The IMAGINE study: A phase 3b open label, single arm study to assess the effect of depemokimab on airway structure and function in asthma with Type 2 inflammation characterized by an eosinophilic phenotype utilizing quantitative high-resolution CT and bronchoscopic airway sampling in a sub study

This phase 3b open-label, single-arm study evaluates the effects of depemokimab on airway structural and functional parameters in patients with asthma with Type 2 inflammation characterized by an eosinophilic phenotype. The primary objective is to describe the change from baseline (Week 0) in total mucus plug volume measured at total lung capacity (TLC) at Week 26 following treatment with depemokimab. This endpoint is clinically relevant as mucus plugging represents a significant contributor to airway obstruction and disease morbidity in eosinophilic asthma, and its quantification via imaging may provide objective assessment of treatment impact on airway pathology. The secondary objective is to describe the change from baseline (Week 0) in airway wall thickness measured at TLC at Week 52 following treatment with depemokimab. Assessment of airway wall remodeling over an extended treatment period addresses the potential disease-modifying effects of targeted anti-eosinophilic therapy on structural airway changes associated with chronic Type 2 inflammation.

This clinical trial enrolled a total of **51 participants** diagnosed with **asthma** with **type 2 inflammation** characterized by an **eosinophilic phenotype**. The study population included both male and female participants aged 18 years and older. Participants were required to have a documented clinical diagnosis of asthma for at least 2 years, with evidence of an eosinophilic phenotype demonstrated by a **blood eosinophil count** of ≥300 cells/μL and **exhaled nitric oxide (FeNO)** measure of ≥25 ppb. The trial population was selected based on uncontrolled asthma status, indicated by an **Asthma Control Questionnaire (ACQ5)** score greater than 1.5, and persistent **airflow obstruction** with pre-bronchodilator **FEV1** less than 80% predicted. Participants had a history of at least 2 **exacerbations** requiring treatment with **systemic corticosteroids** in the 12 months prior to screening, despite regular treatment with medium or high dose **inhaled corticosteroids (ICS)**. All participants were receiving at least one additional **asthma controller medication** such as **long-acting beta-agonist (LABA)**, **long-acting muscarinic antagonist (LAMA)**, **leukotriene receptor antagonist (LTRA)**, or **theophylline** for at least 3 months. Female participants of childbearing potential were required to use highly effective contraceptive methods. A subset of participants enrolled in a biopsy sub-study had post-bronchodilator FEV1 ≥50% predicted, no known increased risk for bleeding, normal screening **platelet count**, no current **anticoagulant** or **antiplatelet therapy**, and no contraindications to **bronchoscopy** with **endobronchial biopsy**.

This is a phase 3b, open-label, single-arm study designed to assess the effect of depemokimab on airway structure and function in participants with asthma with type 2 inflammation characterized by an eosinophilic phenotype. The study utilizes quantitative high-resolution CT imaging and includes a bronchoscopic airway sampling sub-study. The investigational medicinal product is administered as a solution for injection via the subcutaneous route. The maximum treatment period is 26 weeks. The estimated recruitment start date is November 2025, with an estimated study completion date in February 2028.

The primary objective is to describe the change from baseline at Week 0 in total mucus plug volume measured at total lung capacity at Week 26 following treatment with depemokimab. The secondary endpoint evaluates the change from baseline in airway wall thickness measured at total lung capacity at Week 52. The study aims to provide insights into the structural and functional changes in the airways of participants receiving this biologic therapy.

Eligible participants must be at least 18 years of age with a documented clinical diagnosis of asthma for at least 2 years. Key inclusion criteria include an eosinophilic phenotype evidenced by a blood eosinophil count of at least 300 cells/μL at screening or documented within 3 months prior to screening, an exhaled nitric oxide measure of at least 25 ppb recorded at screening, and a history of at least 2 exacerbations requiring treatment with systemic corticosteroids in the 12 months prior to screening despite the use of medium to high dose inhaled corticosteroids. Participants must demonstrate uncontrolled asthma indicated by an ACQ5 score greater than 1.5 and persistent airflow obstruction as indicated by pre-bronchodilator FEV1 less than 80% predicted at screening. Current treatment with at least one additional asthma controller medication besides inhaled corticosteroids for at least 3 months is required, such as LABA, LAMA, leukotriene receptor antagonist, or theophylline.

For the bronchoscopic sub-study, additional inclusion criteria apply. Participants must have post-bronchodilator FEV1 at least 50% predicted and no known increased risk for bleeding, including no history of easy bleeding, bruising, or known bleeding diathesis, no current anticoagulant and antiplatelet therapy, no acetylsalicylic acid use within 2 weeks of the planned procedure, and a normal screening platelet count. Participants must have no specific contraindication to bronchoscopy with endobronchial biopsy in the opinion of the investigator and no history of allergic reaction to local anesthesia or general anesthetic agent. Female participants of childbearing potential must have a negative pregnancy test within 24 hours before the first dose of study intervention and must use a highly effective contraceptive method with a failure rate of less than 1% per year from 14 days prior to and during the study intervention period and for at least 35 weeks after the last dose of study intervention.

The study involves a screening visit to assess eligibility, followed by a baseline visit at Week 0 where the first dose of depemokimab is administered and baseline measurements including high-resolution CT imaging are performed. Participants will attend follow-up visits at regular intervals throughout the 26-week treatment period for clinical assessments, safety monitoring, and administration of study intervention. A key assessment visit occurs at Week 26 to evaluate the primary endpoint, with quantitative high-resolution CT imaging repeated to measure changes in total mucus plug volume. A final assessment visit is conducted at Week 52 to evaluate secondary endpoints, including changes in airway wall thickness. For participants enrolled in the bronchoscopic sub-study, bronchoscopy with airway sampling is performed at designated time points as specified in the protocol. The expected duration of participant involvement is 52 weeks from baseline. Participants may be withdrawn from the study early due to withdrawal of consent, adverse events, protocol deviations, pregnancy, loss to follow-up, or at the discretion of the investigator if continuation is not in the best interest of the participant.

The experimental treatment in this clinical trial is depemokimab, a biologic investigational medicinal product manufactured by GlaxoSmithKline. Depemokimab is supplied as a solution for injection in a pharmaceutical form suitable for subcutaneous administration. The active substance, depemokimab, is classified as a protein-based therapeutic agent. The sponsor product code for this investigational product is GSK3511294, and it is authorized under Manufacturing and Importation Authorization (MIA) number MIA (IMP) 20377. The maximum treatment period for depemokimab administration in this study is 26 weeks. The concentration of the solution is expressed in milligrams per milliliter (mg/ml). This is a phase 3b open-label, single-arm study design, indicating that all participants will receive the experimental treatment without a placebo or active comparator group.

The study is designed to assess the effect of depemokimab on airway structure and function in participants with asthma characterized by Type 2 inflammation and an eosinophilic phenotype. The trial utilizes quantitative high-resolution computed tomography (CT) and bronchoscopic airway sampling in a substudy component. The primary objective is to evaluate the change from baseline at Week 0 in total mucus plug volume measured at total lung capacity at Week 26 following treatment with depemokimab. Participant compliance monitoring and adherence to the dosing schedule will be implemented throughout the treatment period to ensure protocol compliance and data integrity.

Efficacy will be assessed through the evaluation of changes in airway structure and function utilizing quantitative high-resolution computed tomography (CT) imaging. The primary endpoint is the change from baseline at Week 0 in total **mucus plug volume** measured at **total lung capacity** (TLC) at Week 26 following treatment with **depemokimab**. A secondary endpoint includes the change from baseline in **airway wall thickness** measured at TLC at Week 52. These parameters will provide objective measures of structural airway remodeling and mucus obstruction in participants with **asthma** with Type 2 inflammation characterized by an **eosinophilic phenotype**. The study also incorporates bronchoscopic airway sampling in a sub-study to further evaluate airway changes. Assessment timepoints are established at Week 26 for the primary efficacy evaluation and at Week 52 for secondary efficacy outcomes.