A Study of AZD8233 in Participants With Dyslipidemia.

Phase 1

Completed

Brief Summary: A Phase 1 and 2 Study of AZD8233 in Participants with Dyslipidemia and this study consists of Part A , Part B and Part C. Part A is designed as a randomized, single-blind (blinding of participants and sites), placebo-controlled, multiple dose, phase 1 study. Part B is designed as a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 study. Part C is designed as a randomized , single-blind (blinding of participants and sites), placebo-controlled, multiple dose, phase 1 study.

Detailed Description: Part A: This is designed as a randomized, single-blind (blinding of participants and sites), placebo-controlled, multiple dose, phase 1 study.

Approximately 11 Japanese participants will be randomized in an 8:3 ratio into 1 of the 2 single-blinded treatment arms; AZD8233 high dose or placebo. Participants will be dosed SC on Days 1, 8, 29, and 57.

Part B:This is designed as a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 study. Approximately 60 Japanese participants will be randomized in a 1:1:1 ratio into 1 of the 4 double-blinded treatment arms; AZD8233 low dose, AZD8233 medium dose, or placebo. Participants will be dosed SC on Days 1, 29, and 57.

Part C:This is designed as a randomized, single-blind (blinding of participants and sites), placebo-controlled, multiple dose, phase 1 study.

Approximately 11 Japanese participants will be randomized in an 8:3 ratio into 1 of the 2 single-blinded treatment arms; AZD8233 medium dose or placebo. Participants will be dosed SC on Days 1, 29, and 57.

Recruitment & Eligibility

Inclusion Criteria

Part A

Participants must be 20 to 60 years of age inclusive, at the time of signing the informed consent
Participants who have a fasting LDL-C ≥ 70 mg/dL but < 140 mg/dL at screening
Participants who have fasting triglycerides < 400 mg/dL at screening
Participants who should be receiving statin therapy
Participants who should be on stable medication for a certain time period prior to randomization
Body mass index (BMI) between 19 and 40 kg/m2
Females must not be pregnant and must have a negative pregnancy test at screening and randomisation, must not be lactating , and must be of nonchild-bearing potential

Part B

Participants must be 20 to 75 years of age inclusive, at the time of signing the informed consent
Have a fasting LDL-C ≥ 70 mg/dL but < 190 mg/dL at screening (Visit 2)
Have fasting triglycerides < 400 mg/dL at screening (Visit 2)
Should be receiving statin therapy
LDL-lowering medications should be on stable dosing for ≥ 3 months prior to screening with no planned medication or dose change during study participation
BMI between 19 and 40 kg/m2
Female participants must not be pregnant and must have a negative pregnancy test at screening and randomisation, must not be lactating, and must not be of childbearing potential

Part C

Participants must be 20 to 60 years of age inclusive, at the time of signing the informed consent
Participants who have a fasting LDL-C ≥ 70 mg/dL but < 140 mg/dL at screening
Participants who have fasting triglycerides < 400 mg/dL at screening
Participants who should be receiving statin therapy
Participants who should be on stable medication for a certain time period prior to randomization
Body mass index (BMI) between 19 and 40 kg/m2
Females must not be pregnant and must have a negative pregnancy test at screening and randomisation, must not be lactating , and must be of nonchild-bearing potential

Key

Exclusion Criteria

Part A

eGFR < 60 mL/min/1.73m2 using the Japanese equation
Blood dyscrasias with increased risk of bleeding including idiopathic thrombocytopenic purpura and thrombotic thrombocytopenic purpura or symptoms of increased risk of bleeding. Or participants receiving anti-coagulation therapy
History of major bleed or high-risk of bleeding diathesis
Subjects with a high 10-year risk of coronary heart disease as calculated using the Suita score
Heart rate after 10 minutes of sitting rest < 50 or > 100 beats per minute
Uncontrolled hypertension defined as sitting SBP > 140 mmHg or DBP > 90 mmHg

Part B

eGFR < 40 mL/min/1.73m2 using the Japanese equation at Visit 1
Poorly controlled type 2 diabetes mellitus (T2DM), defined as Haemoglobin A1c (HbA1c) > 10% at Visit 1
Acute ischaemic cardiovascular event in the last 12 months prior to randomization
Heart failure with New York Heart Association (NYHA) Class III-IV
High-risk of bleeding diathesis as judged by the Investigator
Uncontrolled hypertension defined as sitting SBP > 160 mmHg or DBP > 90 mmHg at Visit 1 or Visit 3
Heart rate after 10 minutes sitting rest < 50 bpm or > 100 bpm at Visit 1 or Visit 3

Part C

eGFR < 60 mL/min/1.73m2 using the Japanese equation
Blood dyscrasias with increased risk of bleeding including idiopathic thrombocytopenic purpura and thrombotic thrombocytopenic purpura or symptoms of increased risk of bleeding. Or participants receiving anti-coagulation therapy
History of major bleed or high-risk of bleeding diathesis
Subjects with a high 10-year risk of coronary heart disease as calculated using the Suita score
Heart rate after 10 minutes of sitting rest < 50 or > 100 beats per minute
Uncontrolled hypertension defined as sitting SBP > 140 mmHg or DBP > 90 mmHg

Primary Outcome Measures

Name	Time	Method
Part B: Change in LDL-C in Serum at Week 12	Baseline to week 12	Part B: Change from baseline in LDL-C at week 12. Results are based on Mixed Model Repeated Measures (MMRM) analysis on the log-transformed change from baseline. Log-transformed change from baseline is calculated as the visit value in log minus the baseline value in log. The results from the model are then back transformed. Note: log(week 12 data) - log(baseline data) = log(week12/baseline), which is a ratio

Secondary Outcome Measures

Name	Time	Method
Part B: Percentage Change From Baseline in LDL-C in Serum at Week 12	Measurement at baseline and week 12	Percentage change from baseline to week 12 in Low-density Lipoprotein Cholesterol (LDL-C) in serum
Part B: Change in PCSK9 in Plasma at Week 12	Baseline to week 12	Part B: Change from baseline in PCSK9 in plasma at week 12. Results are based on Mixed Model Repeated Measures (MMRM) analysis on the log-transformed change from baseline. Log-transformed change from baseline is calculated as the visit value in log minus the baseline value in log. The results from the model are then back transformed. Note: log(week 12 data) - log(baseline data) = log(week12/baseline), which is a ratio
Part B: Percentage Change From Baseline in PCSK9 in Plasma at Week 12	Measurement at baseline and week 12	Percentage change from baseline to week 12 in proprotein convertase subtilisin/kexin type-9 (PCSK9) in plasma
Part A & Part C: AUC (0-24) of AZD8233	Day 1 and Day 57	Area Under the plasma concentration time curve from time 0 to time 24 hours
Part A & Part C: Cmax of AZD8233	Day 1 and Day 57	Maximum plasma concentration
Part A & Part C: t1/2 of AZD8233	Day 1 and Day 57	Terminal half-life
Part A & Part C: CL/F (L/h) of AZD8233	Day 1 and Day 57	Apparent plasma clearance
Part A & Part C: Vz/F (L)	Day 1 and Day 57	Apparent Volume of distribution during the terminal phase