Leqvio - 5333 - EPAR - Europa

1 Official address Domenico Scarlattilaan 6 1083 HS Amsterdam The Netherlands An agency of the European Union Address for visits and deliveries Refer to Send us a question Go to Telephone +31 (0)88 781 6000 European Medicines Agency, 2021. Reproduction is authorised provided the source is acknowledged. 15 October 2020 EMA/696912/2020 Committee for Medicinal Products for Human Use (CHMP) Assessment report Leqvio International non-proprietary name: inclisiran Procedure No. EMEA/H/C/005333/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. Assessment report EMA/696912/2020 Page 2/143 Administrative information Name of the medicinal product: Leqvio applicant: Novartis Europharm Limited Vista Building Elm Park Merrion Road Dublin 4 IRELAND Active substance: INCLISIRAN International Non-proprietary Name/Common Name: inclisiran Pharmaco-therapeutic group (ATC Code): lipid modifying agents, plain, other lipid modifying agents (C10AX) Therapeutic indication(s): treatment for primary hypercholesterolaemia or mixed dyslipidaemia Pharmaceutical form(s): Solution for injection Strength(s): 284 mg Route(s) of administration: Subcutaneous use Packaging: pre-filled syringe (glass) Package size(s).

2 1 pre-filled syringe Assessment report EMA/696912/2020 Page 3/143 Table of contents 1. Background information on the procedure .. 12 Submission of the dossier .. 12 Steps taken for the assessment of the product .. 13 2. Scientific discussion .. 14 Problem statement .. 14 Disease or condition .. 14 Epidemiology .. 14 Aetiology and pathogenesis .. 15 Clinical presentation .. 15 Management .. 16 Quality aspects .. 17 Introduction .. 17 Active Substance .. 18 General information .. 18 Manufacture, characterisation and process controls .. 20 23 Stability .. 23 Finished Medicinal Product .. 24 Description of the product and Pharmaceutical development .. 24 Manufacture of the product and process controls .. 25 Product specification .. 25 Stability of the product.

3 26 Adventitious agents .. 27 Discussion on chemical, pharmaceutical and biological aspects .. 27 Conclusions on the chemical, pharmaceutical and biological aspects .. 27 Recommendations for future quality 27 Non-clinical aspects .. 28 Introduction .. 28 Pharmacology .. 30 33 Toxicology .. 36 Ecotoxicity/environmental risk assessment .. 42 Discussion on non-clinical 42 Conclusion on the non-clinical aspects .. 43 Clinical aspects .. 43 Introduction .. 43 47 Pharmacodynamics .. 51 Discussion on clinical pharmacology .. 66 Conclusions on clinical pharmacology .. 67 Clinical efficacy .. 68 Dose response 68 Main studies .. 68 Assessment report EMA/696912/2020 Page 4/143 Discussion on clinical efficacy .. 108 Conclusions on the clinical efficacy.

4 112 Clinical safety .. 112 Discussion on clinical safety .. 127 Conclusions on the clinical safety .. 129 Risk Management Plan .. 130 Pharmacovigilance .. 133 New Active Substance .. 133 Product information .. 133 User consultation .. 133 Additional monitoring .. 133 3. Benefit-Risk 134 Therapeutic Context .. 134 Disease or condition .. 134 Available therapies and unmet medical need .. 134 Main clinical studies .. 135 Favourable effects .. 136 Uncertainties and limitations about favourable effects .. 136 Unfavourable effects .. 137 Uncertainties and limitations about unfavourable effects .. 137 Effects Table .. 138 Benefit-risk assessment and discussion .. 140 Importance of favourable and unfavourable effects .. 140 Balance of benefits and risks.

5 141 Conclusions .. 142 4. Recommendations .. 142 Assessment report EMA/696912/2020 Page 5/143 List of abbreviations ACC American College of Cardiology ADA Anti-drug antibodies ADR Adverse drug reaction AE Adverse event Ago2 Argonaute RISC Catalytic Component 2 AHA American Heart Association ALN-PCSSC Inclisiran ALP Alkaline phosphatase ALT Alanine aminotransferase ANCOVA Analysis of covariance Apo-A1 Apolipoprotein A1 ANOVA Analysis of variance Apo-B Apolipoprotein B AS Antisense ASCVD Atherosclerotic cardiovascular disease ASGPR Asialoglycoprotein receptor AST Aspartate aminotransferase AUC Area under curve AUC0-inf Area under the concentration-time curve from time zero to infinity AUC0-24h Area under the curve from time 0 to 24 hours AX-HPLC anion exchange HPLC BL Baseline BMI Body mass index

6 BP Blood Pressure BUN Blood urea nitrogen bw Body weight CHD Coronary Heart Disease CHMP Committee for Medicinal Products for Human Use CI Confidence interval Assessment report EMA/696912/2020 Page 6/143 CIOMS Council for International Organizations of Medical Sciences CL/F Apparent total clearance from plasma CLR Renal clearance Cmax Maximum observed concentration CMQ Custom MedDRA query Cosc Concentration CP Child-Pugh CPG Controlled pore glass CPK Creatine phosphokinase CPP Critical process parameter CQA Critical Quality Attribute CrCl Creatinine clearance CRF Case report form CRP C-reactive protein CS Clinically significant CSR Clinical study report CV Cardiovascular CVA Cerebrovascular accident CVD Cardiovascular disease CV% Coefficient of variation % CYP Cytochrome DBL Database Lock DBP Diastolic blood pressure DDI Drug-drug interaction dL Decilitre DOE Design of experiments EAS European Atherosclerosis Society EC European Commission ECG Electrocardiogram eCRF Electronic case report form EEA European Economic Area eGFR Estimated glomerular filtration rate ELISA Enzyme-linked immunosorbent assay Assessment report EMA/696912/2020 Page 7/143 EMA European Medicines Agency EMSA Electrophoretic mobility shift assay EOS End of study ESC European Society of Cardiology ESRD End-stage renal disease EtO Ethylene oxide EU Endotoxin units EU European Union FAS Full analysis set FBS Foetal bovine serum FDA Food and Drug Administration FIH First in Human FH Familial hypercholesterolaemia Fe Fraction FPFV First Patient

7 First Visit FTIR Fourrier Transform Infrared Spectroscopy GalNAc N-Acetylgalactosamine GAPDH Glyceraldehyde 3-phosphate dehydrogenase GCP Good clinical practices GFR Glomerular filtration rate GLP Good laboratory practices GMP Good manufacturing practices HBA1c Glycated haemoglobin A1c HDL-C High density lipoprotein cholesterol HPDE High Density Polyethylene HeFH Heterozygous familial hypercholesterolaemia HF Hepatic function HI Hepatic impairment HLM Human liver microsomes HoFH Homozygous familial hypercholesterolaemia hPCSK9 Human proprotein convertase subtilisin/kexin type 9 HPLC High performance liquid chromatography HR Heart rate Assessment report EMA/696912/2020 Page 8/143 hsCRP High sensitivity C-reactive protein ICH International Conference on Harmonisation IDMC Independent Data Monitoring Committee IC50 Plasma concentration yielding 50% of maximal inhibition INR International normalised ratio IPRP-HPLC Ion-pair reversed phase HPLC IR Infrared IRB Institutional review board ISAP Integrated Statistical Analysis Plan ISS Integrated Summary of Safety ITT Intent-to-treat ITT Intention to Treat kg Kilogram LC-MS Liquid chromatography mass spectrometry LDL Low-density lipoprotein LDL-C Low-density lipoprotein cholesterol LDLR Low Density Lipoprotein Receptor LLN Lower limit of normal LLOQ Lower limit of quantitation LMT Lipid-modifying therapy Lp(a) Lipoprotein (a)

8 Lp-PLA2 Lipoprotein-associated phospholipase A2 LOESS locally weighted scatterplot smoothing LS Least Squares MAA Marketing authorisation application mAbs Monoclonal Antibodies MACE Major cardiovascular event MAD Multiple ascending dose MAR Missing-at-random MD Multiple-dose MedDRA Medical Dictionary for Regulatory Activities mg Milligram Assessment report EMA/696912/2020 Page 9/143 mL Milliliter MI Myocardial Infarction mITT Modified intent-to-treat mmHg Millilitres of mercury mmol Millimole MMRM Mixed Model for Repeated Measures mRNA Messenger ribonucleic acid MS Mass Spectrometry MTD Maximum tolerated dose MTP inhibitor Microsomal Triglyceride Transfer Protein Inhibitor MNAR Missing Not at Random m2 Meter squared n Number of patients N/A Not applicable NADPH Nicotinamide adenine dinucleotide phosphate NAFLD Non-alcoholic fatty liver disease NASH Non-alcoholic steatohepatitis NCA Non-compartmental analysis NLT Not less than NMR Nuclear Magnetic Resonance NMT Not more than No Number NOD New onset of diabetes Non-HDL-C Non High Density Lipoprotein Cholesterol NQ Not quantifiable ng Nanogram PBS Protein binding system PCS Potentially clinically significant PCSK9 Proprotein convertase subtilisin/kexin type 9 PD Pharmacodynamic PDCO Paediatric committee PFS Pre-filled syringe Assessment report EMA/696912/2020 Page 10/143 Ph.

9 Eur. European pharmacopoeia PI Product information PIP Paediatric investigation plan PK Pharmacokinetic PMM Pattern Mixture Model Pos Positive PP Polypropylene PPQ Process performance qualification PT Preferred term QP Qualified person QTc QT interval corrected QTcF QT interval corrected Fridericia correction QTPP Quality target product profile QWBA Quantitative whole body autoradiography / autoradioluminography REC Recommendation REML Restricted maximum likelihood RISC Ribonucleic acid-induced silencing complex RNA Ribonucleic acid RNAi Ribonucleic acid interference RRT Relative retention time S Sense SAD Single-ascending dose SAE Serious adverse event SBP Systolic blood pressure SC Subcutaneous SAD Single ascending dose SD Standard deviation siRNA Small interfering ribonucleic acid SmPC Summary of product characteristics SMQ Standardised MedDRA query SOC System organ class Statin HMG-CoA (3-hydroxy3-methyl-glutaryl-coenzyme A)

10 Reductase inhibitor TC Total cholesterol Assessment report EMA/696912/2020 Page 11/143 TEAE Treatment-emergent adverse event TESAE Treatment-emergent serious adverse event TG Triglycerides Tmax Time to maximum concentration observed TNF- Tumour necrosis factor-alpha t Elimination half-life UHPLC-TOF-MS ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry ULN Upper limit of normal ULOQ upper limit of quantification US united states USA united states of america USP united states pharmacopoeia UV Ultraviolet Vz/F Volume of distribution WHO World Health Organisation Assessment report EMA/696912/2020 Page 12/143 1. Background information on the procedure Submission of the dossier The applicant Novartis Europharm Limited submitted on 9 January 2020 an application for marketing authorisation to the European Medicines Agency (EMA) for Leqvio , through the centralised procedure under Article 3 (2) (a) of Regulation (EC) No 726/2004.