This is a Phase 2a, multicentre, randomised, placebo-controlled, double-blind, parallel-group study to evaluate the efficacy, safety and PK of AZD4604 administered BID using a dry-powder inhaler at one dose level over a 12-week Treatment period in adult participants with uncontrolled moderate-to-severe asthma.

Inclusion Criteria:

1. 18 to 80 years of age inclusive, at the time of signing the informed consent.

2. Treated with medium-high dose ICS in combination with LABA at a stable dose for at least 28 days prior to Visit 1.

   Note: EU participants must be treated with high dose ICS in combination with LABA at a stable dose for at least 28 days prior to V1.

3. Documented history of ≥ 1 severe asthma exacerbation within 1 year prior to Visit 1.

4. Morning pre-BD FEV1 ≥ 40% predicted at Visit 1 and Visit 3.

5. Able to perform acceptable lung function testing for FEV1 according to ATS/ERS 2019 acceptability criteria.

6. Documented evidence of asthma in the 10 years up to or including Visit 1. A clinical diagnosis of asthma must be documented at least 12 months prior to Screening (Visit 1).

7. An ACQ-6 score ≥ 1.5 at Visit 1 and at Visit 3.

9. Body weight of ≥ 40 kg and body mass index of < 35 kg/m2. 10. Contraceptive use by females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. There are no restrictions on male participants or their female partners

At the end of the Run-in period (Visit 3), participants must fulfil the following additional criteria in order to be randomised into the study and enter the Treatment period:

1. Pre-BD FEV1 ≥ 40%.
2. A pre-BD/pre-IMP dose FEV1 at Visit 3 that has not increased or decreased by 20% or more from the pre-BD FEV1 recorded at Visit 1 and at Visit 2.
3. An ACQ-6 score of ≥ 1.5.
4. At least 80% compliance with usual asthma background medication during Run-in period (from Visit 2 to Visit 3) based on the daily asthma ePROs.
5. Minimum 80% compliance with daily eCOAs (electronic Clinical Outcome Assessments) during the 14 days preceding Visit 3.
6. For female of child bearing potential participants, a negative urine pregnancy test prior to administration of IMP.

Exclusion Criteria:

1. A severe asthma exacerbation within 8 weeks prior to randomisation.

2. History of herpes zoster reactivation.

3. Participants with a significant COVID-19 illness within 6 months of enrolment.

4. Clinically important pulmonary disease other than asthma.

5. Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, psychiatric, or major physical impairment that is not stable in the opinion of the investigator and could:

   • affect the safety of the participant throughout the study,
   • influence the findings of the study or the interpretation, or
   • impede the participant's ability to complete the entire duration of study.

6. Any clinically significant cardiac or cerebrovascular disease.

7. History of venous thromboembolism.

8. Participants who, as judged by the investigator, have evidence of active TB, or latent TB without completion of an appropriate course of treatment or appropriate ongoing prophylactic treatment.

9. Participants with a recent history of, or who have a positive test for, infective hepatitis or unexplained jaundice, or participants who have been treated for HIV.

10. Current or prior history of alcohol or drug abuse (including marijuana and marijuana containing valid prescriptions), as judged by the investigator.

11. History of malignancy other than superficial basal cell carcinoma.

12. Treatment with systemic corticosteroid within 4 weeks (oral) or 8 weeks (intramuscular) before Visit 1.

13. Any immunosuppressive therapy within 12 weeks prior to Visit 1.

14. Treatment with marketed biologics within 6 months of Visit 1 or 5 half-lives, whichever is longer.

15. Inhaled corticosteroid plus fast-acting β2 agonist as a reliever is not allowed 15 days prior to Visit 1, during Screening/Run-in and throughout the Treatment period and preferably 1 week after the last dose of IMP.

16. Live, attenuated, or mRNA vaccines within 4 weeks of Visit 1.

17. Immunoglobulin or blood products within 4 weeks of Visit 1.

18. Any immunotherapy within 6 months of Visit 1, except for stable maintenance dose allergen-specific immunotherapy started at least 4 weeks prior to Visit 1 and expected to continue through to the end of the Follow-up period.

19. Concurrent enrolment in another interventional clinical study

20. Participant treated with any investigational drug within 4 months or 5 half-lives, whichever is longer, prior to Visit 1.

21. Participants with a known hypersensitivity to AZD4604 or any of the excipients of the product.

22. Abnormal findings identified on physical examination, ECG, or laboratory testing.

23. For female participants only - currently pregnant (confirmed with positive pregnancy test) or breast-feeding.

24. Current smokers or participants with smoking history ≥ 10 pack-years.

25. Participants with a known long-term exposure to occupational asbestos, silica, radon, heavy metals, and polycyclic aromatic hydrocarbons.

26. Positive family history of primary lung cancer in first degree relatives (mother, father, sisters, brothers and children).

27. Positive urine cotinine test or exhaled carbon monoxide test at Visit 1 and at any timepoint throughout the study.

28. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).

29. Judgement by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.

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

31. Major surgery within 8 weeks prior to Visit 1, or planned inpatient surgery, major dental procedure or hospitalisation during Screening, Treatment, or Follow-up periods.