A Study to Assess Safety, Tolerability, and Pharmacokinetics of AZD0186

This study will assess the safety, tolerability, and pharmacokinetics of AZD0186 following single ascending doses (SAD) via oral administration in healthy adult participants.

This is a Phase 1, First-in-Human (FIH), randomized, single-blind, sponsor-open, placebo-controlled, SAD sequential group design study.

This study consists of four parts: Part 1, Part 2, Part 3, and Part 4.

The study will comprise of the following:

Part 1, Part 2, Part 3, and Part 4:

* A Screening Period of maximum 28 days.
* A Treatment Period during which subjects will be resident at the Clinical Unit from 2 days before IMP (Investigational Medicinal Product) administration (Day -2) until at least 48 hours after IMP administration; discharged on Day 3.

Part 4:

• A second Treatment Period during which subjects will be resident at the Clinical Unit from the day of the Follow-up Visit (Day 7 ±1 days after the last IMP dose) until at least 48 hours after the second IMP administration; discharged on Day 10.

Part 1, Part 2, Part 3, and Part 4:

• A Follow-up Visit after 7 (Part 1, Part 2, and Part 3) or 14 (Part 4) ±1 day after the last IMP dose.

Eligibility Criteria:
Inclusion Criteria:

* Provision of signed and dated, written informed consent prior to any study specific procedures.
* Healthy male and female subjects aged 18 to 55 years with suitable veins for cannulation or repeated venipuncture.
* Females must have a negative pregnancy test at the Screening Visit and on admission to the Clinical Unit, must not be lactating and must be of non-childbearing potential, confirmed at the Screening Visit.
* Have a BMI between:

  1. Part 1: 18 to 32 kg/m2 inclusive,
  2. Part 2 and Part 3: 18 to 32 kg/m2 inclusive,
  3. and weigh at least 50 kg (males and females).
* Provision of signed, written, and dated informed consent for optional genetic/biomarker research.
* For the healthy Japanese cohort (Part 2): healthy subjects are to be Japanese (eg, natives of Japan or Japanese Americans), defined as having both parents and 4 grandparents who are Japanese.
* For the healthy Chinese cohort (Part 3): healthy male and female (of non-childbearing potential) healthy Chinese subjects for whom both parents and all grandparents are Chinese and not lived outside of China for more than 10 years.

Exclusion Criteria:

* History of any clinically important disease or disorder which may either put the healthy subject at risk because of participation in the study,or influence the results or the healthy subject's ability to participate in the study.
* History or presence of gastrointestinal, hepatic, or renal disease, or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs.
* Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IMP.
* Presence of any retinal (including intraretinal) abnormality detected by ophthalmological examination including indirect ophthalmoscopy, fundoscopy or OCT.
* Presence of any factors that predispose to retinal detachment including lattice degeneration, retinal hole, or high myopia (-10 diopters or higher) found on ophthalmological examination.
* History of retinal detachment in either eye.
* History of treated or untreated retinal holes.
* Any clinically important abnormalities across the ophthalmological examinations.
* Any laboratory values with the following deviations:

  1. Alanine aminotransferase \> ULN
  2. Aspartate aminotransferase \> ULN
  3. eGFR \< 90 mL/minute/1.73 m2 (calculated using the Chronic Kidney Disease Epidemiology Collaboration formula)
  4. White blood cell count \< LLN
  5. Hemoglobin \< LLN
* Any clinically important abnormalities in clinical chemistry, hematology or urinalysis results.
* Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody and HIV.
* Abnormal vital signs, after 10 minutes supine rest, defined as any of the following:

  1. Systolic BP \< 90 mmHg or \> 140 mmHg.
  2. Diastolic BP \< 50 mmHg or \> 90 mmHg.
  3. Heart rate \< 45 or \> 85 bpm.
* Any clinically important abnormalities in rhythm, conduction or morphology of the resting ECG and any clinically important abnormalities in the 12-lead ECG that may interfere with the interpretation of QTc interval changes, including abnormal ST and T-wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy.
* Known or suspected history of drug abuse.
* Current smokers or those who have smoked or used nicotine products within the previous 3 months.
* History of alcohol abuse or excessive intake of alcohol.
* Positive screen for drugs of abuse or cotinine at screening or admission to the Clinical Unit or positive screen for alcohol on admission to the Clinical Unit prior to the first administration of the IMP.
* History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the Investigator or history of hypersensitivity to drugs with a similar chemical structure or class to GLP-1 RA.
* Any condition that would have interfered with the evaluation of the IMP or interpretation of subject safety or study results.
* Lifetime history of schizophrenia or other psychosis or bipolar disorder or suicide attempts, major depressive disorder, or self-reported suicidal ideation.
* Healthy subjects with a history of MTC, multiple endocrine neoplasia syndrome type 2, or healthy subjects with a screening/baseline serum calcitonin ≥ 50 pg/mL.
* History of gastrointestinal abnormality that could affect gastrointestinal motility.
* Excessive intake of caffeine containing drinks or food.
* Plasma donation within one month of the Screening Visit or any blood donation/blood loss \> 500 mL during the 3 months prior to the Screening Visit.
* Has received another new chemical entity within 30 days or 5 half-lives of the first administration of IMP in this study.
* Previous bone marrow transplant.
* Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection.