A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia (HoFH)

A Two-Part (Double-Blind Placebo Controlled/Open-Label) Multicenter Study to Evaluate Safety, Tolerability, and Efficacy of Inclisiran in Subjects With Homozygous Familial Hypercholesterolemia (Hofh) (ORION-5)

This study was a Phase III,A two-part (double-blind placebo-controlled/open-label) multicenter study to evaluate safety, tolerability, and efficacy of inclisiran in subjects with homozygous familial hypercholesterolemia (HoFH).

This study had two sequential parts:

• Part 1: 6-month double-blind period in which subjects were randomized to receive either inclisiran or placebo
• Part 2: 18-month open-label follow-up period; placebo-treated subjects from Part 1 were transitioned to inclisiran at Day 180 and all subjects who participated in an open-label follow-up period of inclisiran only

Inclusion Criteria:

1. Diagnosis of HoFH by genetic confirmation or a clinical diagnosis based on a history of an untreated LDL-C concentration >500 mg/dL (13 mmol/L) together with either xanthoma before 10 years of age or evidence of heterozygous familial hypercholesterolemia in both parents
2. Stable on a low-fat diet.
3. Subjects on statins should be receiving a maximally tolerated dose. Maximum tolerated dose is defined as the maximum dose of statin that can be taken on a regular basis without intolerable adverse events.
4. Subjects not receiving statins must have documented evidence of intolerance to at least two different statins.
5. Subjects on lipid-lower therapies (such as statin and/or ezetimibe) should be on a stable dose for ≥30 days before screening with no planned medication or dose change during study participation.
6. Fasting central laboratory LDL-C concentration ≥130 mg/dL (3.4 mmol/L).
7. Triglyceride concentration <400 mg/dL (4.5 mmol/L)
8. No current or planned renal dialysis or renal transplantation
9. Subjects on a documented regimen of LDL or plasma apheresis will be allowed to continue the apheresis during the study, if needed.
10. Subjects must be willing and able to give written informed consent before initiation of any study-related procedures. The subject should be willing to comply with all required study procedures.
11. Willing to follow all study procedures including adherence to dietary guidelines, study visits, fasting blood draws, and compliance with study treatment regimens.

Exclusion Criteria:

1. Use of Mipomersen or Lomitapide therapy within 5 months of screening

2. Treatment (within 90 days of screening) with monoclonal antibodies directed towards PCSK9

3. New York Heart Association (NYHA) class IV heart failure or last known left ventricular ejection fraction <25%

4. Major adverse cardiovascular event within 3 months prior to randomization

5. Planned cardiac surgery or revascularization

6. Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg prior to randomization despite anti-hypertensive therapy

7. 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 ULN, or total bilirubin >2x upper limit of normal (ULN) at screening confirmed by a repeat measurement at least 1 week apart

8. Severe concomitant noncardiovascular disease that carries the risk of reducing life expectancy to less than the duration of the trial

9. History of malignancy that required surgery (excluding local and wide-local excision), radiation therapy and/or commencement of systemic therapy as treatment during the 3 years prior to randomization

10. Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least one acceptable effective method of 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 their 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 enrolment
    3. Women who are surgically sterilized at least 3 months prior to enrolment

11. Known history of alcohol and/or drug abuse within 5 years

12. 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

13. 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] judgment) if he/she participates in the clinical study

14. Any underlying known disease, or surgical, physical, or medical condition that, in the opinion of the Investigator, might interfere with the interpretation of clinical study results

15. Treatment with other investigational medicinal products or devices within 30 days or 5 half-lives of the screening visit, whichever is longer

16. Previous participation in the study

17. Hypersensitivity to any of the ingredients of Inclisiran

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