the Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Effects in Adult Subjects With Elevated LDL-C

Study Overview
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Brief Summary
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This is a randomized, placebo-controlled, single ascending-dose (SAD) study of administered SC to adult subjects with elevated LDL-C. Subjects who have signed an Ethics Committee (EC)-approved informed consent form (ICF) and have met all the protocol eligibility criteria during screening may be enrolled into the study.

Official Title
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A Phase 1, Randomized, Single-blinded, Placebo-controlled, Single-ascending-dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Effects in Adult Subjects With Elevated LDL-C

Conditions
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To Reduce the LDL-C Level in Hypercholesteremia Patients

Intervention / Treatment
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* Drug: RN0191


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects, aged 18 to 60 years, inclusive Body mass index between 18 and 32 kg/m2, inclusive, with body weight > 45 kg for females and >50 kg for males Serum LDL-C ≥100 mg/dL (2.6 mmol/L) at screening and Day -1 (Note: If the examination was conducted between D-7 and D-2 at the time of screening, it does not need to be repeated at D-1) Fasting triglycerides < 400 mg/dL (<4.52 mmol/L) at screening and Day -1(Note: If the examination was conducted between D-7 and D-2 at the time of screening, it does not need to be repeated at D-1) Exclusion Criteria: Diagnosis and criteria for inclusion: Inclusion Criteria for all subjects 1. Male and female subjects, aged 18 to 60 years, inclusive 2. Body mass index between 18 and 32 kg/m2, inclusive, with body weight > 45 kg for females and >50 kg for males 3. Serum LDL-C ≥100 mg/dL (2.6 mmol/L) at screening and Day -1 (Note: If the examination was conducted between D-7 and D-2 at the time of screening, it does not need to be repeated at D-1) 4. Fasting triglycerides < 400 mg/dL (<4.52 mmol/L) at screening and Day -1(Note: If the examination was conducted between D-7 and D-2 at the time of screening, it does not need to be repeated at D-1) Exclusion Criteria for all subjects Any uncontrolled or serious disease, or any medical or surgical condition, (excluding superficial local surgery), including but not limited to neoplasm, autoimmune disease, infectious disease, allergy, liver dysfunction and renal dysfunction, that may interfere with participation the clinical study and/or put the subjects at significant risk (according to Investigator's judgement) if he/she participates in the clinical study An underlying known disease or medical condition that may potentially have effects on general safety assessment, or on lipid or glucose metabolism, or surgical condition, including but not limited to bariatric surgery, that, in the opinion of the Investigator, might interfere with interpretation of the clinical study results Active serious mental illness or psychiatric disorder, including but not limited to schizophrenia, bipolar disorder or severe depression requiring current pharmacological intervention History or presence of cardiovascular disease (including peripheral arterial and cerebrovascular disease) such as, but not limited to, a history of tip-twisting ventricular tachycardia, symptomatic ventricular arrhythmia, or a personal or family history of short QT syndrome, long QT syndrome, or investigator-defined abnormal and clinically significant hyperkalemia, hypokalemia Systolic blood pressure (SBP) > 140 mmHg or diastolic blood pressure (DBP) > 90 mmHg after 5 minutes supine rest (one repeat measurement allowed at screening period; the average should be calculated for eligibility assessment). Diagnosis of diabetes mellitus, excluding resolved gestational diabetes mellitus Received any medication, including but not limited to statins, ezetimibe or lipid-altering nutrients, within 30 days prior to screening, or PCSK9 antibody within 90 days prior to screening, or any LDL-C-lowering siRNA therapy within 12 months prior to screening Used prescription drugs within 14 days or 7 half-lives (whichever is longer) before the first dose of study drug, with the exception of hormone replacement and contraception therapy Used over-the-counter medication, excluding routine vitamins, within 7 days before the first dose of study drug, unless determined by the Investigator and Sponsor to be not clinically relevant, and unlikely to impact blood cholesterol level. Alanine aminotransferase (ALT) and/or Aspartate aminotransaminase (AST) > 1.5 × upper limit of normal (ULN) at Screening (one repeat screen test allowed), and for subjects with ALT and or AST > ULN and ≤ 1.5 × ULN, considered clinically relevant by the Investigator. International Normalized Ratio (INR) above the upper limit of the normal reference range (based on local laboratory reference ranges) at screening and judged clinically significant by the investigator Positive serologic test of hepatitis B virus, hepatitis C virus, or human immunodeficiency virus infection at screening Abnormal thyroid function Clinically significant illness within 7 days before the first dose of study drug Symptomatic heart failure (Per New York Heart Association guideline), unstable angina, myocardial infarction, severe cardiovascular disease (ejection fraction <20%, transient ischemic attack (TIA) or cerebrovascular accident (CVA) within 6 months prior to study entry. Smoking (≥5 cigarettes per day), use of smoking cessation products or nicotine-containing products within 3 months prior to administration of study medication; or inability to discontinue the use of any tobacco-based products after enrollment until the entire trial period Having a history of regular alcohol consumption (14 units of alcohol per week: 1 unit = 285 mL of beer; 25 mL of spirits; 125 mL of wine) within 3 months prior to Screening, or have an abnormal alcohol breath test result prior to enrollment Prior history of substance abuse or positive urine drug screen at screening/ baseline visit Donation of more than 500 mL of blood within 90 days, or plasma donation within 30 days before the dosing of study drug History of multiple drug allergies or history of allergic reaction to an oligonucleotide or N-acetylgalactosamine (GalNAc) History of intolerance to SC injection or relevant abdominal scarring (surgical, burns, etc.) Any conditions which, in the opinion of the Investor, would make the subject unsuitable for enrollment or could interfere with the subjects' participation in or completion of the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Sequential Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: cohort 1<br>or placebo | Drug: RN0191<br>* This is a randomized, placebo-controlled, single ascending-dose (SAD) study of RN0191 administered SC to adult subjects with elevated LDL-C. Subjects who have signed an Ethics Committee (EC)-approved informed consent form (ICF) and have met all the protocol eligibility criteria during screening may be enrolled into the study.<br>|
| Experimental: Cohort 2<br>or placebo | Drug: RN0191<br>* This is a randomized, placebo-controlled, single ascending-dose (SAD) study of RN0191 administered SC to adult subjects with elevated LDL-C. Subjects who have signed an Ethics Committee (EC)-approved informed consent form (ICF) and have met all the protocol eligibility criteria during screening may be enrolled into the study.<br>|
| Experimental: Cohort 3<br>or placebo | Drug: RN0191<br>* This is a randomized, placebo-controlled, single ascending-dose (SAD) study of RN0191 administered SC to adult subjects with elevated LDL-C. Subjects who have signed an Ethics Committee (EC)-approved informed consent form (ICF) and have met all the protocol eligibility criteria during screening may be enrolled into the study.<br>|
| Experimental: Cohort 4<br>or placebo | Drug: RN0191<br>* This is a randomized, placebo-controlled, single ascending-dose (SAD) study of RN0191 administered SC to adult subjects with elevated LDL-C. Subjects who have signed an Ethics Committee (EC)-approved informed consent form (ICF) and have met all the protocol eligibility criteria during screening may be enrolled into the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the safety and tolerability of RN0191 administered as escalating single subcutaneous (SC) doses in adult subjects with elevated low-density lipoprotein-cholesterol (LDL-C) | This is a randomized, placebo-controlled, single ascending-dose (SAD) study of RN0191 administered SC to adult subjects with elevated LDL-C. Subjects who have signed an Ethics Committee (EC)-approved informed consent form (ICF) and have met all the protocol eligibility criteria during screening may be enrolled into the study. | For each subject in the study, the duration of the study clinic visits is approximately 18 weeks from screening to Day 85 EOS examination. |