A Study to Investigate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AZD4954 in Healthy Adult Participants With or Without Elevated Lipoprotein (a) (Lp[a]) Levels, and Participants With Dyslipidemia

This is a first time in human, placebo-controlled, single and multiple ascending dose (SAD and MAD) study in healthy male and female participants (Part A) or healthy participants with elevated Lp(a) levels (≥ 30 mg/dL) and participants with dyslipidemia with elevated Lp(a) levels (≥ 70 mg/dL) and low-density lipoprotein cholesterol (LDL-C) ≥ 70 mg/dL and < 190 mg/dL (Part B).

The study consists of 2 parts: Part A (SAD) and Part B (MAD).

Part A of the study will consist of Part A1 and Part A2, comprising:

• A Screening Period of maximum 28 days.
• Admission to study site (Day -1).
• A Treatment Period (Day 1 to Day 15 at the study site) with a single dose of AZD4954 or placebo on Day 1.
• A Follow-up Visit within 26 to 30 days after the study intervention dose for all cohorts (Day 29 ±2 days).

Part B has 3 types of MAD cohorts - global cohorts with healthy participants, global cohort with participants with dyslipidemia, and a Japanese cohort. The global MAD cohorts (healthy participants) and Japanese MAD cohort will comprise:

• A Screening Period of maximum 28 days.
• Admission to study site (Day -1).
• A Treatment Period during which participants will receive either AZD4954 or placebo once daily for 21 days (Day 1 to 21).
• A Follow-up Visit within 26 to 30 days after the last study intervention dose (Day 49 ±2 days).

The global MAD cohort (participants with dyslipidemia) will comprise:

• A Screening Period of maximum 28 days.
• Residential study site visits from Day -1 to Day 2 and Day 21 to Day 22.
• Non-residential study site visits on Day 8 and Day 15.
• A Treatment Period during which participants will receive either AZD4954 or placebo once daily for 21 days (Day 1 to 21).
• A Follow-up Visit within 26 to 30 days after the last study intervention dose (Day 49 ± 2 days).

Inclusion criteria

All Parts:

• Participants with plasminogen level (concentration) within normal range at the Screening Visit.
• All females must have a negative pregnancy test at the Screening Visit and on admission to the study site.
• Females of childbearing potential must not be lactating and if heterosexually active must agree to use an approved method of highly effective contraception.
• Females of non-childbearing potential must be confirmed at the Screening Visit.
• Sexually active fertile male participants with partners of childbearing potential must adhere to the study specific contraception methods from the time of first administration of study intervention until 3 months after the study Follow-up Visit.

Parts A and B (Healthy Participants):

• Male and female participants aged 18 to 65 years with suitable veins for cannulation or repeated venipuncture.
• Have a body mass index (BMI) between 18 and 35 kg/m² inclusive.
• For Japanese and Chinese participants (Parts A and B):

• A Japanese participant is defined as having both parents and 4 grandparents who are ethnically Japanese. This includes second and third generation Japanese whose parents or grandparents are living in a country other than Japan.
• A Chinese participant is defined as having both parents and 4 grandparents who are ethnically Chinese. This includes second and third generation Chinese whose parents or grandparents are living in a country other than China.

Part B (Healthy Participants):

• Participants must have elevated Lp(a) ≥ 30 mg/dL at the Screening Visit.

Part B (Participants with Dyslipidemia):

• Male and female participants aged 18 to 70 years with suitable veins for cannulation or repeated venipuncture.
• Have a BMI > 18 kg/m².
• Participants must have elevated Lp(a) ≥ 70 mg/dL at the Screening Visit.
• Participants with a fasting LDL-C ≥ 70 mg/dL and < 190 mg/L at the Screening Visit.
• Participants should be receiving moderate or high-intensity statin therapy for ≥ 2 months prior to the Screening Visit, according to the American College of Cardiology/American Heart Association guidelines on blood cholesterol management.
• Participants with documented coronary artery disease, stroke, or peripheral artery disease or at moderate or high risk for an atherosclerotic cardiovascular disease event.
• There should be no planned medication or dose change during study participation.

Exclusion criteria

All Parts:

• History of any clinically important disease or disorder.
• 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 study intervention.
• Participants with known bleeding or coagulation disorders.
• Participants who have an elevated high-sensitivity C-reactive protein (> 3 mg/L) or have a prothrombin time/international normalized ratio (PT/INR) or activated partial thromboplastin time (aPTT) > 1.25 times × upper limit normal (ULN).
• Any clinically important abnormalities in hematology, coagulation, clinical chemistry, urinalysis, abnormal vital signs or abnormal laboratory values.
• Any positive result on Screening for serum hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C virus (HCV) or human immunodeficiency virus (HIV).
• Any clinically important abnormalities in rhythm, conduction, or morphology of the resting 12-lead electrocardiogram (ECG) at Screening.
• Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to the first administration of study intervention.

Parts A and B (Healthy Participants):

• Use of any prescribed or nonprescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, intake of > 3 × daily recommended levels of vitamins and minerals during the 2 weeks prior to the first administration of study intervention or longer if the medication has a long half-life.
• Current smokers or those who have smoked or used nicotine products.

Part B (Participants with Dyslipidemia):

• Acute ischemic cardiovascular event in the last 12 months prior to randomization.
• Poorly controlled diabetes.
• Previous administration of Lp(a) inhibitor.
• Have uncontrolled hypertension.
• Abnormal vital heart rate.