secondary endpoints including the number of moderate or severe attacks, attacks requiring on-demand treatment, and changes in quality of life scores.

Participants will receive either Navenibart or a matching placebo administered via subcutaneous injection. The maximum daily dose of Navenibart is 600 mg, with a total maximum dose of 1200 mg over the treatment period. Conditions that may lead to early termination from the study include the occurrence of significant adverse events or failure to adhere to the study protocol. The trial is not classified as low intervention, and it is essential that participants meet all inclusion criteria and none of the exclusion criteria to ensure the integrity and validity of the study results.

The clinical trial involves the administration of **Navenibart**, an experimental medication designed to evaluate its efficacy and safety in participants with **Hereditary Angioedema** (HAE). Navenibart is a **sterile solution** formulated as a humanised IgG1 kappa (YTE) monoclonal antibody targeting plasma kallikrein. The pharmaceutical form of Navenibart is a sterile solution, and it is administered via **subcutaneous use**. The dosing regimen for Navenibart includes a maximum daily dose of 600 mg, with a total maximum dose of 1200 mg over a treatment period of up to 91 days. The active substance, Navenibart, is derived from a protein of other origin, and it is not a paediatric formulation. The trial aims to assess the superiority of Navenibart compared to placebo in preventing HAE attacks in adults and to evaluate its efficacy, safety, and tolerability in adolescents.

The study also includes a **matching placebo** for Navenibart, which serves as the comparator treatment in this double-blind, placebo-controlled trial. The placebo is designed to match the experimental medication in appearance and administration route, ensuring the blinding of participants and investigators. The placebo does not contain any active substance and is used to evaluate the true efficacy of Navenibart by comparing outcomes between the treatment and placebo groups. The trial's design ensures that neither the participants nor the investigators are aware of the treatment assignments, maintaining the integrity of the study results.

The efficacy of Navenibart in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the number of time-normalized investigator-confirmed **Hereditary Angioedema (HAE)** attacks during the 6-month treatment period. Secondary endpoints include the number of moderate or severe investigator-confirmed HAE attacks, the number of attacks requiring on-demand treatment, and the percent reduction in monthly investigator-confirmed HAE attacks during the treatment period compared to the run-in period. Additionally, the time to the first investigator-confirmed HAE attack after the first and second dose will be evaluated, along with the number of participants responding to treatment, defined by a reduction of ≥ 50%, ≥ 70%, or ≥ 90% in attack rate from the run-in period. The number of participants with no investigator-confirmed HAE attacks during the treatment period and changes from baseline in the Angioedema Quality of Life questionnaire total score will also be assessed. The incidence of treatment-emergent adverse events is included as another pre-specified outcome measure.