A Study to Assess the Efficacy and Safety of Multiple Dose Levels of AZD7594 Administered Once Daily by Inhalation in Asthmatic Subjects

This is a randomised, placebo-controlled, double-blind multi center (8 countries: Europe,
United States [US], South Africa, and Japan) study conducted on 714 subjects (102 subject per
arm) with asthma symptomatic on low dose inhaled corticosteroids (ICS). The study consists of
3 periods:

- Run-in period (21-28 days; visits 1 to 3)

- Treatment period (12-week; Visits 4 to 7)

- Follow-up (1-week; visit 8).

The Run-in period consist of 3 visits: Screening visit (1), reversibility visit (2) and
randomization visit (3). All subjects will sign an informed consent form (ICF) prior to
participating in any study-specific procedures. Subjects found to be eligible at Visit 1
(Screening Visit) will discontinue all asthma medications and switch to low dose budesonide
(200 μg twice a day [BID] in Europe and 180 μg BID in US) and rescue medication will be taken
as needed. Subjects on long-acting beta agonist (LABA), fixed dose combination ICS/LABA
treatment or a long-acting muscarinic antagonist (LAMA) will return for Visit 2 between 2 to
7 days after Visit 1 to have a sufficient wash-out time of their asthma medications. If
reversibility criteria are met at Visit 2, subjects will proceed to Visit 3 (Randomization
will occur within 21 to 28 days of Visit 1). At Visit 3, subjects who remain symptomatic
while on low dose budesonide will be randomized in an overall ratio of 1:1:1:1:1:1:1 to one
of 7 possible treatments and will receive inhalation powder via oral route:

- AZD7594 DPI 55μg [nominal strength]/50 μg [delivered dose] (QD)

- AZD7594 DPI 99 μg/90 μg QD

- AZD7594 DPI 198 μg/180 μg QD

- AZD7594 DPI 396 μg/360 μg QD

- AZD7594 DPI 792 μg/720 μg QD

- Placebo for AZD7594 QD

- FF 100 μg QD (open-label) The follow-up will be done by telephone contact within 7 to 10
days after Visit 7 or last investigational product (IP) intake.

The total duration of the study will be between 113 to 135 days for each individual subject
and is planned to run approximately 12 months (it should not exceed 18 months).

Inclusion criteria

1. Provision of informed consent prior to any study-specific procedures 2. Men and women 18
to 85 years of age, inclusive 3. Patients need to be non-smokers or ex-smokers (have quit e
cigarettes or other inhaled tobacco products ≥6 months before Visit 1) with a total smoking
history of less than 10 pack-years (not applicable for e cigarettes) 4. Documented clinical
diagnosis of asthma for ≥6 months before Visit 1 5. Patients on stable medium to high dose
ICS (equivalent of budesonide >400 μg/day) or low to medium dose ICS/LABA for at least 4
weeks prior to screening (Visit 1) (Appendix A, GINA, 2018) 6. Patients must demonstrate
reversibility to inhaled bronchodilators at Visit 2 (a ≥12% and ≥200 mL improvement in FEV1
after administration of a 4 puffs of salbutamol/albuterol) 7. Pre-bronchodilator FEV1 at
Visit 3 between 40% and 90% predicted 8. At Visit 3, patients need to be symptomatic on low
dose ICS as evidenced by combined daily asthma mean symptom score of >1 over the previous 7
days or SABA use on ≥3 of the last 7 days during the Run-in Period 9. Demonstrate the
ability to use the study inhalation device properly 10. Patient able to perform acceptable
pulmonary function testing for FEV1 according to American Thoracic Society/European
Respiratory Society (ATS/ERS) acceptability criteria 11. Patient is willing and able to
follow study procedures and restrictions. Women of child bearing potential (WOCBP) should
be stable on their chosen method of highly effective birth control for a minimum of 3
months prior to Visit 1, and willing to use that for the entire duration of the study (from
the time they sign the informed consent), and for 1 month after the last dose of IP 12. For
optional inclusion in the Gx component of the study, patients must provide separate
informed consent for the genomic sampling and analysis Exclusion criteria

1. Known or suspected hypersensitivity to any of the IPs, including budesonide, or
excipients, including lactose

2. Systemic steroid use within the 6 weeks before Visit 1

3. Concomitant chronic respiratory disease

4. History or clinical suspicion of any clinically relevant or active disease or disorder
which, in the opinion of the Investigator, may either put the patient at risk because
of participation in the study, or influence the results or the patient's ability to
participate in the study, or any other safety concerns in the opinion of the
Investigator

5. Use of prohibited medications that cannot be stopped during the entire period of the
study (starting Visit 1).

6. Patients with <80% eDiary compliance during Run in Period at Visit 3

7. ACQ-5 of ≥3 at Visit 1, Visit 2, or Visit 3

8. Daily rescue use of SABA ≥12 puffs for ≥3 consecutive days at any time during Run-in
Period, before randomisation

9. Any clinically important abnormalities in rhythm, conduction or morphology of the
digital ECG at rest and any abnormalities in the digital ECG (at Visit 1 or Visit 3)
that, as considered by the Investigator, may interfere with the interpretation of QT
interval corrected (QTc) interval changes

10. Prolonged QT interval corrected using Fridericia's formula (QTcF) ≥450 msec based on
ECG at Visit 1 or Visit 3; or family history of long QT syndrome

11. PR (PQ) interval prolongation (>240 msec), intermittent second or third degree
atrial-ventricular (AV) block or AV dissociation at Visit 1 or Visit 3

12. Patients with implantable cardiac defibrillator and patients with sustained
symptomatic ventricular and/or atrial tachyarrhythmia

13. Patients with unstable angina pectoris or stable angina pectoris classified higher
than Canadian Cardiovascular Society Class II, or a myocardial infarction or stroke
within 6 months before Visit 1

14. History of hospitalisation within 12 months before Visit 1 caused by heart failure or
a diagnosis of heart failure higher than New York Heart Association Class II

15. Patients who are positive for hepatitis B surface antigen (HBsAg), hepatitis C virus
(HCV) antibody or human immunodeficiency virus (HIV) at Visit 1

16. Donation of blood (≥ 450 mL) within 3 months or donation of plasma within 14 days
before Visit 1

17. Suspected poor capability to follow instructions of the study, as judged by the
Investigator

18. Previous participation or prior screen failure in the current study, or participation
in any other research study within 1 month prior to Visit 1

19. Patient under treatment with biologicals such as monoclonal antibodies or chimeric
biomolecules including omalizumab, mepolizumab, and reslizumab within 6 months or 5
half-lives before Visit 1, whichever is longer

20. Patient treated with any investigational drug within 30 days (or 5 half-lives,
whichever is longer) prior to Visit 1

21. History of or current alcohol or drug abuse (including marijuana), as judged by the
Investigator

22. Planned in-patient surgery, major dental procedure or hospitalisation during the study

23. Pregnant woman or lactating woman

24. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff, contract research organisation staff and/or staff at the study centre)

25. Suspicion of Gilbert's syndrome

26. Vulnerable persons (eg, persons kept in detention)