A Phase III, Multicentre, Randomized, Double-blind, Chronic-dosing, Parallel-group, Placebo-controlled Study to Evaluate the Efficacy and Safety of Two Dose Regimens of Tozorakimab in Participants with Symptomatic Chronic Obstructive Pulmonary Disease (COPD) with a History of COPD Exacerbations (Oberon)

The primary objective is to evaluate the effect of two dose regimens of tozorakimab as add-on therapy to standard of care compared with standard of care plus placebo on the rate of moderate to severe exacerbations in former smokers with chronic obstructive pulmonary disease (COPD). This objective addresses a clinically significant endpoint in COPD management, as exacerbation frequency is a key determinant of disease progression, healthcare utilization, and patient prognosis in this population.

The secondary objectives include:

• To evaluate the effect of two dose regimens of tozorakimab as add-on to standard of care compared with standard of care plus placebo on: the rate of moderate to severe COPD exacerbations in former and current smokers; change in pre-bronchodilator and post-bronchodilator lung function; respiratory symptoms; respiratory health status and health-related quality of life; time to moderate to severe COPD exacerbations; severe COPD exacerbations; COPD health status and health-related quality of life; COPD-related healthcare resource utilization; and daily rescue medication use.

• To evaluate the pharmacokinetics and immunogenicity of two dose regimens of tozorakimab.

• To assess the safety and tolerability of two dose regimens of tozorakimab as add-on to standard of care compared with standard of care plus placebo.

This clinical trial enrolled a total of **581 participants** diagnosed with **Chronic Obstructive Pulmonary Disease (COPD)**. The study population consisted of both **male and female subjects** aged **40 years and older**. Participants were former smokers with a documented smoking history of at least 10 pack-years. The trial population was selected based on specific clinical characteristics, including a documented COPD diagnosis for at least one year, post-bronchodilator FEV1/FVC ratio less than 0.70, and post-bronchodilator FEV1 greater than 20% of predicted normal value. Eligible participants had experienced at least 2 moderate or at least 1 severe COPD exacerbation within the 12 months prior to enrollment. All participants were required to be on optimized inhaled dual or triple therapy at a stable dose for at least 3 months before enrollment. Additionally, participants demonstrated significant symptom burden with a CAT total score of at least 10, including scores of at least 2 on both phlegm and cough assessment items. The study included a vulnerable population.

This is a Phase III, multicenter, randomized, double-blind, chronic-dosing, parallel-group, placebo-controlled clinical trial evaluating the efficacy and safety of two dose regimens of **tozorakimab** in participants with symptomatic **chronic obstructive pulmonary disease** (COPD) with a history of COPD exacerbations. The trial is designed to assess tozorakimab as an add-on to standard of care compared with standard of care plus **placebo** in former smokers. The primary objective is to evaluate the effect of two dose regimens of tozorakimab on the rate of moderate to severe exacerbations. The primary endpoint is the annualized rate of moderate to severe COPD exacerbations in participants who are former smokers.

The investigational medicinal product tozorakimab is administered as a **solution for injection** via **subcutaneous** route, with a maximum treatment period of 52 weeks. The placebo comparator is tozorakimab-placebo. **Salbutamol sulfate**, a **short-acting beta2-agonist**, is used as an auxiliary medicinal product administered via **inhalation**, with a maximum daily dose of 800 µg and a maximum total dose of 1600 µg over the same 52-week treatment period.

Eligible participants must be at least 40 years of age with a documented diagnosis of COPD for at least one year prior to enrollment. Key inclusion criteria include post-bronchodilator **FEV1/FVC** ratio less than 0.70, post-bronchodilator FEV1 greater than 20% of predicted normal value, and a documented history of at least 2 moderate or at least 1 severe COPD exacerbation within 12 months prior to enrollment. Participants must be on documented optimized inhaled dual or triple therapy at a stable dose for at least 3 months prior to enrollment, have a smoking history of at least 10 pack-years, and demonstrate a **CAT** (COPD Assessment Test) total score of at least 10, with each of the phlegm (sputum) and cough items scoring at least 2.

The estimated recruitment start date for this trial is January 29, 2024, with an estimated completion date of May 4, 2026. The total duration of participant involvement is expected to be up to 52 weeks of treatment. The trial involves multiple study visits including screening, randomization, treatment visits, and an end-of-study visit to assess efficacy and safety outcomes throughout the study period.

The experimental medication **Tozorakimab** (sponsor product code: MEDI3506) is administered as a **solution for injection** via **subcutaneous** route. The active substance is tozorakimab, a protein of biological origin. The maximum treatment period is 52 weeks. Two dose regimens of tozorakimab are evaluated in this study as add-on therapy to standard of care. The medicinal product is manufactured by AstraZeneca AB.

**Placebo** matching tozorakimab is administered to participants in the control group. The placebo is used to maintain the **double-blind** design of the study and is administered for a maximum treatment period of 52 weeks. The pharmaceutical form and route of administration correspond to those of the active treatment to ensure blinding integrity.

**Salbutamol sulfate** is used as an auxiliary medicinal product throughout the study. This **short-acting beta2-agonist** is administered via **inhalation**. The maximum daily dose is 800 micrograms, with a maximum total dose of 1600 micrograms. Salbutamol sulfate is available for use as rescue medication for a maximum treatment period of 52 weeks. The substance is of chemical origin and is classified under ATC code R03AC02.

All investigational medicinal products are administered as part of a **chronic-dosing**, **parallel-group** study design in participants with symptomatic **chronic obstructive pulmonary disease** with a history of exacerbations. The study evaluates the efficacy and safety of tozorakimab compared with placebo, both administered in addition to standard of care therapy. Participant compliance monitoring procedures are implemented throughout the treatment period to ensure adherence to the prescribed dosing schedules.

Efficacy will be assessed by evaluating the annualized rate of moderate to severe chronic obstructive pulmonary disease exacerbations in participants who are former smokers. This parameter serves as the primary endpoint for determining the therapeutic effect of tozorakimab as add-on therapy to standard of care compared with placebo plus standard of care.