A Multicentre, Parallel-group, Phase IIb, Randomised, Double blind, Placebo-controlled, 4-Arm, 24-Week Study to Evaluate the Efficacy and Safety of AZD6793 Tablets in Adult Participants with Moderate to Very Severe Chronic Obstructive Pulmonary Disease (PRESTO).

The primary objective of this study is to evaluate the effect of AZD6793 compared to placebo on the rate of moderate or severe chronic obstructive pulmonary disease exacerbations. This endpoint is clinically relevant as exacerbation frequency is a key indicator of disease progression and patient morbidity in COPD.

The secondary objectives include:

• To evaluate the effect of AZD6793 as compared to placebo on COPD exacerbations;

• To evaluate the effect of AZD6793 as compared to placebo on COPDCompEx events;

• To evaluate the effect of AZD6793 as compared to placebo on measures of lung function;

• To evaluate the effect of AZD6793 compared to placebo on symptoms and health-related quality of life;

• To assess the pharmacokinetics of AZD6793 in participants with COPD;

• To assess the safety and tolerability of AZD6793 as compared to placebo in participants with moderate to very severe COPD.

The clinical trial enrolled a total of **846 participants** diagnosed with **moderate to very severe Chronic Obstructive Pulmonary Disease (COPD)**. The study population consisted of both male and female adults aged **40 years and older**. Participants were required to have a documented primary diagnosis of COPD for at least 12 months prior to enrollment, with **post-bronchodilator FEV1** ranging from 25% to less than 80% of predicted normal values and **pre-bronchodilator FEV1/FVC ratio** less than 0.7. All participants had a history of frequent exacerbations, specifically at least two moderate or one severe COPD exacerbation in the 12 months before screening, and were maintained on a stable regimen of inhaled triple or dual maintenance therapy for at least three months prior to screening. The study population included current or former smokers with a smoking history of at least **10 pack-years**. Participants were clinically stable and exacerbation-free for four weeks prior to enrollment and at randomization, with a **COPD Assessment Test (CAT) score** of 10 or higher indicating significant symptom burden. Women of childbearing potential were required to have negative pregnancy tests at screening and randomization visits.

This is a multicentre, parallel-group, phase IIb, **randomised**, **double-blind**, **placebo-controlled**, 4-arm study designed to evaluate the efficacy and safety of **AZD6793** film-coated tablets administered via **oral use** in adult participants with moderate to very severe **chronic obstructive pulmonary disease**. The study utilizes a synthetic product of chemical origin as the active investigational medicinal product, with a corresponding placebo comparator. The trial is categorized as a phase IIb study with an estimated recruitment start date in October 2025 and an estimated completion date in November 2027. The maximum treatment period for participants is **24 weeks**.

The primary objective is to evaluate the effect of AZD6793 compared to placebo on the rate of moderate or severe COPD exacerbations. The **primary endpoint** is the annualised rate of moderate or severe COPD exacerbations. Secondary endpoints include time to first moderate or severe COPD exacerbation, annualised rate of COPD exacerbations associated with emergency room visits, urgent care visits, or hospitalisations, annualised rate of severe COPD exacerbations defined as exacerbations resulting in hospitalisation or death due to COPD, annualised rate of COPDCompEx events, time to first COPDCompEx event, change from baseline in pre-bronchodilator and post-bronchodilator **FEV1** at Week 12 and Week 24, change from baseline over 24 weeks in Breathlessness, Cough and Sputum Scale total score, **COPD Assessment Test** total score, St George's Respiratory Questionnaire total and domain scores, AZD6793 plasma concentrations at specific timepoints, and safety and tolerability evaluations.

Principal inclusion criteria require participants to be at least 40 years of age at the time of informed consent with a documented primary diagnosis of moderate to very severe COPD for at least 12 months prior to enrolment. Participants must have pre-bronchodilator FEV1/FVC less than 0.7 at the initial visit and pre- and post-bronchodilator FEV1/FVC less than 0.7, with post-bronchodilator FEV1 at least 25% to less than 80% of predicted normal at the subsequent visit. A documented history of at least 2 moderate or at least 1 severe COPD exacerbations in the 12 months prior to screening is required. Participants must have a documented stable regimen of inhaled triple maintenance therapy or inhaled dual maintenance therapy for at least 3 months prior to screening, a CAT score of at least 10 at the initial visit, and be current or ex-smokers with a cigarette smoking history of at least 10 pack-years. Participants must be clinically stable and free from an exacerbation of COPD for 4 weeks prior to the initial visit and remain exacerbation free at randomisation. Women of child-bearing potential must have a negative pregnancy test at the initial visit and at randomisation.

Safety and tolerability will be assessed through monitoring of **adverse events**, **serious adverse events**, adverse events of special interest including X-ray confirmed **pneumonia**, serious infections, **herpes zoster** infections, severe COVID-19 infections, haematology events such as **anaemia**, **neutropenia**, and **thrombocytopaenia**, skin and hair depigmentation events during skin examinations, vital signs, physical examinations, clinical laboratory assessments including clinical chemistry, male reproductive hormones, haematology, and urinalysis, and **electrocardiograms**. Participants may be subject to early termination from the study based on specific conditions including safety concerns, loss to follow-up, withdrawal of consent, protocol violations, or investigator discretion. The expected length of participant involvement is approximately 24 weeks of treatment with additional follow-up visits as specified in the protocol.

The experimental medication AZD6793 is administered as a film-coated tablet formulation for oral use. The active substance AZD6793 is a synthetic product of chemical origin manufactured by AstraZeneca AB. The study employs multiple dosage strengths of AZD6793 film-coated tablets, all administered via the oral route. The maximum treatment period is established at 24 weeks. The investigational medicinal product is not a paediatric formulation and does not hold orphan drug designation.

The study includes a placebo comparator designated as AZD6793 Placebo, which serves as the control treatment in this randomized, double-blind, placebo-controlled trial design. The placebo is utilized to enable comparison with the active treatment arms and to assess the efficacy and safety profile of the experimental medication.

The trial is designed as a 4-arm study configuration, incorporating multiple treatment groups to evaluate different aspects of the investigational product. The treatment duration spans 24 weeks for all study arms. Participants receive their assigned treatment according to the randomization scheme in this parallel-group design. The study protocol maintains blinding procedures to ensure the integrity of efficacy and safety assessments throughout the treatment period.

Efficacy will be assessed using multiple parameters to evaluate the effect of **AZD6793** in participants with moderate to very severe **chronic obstructive pulmonary disease**. The primary efficacy endpoint is the annualized rate of moderate or severe COPD exacerbations. Secondary efficacy endpoints include time to first moderate or severe COPD exacerbation, annualized rate of COPD exacerbations associated with emergency room visits, urgent care visits, or hospitalizations, and annualized rate of severe COPD exacerbations, defined as exacerbations resulting in hospitalization or death due to COPD. Additional secondary endpoints comprise the annualized rate of COPDCompEx events and time to first COPDCompEx event.

Lung function will be assessed through change from baseline in pre-bronchodilator FEV1 at Week 12 and Week 24, as well as change from baseline in post-bronchodilator FEV1 at Week 12 and Week 24. Patient-reported outcomes will be evaluated through change from baseline over 24 weeks in the Breathlessness, Cough and Sputum Scale total score, COPD Assessment Test total score, and St George's Respiratory Questionnaire total and domain scores. Plasma concentrations of **AZD6793** will be measured at specific timepoints to support efficacy assessments.