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30 January 2020EMA/CHMP/86202/2020Committee for Medicinal Products for Human Use (CHMP)Assessment reportNilemdoInternational non-proprietary name: bempedoic acidProcedure No. EMEA/H/C/004958/0000NoteAssessment report as adopted by the CHMP with all information of a commercially confidentialnature deleted.Official address Domenico Scarlattilaan 6 1083 HS Amsterdam The NetherlandsAddress for visits and deliveries Refer to www.ema.europa.eu/how-to-find-usSend us a question Go to www.ema.europa.eu/contactTelephone 31 (0)88 781 6000An agency of the European Union European Medicines Agency, 2020. Reproduction is authorised provided the source is acknowledged.

Administrative informationName of the medicinal product:NilemdoApplicant:FGK Representative Service GmbHHeimeranstrasse 3580339 MunchenGERMANYActive substance:BEMPEDOIC ACIDInternational Non-proprietarybempedoic acidName/Common Name:Pharmaco-therapeutic groupLipid modifying agents, other lipid modifying agents(ATC Code):(C10AX15)Therapeutic indication(s):Nilemdo is indicated in adults with primaryhypercholesterolaemia (heterozygous familial andnon-familial) or mixed dyslipidaemia, as an adjunct todiet: in combination with a statin or statin with otherlipid lowering therapies in patients unable to reachLDL-C goals with the maximum tolerated dose of astatin (see sections 4.2, 4.3, and 4.4) or, alone or in combination with other lipid-loweringtherapies in patients who are statin-intolerant, orfor whom a statin is contraindicated.Pharmaceutical form(s):Film-coated tabletStrength(s):180 mgRoute(s) of administration:Oral usePackaging:blister (PVC/alu)Package size(s):10 tablets, 28 tablets, 30 tablets, 90 tablets, 98tablets and 100 tabletsAssessment reportEMA/CHMP/86202/2020Page 2/154

Table of contents1. Background information on the procedure . 81.1. Submission of the dossier . 81.2. Steps taken for the assessment of the product . 92. Scientific discussion . 102.1. Problem statement . 102.1.1. Disease or condition . 102.1.2. Epidemiology and risk factors, screening tools/prevention . 102.1.3. Biologic features. Aetiology and pathogenesis. . 122.1.4. Clinical presentation, diagnosis, prognosis . 122.1.5. Management . 132.2. Quality aspects . 162.2.1. Introduction . 162.2.2. Active Substance . 162.2.3. Finished Medicinal Product . 192.2.4. Discussion on chemical, pharmaceutical and biological aspects . 212.2.5. Conclusions on the chemical, pharmaceutical and biological aspects . 222.2.6. Recommendation(s) for future quality development . 222.3. Non-clinical aspects . 222.3.1. Introduction . 222.3.2. Pharmacology . 222.3.3. Pharmacokinetics. 272.3.4. Toxicology . 302.3.5. Ecotoxicity/environmental risk assessment . 362.3.6. Discussion on non-clinical aspects. 362.3.7. Conclusion on the non-clinical aspects . 372.4. Clinical aspects . 372.4.1. Introduction . 372.4.2. Pharmacokinetics. 412.4.3. Pharmacodynamics . 482.4.4. Discussion on clinical pharmacology . 522.4.5. Conclusions on clinical pharmacology . 562.5. Clinical efficacy . 562.5.1. Dose response studies. 562.5.2. Main studies . 622.5.3. Discussion on clinical efficacy . 962.5.4. Conclusions on the clinical efficacy . 1012.6. Clinical safety . 1022.6.1. Discussion on clinical safety . 1292.6.2. Conclusions on the clinical safety . 1342.7. Risk Management Plan . 1352.8. Pharmacovigilance . 1382.9. New Active Substance . 1382.10. Product information . 139Assessment reportEMA/CHMP/86202/2020Page 3/154

2.10.1. User consultation . 1392.10.2. Additional monitoring . 1393. Benefit-Risk Balance. 1403.1. Therapeutic Context . 1403.1.1. Disease or condition. 1403.1.2. Available therapies and unmet medical need . 1413.1.3. Main clinical studies . 1413.2. Favourable effects . 1423.3. Uncertainties and limitations about favourable effects . 1433.4. Unfavourable effects . 1443.5. Uncertainties and limitations about unfavourable effects . 1453.6. Effects Table . 1483.6.1. Benefit-risk assessment and discussion . 1503.6.2. Importance of favourable and unfavourable effects . 1503.6.3. Balance of benefits and risks . 1513.6.4. Additional considerations on the benefit-risk balance . 1533.7. Conclusions . 1534. Recommendations . 153Assessment reportEMA/CHMP/86202/2020Page 4/154

List of abbreviationsAbbreviationDefinitionACCAmerican College of CardiologyACLAdenosine triphosphate citrate lyaseACSVL1Very long-chain acyl-CoA synthetase 1AHAAmerican Heart AssociationALTAlanine aminotransferaseANCOVAAnalysis of covarianceapo BApolipoprotein BASCVDAtherosclerotic cardiovascular diseaseASTAspartate aminotransferase increasedAUCArea under the curveBMIBody mass indexBCSBiopharmaceutics Classification SystemBUNBlood urea nitrogenBfArMBundesinstitut für Arzneimittel und MedizinprodukteCETPCholesteryl ester transfer proteinCHDCoronary heart diseaseCKCreatine kinaseCoACoenzyme ACmaxmaximum plasma concentrationCVCardiovascularCVDCardiovascular diseaseCVOTCardiovascular outcome(s) trialCYPCytochrome P450DMEPDivision of Metabolism and Endocrinology ProductseCTDElectronic common technical documentEASEuropean Atherosclerosis SocietyeGFREstimated glomerular filtration rateEMAEuropean Medicines AgencyEOP2End of Phase 2ESCEuropean Society of CardiologyESP15228Active Phase 1 metabolite of ETC-1002ESP15228-glucuronideInactive acyl glucuronide metabolite of ESP15228ETC-1002Analyte of bempedoic acid measured in plasma, urine, or fecesEUEuropean UnionFASFull analysis setFDAFood and Drug AdministrationFCMPFixed combination medicinal productAssessment reportEMA/CHMP/86202/2020Page 5/154

AbbreviationDefinitionFHFamilial hypercholesterolemiaHbA1cHemoglobin A1cHeFHHeterozygous familial hypercholesterolemiahERGHuman ether-à-go-go-related geneHMG-CoA3-hydroxy-3-methyl-glutaryl-coenzyme AhsCRPHigh-sensitivity C-reactive proteinICHInternational Council for HarmonisationIMPInvestigational medicinal productINDInvestigational new drugIRImmediate releaseIVRSInteractive voice response systemLC-MS/MSLiquid chromatography tandem mass spectrometryLDLLow-density lipoproteinLDL-CLow-density lipoprotein cholesterolLDL-RLow-density lipoprotein receptorLLNLower limit of normalLMTLipid-modifying therapyLSLeast squareMAAMarketing Authorisation ApplicationMACEMajor adverse cardiovascular eventsMDRDModification of Diet in Renal DiseaseMEBMedicines Evaluation BoardMHRAMedicines and Healthcare products Regulatory AgencyNDANew drug applicationnon-HDL-CNon-high density lipoprotein cholesterolNIHNational Institutes of HealthNOAELNo-observed-adverse-effect levelNPC1L1Niemann-Pick C1-Like 1OATOrganic anion transporterOLEOpen-label extensionPCSK9Proprotein convertase subtilisin/kexin type 9PDPharmacodynamic(s)PIPPediatric Investigational PlanPKPharmacokinetic(s)POPPKPopulation pharmacokineticQDOnce dailySAPStatistical analysis planSAWPScientific Advice Working PartySDStandard deviationAssessment reportEMA/CHMP/86202/2020Page 6/154

AbbreviationDefinitionSMQStandard Medical QuerySOCSystem Organ ClasstmaxTime to maximum observed plasma concentrationTCTotal cholesterolUGTIridine 5' diphospho-glucuronosyltransferaseULNUpper limit of normalUSUnited StatesVLDLVery-low density lipoproteinWHOWorld Health OrganizationAssessment reportEMA/CHMP/86202/2020Page 7/154

1. Background information on the procedure1.1. Submission of the dossierThe applicant FGK Representative Service GmbH submitted on 12 February 2019 an application formarketing authorisation to the European Medicines Agency (EMA) for Nilemdo, through the centralisedprocedure under Article 3 (2) (a) of Regulation (EC) No 726/2004. The eligibility to the centralisedprocedure was agreed upon by the EMA/CHMP on 14 December 2017.The applicant applied for the following indication:Nilemdo is indicated in adults with primary hypercholesterolaemia (heterozygous familial andnon-familial) or mixed dyslipidaemia, as an adjunct to diet: in combination with a statin or statin with other lipid lowering therapies in patients unable toreach LDL-C goals with the maximum tolerated dose of a statin or, alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant,or for whom a statin is contraindicated.The effect of Nilemdo on cardiovascular morbidity and mortality has not yet been determined.The legal basis for this application refers to:Article 8.3 of Directive 2001/83/EC - complete and independent applicationThe application submitted iscomposed of administrative information, complete quality data, non-clinical and clinical data based onapplicants’ own tests and studies and/or bibliographic literature substituting/supporting certain test(s)or study(ies).Information on Paediatric requirementsPursuant to Article 7 of Regulation (EC) No 1901/2006, the application included an EMA Decision(s)P/0185/2018 on the agreement of a paediatric investigation plan (PIP).At the time of submission of the application, the PIP P/0185/2018 was not yet completed as somemeasures were deferred.Information relating to orphan market exclusivitySimilarityPursuant to Article 8 of Regulation (EC) No. 141/2000 and Article 3 of Commission Regulation (EC) No847/2000, the applicant did not submit a critical report addressing the possible similarity withauthorised orphan medicinal products because there is no authorised orphan medicinal product for acondition related to the proposed indicatio

Human ether-à-go-go-related gene . HMG-CoA : 3-hydroxy-3-methyl-glutaryl-coenzyme A . hsCRP : High-sensitivity C-reactive protein . ICH : International Council for Harmonisation IMP . Investigational medicinal product : IND . Investigational new drug : IR . Immediate release : IVRS . Interactive voice response system : LC-MS/MS . Liquid chromatography tandem mass spectrometry : LDL . Low .