Clinical trial NCT06980428: A Study to Investigate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AZD4954 in Healthy Adult Participants With or Without Elevated Lipoprotein (a) (Lp[a]) Levels
Official title: 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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
Conditions: Healthy Participants
Keywords: Dyslipidemia
Lipoprotein(a)
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2025-05-20
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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.

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 (of non-childbearing potential) participants (Part A) or healthy participants (of non-childbearing potential) with elevated Lp(a) levels (≥ 30 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 IMP dose for all cohorts (Day 29 ±2 days).

Part B of the study 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) in the global MAD cohorts and for 14 days (Day 1 to 14) in Japanese MAD cohorts.
* A Follow-up Visit within 26 to 30 days after the last IMP dose (Day 42 ±2 days).

Eligibility criteria: Inclusion Criteria:

Parts A and B:

* 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 Clinical Unit.
* 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.
* 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.

     Only Part B:
* For Part B (Global MAD Cohorts), at the Screening Visit participants must have elevated Lp(a) ≥ 30 mg/dL.

Exclusion Criteria:

Parts A and B:

* 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) 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.

Primary outcomes:
measure: Part A: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From Screening (Day -28 to Day -2) to Follow-up visit (Up to Day 29)
measure: Part B: Number of participants with AEs and SAEs
timeFrame: From Screening (Day -28 to Day -2) to Follow-up visit (Up to Day 49)
Secondary outcomes:
measure: Part A: Area under concentration-time curve from time 0 to infinity (AUCinf)
timeFrame: Up to Day 29
measure: Area under concentration-curve from time 0 to the last quantifiable concentration (AUClast)
timeFrame: Part A: Up to Day 29; Part B: Up to Day 49
measure: Part B: Area under concentration-time curve in the dosing interval (AUCtau)
timeFrame: Up to Day 49
measure: Dose normalized AUClast (AUClast/D)
timeFrame: Part A: Up to Day 29; Part B: Up to Day 49
measure: Dose normalized AUCinf (AUCinf/D)
timeFrame: Part A: Up to Day 29; Part B: Up to Day 49
measure: Part B: Dose normalized AUCtau (AUCtau/D)
timeFrame: Up to Day 49
measure: Apparent total body clearance (CL/F)
timeFrame: Part A: Up to Day 29; Part B: Up to Day 49
measure: Maximum observed drug concentration (Cmax)
timeFrame: Part A: Up to Day 29; Part B: Up to Day 49
measure: Dose normalized Cmax (Cmax/D)
timeFrame: Part A: Up to Day 29; Part B: Up to Day 49
measure: Terminal elimination half-life (t1/2λz)
timeFrame: Part A: Up to Day 29; Part B: Up to Day 49
measure: Time of last quantifiable concentration (tlast)
timeFrame: Part A: Up to Day 29; Part B: Up to Day 49
measure: Time to reach maximum observed concentration (tmax)
timeFrame: Part A: Up to Day 29; Part B: Up to Day 49
measure: Apparent volume of distribution based on the terminal phase (Vz/F)
timeFrame: Part A: Up to Day 29; Part B: Up to Day 49
measure: Individual and cumulative amount of unchanged drug excreted into urine from time t1 to time t2 (Ae[t1-t2])
timeFrame: Part A: Up to Day 15; Part B: Up to Day 22
measure: Cumulative amount of unchanged drug excreted into urine (Aeinf)
timeFrame: Part A: Up to Day 15; Part B: Up to Day 22
measure: Individual and cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 (fe[t1-t2])
timeFrame: Part A: Up to Day 15; Part B: Up to Day 22
measure: Renal clearance (CLR)
timeFrame: Part A: Up to Day 15; Part B: Up to Day 22
measure: Part B: Absolute change from baseline in serum Lp(a)
timeFrame: Up to Day 49
measure: Part B: Relative change from baseline in serum Lp(a)
timeFrame: Up to Day 49
measure: Part B: Absolute change from baseline in Lp(a) intact assay
timeFrame: Up to Day 49
measure: Part B: Relative change from baseline in Lp(a) intact assay
timeFrame: Up to Day 49
Other outcomes:
Locations:
city: Glendale
country: United States
facility: Research Site
state: California
city: Brooklyn
country: United States
facility: Research Site
state: Maryland
Study officials:
References: