AZD8233 has not been evaluated in clinical studies previously. This is a first-in-human (FiH) study. This study will assess the safety, tolerability and pharmacokinetics (PK) of AZD8233, following subcutaneous (SC) administration of single ascending dose (SAD) of AZD8233. This study will also investigate the pharmacodynamics (PD) of AZD8233 by investigating the effect of AZD8233 on levels of cholesterol and related biomarkers.

This randomized, single-blind, placebo-controlled study will be conducted at a single study center in United States of America. Up to 56 healthy male subjects with elevated LDL-C levels, aged 18 to 60 years will be randomized into this study. This study will consist of 5 cohorts with 8 subjects in each. Depending on emerging data, 2 additional cohorts may be added to test additional dose levels at the discretion of the sponsor, if the pre-defined exposure limits and stopping criteria have not been reached at previous administered doses. The study will comprise of 3 periods:

• A screening period of maximum 28 days.
• A treatment period:
• A follow-up period of 16 weeks

In each cohort, 6 subjects will be randomized to receive a single SC dose of AZD8233 and 2 subjects randomized to receive placebo. Single dose of AZD8233 SC injection (40 mg/mL) will be administered in each cohort as follows:

Cohort 1: Dose 1 (starting dose) Cohort 2: Dose 2 (provisional dose) Cohort 3: Dose 3 (provisional dose) Cohort 4: Dose 4 (provisional dose) Cohort 5: Dose 5 (provisional dose) Dosing for each ascending dose cohort will proceed with 2 subjects in a sentinel cohort, such that 1 subject will be randomized to receive placebo and 1 subject will be randomized to receive AZD8233.

In the treatment period, the sentinel and non-sentinel subjects will be resident at the clinical unit from the day before IMP administration (Day -1) until at least 72 hours and 48 hours after IMP administration, respectively.

Sentinel will have 10 follow-up visits (1, 2, 3, 4, 6, 8, 10, 12, 14 and 16 weeks post-dose). Non-sentinel subjects will have 11 follow-up visits (on Day 4 and 1, 2, 3, 4, 6, 8, 10, 12, 14 and 16 weeks post-dose).

The follow-up period (16 weeks) has been selected based on the predicted terminal half-life of AZD8233 in man (predicted to be 2 to 3 weeks), to cover at least 5 half-lives.

Following review of data from the study, the Safety Review Committee (SRC) may decide to:

• Adjust the window for sentinel dosing.
• Adjust the length of data collection prior to dose-escalation diction.
• Prolong the length of the stay at the Clinical Unit.
• Adjust the timing and number of assessments and/or blood/urine samples for subsequent cohorts.
• Adjust the length of the Follow-up Period. Each subject will be involved in the study for up to 20 weeks.

Inclusion Criteria:

1. Provision of signed and dated, written informed consent before any study specific procedures.
2. Healthy male subjects aged 18 to 60 years (inclusive at Screening Visit) with suitable veins for cannulation or repeated venipuncture.
3. Have a body mass index (BMI) between 18 and 32 kg/m2 inclusive and weigh at least 60 kg and no more than 100 kg inclusive at the Screening Visit and Day -1.
4. Have a LDL-C ≥ 100 mg/dL < 190 mg/dL at the Screening Visit and Day -1, test may be repeated once for each visit at the discretion of the Investigator if out of the range.
5. Provision of signed, written and dated informed consent for optional genetic/biomarker research. If a subject declines to participate in the genetic component of the study, there will be no penalty or loss of benefit to the subject. The subject will not be excluded from other aspects of the study described in this protocol.

Exclusion Criteria:

1. History of any clinically important disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study.

2. History or presence of GI, hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs.

3. Any clinically important illness, medical/surgical procedure or trauma within 4weeks of the first administration of IMP.

4. Any laboratory values with the following deviations at the Screening Visit and/or Day -1, test may be repeated once for each visit at the discretion of the Investigator if out of range:

   4.1.Alanine aminotransferase (ALT)> upper limit of normal (ULN). 4.2.Aspartate aminotransferase (AST)> ULN. 4.3.Creatinine > ULN. 4.4.White blood cell (WBC)< LLN. 4.5.Hemoglobin< LLN. 4.6.Platelet count ≤150000/μL. 4.7.Activated partial thrombin time greater than ULN and PT greater than ULN. 4.8.Have an eGFR < 60mL/min. 4.9.Have an urinary albumin-to-creatinine ratio(ACR)> 3mg/μmol (30mg/g).

5. Any other clinically important abnormalities in clinical chemistry, hematology or urinalysis results, than those described under exclusion criterion number 4, as judged by the Investigator.

6. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody and human immunodeficiency virus (HIV).

7. Abnormal vital signs, after 10 minutes supine rest, with the following deviations at the Screening Visit and/or Day -1, test may be repeated once for each visit at the discretion of the Investigator if out of range:

   7.1.Systolic BP< 90mmHgor> 140mmHg. 7.2.Diastolic BP< 50mmHgor > 90mmHg. 7.3.Heart rate < 45 or > 85 beats per minute(bpm).

8. 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 changes, including abnormal ST-T-wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy at the Screening Visit or Day -1, test may be repeated once for each visit, at the discretion of the Investigator if out of range.

   8.1. Prolonged QTcF > 450 ms. 8.2. Shortened QTcF < 340 ms. 8.3. Family history of long QT syndrome. 8.4. PR (PQ) interval shortening < 120 ms (PR > 110 ms but < 120 ms is acceptable if there is no evidence of ventricular pre-excitation).

   8.5. PR (PQ) interval prolongation (> 240 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree atrioventricular (AV) block, or AV dissociation.

   8.6. Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS > 110 ms. Subjects with QRS > 110 ms but < 115 ms are acceptable if there is no evidence of e.g., ventricular hypertrophy or pre-excitation.

9. Known or suspected history of drug abuse as judged by the Investigator.

10. Current smokers or those who have smoked or used nicotine products (including e-cigarettes) within the previous 3 months before the Screening Visit.

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

12. Positive screen for drugs of abuse, alcohol, or cotinine (nicotine) at the Screening Visit or positive screen for drugs of abuse or alcohol, on admission to the Clinical Unit.

13. 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.

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

15. Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks before the first administration of IMP.

16. Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times t he recommended daily dose) and minerals during the 2 weeks before the first administration of IMP or longer if the medication has a long half-life.

17. 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.

18. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the first administration of IMP in this study. The period of exclusion begins 3 months after the final dose or 1 month after the last visit whichever is the longest. Note: subjects consented and screened, but not randomized in this study or a previous Phase 1 study, are not excluded.

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

20. Judgment by the Investigator that the subject should not participate in the study if they have any ongoing or recent (i.e., during the Screening Period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions and requirements.

21. Subjects who are vegans or have medical dietary restrictions.

22. Subjects who cannot communicate reliably with the Investigator.

23. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

    In addition, any of the following is regarded as a criterion for exclusion from the genetic research:

24. Previous bone marrow transplant.

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

Healthy male subjects with elevated LDL-C levels, aged 18 to 60 years that weigh at least 60 kg and no more than 100 kg inclusive.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

This study is single-blind with regard to treatment (AZD8233 or placebo) at each dose level.

AZD8233 and placebo will be matched for formulation, appearance and amount. Subjects randomized to placebo will receive the same volume of injection as subjects on active drug.