Efficacy and Safety Evaluation of AZD4604 in Adults with Moderate-to-Severe Asthma Uncontrolled on Medium-High Dose ICS-LABA

The primary objective of this study is to evaluate the **clinical efficacy** of AZD4604 1.4 mg BID compared to placebo in adult participants with moderate-to-severe uncontrolled asthma. This is clinically relevant as it aims to determine the potential of AZD4604 to improve asthma control in patients who are not adequately managed with medium-high dose ICS-LABA, which is a common treatment regimen.

Secondary objectives include:

• Evaluating the effect of AZD4604 on airway inflammation as measured by FeNO, which is important for understanding the drug's impact on underlying inflammatory processes in asthma.
• Assessing the effect of AZD4604 1.4 mg BID on cough compared to placebo, providing insights into symptom relief for patients.
• Evaluating the pharmacokinetics (PK) of AZD4604 in all participants after 4 weeks and 12 weeks of dosing, which is crucial for understanding the drug's absorption, distribution, metabolism, and excretion.

The clinical trial involves a total of **196 participants** who are adult patients with **moderate-to-severe asthma** that is uncontrolled on medium-high dose ICS-LABA. The study population includes both male and female subjects, aged between **18 to 80 years**. Participants were selected based on specific criteria, including a documented history of asthma and the ability to perform acceptable lung function testing. The trial does not include a vulnerable population. Participants are required to have a body weight of at least 40 kg and a body mass index of less than 35 kg/m². Lifestyle considerations such as compliance with asthma medication and the ability to use electronic devices for assessments are relevant to the study. The trial aims to evaluate the clinical efficacy of AZD4604 1.4 mg BID compared to placebo in this specific population.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of AZD4604 in adult patients with moderate-to-severe asthma that is uncontrolled on medium-high dose ICS-LABA. The trial will involve the administration of AZD4604 at a dose of 1.4 mg twice daily for a duration of twelve weeks. The study will include a placebo group for comparison, ensuring the reliability of the results. The trial is expected to commence on November 6, 2023, and conclude by November 19, 2025, with the total duration of participant involvement being approximately twelve weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, asthma history, and lung function. Following the screening, a run-in period will be conducted to ensure compliance with asthma medication and electronic clinical outcome assessments. Participants who meet the criteria at the end of the run-in period will be randomized into the treatment phase. During the treatment phase, follow-up visits will occur at regular intervals, including assessments at Week 4 and Week 12, to monitor changes in lung function, asthma control, and symptom scores. The primary endpoint is the time to the first CompEx event, while secondary endpoints include changes in pre-BD FEV1, CAAT, ACQ-6 scores, and peak expiratory flow rates.

The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted to evaluate the overall efficacy and safety of the treatment. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial aims to provide valuable insights into the potential benefits of AZD4604 for patients with uncontrolled asthma, contributing to the advancement of therapeutic options in this field.

The clinical trial involves the administration of **AZD4604**, an experimental medication formulated as an **inhalation powder**. The active substance in AZD4604 is a chemical compound identified as (2R)-N-[3-(5-fluoro-2-{[2-fluoro-3-(methylsulfonyl)phenyl]amino}-4-pyrimidinyl)-1H-indol-7-yl]-3-methoxy-2-(4-methyl-1-piperazinyl)propanamide-1-hydroxy-2-naphthoic acid. The medication is administered via the **inhalation** route. The dosing regimen for AZD4604 is 1.4 mg administered twice daily (BID), with a maximum daily dose of 2.8 mg and a total maximum dose of 246.4 mg over the treatment period. The treatment duration is set for 12 weeks. The pharmaceutical form is designed for adult patients with moderate to severe asthma that is uncontrolled on medium-high dose ICS-LABA therapy.

In addition to the experimental treatment, the study includes a **placebo** group. The placebo is designed to match the experimental medication in appearance and administration method but contains no active pharmaceutical ingredient. The placebo is administered under the same conditions as AZD4604, ensuring a double-blind study design. This allows for the evaluation of the efficacy and safety of AZD4604 compared to the placebo in the target patient population.

The efficacy of AZD4604 in the treatment of moderate-to-severe uncontrolled asthma will be assessed through a series of primary and secondary endpoints. The primary endpoint is the time to the first **CompEx** (composite endpoint for exacerbation) event. Secondary endpoints include changes from baseline in pre-bronchodilator forced expiratory volume in one second (FEV1) at Week 4 and Week 12, changes in the **CAAT** (Control of Allergic Asthma Test) and **ACQ-6** (Asthma Control Questionnaire) scores at the same time points, and average morning and evening peak expiratory flow (PEF) at Week 4, Week 12, and averaged over the 12-week treatment period. Additionally, daily asthma symptom scores, including total, daytime, and night-time scores, will be evaluated at Week 4 and Week 12.

These efficacy parameters will be measured using validated scales and instruments, ensuring the reliability and accuracy of the data collected. The schedule for these assessments is structured to capture both short-term and longer-term effects of the treatment, with key timepoints at Week 4 and Week 12, as well as an overall assessment over the 12-week treatment period. The data collected will be analyzed to determine the clinical efficacy of AZD4604 compared to placebo, providing insights into its potential benefits for patients with moderate-to-severe uncontrolled asthma.