Assessment Report
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26 January 2017 EMA/CHMP/853224/2016 Committee for Medicinal Products for Human Use (CHMP) Assessment report Xeljanz International non-proprietary name: tofacitinib Procedure No. EMEA/H/C/004214/0000 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 5520 Send a question via our website www.ema.europa.eu/contact An agency of the European Union Table of contents 1. Background information on the procedure .............................................. 9 1.1. Submission of the dossier ..................................................................................... 9 1.2. Steps taken for the assessment of the product ...................................................... 10 2. Scientific discussion .............................................................................. 11 2.1. Problem statement ............................................................................................. 11 2.2. Quality aspects .................................................................................................. 16 2.3. Non-clinical aspects ............................................................................................ 24 2.4. Clinical aspects .................................................................................................. 36 2.5. Clinical efficacy .................................................................................................. 51 2.6. Clinical safety .................................................................................................. 108 2.7. Risk Management Plan ...................................................................................... 140 2.8. Pharmacovigilance ........................................................................................... 147 2.9. New Active Substance ...................................................................................... 147 2.10. Product information ........................................................................................ 147 3. Benefit-Risk Balance ........................................................................... 148 3.1. Therapeutic Context ......................................................................................... 148 3.2. Favourable effects ............................................................................................ 149 3.3. Uncertainties and limitations about favourable effects ........................................... 150 3.4. Unfavourable effects ......................................................................................... 150 3.5. Effects Table .................................................................................................... 152 3.6. Benefit-risk assessment and discussion ............................................................... 153 3.7. Conclusions ..................................................................................................... 154 4. Recommendations ............................................................................... 154 Assessment report EMA/CHMP/853224/2016 Page 2/158 List of abbreviations Non Clinical abbreviations ADME Absorption, distribution, metabolism, and excretion AEs Adverse events Ag Antigen AIA Adjuvant induced arthritis ALT Alanine aminotransferase APA Action potential amplitude APD Action potential duration APD50 Action potential duration at 50% repolarization APD90 Action potential duration at 90% repolarization AST Asparate aminotransferase AUC Area under concentration-time curve AUC24 AUC from time 0 to 24 hours postdose AUCt AUC from 0 to time t last postdose BAT Brown adipose tissue BCRP Breast cancer resistant protein BID Twice a day BP Blood pressure bpm Beats per minute BrDU 5-bromo-2’-deoxyuridine BUN Blood urea nitrogen BW Body weight Ca Calcium Cav Average steady state concentration CaMK2α Ca2+/modulin-dependent protein kinase CD16 Cluster of differentiation 16 CD4 Cluster of differentiation 4 CD8 Cluster of differentiation 8 CE Cholesterol ester CHO Chinese hamster ovary CIA Collagen induced arthritis CL Clearance Cmax Maximum (peak) observed drug concentration Cmin Minimum observed concentration CNS Central nervous system CNTF Ciliary neurotrophic factor ConA ConconavalinA CRP C-reactive protein CYP Cytochrome P isoenzyme DA Dopamine agonist DC Dendritic cells DCAMKL3 Doublecortin and CAM kinase-like 3 kinase DDI Drug-drug interaction DEREK Deductive Estimation of Risk from Existing Knowledge DNA Deoxyribonucleic acid DMARD disease-modifying anti-rheumatic drug DMSO Dimethyl sulfoxide E Predicted extraction ratio EBV Epstein Barr Virus ECG Electrocardiogram ED50 Effective dose, median EFD Embryo-fetal development EPO Erythropoietin F Female FACS Flourescent activated cell sorting Assessment report EMA/CHMP/853224/2016 Page 3/158 fu Fraction of drug free (unbound) in serum/plasma GALT Gut associated lymphoid tissue GD Gestation Day GFR Glomerular filtration rate GGT Gamma-glutamyltransferase GLP Good Laboratory Practice G-CSF Granulocyte Colony Stimulating Factor GM-CSF Granulocyte-Macrophage Colony Stimulating Factor HCT Hematocrit HDL High density lipoprotein HEK Human embryonic kidney hERG Human ether- à -go-go related gene HGB Hemoglobin OATP Human organic anion transporting polypepetide OCT2 Human organic cation transporter hPBMCs Human peripheral blood mononuclear cells hWB Human whole blood HU03 Human erythro-leukemia cell line IC50 50% inhibition concentration ICH International Conference on Harmonisation IFNα Interferon alpha IFNγ Interferon gamma Ig Immunoglobulin IHC Immunohistochemistry IL Interleukin IV Intravenous JAK Janus kinase KCl Potassium chloride Ki Inhibition constant KLH Keyhole limpet hemocyanin LC-MS/MS Liquid chromatorgraphy tandem mass spectrometry LCV Lymphocryptovirus LDL Low-density lipoprotein LH Luteinizing hormone LIF Leukemia inhibitory factor LLNA Local lymph node assay LOEL Lowest observed effect level LPS Lipopolysaccharide M Male MAP Mean arterial blood pressure MATE Multidrug and toxic compound extrusion MDCK Madin-Darby canine kidney MDR Multidrug resistance protein MEC Molar extiniction coefficient ML2 Melatonin receptor 2 MMF Mycophenalate MPE Mean photo effect mRNA Messenger RNA MRP Multidrug resistance associated protein MS Mass spectrometry MTD Maximum tolerated dose mWB Mouse whole blood NA Not applicable NADPH Nicotinamide adenine dinucleotide phosphate ND Not determined NE Norepinephrine ng/mL Nanogram/milliliter NK Natural killer nM Nanomolar Assessment report EMA/CHMP/853224/2016 Page 4/158 NOAEL No observed adverse effect level NOEL No observed effect level NRU Neutral red uptake NS No sample OECD Organisation for Economic Cooperation and Development OSM Oncostatin M PBMC Peripheral blood mononuclear cell P-gp P-glycoprotein PIF Photo-irritancy factor PL Plasma lipids PK/PD Pharmacokinetic/Pharmacodynamic PND Post natal day PRL Prolactin PTLD Post-transplant Lymphoproliferative Disorder QD Once a day QOD Every other day QWBA Quantitative whole body autoradioluminography RA Rheumatoid Arthritis RBC Red blood count RCT Reverse cholesterol transport RMP Resting membrane potential SAR Structure activity relationship SC Subcutaneous SCID Severe combined immunodeficiency SI Stimulation index STAT Signal transducer and activator of transcription TC Total cholesterol TCR T-cell receptor TGF Tissue growth factor TID Three times a day TK Toxicokinetic Tmax Time to reach peak concentration following drug administration TNF Tumor necrosis factor Treg Suppressor T cells TyK2 Tyrosine kinase 2 UDS Unscheduled DNA synthesis UGT Uridine diphosphate-glucuronyltransferase US United States UVA-UVB UltravioletA-UltravioletB UVR Ultraviolet radiation VEGF Vascular endothelial growth factor Vmax Velocity of depolarization Vss Volume of distribution at steady state WBC White blood cell WHO World Health Organization WOCBP Women of childbearing potential Clinical abbreviations ACPA anti-cyclic citrullinated peptide antibodies ACR American College of Rheumatology ACR20 ACR criteria 20% response ACR50 ACR criteria 50% response ACR70 ACR criteria 70% response AE Adverse Event ACPA anti-cyclic citrullinated peptide antibodies or anti-citrullinated peptide antibodies ADME Absorption, Distribution, Metabolism, Excretion All RA Phase 2, Phase 3, and LTE studies ALC absolute lymphocyte count Assessment report EMA/CHMP/853224/2016 Page 5/158 ATP Adenosine triphosphate AUC Area under the concentration-time curve BA bioavailability BCC Basal cell carcinoma BCS Biopharmaceutics Classification System bDMARD biologic disease modifying anti-rheumatic drug BE bioequivalence BID Twice Daily BL baseline BMI body mass index CDAI Clinical Disease Activity Index CHMP Committee for Medicinal Products for Human Use CI Confidence Interval Cmax Maximum peak plasma concentration CMI cell-mediated immunity CMV Cytomegalovirus CORRONA Consortium of Rheumatology Researchers of North America COPD Chronic obstructive pulmonary disease CK Creatine Kinase CPK creatine phosphokinase CRF Case Report Form CRP C-Reactive Protein CS corticosteroid CSA Cyclosporine A csDMARD Conventional synthetic disease modifying anti-rheumatic drug CSR Clinical study report CTLA4-IgG cytotoxic T-lymphocyte-associated protein 4 immunoglobin CV Cardiovascular CVD Cardiovascular disease CYP Cytochrome P450 dL Decilitre DAS Disease Activity Score Using 28 joint counts DAS28-4(CRP)