YN001 in Healthy Subjects and Patients With Coronary Atherosclerosis

Study Overview
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Brief Summary
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This study consists of two parts. Part I (phase Ia) is a randomized, double-blind, placebo-controlled, single and multiple ascending dose study in healthy adult subjects. Part II (phase Ib) is a multicenter, randomized, controlled, open label, multiple ascending dose study in patients with coronary atherosclerosis.

Detailed Description
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Part I (phase Ia) is designed to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending doses of intravenously administered YN001, and to evaluate the effect of SAD of intravenously administered YN001 on the QT/QTc interval, and the immunogenicity of MAD of intravenously administered YN001 in healthy subjects. Part II (phase Ib) is designed to evaluate the safety, tolerability, pharmacokinetics, preliminary efficacy, immunogenicity, and the effect on cytokine changes of MAD of intravenously administered YN001 in patients with coronary atherosclerosis.

Official Title
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A Phase I Trial to Evaluate the Safety, Pharmacokinetics, and Preliminary Efficacy of SAD and MAD of YN001 in Healthy Subjects and MAD of YN001 in Patients With Coronary Atherosclerosis

Conditions
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Atherosclerotic Cardiovascular Disease

Intervention / Treatment
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* Drug: YN001
* Drug: Placebo for YN001
* Drug: rosuvastatin calcium tablets


Participation Criteria
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Eligibility Criteria
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Part I- Inclusion Criteria: Fully understand the purposes, features, and methods of the study and the possible adverse reactions, voluntarily participate in the study as a subject, and sign the informed consent form (ICF) before performing any assessment. Chinese healthy male or female subjects between 18 and 55 years (inclusive, at the time of signing the ICF). A Body Mass Index (BMI) of 18 28 kg/m2 (inclusive), with a body weight of at least 50 kg for males and 45 kg for females. Be in good general health at discretion of the investigator. Female subjects must be non-pregnant and non-lactating, and women of childbearing potential (including the male subject's female companion) must agree to use effective method of contraception from the screening period to 3 months after receiving their last dose of the investigational drug. Willing and able to comply with the requirements of protocol. Part I- Exclusion Criteria: Prior treatment with other investigational drug(s) within 3 months or 5 half-lives, whichever is longer, prior to the first dosing. Prior treatment with any prescription drugs, or any type of vaccination within 2 weeks prior to the first dosing. Presenting with history of severe food allergy. Allergy to multiple kinds of drugs or presenting with history of allergic reactions to any components of the study drug. Known any clinically abnormal diseases or factors that, in the opinion of the investigator, makes the subject inappropriate for inclusion in this study. Presence of hypothyroidism. Presenting and/ or relapse history (within the last 3 years) of acute or chronic bronchospastic disease (including asthma and chronic obstructive pulmonary disease, treated, or not treated) or cardiac dysfunction or myocardial infarction. Known inflammatory bowel disease, ulcers, gastrointestinal or rectal bleeding within 6 months prior to the first dosing. Presenting with history of pancreatic injury or pancreatitis within 6 months prior to the first dosing. Presence of symptoms of urinary obstruction or difficulty in voiding. Presenting and/ or relapse history (within the last 3 years) of autonomic dysfunction (e.g., recurrent episodes of fainting, palpitations, etc.). Evidence of major diseases that not recovered within 2 weeks prior to the first dosing, or major surgery is expected during the study. Presenting with history of impaired renal function defined by clinically significantly abnormal creatinine or BUN(Blood Urea Nitrogen) and/ or urea values, or abnormal urinary constituents (e.g., albuminuria). Presence of liver disease or liver injury, defined by abnormal liver function tests. Donation or blood loss is more than 400 mL within 3 months prior to screening. Use more than 10 cigarettes per day or habitual use of nicotine-containing products within 3 months prior to screening. Presenting with history of drug abuse within 12 months prior to screening, or use of any drugs within 3 months prior to screening, or a positive result of drug abuse screen at screening. Consumption of more than 14 standard drinks of alcohol per week within 3 months prior to screening, or consumption of alcohol-containing products 48 hours prior to the first dosing or having positive alcohol breath test at baseline. Positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV), human immunodeficiency virus (HIV), or treponema pallidum antibody (TP-Ab). Presence of any other diseases or conditions that, in the opinion of the investigator, would make it unsuitable for the subject to participate in this study. Part II- Inclusion Criteria: Fully understand the purposes, features, and methods of the study and the possible adverse reactions, voluntarily participate in the study as a subject, and sign the ICF before performing any assessment. Chinese male or female subjects between 18 and 75 years (inclusive, at the time of signing the ICF). Patients diagnosed with confirmed coronary atherosclerosis and 25-75% stenosis. Vulnerable plaque determined by an optical coherence tomography (OCT) examination. Targeted segment of vessel must be at least 40 mm in length. Female subjects must be non-pregnant and non-lactating, and women of childbearing potential (including the male subject's female companion) must agree to use effective method of contraception from the screening period to 3 months after receiving their last dose of the investigational drug. Willing and able to comply with the requirements of protocol. Part II- Exclusion Criteria: Prior treatment with other investigational drug(s) within 30 days or 5 half-lives, whichever is longer, prior to the first dosing. Prior treatment with any supplements known to alter the study drug's metabolism or other supplements judged by the investigator to influence the study drug within 2 weeks prior to the first dosing. Any type of vaccination prior to the first dosing. Presence of moderate or heavily calcification lesion in target vessel. Known heterozygous or homozygous familial hypercholesterolemia. Relapse and highly symptomatic arrhythmia uncontrolled by drugs within the past 3 months. Presenting with history of any type of stroke. Known inflammatory bowel disease, ulcers, gastrointestinal or rectal bleeding within 6 months prior to the first dosing. Presenting with history of pancreatic injury or pancreatitis within 6 months prior to the first dosing. Evidence of major diseases that not recovered within 2 weeks prior to the first dosing, or major surgery is expected during the study. Presenting with history of malignancy, or cancer within the past 2 years. Presence of any type of autoimmune disease. Allergy to multiple food or drugs or presenting with history of allergic reactions to any components of the study drug. Prior treatment with CABG(coronary artery bypass graft), PCI(Percutaneous coronary intervention), heart transplantation, SAVR(Surgical aortic valve replacement)/TAVR(Transcatheter aortic valve replacement), etc., or CABG, PCI(Percutaneous coronary intervention), heart transplantation, SAVR/TAVR, etc., is planned during the study. Left ventricular ejection fraction (LVEF) <40%. Left main coronary artery stenosis ≥ 50%. Uncontrolled hypertension, defined as systolic blood pressure≥150 mmHg or diastolic blood pressure≥100 mmHg in resting status. Active liver disease or hepatic dysfunction. Presence of renal insufficiency. Positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV), human immunodeficiency virus (HIV), or treponema pallidum antibody (TP-Ab). Presence of any other diseases or conditions that, in the opinion of the investigator, would make it unsuitable for the subject to participate in this study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: YN001<br>YN001 will be administrated intravenous by single ascending dose, multiple ascending doses weekly or twice a week. | Drug: YN001<br>* In single ascending dose (SAD) part of study in health subjects, YN001 will be administrated one time with dosage from 10 mg to 120 mg (planned). In multiple ascending doses (MAD) part of study in health subjects, YN001 will be given twice a week from 5 mg to 40 mg for 2 weeks. In MAD part of study in patients with coronary atherosclerosis, YN001 will be injected weekly or twice a week from 5mg to 40mg for 4 weeks.<br>|
| Placebo Comparator: Part I-Matching placebo for YN001<br>Matching placebo for YN001 will be administrated intravenous. | Drug: Placebo for YN001<br>* The injection solution to mimic the YN001<br>* Other names: Placebo;|
| Active Comparator: Part II-Rosuvastatin calcium tablets<br>Rosuvastatin calcium tablets will be given by orally. | Drug: rosuvastatin calcium tablets<br>* In MAD part of study in patients with coronary atherosclerosis, Rosuvastatin calcium tablets will be taken orally by 10 mg daily for 4 weeks.<br>* Other names: Crestor®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part I: The safety and tolerability of YN001 in healthy subjects. | To evaluate the incidence of Adverse Events as Assessed by CTCAE v5.0, Clinically Significant Laboratory Abnormalities, Clinically Significant Electrocardiogram Abnormalities, Clinically Significant Vital Signs Abnormalities, Clinically Significant Physical Examination Abnormalities. | Up to 14 days post last dose | 
| Part I: Maximum plasma concentration(Cmax) of YN001 | To evaluate the pharmacokinetics (PK) characteristics of of intravenously administered YN001 in healthy subjects | Up to 168 hours of post initiation of last dose | 
| Part I: Time of maximum concentration (Tmax) of YN001 | To evaluate the pharmacokinetics (PK) characteristics of of intravenously administered YN001 in healthy subjects. | Up to 168 hours of post initiation of last dose | 
| Part I: Elimination half-life (t1/2) of YN001 | To evaluate the pharmacokinetics (PK) characteristics of of intravenously administered YN001 in healthy subjects. | Up to 168 hours of post initiation of last dose | 
| Part I: Area under the plasma concentration-time curve from time 0 to the collection time point of the last measurable concentration (AUC0-t) of YN001 | To evaluate the pharmacokinetics (PK) characteristics of of intravenously administered YN001 in healthy subjects. | Up to 168 hours of post initiation of last dose | 
| Part II: The safety and tolerability of intravenously administered YN001 in patients with coronary atherosclerosis. | To evaluate the incidence of Adverse Events as Assessed by CTCAE v5.0, Clinically Significant Laboratory Abnormalities, Clinically Significant Electrocardiogram Abnormalities, Clinically Significant Vital Signs Abnormalities, Clinically Significant Physical Examination Abnormalities, Clinically Significant Echocardiogram Abnormalities. | Up to 14 days post last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part I: C-QTc analysis | To evaluate the effect of SAD of YN001 on QT/QTc interval prolongation and relationship between YN001 exposure and QT/QTc Interval changes in Chinese healthy subjects. | Pre-dose and up to 48 hours post initiation of infusion | 
| Part I: Immunogenicity analysis | To evaluate the immunogenicity of MAD of intravenously administered YN001 in Chinese healthy subjects. | Up to 96 hours of post initiation of last dose | 
| Part II: Maximum plasma concentration(Cmax) of YN001 | To evaluate the pharmacokinetics (PK) characteristics of of intravenously administered YN001 in patients with coronary atherosclerosis. | Up to 96 hours of post initiation of last dose | 
| Part II: Time of maximum concentration (Tmax) of YN001 | To evaluate the pharmacokinetics (PK) characteristics of of intravenously administered YN001 in patients with coronary atherosclerosis. | Up to 96 hours of post initiation of last dose | 
| Part II: Elimination half-life (t1/2) of YN001 | To evaluate the pharmacokinetics (PK) characteristics of of intravenously administered YN001 in patients with coronary atherosclerosis. | Up to 96 hours of post initiation of last dose | 
| Part II: Area under the plasma concentration-time curve from time 0 to the collection time point of the last measurable concentration (AUC0-t) of YN001 | To evaluate the pharmacokinetics (PK) characteristics of of intravenously administered YN001 in patients with coronary atherosclerosis. | Up to 96 hours of post initiation of last dose | 
| Part II: Change in percent atheroma volume (PAV) of coronary plaque comparing to baseline | PAV will be determined by intravascular ultrasound (IVUS) | End of 4 weeks of treatment | 
| Part II: Change in total atheroma volume (TAV) of coronary plaque comparing to baseline | TAV will be determined by intravascular ultrasound (IVUS) | End of 4 weeks of treatment | 
| Part II: Change in coronary minimal lumen area (MLA) comparing to baseline | MLA will be determined by intravascular ultrasound (IVUS) | End of 4 weeks of treatment | 
| Part II: Change in maximum lipid arc and lipid core length of coronary plaque comparing to baseline | lipid arc and lipid core length will be determined by optical coherence tomography (OCT) | End of 4 weeks of treatment | 
| Part II: Change in minimum fibrous cap thickness (FCT) of coronary plaque comparing to baseline | FCT will be determined by optical coherence tomography (OCT) | End of 4 weeks of treatment | 
| Part II: Change in detection rate of macrophage cluster within coronary plaque comparing to baseline | detection rate of macrophage cluster will be determined by optical coherence tomography (OCT) | End of 4 weeks of treatment | 
| Part II: Immunogenicity analysis | To evaluate the immunogenicity of MAD of intravenously administered YN001 in Chinese patients with coronary atherosclerosis. | Up to 96 hours of post initiation of last dose | 
| Part II: Cytokines analysis | To evaluate the effect of MAD of intravenously administered YN001 on Cytokines levels in Chinese patients with coronary atherosclerosis. | Up to 96 hours of post initiation of last dose |