Study of Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Inclisiran in Chinese Participants With Elevated Serum LDL-C

Study Overview
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Brief Summary
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Study to evaluate the pharmacokinetics and pharmacodynamics of inclisiran treatment given as single subcutaneous injection in Chinese participants with elevated low-density lipoprotein cholesterol (LDL-C) despite treatment with LDL-C lowering therapies

Detailed Description
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The purpose of the study is to characterize pharmacokinetics, pharmacodynamics, safety and tolerability of inclisiran in Chinese participants with elevated serum LDL-C to support inclisiran registration in China.Inclisiran is a long acting RNA therapeutic agent that inhibits the synthesis of PCSK9, leading to reduced circulating LDL-C levels. Three pivotal Phase III studies have been conducted primarily in non-Asian participants to support New Drug Application/Marketing Authorization Application approval of inclisiran globally. This study design is based on the hypothesis that the global inclisiran clinical data primarily obtained in Caucasian participants could be appropriately extrapolated to Chinese participants.

Official Title
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A Placebo-controlled, Participant, Investigator and Sponsor Blinded, Randomized Study to Evaluate the Pharmacokinetics and Pharmacodynamics of Inclisiran Treatment Given as Single Subcutaneous Injection in Chinese Participants With Elevated Low-density Lipoprotein Cholesterol (LDL-C) Despite Treatment With LDL-C Lowering Therapies (ORION-14)

Conditions
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Hyperlipidemia

Intervention / Treatment
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* Drug: 100 mg inclisiran sodium (equivalent to 94.5 mg inclisiran)
* Drug: Placebo
* Drug: 300 mg inclisiran sodium (equivalent to 284 mg inclisiran)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent must be obtained before any assessment is performed. Male or female participants ≥ 18 years of age at screening Participants should meet fasting serum LDL-C ≥ 100 mg/dL (≥ 2.6 mmol/L) at screening Participants should meet fasting triglyceride < 400 mg/dL (< 4.52 mmol/L) at screening Participants should be receiving a maximally tolerated dose of statin#. For all participants, all the lipid-lowering therapy/ies (such as but not limited to statins and/or ezetimibe) should have remained stable (stable dose and no medication change) for ≥ 30 days before screening with no planned medication or dose change during study participation. #Maximum tolerated dose was defined as the maximum dose of statin that could be taken on a regular basis without intolerable AEs. Participants not receiving statin must have a documented evidence of intolerance to all doses of at least 2 different statins (or the corresponding local definition of complete intolerance to statins) Exclusion Criteria: Participants diagnosed with any of following: homozygous familial hypercholesterolemia, New York Heart Association class III & IV heart failure, Type 2 diabetes, severe hypertension, active liver disease, HIV infection or any uncontrolled or serious disease; History of drug abuse or unhealthy alcohol use, malignancy of any organ system, or or allergy to the investigational compound/compound class; Major adverse cardiovascular event within 3 months prior to randomization; Calculated glomerular filtration rate ≤30 mL/min by estimated glomerular filtration rate (eGFR) using standardized clinical methodology; Use of other investigational drugs or planned use of other investigational products or devices; Women of child-bearing potential unless they are using basic methods of contraception during dosing of investigational drug (total abstinence, sterilization, barrier methods, hormonal contraception, intrauterine device); Treatment with monoclonal antibodies inhibiting PCSK9 within 90 days prior to screening. Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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
Interventional Model Description: This is a placebo-controlled study of inclisiran sodium given as a single subcutaneous injection of either 100 mg and 300 mg.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 300 mg inclisiran sodium (equivalent to 284 mg inclisiran)<br>300 mg inclisiran sodium (equivalent to 284 mg inclisiran) x 1 dose (n=15) at Day 1 | Drug: 300 mg inclisiran sodium (equivalent to 284 mg inclisiran)<br>* 300 mg inclisiran sodium (equivalent to 284 mg inclisiran) in 1.5 mL solution. Subcutaneous administration at Day 1<br>* Other names: KJX839;|
| Experimental: 100 mg inclisiran sodium (equivalent to 94.5 mg inclisiran)<br>100 mg inclisiran sodium (equivalent to 94.5 mg inclisiran) x 1 dose (n=15) at Day 1 | Drug: 100 mg inclisiran sodium (equivalent to 94.5 mg inclisiran)<br>* 100 mg inclisiran sodium (equivalent to 94.5 mg inclisiran) in 0.5 mL solution. Subcutaneous administration at Day 1<br>* Other names: KJX839;|
| Placebo Comparator: Placebo<br>Placebo x 1 dose (n=10) at Day 1 | Drug: Placebo<br>* Inclisiran sodium 0mg (equivalent to inclisiran 0 mg) in 1.5 mL solution. Subcutaneous administration at Day 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK parameters (Cmax) maximum peak observed plasma inclisiran concentration in treated participants | Pharmacokinetics parameters of inclisiran | 0-48 hours post-dose | 
| PK parameters (Tmax) time to reach maximum peak plasma inclisiran concentration in treated participants | Pharmacokinetics parameters of inclisiran | 0-48 hours post-dose | 
| PK parameters (T1/2) the elimination half-life associated with the terminal slope of a semi-logarithmic concentration-time curve in inclisiran treated participants | Pharmacokinetics parameters of inclisiran | 0-48 hours post-dose | 
| PK parameters (AUC) area under the plasma concentration-time curve in inclisiran treated participants | Pharmacokinetics parameters of inclisiran | 0-48 hours post-dose | 
| Percentage change in Proprotein convertase subtilisin kexin 9 (PCSK9) from baseline overtime | Pharmacodynamics effects of inclisiran | Baseline to Days 5, 8, 15, 30, 60 and 90 | 
| Percentage change in Low density lipoprotein cholesterol (LDL-C) from baseline overtime | Pharmacodynamics effects of inclisiran | Baseline to Days 5, 8, 15, 30, 60 and 90 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change from baseline to Days 30, 60 and 90 in PD parameter Proprotein convertase subtilisin kexin 9 (PCSK9) | Pharmacodynamics differences between inclisiran and placebo | Baseline to Days 30, 60 and 90 | 
| Percent change from baseline to Days 30, 60 and 90 in PD parameter Low density lipoprotein cholesterol (LDL-C) | Pharmacodynamics differences between inclisiran and placebo | Baseline to Days 30, 60 and 90 | 
| Rate of formation of anti-drug antibodies to Inclisiran | Immunogenicity of inclisiran | Baseline, Days 30 and 90 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inclisiran, KJX839, LDL-C, Pharmacokinetics and pharmacodynamics, Chinese participants with elevated serum LDL-C