The purpose of the study is to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple ascending doses of AZD4954 in healthy 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):

  1. 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.

  2. 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.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests 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 PhRMA 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 anonymized individual patient-level data via secure research environment Vivli.org. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.