22 June 2017 EMA/449689/2017 Committee for Medicinal Products for Human Use (CHMP) Assessment report Maviret International non-proprietary name: glecaprevir / pibrentasvir Procedure No. EMEA/H/C/004430/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2017. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 6 1.1. Submission of the dossier ...................................................................................... 6 1.2. Steps taken for the assessment of the product ......................................................... 7 2. Scientific discussion ................................................................................ 8 2.1. Problem statement ............................................................................................... 8 2.1.1. Disease or condition ........................................................................................... 8 2.1.2. Epidemiology .................................................................................................... 8 2.1.3. Aetiology and pathogenesis ................................................................................ 8 2.1.4. Clinical presentation ........................................................................................... 9 2.1.5. Management ..................................................................................................... 9 2.2. Quality aspects .................................................................................................. 10 2.2.1. Introduction .................................................................................................... 10 2.2.2. Active Substance ............................................................................................. 10 2.2.3. Finished Medicinal Product ................................................................................ 16 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 19 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 19 2.2.6. Recommendation for future quality development ................................................. 19 2.3. Non-clinical aspects ............................................................................................ 20 2.3.1. Introduction .................................................................................................... 20 2.3.2. Pharmacology ................................................................................................. 20 2.3.3. Pharmacokinetics............................................................................................. 21 2.3.4. Toxicology ...................................................................................................... 22 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 26 2.3.6. Discussion on non-clinical aspects...................................................................... 30 2.3.7. Conclusion on the non-clinical aspects ................................................................ 32 2.4. Clinical aspects .................................................................................................. 32 2.4.1. Introduction .................................................................................................... 32 2.4.2. Pharmacokinetics............................................................................................. 33 2.4.3. Pharmacodynamics .......................................................................................... 51 2.4.4. Discussion and conclusion on clinical pharmacology ............................................. 60 2.5. Clinical efficacy .................................................................................................. 64 2.5.1. Dose response studies...................................................................................... 64 2.5.2. Main studies ................................................................................................... 66 Summary of main efficacy results ............................................................. 86 2.5.3. Discussion on clinical efficacy .......................................................................... 100 2.5.4. Conclusions on clinical efficacy ........................................................................ 103 2.6. Clinical safety .................................................................................................. 103 2.6.1. Discussion on clinical safety ............................................................................ 111 2.6.2. Conclusions on the clinical safety ..................................................................... 112 2.7. Risk Management Plan ...................................................................................... 113 2.8. Pharmacovigilance ............................................................................................ 116 2.9. New Active Substances ..................................................................................... 116 2.10. Product information ........................................................................................ 117 Assessment report EMA/449689/2017 Page 2/126 2.10.1. User consultation ......................................................................................... 117 2.10.2. Additional monitoring ................................................................................... 117 3. Benefit-Risk Balance............................................................................ 117 3.1. Therapeutic Context ......................................................................................... 117 3.1.1. Disease or condition ....................................................................................... 117 3.1.2. Available therapies and unmet medical need ..................................................... 117 3.1.3. Main clinical studies ....................................................................................... 118 3.2. Favourable effects ............................................................................................ 119 3.3. Uncertainties and limitations about favourable effects ........................................... 120 3.4. Unfavourable effects ......................................................................................... 121 3.5. Uncertainties and limitations about unfavourable effects ....................................... 121 3.6. Effects Table .................................................................................................... 122 3.7. Benefit-risk assessment and discussion ............................................................... 123 3.7.1. Importance of favourable and unfavourable effects ............................................ 123 3.7.2. Balance of benefits and risks ........................................................................... 124 3.8. Conclusions ..................................................................................................... 124 4. Recommendations ............................................................................... 125 Assessment report EMA/449689/2017 Page 3/126 List of abbreviations AASLD American Association for the Study of Liver Disease AE adverse event ALT alanine aminotransferase AUC area under the plasma concentration-time curve AUC24 area under the plasma concentration-time curve for the 24-hour dosing interval BCRP breast cancer resistance protein BMI body mass index BOC boceprevir BP baseline polymorphism BSEP bile salt export pump CHMP Committee for Medicinal Products for Human Use CI confidence interval CKD chronic kidney disease Cmax maximum plasma concentration Cmin minimum plasma concentration C-P Child-Pugh CV coefficient of variation CYP cytochrome P450 DAA direct-acting antiviral agent DCV daclatasvir DDI drug-drug interaction DSV dasabuvir eGFR estimated glomerular filtration rate EASL European Association for Study of Liver ELB elbasvir ESRD end-stage renal disease fe fraction of dose eliminated in the urine FDC fixed dose combination GLE glecaprevir GT genotype GZV grazoprevir HBV hepatitis B virus HCC hepatocellular carcinoma HCV hepatitis C virus HIV-1 human immunodeficiency virus-1 HV healthy volunteers ICH International Council for Harmonisation IFN interferon IRR Integrated Resistance Report ITT intention-to-treat IVIVC in vitro and in vivo correlation LDV ledipasvir Max maximum Min minimum mITT-VF modified intention-to-treat population excluding subjects who did not achieve SVR12 due to nonvirologic reasons N/A not applicable NPRS TN subjects + P/R- or SOF/R-experienced subjects NS3 nonstructural viral protein 3 NS3/4A nonstructural viral protein 3/4A NS5A nonstructural viral protein 5A OATP organic anion transporting polypeptide OBV ombitasvir OTVF on-treatment virologic failure P pegylated interferon or interferon P/R regimens containing interferon, pegylated interferon, and ribavirin pegIFN pegylated interferon P-gp P-glycoprotein Assessment report EMA/449689/2017 Page 4/126