Phase 2a Randomized, Double‑Blind, Placebo‑Controlled Study of Subcutaneous SAR445399 on Mucus Plug Score in Adults with Non‑Cystic Fibrosis Bronchiectasis

The primary objective is to determine whether SAR445399 reduces the mucus plug score compared with placebo in adults with Non-cystic fibrosis bronchiectasis, addressing a key pathophysiological component that drives airflow limitation and exacerbation risk. Secondary objectives include:

• Evaluation of the effect of SAR445399 versus placebo on pulmonary function parameters.
• Assessment of the incidence of pulmonary exacerbations and of severe pulmonary exacerbations.
• Characterization of safety and tolerability outcomes.
• Characterization of the pharmacokinetic profile of SAR445399.
• Evaluation of immunogenicity of SAR445399.

The trial enrolled 72 participants diagnosed with non‑cystic fibrosis bronchiectasis. Eligible individuals were aged 18 to 80 years, included both male and female subjects, and were considered vulnerable according to protocol. Inclusion required chronic sputum production for at least three months, a history of at least two physician‑prescribed antibiotic courses for pulmonary exacerbations within the preceding 12 months, radiologic confirmation of bronchiectasis on high‑resolution CT, a baseline mucus plug score of 4 or higher, and a post‑bronchodilator FEV1 of 30% or greater of predicted normal. Participants were selected based on documented clinical history consistent with the disease and meeting these radiologic and functional criteria, resulting in a generally stable patient population at screening.

The study is a Phase 2a, randomized, double‑blind, placebo‑controlled, parallel‑group trial evaluating subcutaneous SAR445399 versus a matched placebo in adults aged 18–80 with Non-cystic fibrosis bronchiectasis. After an initial screening visit to confirm eligibility (clinical history, HRCT, mucus plug score ≥ 4, sputum production, and post‑bronchodilator FEV₁ ≥ 30% predicted), participants are randomized and receive the first dose at the baseline visit. Subsequent study visits are scheduled at approximately weeks 4, 12, 24, 36, and 52 to assess the primary endpoint (change in mucus plug score at week 24) and secondary endpoints including FEV₁ changes, pulmonary exacerbation rates, safety laboratory parameters, electrocardiograms, plasma drug concentrations, and anti‑drug antibody status. The end‑of‑study visit occurs at week 52, completing a total participant involvement of roughly one year. Early termination may occur for any participant experiencing a serious adverse event, meeting predefined safety stopping criteria, withdrawing consent, or failing to adhere to protocol requirements.

The trial enrolls adult participants with non‑cystic fibrosis bronchiectasis. The investigational product, SAR445399, is supplied as a powder for solution for injection and is administered by subcutaneous injection at a dose of 00 mg per administration according to the dosing schedule defined in the protocol.

The control arm receives a matched placebo, which contains no active substance and is identical in appearance to the investigational product.

Both study treatments are prepared immediately before administration by qualified personnel. Participant compliance is monitored by recording each dose in the electronic case report form and by accounting for returned vials. Immediate post‑administration observations are performed to assess any acute reactions.

Efficacy will be evaluated primarily by the change from baseline to Week 24 in the mucus plug score (MPS) derived from chest high‑resolution computed tomography (HRCT). HRCT images will be obtained at screening, baseline, and Week 24, and the MPS will be quantified by a centralized imaging core laboratory using a validated scoring system.

Secondary efficacy assessments include changes from baseline to Weeks 24 and 52 in forced expiratory volume in 1 second (FEV1), measured pre‑ and post‑bronchodilator using standardized spirometry according to ATS/ERS guidelines. The annualized rate of pulmonary exacerbation (PEx) will be calculated for the periods baseline to Week 24 and baseline to Week 52, and responder analyses will determine the proportion of participants who remain exacerbation‑free (including severe exacerbations) over the respective 24‑ and 52‑week intervals. All efficacy parameters will be collected at the specified study visits, and changes from baseline will be analyzed using appropriate statistical models to compare SAR445399 with placebo.