Study of Efficacy, Safety, Tolerability and Quality of Life of Inclisiran (KJX839) vs Placebo, on Top of Ongoing Individually Optimized Lipid-lowering Therapy, in Participants With Hypercholesterolemia

Key Inclusion Criteria:

Participants eligible for inclusion in this study must meet all of the following criteria:

1. Written informed consent must be obtained before any assessment is performed.

2. Male or female participants ≥18 years of age.

3. Participants categorized as very high or high CV risk, as defined below:

•Very high risk participants with at least one of the following: A. DocumentedAtherosclerotic Cardiovascular Disease (ASCVD) i) Acute Coronary Syndrome: Unstableangina or myocardial infarction ii) Stable angina iii) Unequivocally documentedASCVD upon prior imaging v) Stroke and Transient Ischaemic Attack (TIA) vi)Peripheral Artery Disease (PAD) B. Diabetes mellitus (DM) with target organ damage (defined as microalbuminuria, retinopathy, or neuropathy), or at least ≥ 3 majorrisk factors, or early onset of Type 1 DM of long duration (> 20 years) C. Acalculated SCORE2 ≥ 7.5% for age < 50 years; SCORE2 ≥ 10% for age 50-69 years;SCORE2-OP ≥ 15% for age ≥ 70 years to estimate 10-year risk of fatal and non-fatalCVD D. Pre-existing diagnosis of heterozygous familial hypercholesterolemia (HeFH)with ASCVD or with another major risk factor. OR

•High risk participants with at least one of the following: A. Markedly elevatedsingle risk factors, in particular total cholesterol > 310 mg/dL, LDL-C > 190 mg/dL,or blood pressure ≥ 180/110 mmHg B. Pre-existing diagnosis of HeFH without othermajor risk factors C. DM without target organ damage (defined as microalbuminuria,retinopathy, or neuropathy), with DM duration ≥ 10 years or other additional riskfactor D. Moderate chronic kidney disease (eGFR 30-59 mL/min/1.73m2) E. A calculatedSCORE2 2.5 to <7.5% for age under 50 years; SCORE2 5 to <10% for age 50-69 years;SCORE2-OP 7.5 to <15% for age ≥70 years to estimate 10-year risk of fatal andnon-fatal CVD as defined by the cardiovascular risk categories in the 2019 ESC/EASguideline (Mach et al 2020)

4. LDL-C levels:

5. in participants with very high cardiovascular risk: serum LDL-C ≥55 mg/dL

6. in participants with high cardiovascular risk: serum LDL-C ≥70 mg/dL

7. Participant on a stable dose of a statin for ≥ 30 days.

8. Up to approximately 20% of total participants can be on a stable dose (for ≥ 30 daysprior to screening) of another LLT on top of statin such as a cholesterol absorbinginhibitor or a bile acid sequestrant, or alternatively, an adenosine triphosphatecitrate lyase (ACL) inhibitor, as indicated.

9. Fasting triglyceride < 400 mg/dL. At Baseline:

10. Fasting triglyceride < 400 mg/dL.

11. Before randomization, despite being treated with the individual MTD of a statin for ≥ 30 days and, if applicable, with another LLT on top of statin (stable for ≥ 30days),

12. in participants with very high cardiovascular risk: serum LDL-C ≥ 55mg/dL.

13. in participants with high cardiovascular risk: serum LDL-C ≥ 70mg/dL.

Key Exclusion Criteria: Participants meeting any of the following criteria are not eligible for inclusion in this study.

1. Severe concomitant non-CV disease that is expected to reduce life expectancy to lessthan 2 years at screening or baseline visit.

2. Participants on more than one other lipid-lowering drug on top of statin atscreening visit.

3. Pre-existing diagnosis of homozygous familial hypercholesterolemia at screening orbaseline visit.

4. Secondary hypercholesterolemia, e.g. hypothyroidism or nephrotic syndrome atscreening or baseline visit.

5. Previous (within 90 days of screening), current or planned treatment with amonoclonal antibody (mAb) directed towards PCSK9 (e.g. evolocumab, alirocumab) atscreening or baseline visit.

6. Previous exposure to inclisiran or any other non-mAb PCSK9 targeted therapy, eitheras an investigational or marketed drug within 2 years prior to screening or baselinevisit.

7. Previous, current or planned treatment with LDL-apheresis at screening or baselinevisit.

8. Participants with known intolerance to rosuvastatin at screening or baseline visit.

9. History of hypersensitivity to any of the study treatments, inclisiran orrosuvastatin, or its excipients or to drugs of similar chemical classes at screeningor baseline visit.

10. Participants taking gemfibrozil at screening or baseline visit.

11. Liver and CK: (a) Active liver disease defined as any current infectious,neoplastic, or metabolic pathology of the liver or (b) unexplained alanineaminotransferase (ALT), aspartate aminotransferase (AST) elevation >3x ULN, or totalbilirubin elevation > 2x ULN (except for participants with Gilbert's syndrome), or (c) creatine kinase (CK) >5x ULN at screening or baseline visit.

12. Participant with severe renal impairment defined by eGFR <30 mL/min/1.73m2 ascalculated by the Modification in Diet in Renal Disease (MDRD) formula at screeningor baseline visit.

13. Acute coronary syndrome, ischemic stroke or TIA, coronary revascularization orperipheral arterial revascularization procedure or amputation due to atheroscleroticdisease < 3 months prior to the screening or baseline visit.

14. Planned or expected cardiac, cerebrovascular or peripheral artery surgery orcoronary revascularization within the study duration.

15. Heart failure New York Heart Association (NYHA) class IV at screening or baselinevisit.

16. History of malignancy that required surgery (excluding local and wide-localexcision), radiation therapy and/or systemic therapy (excluding systemic adjuvanttherapies given to prevent cancer recurrence eg: hormonotherapy for prostate orbreast cancer) during the 3 years prior to screening or baseline visit.

17. Participant with myopathy at screening or baseline visit.

18. Participant receiving concomitant ciclosporin at screening or baseline visit.

19. Participants that are predisposed to the development of renal failure secondary torhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic,endocrine and electrolyte disorders; or uncontrolled seizures).

20. Participants with rare hereditary problems of galactose intolerance, the Lapplactase deficiency or glucose-galactose-malabsorption.

21. Unwillingness or inability (e.g. physical or cognitive) to comply with studyprocedures (including study visits, fasting blood draws and compliance with studytreatment regimens), and medication administration (injections) and schedule.Participant should be able and willing to read, understand and answerquestionnaires.

22. Any surgical or medical condition, which in the opinion of the investigator, mayplace the participant at higher risk from his/her participation in the study, or islikely to prevent the participant from complying with the requirements of the studyor completing the study at screening or baseline visit.

23. Use of other investigational drugs within 5 half-lives, 30 days or until theexpected pharmacodynamic effect has returned to baseline (e.g. biologics), whicheveris longer or longer if required by local regulation, prior to screening visit.

24. Pregnant or nursing (lactating) women at screening or baseline visit.

25. Women of child-bearing potential, defined as all women physiologically capable ofbecoming pregnant, unless they are using highly effective methods of contraceptionwhile taking study treatment, which includes rosuvastatin, and for 5 days (= 5 timesthe terminal half-life of rosuvastatin) after stopping medication. Highly effectivecontraception methods include:

• Total abstinence (when this is in line with the preferred and usual lifestyleof the participant. Periodic abstinence (e.g. calendar, ovulation,symptothermal, post-ovulation methods) and withdrawal are not acceptablemethods of contraception.

• Female sterilization (have had surgical bilateral oophorectomy with or withouthysterectomy), total hysterectomy, or bilateral tubal ligation at least sixweeks before taking study treatment. In case of oophorectomy alone, only whenthe reproductive status of the woman has been confirmed by follow up hormonelevel assessment.

• Male sterilization (at least 6 months prior to screening). For femaleparticipants on the study, the vasectomized male partner should be the solepartner for that participant.

• Use of oral, (estrogen and progesterone), injected, or implanted hormonalmethods of contraception or placement of an intrauterine device (IUD) orintrauterine system (IUS), or other forms of hormonal contraception that havecomparable efficacy (failure rate < 1%), for example hormone vaginal ring ortransdermal hormone contraception.

In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.

Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate history of vasomotor symptoms). Women are considered not of child bearing potential if they are post-menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessments and she is considered not of child bearing potential.

If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the local ICF.