Efficacy, Safety, and Tolerability of Itepekimab in Non-Cystic Fibrosis Bronchiectasis: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **efficacy** of itepekimab compared with placebo on the occurrence of pulmonary exacerbations (PEs) in patients with non-cystic fibrosis bronchiectasis (NCFB). This is clinically relevant as reducing the frequency of PEs can significantly improve patient outcomes and quality of life in individuals with NCFB, a chronic and debilitating respiratory condition.

Secondary objectives include: - Evaluating the efficacy of itepekimab compared with placebo on the occurrence of pulmonary embolisms (PEs) in NCFB. - Assessing the impact on pulmonary function in NCFB. - Investigating the reduction in antibiotic use in NCFB. - Evaluating health-related quality of life (HRQoL) and health status using the Quality-of-Life Questionnaire – Bronchiectasis (QoL-B) and St. George’s Respiratory Questionnaire (SGRQ) in NCFB. - Assessing the safety and tolerability of itepekimab in NCFB. - Evaluating the pharmacokinetic (PK) profile of itepekimab in NCFB. - Investigating the immunogenicity of itepekimab in NCFB.

The clinical trial involves a total of **215 participants** diagnosed with **bronchiectasis**, specifically focusing on non-cystic fibrosis bronchiectasis (NCFB). The study population includes both male and female subjects, aged between **18 to 85 years**. Participants were selected based on a clinical history consistent with NCFB, characterized by symptoms such as cough, chronic sputum production, and/or recurrent respiratory infections. Additionally, eligible participants must have experienced at least two moderate or one severe pulmonary exacerbation in the past 12 months and have a forced expiratory volume in one second (FEV1) percentage predicted of 30% or greater. The trial includes a vulnerable population, and lifestyle factors such as diet and physical activity were not specified as part of the selection criteria. The sponsor has not provided further information regarding specific lifestyle considerations or additional health status details of the participants.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled, parallel-group** study to evaluate the efficacy, safety, and tolerability of **itepekimab** in participants with non-cystic fibrosis **bronchiectasis**. The trial aims to assess the impact of itepekimab on the occurrence of pulmonary exacerbations (PEs) over the treatment period. Participants will be randomly assigned to receive either itepekimab or a matched placebo, administered via subcutaneous injection. The trial is expected to span approximately 50 weeks, with participant involvement beginning from the screening visit and concluding at the end-of-study visit.

The sequence of study visits includes an initial screening visit to determine eligibility based on criteria such as age (18 to 85 years), clinical history of bronchiectasis, and previous occurrences of PEs. Following successful screening, participants will undergo a baseline visit where initial assessments and randomization occur. Subsequent follow-up visits will be scheduled at regular intervals to monitor the participants' health status, collect data on PEs, and assess any adverse events. The end-of-study visit will mark the conclusion of the participant's involvement, where final evaluations and data collection will take place.

Participants are expected to remain in the study for the entire duration unless specific conditions necessitate early termination. These conditions may include the occurrence of severe adverse events, withdrawal of consent, or any other medical reasons deemed significant by the study investigators. The primary endpoint of the trial is the annualized rate of moderate or severe PEs, while secondary endpoints include time to first PE, percentage of participants who remain PE-free, and changes in lung function and quality of life scores. The trial will also monitor the incidence of treatment-emergent adverse events and the development of anti-itepekimab antibodies.

The clinical trial involves the administration of **Itepekimab**, a human monoclonal antibody targeting interleukin-33. Itepekimab is provided as a **solution for injection in a pre-filled syringe**. The pharmaceutical form is specifically designed for **subcutaneous injection**. The dosing regimen for Itepekimab involves a maximum daily dose of 300 mg, with a total maximum dose of 7800 mg over a treatment period of up to 50 weeks. The administration schedule is determined by the study protocol, and participant compliance is monitored throughout the trial to ensure adherence to the dosing regimen. Itepekimab is developed by Sanofi Aventis Recherche et Développement (SAR) and is identified by the sponsor product code SAR440340.

The study also includes a **matched placebo** for the test product, which serves as the comparator treatment in this randomized, double-blind, placebo-controlled trial. The placebo is designed to match the test product in appearance and administration route to maintain blinding. The placebo is administered via subcutaneous injection, following the same schedule as the experimental treatment. The use of a placebo allows for the assessment of the efficacy, safety, and tolerability of Itepekimab in participants with non-cystic fibrosis bronchiectasis by comparing outcomes between the treatment and control groups.

The efficacy of itepekimab in the treatment of non-cystic fibrosis bronchiectasis will be assessed through a randomized, double-blind, placebo-controlled, parallel-group, Proof-of-Concept study. The primary endpoint for evaluating efficacy is the annualized rate of moderate or severe **Pulmonary Exacerbations (PEs)** over the treatment period. Secondary endpoints include the time to first moderate or severe PE, the percentage of participants who remain PE-free, the annualized rate of severe PEs, and the percentage of participants who remain severe PE-free over the treatment period. Additional secondary endpoints involve the time to first severe PE, changes from baseline in Forced Expiratory Volume in one second (FEV1) at Week 8 and Week 24, and the number of days of new and/or added antibiotic use.

Further assessments will include changes from baseline in the Quality of Life-Bronchiectasis (QOL-B) Respiratory Symptoms Domain Score at Week 24, changes from baseline in the St. George's Respiratory Questionnaire (SGRQ) total score at Week 24, and the percentage of participants with a decrease from baseline of at least 4 points in the SGRQ total score at Week 24. Safety and tolerability will be monitored through the incidence of treatment-emergent adverse events (TEAEs), adverse events of special interest (AESIs), serious adverse events (SAEs), and adverse events leading to permanent study treatment discontinuation. Serum concentrations of itepekimab and the incidence of treatment-emergent anti-itepekimab antibodies (ADA) responses will also be evaluated from baseline to the end of the study.