Trial to Assess the Effect of Long Term Dosing of Inclisiran in Subjects With High CV Risk and Elevated LDL-C

The purpose of this extension study was to evaluate the efficacy, safety, and tolerability of long-term dosing of Inclisiran. The study was a global multicenter study.

This study was an open label, long term extension study in subjects with atherosclerotic cardiovascular disease (ASCVD), ASCVD-risk equivalents (eg, diabetes and familial hypercholesterolemia), or heterozygous familial hypercholesterolemia (HeFH) and elevated low density lipoprotein cholesterol (LDL-C) despite maximum tolerated dose of LDL-C lowering therapies who have completed the inclisiran Phase II trial MDCO-PCS-16-01 (ORION-3; NCT03060577), or any of the following Phase III lipid lowering studies: MDCO-PCS-17-03 (ORION-9; NCT03397121), MDCO-PCS-17-04 (ORION-10; NCT03399370), or MDCO-PCS-17-08 (ORION-11; NCT03400800).

The End of Study (EOS) visit in the previous feeder studies was Day 1 in this extension study.The duration that each subject participated in this study was a maximum of 3 years. However, for subjects from the Study ORION-3, the Sponsor decided to end the study prior to completion of their full 3-year of participation. It is recorded in the database as discontinuation was due to Sponsor's decision.

In this Phase III extension study, the same study drug of inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) was administered as a single subcutaneous (SC) dose every 180 days from the last dose in previous feeder study (except for subjects newly initiating inclisiran, who received the first two doses 90 days apart) until the end of the study.

On Day 1 (EOS visit in the feeder study), subjects from the previous feeder studies received blinded study medication except subjects from Study ORION-3. Subjects who received placebo in the previous Phase III feeder study received blinded inclisiran and subjects who received inclisiran in the previous feeder study received blinded placebo at this visit, so that subjects previously on placebo received the correct dosing regime, i.e. a dose at Day 1, Day 90 and every 180-days thereafter. Subjects previously treated with inclisiran did not need a dose of inclisiran to maintain every 180-dosing regime and therefore, were given placebo in order to maintain the blinding of the feeder study. Subjects that moved over from ORION-3 received the first study medication at Day 90, as this study was already open-label.

On Day 90, all subjects received inclisiran sodium 300 mg. This is 180 days after the last injection in the previous feeder study for subjects that received inclisiran and was the second dose of inclisiran for the subjects that received placebo in the feeder study. The EOS visit occurred at Day 1080.

This extension study allowed subjects continued access to inclisiran treatment and allowed the collection of additional efficacy and safety data for long-term use beyond the end of the feeder studies.

Eligibility Criteria:
Inclusion Criteria:

1. Completion on a previously qualifying inclisiran Phase II trial MDCO-PCS-16-01 (ORION-3), or Phase III lipid lowering ORION feeder study \[MDCO-PCS-17-03 (ORION-9), MDCO-PCS-17-4 (ORION-10), or MDCO-PCS-17-08 (ORION-11)\] meaning the subject received the last dose of study drug and completed the final study visit per applicable protocol.
2. On current lipid-lowering therapies (such as a statin and/or ezetimibe) from previous study with no planned medication or dose change during study participation.
3. Willing and able to give informed consent before initiation of any study-related procedures and willing to comply with all required study procedures.

Exclusion Criteria:

1. Any uncontrolled or serious disease, or any medical or surgical condition, that may either interfere with participation in the clinical study, and/or put the subject at significant risk \[according to investigator's (or delegate's) judgment\] if he/she participates in the clinical study.
2. An underlying known disease, or surgical, physical, or medical condition that, in the opinion of the investigator (or delegate) might interfere with interpretation of the clinical study results.
3. Severe concomitant noncardiovascular disease that carries the risk of reducing life expectancy to less than 3 years,
4. Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver or unexplained alanine aminotransferase (ALT), aspartate aminotransferase (AST), elevation \>3x the upper limit of normal (ULN), or total bilirubin (TBIL) elevation \>2x ULN at the last recorded visit in the feeder study prior to study entry visit.
5. Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least one method of acceptable effective contraception (eg, oral contraceptives, barrier methods, approved contraceptive implant, long-term injectable contraception, intrauterine device) for the entire duration of the study. Exemptions from this criterion:

   1. Women \>2 years postmenopausal (defined as 1 year or longer since last menstrual period) and more than 55 years of age.
   2. Postmenopausal women (as defined above) and less than 55 years of age with a negative pregnancy test within 24 hours of randomization.
   3. Women who are surgically sterilized at least 3 months prior to enrollment.
6. Planned use of other investigational medicinal products other than inclisiran or devices during the course of the study.
7. Any condition that according to the investigator could interfere with the conduct of the study, such as but not limited to:

   1. Subjects who are unable to communicate or to cooperate with the investigator
   2. Unable to understand the protocol requirements, instructions and study-related restrictions, the nature, scope, and possible consequences of the study (including subjects whose cooperation is doubtful due to drug abuse or alcohol dependency)
   3. Unlikely to comply with the protocol requirements, instructions, and study-related restrictions (eg, uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study)
   4. Have any medical or surgical condition, which in the opinion of the investigator would put the subject at increased risk from participating in the study
   5. Persons directly involved in the conduct of the study.

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.