YN001 in Healthy Subjects and Patients With Coronary Atherosclerosis

Atherosclerotic Cardiovascular Disease Clinical Trial

Official title:

A Phase I/IIa Trial to Evaluate the Safety, Tolerability, PK, and Preliminary Efficacy of Single and Multiple Ascending Doses of YN001 in Healthy Subjects and Multiple Ascending Doses of YN001 in Patient With Coronary Atherosclerosis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06048588
• Other study ID #: YN001-002
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: October 8, 2023
• Est. completion date: November 15, 2024

Study information

• Verified date: April 2024
• Source: Beijing Inno Medicine Co., Ltd.
• Contact: Jamie Zhang, Master
• Phone: 861082599080
• Email: zhangjingmei[@]innovmed.co
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study consists of two parts. The SAD and MAD of part I are a randomized, double-blind, placebo-controlled, single and multiple ascending dose study in healthy adult subjects. The MAD expansion cohort of part I is single arm and multipal ascending dose in heallthy subjects. Part II (phase Ib/IIa) is a multicenter, randomized, controlled, open label, multiple ascending dose study in patients with coronary atherosclerosis.

Description:

Part I (phase Ia) is consists of 2 sections. The sections 1 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. Besides, the section 2 is designed to evaluate the safety and tolerability of multiple intravenous administration of YN001 without pre-medication or with different pre-medication regimens in Chinese healthy subjects.

Part II (phase Ib/IIa) 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 130
• Est. completion date: November 15, 2024
• Est. primary completion date: October 31, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Part I (Phase Ia)-Inclusion criteria:

1. 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.

2. Chinese healthy male or female subjects between 18 and 55 years.

3. 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.

4. Be in good general health at discretion of the investigator based on the results (be normal or abnormal without clinical significance) of medical history, physical examination, vital signs,12-lead ECG, laboratory tests (Hematology; Blood chemistry; Urinalysis, Coagulation and CRP) and viral serology.

5. 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.

6. Willing and able to comply with the requirements of protocol.

Part I (Phase Ia)-Exclusion criteria:

1. Prior treatment with other investigational drug(s) within 3 months or 5 half-lives, whichever is longer, prior to the first dosing.

2. Prior treatment with any prescription drugs, herbal supplements, over the counter (OTC) medication, dietary supplements (vitamins included), or any type of vaccination within 2 weeks prior to the first dosing.

3. Presenting with history of severe food allergy (e.g., anaphylactic reaction). Mild (e.g., non-anaphylactic, hypersensitivity) food allergies such as lactose intolerance/ glucose intolerance are permitted.

4. Allergy to multiple kinds of drugs or presenting with history of allergic reactions to any components of the study drug.

5. Known any clinically abnormal diseases or factors, including but not limited to neurological, cardiovascular, hematological, hepatic, renal, gastrointestinal, respiratory, metabolic, endocrine, immunological, skeletal system diseases, or other reasons that, in the opinion of the investigator, makes the subject inappropriate for inclusion in this study.

6. Presenting with history of myopathy/ myalgia, or susceptible to myopathy/ rhabdomyolysis.

7. Presence of hypothyroidism.

8. 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.

9. Known inflammatory bowel disease, ulcers, gastrointestinal or rectal bleeding within 6 months prior to the first dosing.

10. Presenting with history of pancreatic injury or pancreatitis within 6 months prior to the first dosing.

11. Presence of symptoms of urinary obstruction or difficulty in voiding.

12. Presenting and/ or relapse history (within the last 3 years) of autonomic dysfunction (e.g., recurrent episodes of fainting, palpitations, etc.).

13. Evidence of major diseases that not recovered within 2 weeks prior to the first dosing, or major surgery is expected during the study.

14. Presenting with history of impaired renal function defined by clinically significantly abnormal creatinine or BUN and/ or urea values, or abnormal urinary constituents (e.g., albuminuria).

15. Presence of liver disease or liver injury, defined by abnormal liver function tests.

16. Fasting triglyceride > 3.4 mmol/L.

17. Presenting with history of clinically significant ECG abnormalities, or any of the following abnormalities at screening or baseline. QTcF>470 msec for male, QTcF>480 msec for female.

18. Hemoglobin levels are below 120 g/L for males and 110 g/L for females at screening.

19. Donation or blood loss is more than 400 mL within 3 months prior to screening.

20. Use more than 10 cigarettes per day or habitual use of nicotine-containing products within 3 months prior to screening.

21. 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.

22. 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.

23. Positive for HBsAg, HCV, HIV, TP-Ab.

24. 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 (Phase Ib/IIa)-Inclusion criteria:

1. 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.

2. Chinese male or female subjects between 18 and 75 years.

3. Patients diagnosed with confirmed coronary atherosclerosis and 25-75% stenosis determined by coronary angiography.

4. Suspicion of vulnerable plaque based on clinical practice and determined by OCT examination.

5. Measurable targeted segment by estimation must be at least 40 mm in length.

6. 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.

7. Willing and able to comply with the requirements of protocol.

Part II (Phase Ib/IIa)-Exclusion criteria:

1. Prior treatment with other investigational drug(s) within 30 days or 5 half-lives, whichever is longer, prior to the first dosing.

2. Any type of vaccination within 4 weeks prior to the first dosing.

3. Presence of moderate or heavily calcification lesion in target segment determined by coronary angiography.

4. Known familial hypercholesterolemia.

5. Relapse and highly symptomatic arrhythmia uncontrolled by drugs within the past 3 months, such as ventricular tachycardia, atrial fibrillation with rapid ventricular rate and paroxysmal supraventricular tachycardia.

6. Presenting with history of any type of stroke (cerebral lacunar infarction excluded).

7. Presenting with history of myopathy/ myalgia, or susceptible to myopathy/ rhabdomyolysis.

8. Known inflammatory bowel disease, ulcers, gastrointestinal or rectal bleeding within 6 months prior to the first dosing.

9. Presenting with history of pancreatic injury or pancreatitis within 6 months prior to the first dosing.

10. Evidence of major diseases that not recovered within 2 weeks prior to the first dosing, or major surgery is expected during the study.

11. Any surgical operation is planned during the study.

12. Presenting with history of malignancy.

13. Presence of any type of autoimmune disease.

14. Allergy to multiple food or drugs or presenting with history of allergic reactions to any components of the study drug.

15. Prior treatment with CABG, PCI, heart transplantation, SAVR/TAVR, etc., or CABG, PCI, heart transplantation, SAVR/TAVR, etc., is planned during the study.

16. Life expectancy is less than 1 year.

17. Left ventricular ejection fraction (LVEF) <40%.

18. Left main coronary artery disease, defined as left main coronary artery stenosis=50% by angiographic estimation.

19. Uncontrolled hypertension.

20. Active liver disease or hepatic dysfunction defined by any of ALT, AST, or serum bilirubin exceeding 1.5ULN.

21. Presence of renal insufficiency (eGFR < 30 mL/min/1.73m2).

22. Presence of hypothyroidism.

23. Type 1 diabetes mellitus or poorly controlled type 2 diabetes mellitus.

24. Positive for HBsAg, HCV, HIV, TP-Ab.

25. 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.

Related Conditions & MeSH terms

• Atherosclerosis
• Atherosclerotic Cardiovascular Disease
• Cardiovascular Diseases
• Coronary Artery Disease
• Myocardial Ischemia

Intervention

Drug:
• YN001
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 up to 15 days. In MAD part of study in patients with coronary atherosclerosis, YN001 will be injected weekly or twice a week from 5mg to 40mg up to 85 days.
• Placebo for YN001
The injection solution to mimic the YN001
• rosuvastatin calcium tablets
In MAD part of study in patients with coronary atherosclerosis, Rosuvastatin calcium tablets will be taken orally by 10 mg daily up to 85 days

Locations

Country	Name	City	State
China	Beijing Anzhen Hospital, Capital Medical University	Beijing	Beijing
China	Peking University first hospital	Beijing	Beijing
China	First Hospital of Jilin University	Changchun	Jilin
China	Renji Hospital Shanghai Jiaotong Unv. school of Medicine	Shanghai	Shanghai
China	Renmin Hospital of Wuhan University	Wuhan	Hubei
China	Zhongnan Hospital of Wuhan University	Wuhan	Hubei

Sponsors (1)

Lead Sponsor	Collaborator
Beijing Inno Medicine Co., Ltd.

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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 29 days
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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 29 days
Secondary	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
Secondary	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
Secondary	Part I: Pharmacodynamic evaluation	To evaluate the change LDL-C, HDL-C,TC and TG from baseline to EOT	Up to 96 hours of post initiation of last dose
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Part II: Change in percent atheroma volume (PAV) of coronary plaque comparing to baseline	PAV will be determined by intravascular ultrasound (IVUS)	Up to 91 days or EOT
Secondary	Part II: Change in total atheroma volume (TAV) of coronary plaque comparing to baseline	TAV will be determined by intravascular ultrasound (IVUS)	Up to 91 days or EOT
Secondary	Part II: Change in coronary minimal lumen area (MLA) comparing to baseline	MLA will be determined by intravascular ultrasound (IVUS)	Up to 91 days or EOT
Secondary	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)	Up to 91 days or EOT
Secondary	Part II: Change in minimum fibrous cap thickness (FCT) of coronary plaque comparing to baseline	FCT will be determined by optical coherence tomography (OCT)	Up to 91 days or EOT
Secondary	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)	Up to 91 days or EOT
Secondary	Part II: Change in maximum IMT and plaque thickness	IMT will be determined by carotid ultrasound scans	Up to 91 days or EOT
Secondary	Part II: Change in atherosclerosis plaque located at other arteries	Other arteries plaque will be determined by CTA or MRA	Up to 91 days or EOT
Secondary	Part II: Immunogenicity analysis	To evaluate the immunogenicity of MAD of intravenously administered YN001 in Chinese patients with coronary atherosclerosis.	Up to 91 days or EOT
Secondary	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 91 days or EOT
Secondary	Part II: Pharmacodynamic analysis	Change in LDL-C,HDL-C,TC and TG levels form baseline to EOT	Up to 91 days or EOT