A randomized, double-blind, placebo-controlled, parallel-group, multicenter study of the efficacy and safety of depemokimab in adult participants with COPD with Type 2 inflammation.

The primary objective of this study is to evaluate the efficacy of depemokimab compared with placebo in adult participants with chronic obstructive pulmonary disease (COPD) with Type 2 inflammation. This assessment is clinically relevant for determining whether depemokimab provides therapeutic benefit in this specific COPD phenotype characterized by eosinophilic inflammation, which may represent a distinct patient population requiring targeted biologic therapy.

The secondary objectives include:

• To evaluate depemokimab compared with placebo on additional efficacy endpoints and symptoms.

• To evaluate depemokimab compared with placebo on pooled efficacy endpoints.

This clinical trial enrolled a total of **528 participants** diagnosed with **Chronic Obstructive Pulmonary Disease** (COPD). The study population consisted of both **male and female participants** aged **40 to 80 years** at the time of enrollment. Participants were selected based on having **moderate to severe COPD** with frequent exacerbations, characterized by a post-bronchodilator forced expiratory volume in one second to forced vital capacity ratio of less than 0.70 and a post-bronchodilator forced expiratory volume in one second greater than 30 percent and up to 80 percent of predicted normal values. All participants had an **elevated blood eosinophil count** and a well-documented history of at least 2 moderate or 1 severe exacerbation in the 12 months prior to screening. Regarding lifestyle considerations, participants were current or former cigarette smokers with a **smoking history** of at least 10 pack-years. Participants were required to have a **Body Mass Index** of at least 16 kilograms per square meter. All enrolled individuals were maintained on optimized inhaler therapy consisting of **inhaled corticosteroid** plus **long-acting muscarinic receptor antagonist** plus **long-acting beta2-adrenergic receptor agonist** for at least 6 months prior to screening. The trial population included vulnerable populations as defined by regulatory standards.

This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter phase 3A clinical trial evaluating the efficacy and safety of depemokimab in adult participants with chronic obstructive pulmonary disease (COPD) with type 2 inflammation. The study investigates depemokimab, a biologic administered as a solution for injection via subcutaneous injection using a pre-filled syringe delivery system. The control group receives placebo consisting of sterile 0.9% sodium chloride solution in single-use pre-filled syringes. Salbutamol sulfate inhalation powder is permitted as auxiliary medication for rescue use at a maximum daily dose of 800 micrograms administered via inhalation use.

The primary objective is to evaluate the efficacy of depemokimab compared with placebo. The primary endpoint is the annualized rate of moderate to severe exacerbations. Secondary endpoints include time to first moderate or severe exacerbation, change from baseline in St. George's Respiratory Questionnaire total score at Week 52, change from baseline in Evaluating Respiratory Symptoms in COPD total score at Week 52, annualized rate of exacerbations requiring emergency department visit or hospitalization, and annualized rate of severe exacerbations.

Eligible participants must be between 40 and 80 years of age at the time of informed consent with an elevated blood eosinophil count. Participants must have moderate to severe COPD with frequent exacerbations, defined by a clinically documented history of COPD for at least 1 year, a post-bronchodilator FEV1/FVC ratio of less than 0.70, a post-bronchodilator FEV1 greater than 30% and less than or equal to 80% predicted normal values, and a well-documented history of at least 2 moderate or 1 severe exacerbation in the 12 months prior to screening. Additional inclusion criteria include a COPD assessment test score of 10 or higher at Visit 1, current or former cigarette smoking history of at least 10 pack-years, optimized inhaler therapy consisting of inhaled corticosteroid plus long-acting muscarinic receptor antagonist plus long-acting beta2-adrenergic receptor agonist for at least 6 months prior to screening, and body mass index of 16 kg/m² or higher.

The maximum treatment period for depemokimab is 104 weeks. The estimated recruitment start date is December 31, 2025, and the estimated study completion date is December 31, 2029. Study visits include a screening visit for participant enrollment and eligibility assessment, follow-up visits for efficacy and safety evaluations including assessment of exacerbation rates and quality of life measures, and an end-of-study visit. Participant involvement extends through the treatment period and follow-up assessments. Early termination from the study may occur based on specific conditions defined in the protocol.

The experimental treatment in this clinical trial is **depemokimab**, a biologic medicinal product supplied as a **solution for injection** in a pre-filled syringe (PFS). Depemokimab is administered via **subcutaneous injection** using a single-use packaging system. The PFS consists of a 1.0 mL long siliconized Type I glass barrel with a 29-gauge, 0.5 inch thin wall staked needle, sealed with a bromobutyl elastomeric plunger stopper and equipped with a rigid needle shield. The maximum treatment period for depemokimab is **104 weeks**. The device is supplied as a complete packaging and delivery system that includes all product contact materials. The sponsor product code for this investigational medicinal product is GSK3511294.

The **placebo** comparator used in this study consists of sterile 0.9% (w/v) **sodium chloride solution** provided in single-use pre-filled syringes. The placebo is formulated to match the appearance and delivery method of the active treatment to maintain blinding throughout the double-blind study design.

**Salbutamol sulfate** is permitted as auxiliary medication in this trial. It is supplied as Novolizer Salbutamol 100 micrograms per dose, an **inhalation powder** for **inhalation use**. The maximum daily dose is **800 micrograms** and the maximum total dose per treatment period is **800 micrograms** per day. The maximum treatment period for salbutamol is **1 day**, indicating it is available for use as needed. This small molecule medication is a marketed product authorized in Belgium under marketing authorization number BE260793 and MRP number DE/H/0333/001.

Efficacy will be assessed through multiple parameters evaluating exacerbation rates, symptom burden, and quality of life in participants with chronic obstructive pulmonary disease with Type 2 inflammation. The primary efficacy endpoint is the annualized rate of moderate/severe exacerbations. Secondary efficacy endpoints include time to first moderate/severe exacerbation, change from baseline in St. George's Respiratory Questionnaire total score at Week 52, change from baseline in Evaluating Respiratory Symptoms in Chronic Obstructive Pulmonary Disease total score at Week 52, annualized rate of exacerbations requiring emergency department visit or hospitalization, and annualized rate of severe exacerbations. The COPD assessment test score, measured at baseline with a threshold of 10 or greater, will be utilized as part of the participant characterization. Efficacy assessments will be conducted over a treatment period of up to 104 weeks.