AZD4954 safety and dosing in adults with or without high lipoprotein(a) and in people with dyslipidemia

A Phase I, Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD4954 Following Single and Multiple Ascending Dose Administration to Healthy Participants With or Without Elevated Lp(a) Levels, and Participants With Dyslipidemia

This trial will test single and repeated doses of AZD4954 in healthy adults and adults with high Lp(a) or dyslipidemia to see how safe the drug is and how it behaves in the body.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 136 (estimated)
• Ages: 18 Years to 70 Years
• Sex: All
• Sponsor: AstraZeneca (Industry-sponsored)
• Locations: 6 sites (Glendale, California and 5 other locations)
• Trial ID: NCT06980428 on ClinicalTrials.gov

What this trial studies

This first-in-human, placebo-controlled Phase 1 program uses single ascending dose (Part A) and multiple ascending dose (Part B) designs to characterize safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD4954. Part A enrolls healthy adults with and without elevated Lp(a) for single doses, while Part B includes multiple-dose cohorts of healthy participants, participants with dyslipidemia and elevated Lp(a), and a Japanese cohort. Participants receive AZD4954 or placebo, remain at the research site for supervised dosing and monitoring, and return for follow-up visits to capture safety and biomarker changes. The study includes dose escalation and repeated measures to define dose-related effects on Lp(a), LDL-C, and systemic exposure.

Who should consider this trial

Good fit: Adults aged 18–65 with BMI 18–35 kg/m² and suitable veins, including healthy volunteers, people with elevated Lp(a) (≥30 mg/dL), and those with dyslipidemia plus Lp(a) ≥70 mg/dL and LDL-C between 70 and 190 mg/dL, who meet pregnancy and contraception requirements, are the intended participants.

Not a fit: People outside the age or BMI ranges, those with abnormal plasminogen levels, pregnant or breastfeeding individuals, or those with LDL-C or Lp(a) values outside the specified eligibility ranges are unlikely to be eligible or to benefit from participation.

Why it matters

Potential benefit: If successful, AZD4954 could provide a new oral option to lower Lp(a) or modify lipid-related biomarkers and potentially reduce cardiovascular risk for people with high Lp(a) or dyslipidemia.

How similar studies have performed: Other experimental Lp(a)-lowering approaches such as antisense oligonucleotides and siRNA agents have produced substantial Lp(a) reductions in early trials, so the concept of targeting Lp(a) has promising precedent.

Eligibility criteria

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.

Where this trial is running

Glendale, California and 5 other locations

• Research Site — Glendale, California, United States (Recruiting)
• Research Site — Inverness, Florida, United States (Recruiting)
• Research Site — Jacksonville, Florida, United States (Recruiting)
• Research Site — Port Orange, Florida, United States (Not_yet_recruiting)
• Research Site — Brooklyn, Maryland, United States (Recruiting)
• Research Site — San Antonio, Texas, United States (Recruiting)

Study contacts

• Study coordinator: AstraZeneca Clinical Study Information Center

Conditions Healthy Participants; Dyslipidemia; Lipoprotein; Low-density lipoprotein cholesterol