To Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AZD8233 After Multiple Dose Administration in Subjects With Dyslipidemia

This is a Phase I study to assess the safety, tolerability and pharmacokinetics (PK), and pharmacodynamics (PD) of AZD8233, following subcutaneous (SC) administration of multiple ascending doses (MAD) of AZD8233 in subjects with confirmed dyslipidemia with or without type 2 diabetes.

This study is a Phase 1, randomized, single-blind, placebo-controlled, multiple dose group design in up to 33 male or female subjects with dyslipidemia with or without Type 2 diabetes and performed at multiple study centers. The planned number of cohorts is 3 but up to 5 cohorts may be included if the Safety Review Committee (SRC) considers it necessary. The 3 multiple dose levels of SC AZD8233 planned are:

* Cohort 1: Dose 1 (starting dose).
* Cohort 2: Dose 2 (provisional dose).
* Cohort 3: Dose 3 (provisional dose). Within each of these cohorts, 8 subjects will be randomized to receive AZD8233 and 3 subjects randomized to receive placebo. Cohorts 2 and 3 may be run in parallel if Cohort 3 is a lower dose. If Cohort 3 is a higher dose, the cohorts will be run sequentially. At any time, the dose levels may be adapted by the SRC based on emerging data. The expected duration of each patient in this study is up to 28 weeks with a maximum of 17 visits. Screening will be completed between Days -28 and -1. Each subject will receive single doses of AZD8233 or placebo on Days 1, 8, 29, and 57. The treatment period will consist of 58 days (up to Visit 9), followed by a follow-up period (up to Visit 17).

Following review of data, the SRC may decide to adjust the following for subsequent cohorts:

* The timing and amount of the loading dose.
* The length of the stay at the study site, the timing and number of assessments and/or samples.
* As decided by the SRC, blood and urine samples collected in the study may be used to address any of the other pre-specified study objectives.
* Each subject will be followed up for 16 weeks post last dose.

Eligibility Criteria:
Inclusion Criteria:

1. Provision of signed and dated, written informed consent before any study specific procedures.
2. Must be willing and able to comply with all required study procedures.
3. Male or female subjects aged 18 to 65 years at signing of informed consent.
4. Females must not be pregnant and must have a negative urine pregnancy test at the Screening Visit and on admission to the Clinical Unit, must not be lactating; or must be of non-childbearing potential, confirmed at the Screening Visit by fulfilling one of the following criteria:

   * Postmenopausal defined as 12 months with no menses without an alternative medical cause.
   * Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation.
5. Have suitable veins for cannulation or repeated venipuncture.
6. Have a body mass index between 25 and 40 kg/m2.
7. Have a Low-density lipoprotein (LDL) cholesterol \> 70 but \<190 mg/dL (4.9 mmol/L).
8. Calculated glomerular filtration rate \> 60 mL/min by estimated glomerular filtration rate using chronic kidney disease epidemiology equations.
9. Subjects should be receiving moderate- or high-intensity statin therapy as defined by the American College of Cardiology/American Heart Association guideline on blood cholesterol management
10. Subjects should be on stable medication for a certain time period prior to randomization.
11. Provision of signed, written, and dated informed consent for mandatory and optional genetic research. All subjects in the study, except for healthy volunteers, need to consent to the mandatory genetic component of the study and sign the consent form for the main study.
12. If a healthy volunteer population is included by the SRC, then screen for eligibility criteria and study restrictions for healthy volunteer population.

Exclusion criteria:

1. History or presence of gastrointestinal, hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs.
2. Any uncontrolled or serious disease, or any medical (known major active infection or major hematological, renal, metabolic, gastrointestinal or endocrine dysfunction) or surgical condition that, in the opinion of the Investigator, may either interfere with participation in the clinical study and/or put the participant at significant risk.
3. Blood dyscrasias with increased risk of bleeding including idiopathic thrombocytopenic purpura and thrombotic thrombocytopenic purpura or symptoms of increased risk of bleeding (frequent bleeding gums or nose bleeds).
4. History of major bleed or high-risk of bleeding diathesis.
5. Subjects ≥ 20 years of age with a high 10-year risk of heart disease or stroke as calculated using the atherosclerotic cardiovascular disease (ASCVD) Risk Estimator.
6. Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal carcinoma in-situ, or Stage 1 prostate carcinoma) within the last 10 years.
7. Recipient of any major organ transplant, eg, lung, liver, heart, bone marrow, renal.
8. LDL or plasma apheresis within 12 months prior to randomization.
9. Uncontrolled hypertension defined as supine SBP \>160 mmHg or DBP \>90 mmHg.
10. Heart rate after 10 minutes supine rest \<50 or \>100 bpm.
11. Any laboratory values with the following deviations at the Screening Visit or Day -1, test may be repeated at the discretion of the Investigator if abnormal: Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus; ALT \> 1.5 times (Upper limit of normal \[ULN\]); AST \>1.5 times ULN; Creatinine \> 1.5 mg/dL; WBC \< lower limit of normal (LLN); Hemoglobin \< 12 g/dL in men or \< 11 g/dL in women; Platelet count ≤ LLN; activated partial thromboplastin time \> ULN and prothrombin time \> ULN; urinary albumin-to-creatinine ratio \> 11 mg/μmol.
12. Any clinically important abnormalities in rhythm, conduction or morphology of the resting ECG and any clinically important abnormalities in the 12-lead ECG as considered by the Investigator that may interfere with the interpretation of QTc interval (QTcF \> 450 ms) changes, including abnormal ST-T-wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy, test may be repeated at the discretion of the Investigator if abnormal.
13. Males who are unwilling to use an acceptable method of birth control during the entire study period. Acceptable methods of preventing pregnancy are true abstinence or use together, with their female partner/spouse, birth control pills, injections, implants, patches, or intrauterine devices in combination with a barrier method. A barrier method is not necessary if the female partner is sterilized.
14. Known or suspected history of drug abuse by the Investigator. 15, Smokers with \> 10 cigarettes/day and unable to comply with the nicotine restriction during the study.

16. History of alcohol abuse or excessive intake of alcohol as judged by the Investigator.

17. Positive screen for drugs of abuse at the Screening Visit or admission to the study site.

18. Excessive intake of caffeine-containing drinks or food (eg, coffee, tea, chocolate,) as judged by the Investigator.

19. Use of drugs with cytochrome 450 enzyme inducing properties such as St John's Wort within 3 weeks before the first administration of investigational medicinal product (IMP).

20. Insulin or glucagon-like peptide 1 receptor agonist therapy during last 3 months prior to randomization.

21. Anti-platelet therapy, other than low dose aspirin ≤ 100 mg/day, within 1 month prior to randomization.

22. Mipomersen, or lomitapide within 12 months prior to randomization. 23. Proprotein convertase subtilisin/kexin type 9 inhibition treatment within 6 months prior to randomization.

24. Use of any herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to the first administration of IMP or 5 half-lives, whichever is longer.

25. Previous administration of AZD8233/AZD6615. 26. Received another new chemical entity within 30 days of last follow-up to first administration of the IMP of this study or 5 half-lives from last dose to first administration of IMP, whichever is the longest.

27. Plasma donation within 1 month of the Screening Visit or any blood donation/blood loss \> 500 mL during the 3 months before the Screening Visit.

28. 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 AZD8233.

29. Involvement of any Astra Zeneca or study site employee or their close relatives.

30. Subjects who cannot communicate reliably with the Investigator. 31. Vulnerable subjects, eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

32. Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IMP. History or evidence of any other clinically significant disorder (eg, cognitive impairment), condition or disease other than those outlined above that, in the opinion of the Investigator or AstraZeneca physician, if consulted, may compromise the ability of the subject to give written informed consent, would pose a risk to subject safety, or interfere with the study evaluation, procedures or completion.

33. Subject likely to not be available to complete all protocol required study visits or procedures, to the best of the subject's and Investigator's knowledge.

34. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection.