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

Purpose

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.

Conditions

  • Healthy Participants
  • Dyslipidemia

Eligibility

Eligible Ages
Between 18 Years and 70 Years
Eligible Sex
All
Accepts Healthy Volunteers
No

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.

Study Design

Phase
Phase 1
Study Type
Interventional
Allocation
Randomized
Intervention Model
Sequential Assignment
Primary Purpose
Treatment
Masking
Triple (Participant, Care Provider, Investigator)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Part A1: SAD Cohort 1 - AZD4954 (Dose 1)
Participants will receive a single dose of AZD4954 (Dose 1) or matching placebo on Day 1.
  • Drug: AZD4954
    AZD4954 will be administered orally.
  • Drug: Placebo
    Placebo will be administered orally.
Experimental
Part A1: SAD Cohort 2 - AZD4954 (Dose 2)
Participants will receive a single dose of AZD4954 (Dose 2) or matching placebo on Day 1.
  • Drug: AZD4954
    AZD4954 will be administered orally.
  • Drug: Placebo
    Placebo will be administered orally.
Experimental
Part A1: SAD Cohort 3 - AZD4954 (Dose 3)
Participants will receive a single dose of AZD4954 (Dose 3) or matching placebo on Day 1.
  • Drug: AZD4954
    AZD4954 will be administered orally.
  • Drug: Placebo
    Placebo will be administered orally.
Experimental
Part A1: SAD Cohort 4 - AZD4954 (Dose 4)
Participants will receive a single dose of AZD4954 (Dose 4) or matching placebo on Day 1.
  • Drug: AZD4954
    AZD4954 will be administered orally.
  • Drug: Placebo
    Placebo will be administered orally.
Experimental
Part A1: SAD Cohort 5 - AZD4954 (Dose 5)
Participants will receive a single dose of AZD4954 (Dose 5) or matching placebo on Day 1.
  • Drug: AZD4954
    AZD4954 will be administered orally.
  • Drug: Placebo
    Placebo will be administered orally.
Experimental
Part A1: SAD Optional Cohort 6 - AZD4954 (Dose 6)
Participants will receive a single dose of AZD4954 (Dose 6) or matching placebo on Day 1. This additional cohort may be added depending on the findings.
  • Drug: AZD4954
    AZD4954 will be administered orally.
  • Drug: Placebo
    Placebo will be administered orally.
Experimental
Part A1: SAD Cohort 1 (Japanese) - AZD4954 (Dose 2)
Japanese participants will receive a single dose of AZD4954 (Dose 2) or matching placebo on Day 1.
  • Drug: AZD4954
    AZD4954 will be administered orally.
  • Drug: Placebo
    Placebo will be administered orally.
Experimental
Part A1: SAD Cohort 2 (Japanese) - AZD4954 (Dose 3)
Japanese participants will receive a single dose of AZD4954 (Dose 3) or matching placebo on Day 1.
  • Drug: AZD4954
    AZD4954 will be administered orally.
  • Drug: Placebo
    Placebo will be administered orally.
Experimental
Part A1: SAD Optional Cohort 3 (Japanese) - AZD4954
This additional cohort may be added depending on the findings.
  • Drug: AZD4954
    AZD4954 will be administered orally.
  • Drug: Placebo
    Placebo will be administered orally.
Experimental
Part A1: SAD Cohort 1 (Chinese) - AZD4954 (Dose 5)
Chinese participants will receive a single dose of AZD4954 (Dose 5) or matching placebo at the highest dose level on Day 1.
  • Drug: AZD4954
    AZD4954 will be administered orally.
  • Drug: Placebo
    Placebo will be administered orally.
Experimental
Part A2: SAD Food Effect Cohort - AZD4954 (Dose 2)
Participants will receive a single dose of AZD4954 (Dose 2) or matching placebo with a high-calorie, high-fat breakfast on Day 1.
  • Drug: AZD4954
    AZD4954 will be administered orally.
  • Drug: Placebo
    Placebo will be administered orally.
Experimental
Part A2: SAD Food Effect Cohort - AZD4954 (Dose 3)
Participants will receive a single dose of AZD4954 (Dose 3) or matching placebo with a high-calorie, high-fat breakfast on Day 1.
  • Drug: AZD4954
    AZD4954 will be administered orally.
  • Drug: Placebo
    Placebo will be administered orally.
Experimental
Part B: Global MAD Cohort 1 (healthy participants) - AZD4954 (Dose 1)
Participants will receive multiple doses of AZD4954 (Dose 1) or matching placebo for 21 days.
  • Drug: AZD4954
    AZD4954 will be administered orally.
  • Drug: Placebo
    Placebo will be administered orally.
Experimental
Part B: Global MAD Cohort 2 (healthy participants) - AZD4954 (Dose 2)
Participants will receive multiple doses of AZD4954 (Dose 2) or matching placebo for 21 days.
  • Drug: AZD4954
    AZD4954 will be administered orally.
  • Drug: Placebo
    Placebo will be administered orally.
Experimental
Part B: Global MAD Cohort 3 (healthy participants) - AZD4954 (Dose 3)
Participants will receive multiple doses of AZD4954 (Dose 3) or matching placebo for 21 days.
  • Drug: AZD4954
    AZD4954 will be administered orally.
  • Drug: Placebo
    Placebo will be administered orally.
Experimental
Part B: Optional Global MAD Cohort 4 (healthy participants) - AZD4954
Participants will receive multiple doses of AZD4954 or matching placebo for 21 days. This additional cohort may be added depending on the findings.
  • Drug: AZD4954
    AZD4954 will be administered orally.
  • Drug: Placebo
    Placebo will be administered orally.
Experimental
Part B: MAD Cohort (Japanese) - AZD4954 (Dose 3)
Japanese participants will receive multiple doses of AZD4954 (Dose 3) or matching placebo for 21 days.
  • Drug: AZD4954
    AZD4954 will be administered orally.
  • Drug: Placebo
    Placebo will be administered orally.
Experimental
Part B: Global MAD Cohort (participants with dyslipidemia) - AZD4954 (Dose 1)
Participants with dyslipidemia will receive multiple doses of AZD4954 (Dose 1) or matching placebo for 21 days.
  • Drug: AZD4954
    AZD4954 will be administered orally.
  • Drug: Placebo
    Placebo will be administered orally.

Recruiting Locations

Research Site
Glendale, California 91206

Research Site
Inverness, Florida 34452

Research Site
Jacksonville, Florida 32216

Research Site
Port Orange, Florida 32127

Research Site
Brooklyn, Maryland 21225

Research Site
San Antonio, Texas 78229

More Details

Status
Recruiting
Sponsor
AstraZeneca

Study Contact

AstraZeneca Clinical Study Information Center
1-877-240-9479
information.center@astrazeneca.com

Detailed Description

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).