A Single-blind, Randomized, Placebo-controlled 3 Part Study in Healthy Volunteers and Patients With Mild Asthma to Investigate the Safety, Tolerability, and Pharmacokinetics of Inhaled AZD4604 Following Single and Multiple Ascending Doses and to Investigate the Anti-inflammatory Effect of Inhaled AZD4604

Brief Summary

Detailed Description

Part 1a of the study will be a randomized, single-blind, placebo-controlled, SAD, sequential group design study. Seven inhaled dose levels of AZD4604 are planned to be investigated in cohorts of 8 healthy volunteers, with 6 healthy volunteers randomly assigned to inhaled AZD4604 and 2 healthy volunteers randomly assigned to inhaled placebo in each cohort. Part 1a will comprise of: * A Screening Visit within 28 days before dosing. * A Treatment Period (Day -1 to Day 7, in the Clinical Unit) with a single inhaled dose of AZD4604 or corresponding placebo on Day 1. Although the anticipated systemic exposure and risk for potential adverse systemic effects are considered to be low for AZD4604, healthy volunteers will remain resident at site for additional 6 days of monitoring. * A Final Assessment on day of discharge. In Part 1b, AZD4604 will be administered as a single IV or a PO dose to healthy volunteers in order to compare the PK between IV, PO and inhaled administration. Part 1b will be open-label and consist of 2 dose cohorts, IV and PO, with 6 healthy volunteers in each. Part 1b will comprise of: * A washout period of at least 2 weeks for the healthy volunteers who received inhaled dosing in Part 1a will occur before IV or PO dosing in Part 1b. All healthy volunteers will have a Screening Visit within 28 days of dosing. * A Treatment Period (Day -1 to Day 3, in the Clinical Unit) with a single IV or PO dose of AZD4604 on Day 1. * A Follow-up Visit within 6 ± 1 day after dosing. Part 2 of the study will be a randomized, single-blind, placebo-controlled, MAD, sequential group design. This part of the study will be conducted in up to 32 healthy volunteers. Part 2 will comprise of: * A Screening Visit within 28 days before first dosing. * A Treatment Period (Day -1 to Day 12 in the Clinical Unit) with twice daily (BID) inhaled doses of AZD4604 or placebo on Day 1 to Day 6 (12-hour \[+/- 30 minutes\] intervals between doses), and a single inhaled dose on Day 7. The healthy volunteers will remain resident at site for additional 6 days of monitoring, which is predicted to allow sufficient time for near complete washout (estimated time for \> 97% of the dose to have been eliminated) of any target engagement from the lungs. Healthy volunteers will remain in the Clinical Unit for the duration of the treatment period and will be discharged on Day 13, 6 days after administration of the last dose. * A Final Assessment on day of discharge. Part 3 of the study will be a randomized, single-blind, placebo-controlled, multiple-dose, PK and pharmacodynamic (PD) study part, with daily non-residential visits during the Treatment Period. This part of the study will be conducted in at least 45 patients with mild asthma (16 patients in Cohorts 1 and 2 and at least 29 patients in the Proof of Mechanism \[PoM\] Cohort). Part 3 will comprise of: * A Screening Visit within 42 days before first dosing. * A Treatment Period (Day -3 to Day 15 as daily non-residential visits) with BID inhaled doses of AZD4604 or placebo on Day 1 to Day 9 (12-hour intervals between doses), and a single inhaled dose on Day 10. Dosing will take place at the clinical site and patients will need to visit the site twice daily on Day 1 to Day 9. The anticipated systemic exposure and risk for potential adverse systemic effects are considered to be low for AZD4604, therefore, patients will not be required to be resident at site during the Treatment Period. * A Final Assessment (Day 16) on the last day of the Treatment Period.

Primary Outcomes

Secondary Outcomes

• Part1b: Number of healthy volunteers with AEs(From screening (only SAEs) to follow-up end of treatment visit (6 ± 1 day post-dose))
• Part 1a and Part 2: tmax(From Day 1 to Day 7 (Part 1a) and from Day 1 to Day 13 (Part 2))
• Part1a: AUC (0 - 12)(From Day 1 to Day 7)
• Part 1a and Part 2: λz(From Day 1 to Day 7 (Part 1a) and on Day 7 (Part 2))
• Part 1a and Part 2: t1/2λz(From Day 1 to Day 7 (Part 1a) and on Day 7 (Part 2))
• Part 1a and Part 2: AUC (0 - 24)(From Day 1 to Day 7 (Part 1a) and on Day 7 (Part 2))
• Part 2: Area under plasma concentration-time curve in the dose interval (AUCτ)(From Day 1 to Day 13)
• Part 1a and Part 2: Cmax(From Day 1 to Day 7 (Part 1a) and from Day 1 to Day 13 (Part 2))
• Part 1a and Part 2: AUClast(From Day 1 to Day 7 (Part 1a) and from Day 1 to Day 13 (Part 2))
• Part 1a: AUCinf(From Day 1 to Day 7)
• Part 1a and Part 2: Cmax/D(From Day 1 to Day 7 (Part 1a) and from Day 1 to Day 13 (Part 2))
• Part1a: AUCinf/D(From Day 1 to Day 7)
• Part 2: Dose normalized AUCτ, derived by AUCτ divided by the dose administered (AUCτ/D)(From Day 1 to Day 13)
• Part 1a and Part 2: CL/F(From Day 1 to Day 7 (Part 1a) and on Day 7 (Part 2))
• Part 1a and Part 2: Vz/F(From Day 1 to Day 7 (Part 1a) and on Day 7 (Part 2))
• Part 1a and Part 2: AUClast/D(From Day 1 to Day 7 (Part 1a) and from Day 1 to Day 13 (Part 2))
• Part 1a and Part 2: tlast(From Day 1 to Day 7 (Part 1a) and from Day 1 to Day 13 (Part 2))
• Part 2: Accumulation ratio for Cmax (Rac Cmax)(On Day 7)
• Part 2: Accumulation ratio for AUCτ (Rac AUC)(On Day 7)
• Part 1b: Renal clearance of drug from plasma (CLR)(From Day 1 to Day 2)
• Part 1b: Cumulative amount of unchanged drug excreted into urine from time t1 to time t2 (Ae [t1 - t2])(From Day 1 to Day 2)
• Part 1b: Cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 (fe [t1 - t2])(From Day 1 to Day 2)
• Part 3: AUC(From Days 1 to 16)
• Part 3: Cough severity self-assessment (Visual analog scale)(From Day -3 to -1, and Days 1 to 10)
• Part 2: Cough severity self-assessment (Visual analog scale)(Day-1 to Day 7 (Pre-dose) and Day 8 (Post -dose))
• Part 3: Cmax(From Days 1 to 16)
• Part 3: AUCτ(From Days 1 to 16)
• Part 3: Change from baseline in Fractional exhaled nitric oxide (FeNO) levels(From Day 1 to 10)