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Assessment Report 21 November 2013 EMA/CHMP/688774/2013 Committee for Medicinal Products for Human Use (CHMP) Assessment report Sovaldi International non-proprietary name: sofosbuvir Procedure No. EMEA/H/C/002798/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7455 E-mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2014. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure ............................................ 7 1.1. Submission of the dossier .................................................................................... 7 1.2. Manufacturers .................................................................................................... 8 1.3. Steps taken for the assessment of the product ....................................................... 8 2. Scientific discussion .............................................................................. 9 2.1. Introduction ....................................................................................................... 9 2.2. Quality aspects ................................................................................................ 14 2.2.1. Introduction .................................................................................................. 14 2.2.2. Active Substance ........................................................................................... 14 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(s) for future quality development ........................................... 19 2.3. Non-clinical aspects .......................................................................................... 19 2.3.1. Introduction .................................................................................................. 19 2.3.2. Pharmacology ............................................................................................... 20 2.3.3. Pharmacokinetics ........................................................................................... 21 2.3.4. Toxicology .................................................................................................... 23 2.3.5. Ecotoxicity/environmental risk assessment ....................................................... 29 2.3.6. Discussion on non-clinical aspects .................................................................... 31 2.3.7. Conclusion on the non-clinical aspects .............................................................. 32 2.4. Clinical aspects ................................................................................................ 32 2.4.1. Introduction .................................................................................................. 32 2.4.2. Pharmacokinetics ........................................................................................... 36 2.4.3. Pharmacodynamics ........................................................................................ 40 2.4.4. Discussion on clinical pharmacology ................................................................. 43 2.4.5. Conclusions on clinical pharmacology ............................................................... 43 2.5. Clinical efficacy ................................................................................................ 44 2.5.1. Dose response studies .................................................................................... 45 2.5.2. Main studies.................................................................................................. 47 2.5.3. Discussion on clinical efficacy .......................................................................... 73 2.5.4. Conclusions on the clinical efficacy ................................................................... 80 2.6. Clinical safety .................................................................................................. 80 2.6.1. Discussion on clinical safety ............................................................................ 90 2.6.2. Conclusions on the clinical safety ..................................................................... 91 2.7. Pharmacovigilance ............................................................................................ 91 2.8. Risk Management Plan ...................................................................................... 91 2.9. User consultation ............................................................................................. 96 Assessment report EMA/CHMP/688774/2013 Page 2/100 3. Benefit-Risk Balance ........................................................................... 97 4. Recommendations ............................................................................. 100 Assessment report EMA/CHMP/688774/2013 Page 3/100 List of abbreviations 3TC lamivudine [xxC]- radiolabeled carbon xx AE adverse event ALT alanine aminotransferase ARV antiretroviral AST aspartate aminotransferase ATV atazanavir AUC area under the concentration-time curve BCS biopharmaceutics classification system BMI body mass index BMS Bristol-Myers Squibb CatA cathepsin A CES carboxyl esterase 1 CHC chronic hepatitis C CHMP Committee for Medicinal Products for Human Use CI confidence interval CL/F apparent oral clearance after administration of the dose Cmax maximum observed concentration CsA cyclosporine (cyclosporin A) CYP cytochrome P450 enzyme(s) DAA direct-acting antiviral DDI drug-drug interaction DRV Darunavir DSC differential scanning calorimetry EC European Commission ECxx concentration of a compound inhibiting virus replication by xx% EFV efavirenz eGFR estimated glomerular filtration rate eRVR extended rapid virologic response ESRD end-stage renal disease EU European Union FTC Emtricitabine GC gas chromatography GD gestation day GLP Good Laboratory Practice GMP Good Manufacturing Practice GVS gravimetric vapour sorption HCC hepatocellular carcinoma HCV hepatitis C virus HDPE high density polyethylene Assessment report EMA/CHMP/688774/2013 Page 4/100 HIV, HIV-1 human immunodeficiency virus, type 1 HPLC high performance liquid chromatography ICxx concentration that results in xx% inhibition ICH International Conference on Harmonization (of Technical Requirements for Registration of Pharmaceuticals for Human Use) ICP inductively coupled plasma IL28B Interleukin 28B gene IR infra-red IWRS interactive web response system LDV ledipasvir (GS-5885) LLOQ lower limit of quantitation LOD lower limit of detection MAH marketing authorization holder MedDRA Medical Dictionary for Regulatory Activities N or n number of subjects in a population (N) or subset (n) NIAID National Institute of Allergy and Infectious Diseases NMR nuclear magnetic resonance NMT not more than NOAEL no observed adverse effect level NOR normal operating range NS (3/4A/5A/5B) nonstructural protein (3/4A/5A/5B) NtA Notice to Applicants PD pharmacodynamic(s) PEG pegylated interferon (peginterferon) Pgp p-glycoprotein Ph. Eur. European Pharmacopoeia PK pharmacokinetic(s) pTVR posttransplant virologic response 12 weeks after liver transplant q.d. quaque die (daily) QbD Quality by Design QT electrocardiographic interval between the beginning of the Q wave and termination of the T wave, representing the time for both ventricular depolarisation and repolarisation to occur QTc QT interval corrected for heart rate QTcF QT interval corrected for heart rate using the Fridericia formula /r boosted with ritonavir RAL raltegravir RAP resistance analysis population RBV ribavirin RH relative humidity RNA ribonucleic acid RPV rilpivirine RTV ritonavir SAE serious adverse event Assessment report EMA/CHMP/688774/2013 Page 5/100 SmPC summary of product characteristics SOF sofosbuvir (GS-7977; formerly PSI-7977) SVR, SVRxx sustained virologic response, sustained virologic response at “xx” weeks following completion of all treatment TDF tenofovir disoproxil fumarate TND target not detected TTC threshold of toxicological concern ULN upper limit of the normal range US United States UV ultra-violet Assessment report EMA/CHMP/688774/2013 Page 6/100 1. Background information on the procedure 1.1. Submission of the dossier The applicant Gilead Sciences International Ltd submitted on 19 April 2013 an application for Marketing Authorisation to the European Medicines Agency (EMA) for Sovaldi, through the centralised procedure falling within the Article 3(1) and point 3 of Annex of Regulation (EC) No 726/2004. The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 20 September 2012. The applicant applied for the following indication: Sovaldi is indicated in combination with other agents for the treatment of chronic hepatitis C (CHC) in adults. The legal basis for this application refers to: Article 8.3 of Directive 2001/83/EC - complete and independent application. The applicant indicated that sofosbuvir was considered to be a new active substance. The application submitted is composed of administrative information, complete quality data, non-clinical and clinical data based
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