London, 20 March 2014 EMA/519229/2014 Committee for Medicinal Products for Human Use (CHMP) Withdrawal assessment report Faldaprevir Boehringer Ingelheim International non-proprietary name: Faldaprevir Procedure no. EMEA/H/C/03720 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, 2014. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Recommendations ................................................................................... 4 2. Executive summary ................................................................................. 4 2.1. Problem statement ............................................................................................... 4 2.2. About the product ................................................................................................ 5 2.3. The development programme/compliance with CHMP guidance/scientific advice ........... 5 2.4. General comments on compliance with GMP, GLP, GCP ............................................. 8 2.5. Type of application and other comments on the submitted dossier.............................. 9 3. Scientific overview and discussion .......................................................... 9 3.1. Introduction......................................................................................................... 9 3.2. Quality aspects .................................................................................................... 9 3.3. Non clinical aspects ............................................................................................ 18 3.4. Clinical aspects .................................................................................................. 28 4. Orphan medicinal products .................................................................... 95 5. Benefit risk assessment ......................................................................... 95 5.1. Conclusions ....................................................................................................... 97 Withdrawal assessment report EMA/519229/2014 Page 2/99 List of abbreviations ADME Absorption distribution, metabolism and excretion AE Adverse event ALT Alanine aminotransferase AST Aspartate aminotransferase AUC Area under the curve BD Below detection BLQ Below limit of quantitation BMI Body mass index Cmax Maximum concentration CMH Cochran-Mantel Haenszel DAA Direct-acting antiviral DAVP Division of antiviral products of US FDA DILI Drug-induced liver injury DRESS Drug Reaction with Eosinophilia and Systemic Symptoms DRV Darunavir eGFR eGlomerular filtration rate ETR End of treatment response ETS Early treatment success EVR Early virologic response FAS Full analysis set GMR Geometric mean ratio GT1 Genotype 1 HCV Hepatitis C virus HCV-1 Hepatitis C virus genotype 1 HIV Human immunodeficiency virus IU International unit LD Loading dose LLoQ Lower limit of quantitation LOCF Last observation carried forward LPTCF Last post-treatment value carried forward MedDRA Medical dictionary for drug regulatory affairs NPV Negative predictive value pegIFN Pegylated interferon alfa PfOS Powder for oral solution P-gp P- glycoprotein PI NS3/4A protease inhibitor PPS Per protocol set PPV Positive predictive value QT ECG QT interval RAV Resistance-associated variant RBV Ribavirin RdRp RNA-dependent RNA polymerase RGT Response guided therapy RNA Ribonucleic acid SAE Serious adverse event SCE Summary of clinical efficacy SCS Summary of clinical safety SGC Soft gelatin capsule SMQ Standard MedDRA queries SSC Special search category SVR Sustained virologic response SVR4 Sustained virologic response at 4 weeks after planned cessation of treatment SVR12 Sustained virologic response at 12 weeks after planned cessation of treatment SVR24 Sustained virologic response at 12 weeks after planned cessation of treatment TD Target detected TE Treatment experienced TEN Toxic epidermal necrolysis TN Treatment naïve TND Target not detected VL Viral load Withdrawal assessment report EMA/519229/2014 Page 3/99 1. Recommendations Based on the review of the data on quality, safety and efficacy, the CHMP considers that the application for faldaprevir in the treatment of chronic hepatitis C (CHC) in adults. is not approvable since there are Major Objections on Quality. Details of these Major Objections are in section 6. Briefly, they relate to the following issues: Drug substance: There is inadequate information on the three starting materials (BI 201335 peptide, BI 201335 sulfone and BI 201335 INRF 3 TS) used for the synthesis of faldaprevir. These are complex molecules that contribute significant structural fragments to the final drug substance and they need to be controlled appropriately to ensure consistent quality. Drug product: There are concerns about the changes observed in the dissolution profiles of batches stored under non-refrigerated conditions. The changes are considered to be related to cross linking of the gelatin but a comprehensive evaluation and discussion has not been presented and the data presented are limited. The potential impact of this change on product performance needs to be addressed fully as this may affect the clinical performance of the product. Questions to be posed to additional experts None Inspection issues None New active Substance status Based on the review of the data faldaprevir is to be qualified as a new active substance in itself. See the separate report on NAS status. 2. Executive summary 2.1. Problem statement Hepatitis C virus infection represents a major public health problem because of its potential to lead to serious or life-threatening chronic liver disease. Approximately 130 to 210 million individuals (3% of the world population) are chronically infected with HCV. The prevalence varies markedly from one geographic area to another and within the population assessed. In Western Europe, HCV prevalence ranges from 0.4% to 3%. The prevalence of HCV-related chronic liver disease is increasing, mainly due to the long lag of 20 years or more between initial infection and clinical manifestations of the disease. Six HCV genotypes and a large number of subtypes have been described. They originated from diverse areas in Africa and Asia, and some of them have spread widely throughout the world. Genotype 1 (subtypes 1a and 1b) is by far the most prevalent genotype worldwide, with a higher prevalence of 1b in Europe and 1a in the US. Genotype 3a is highly prevalent in European intravenous drug users. This group is currently experiencing an increasing incidence and prevalence of infections related to HCV Genotype 4. Genotype 2 is found in clusters in the Mediterranean region, while Genotypes 5 and 6 are found more rarely. Withdrawal assessment report EMA/519229/2014 Page 4/99 HCV-associated liver disease progresses over several decades and is accelerated in the presence of cofactors such as alcohol consumption, diabetes mellitus (to which HCV itself appears to predispose), older age at acquisition, human immunodeficiency virus (HIV) co-infection or co-infection with other hepatotropic viruses. Depending on the presence of cofactors, between 10% and 40% of patients with chronic HCV infection will develop cirrhosis. Death related to the complications of cirrhosis may occur at an incidence of approximately 4% per year, whereas hepatocellular carcinoma (HCC) occurs in this population at an estimated incidence of up to 5% per year. Patients diagnosed with HCC have a 33% probability of death during the first year. HCV infection has become the leading cause of primary liver cancers in Europe. Based on models from France to predict death rates due to HCV-related HCC, the peak mortality related for HCV infection is yet to come and currently available therapies are expected to have a modest impact on the mortality rate. These results probably also apply to most other European countries. In the United States the prevalence of HCV infection between the years 1999 and 2002 was 1.6%, approximately equal to 4.1 million persons who are positive for antibody to HCV (anti-HCV), 80% of whom are estimated to be viraemic. Hepatitis C is the principal cause of death from liver disease and the leading indication for liver transplantation in the US. Current medical opinion encourages treatment of HCV infection before cirrhosis and complications of chronic liver disease develop. 2.2. About the product Faldaprevir is an orally bioavailable reversible inhibitor of the hepatitis C NS3/NS4A serine protease, a virally encoded enzyme that is critical for viral replication. Its physical-chemical properties are those of a low molecular weight peptidomimetic with poor aqueous solubility and high protein binding in human plasma. HCV is a 9.6 kilobase single, positive-strand RNA virus and contains a long open reading frame which encodes several structural and non-structural viral proteins. The HCV serine protease is encoded by the NS3/NS4A protein and is essential for the proteolytic cleavage of the HCV translated polyprotein into HCV-specific non-structural enzymes such as the helicase and RNA-dependent RNA polymerase (RdRp) required for viral replication. HCV RdRp lacks a proof-reading function which contributes to the generation of a quasispecies (swarm)