15 December 2016 EMA/13493/2017 Committee for Medicinal Products for Human Use (CHMP) Assessment report Olumiant International non-proprietary name: baricitinib Procedure No. EMEA/H/C/004085/0000 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 2.1.1. Disease or condition ........................................................................................ 11 2.1.2. Epidemiology .................................................................................................. 11 2.1.3. Clinical presentation ........................................................................................ 11 2.1.4. Management ................................................................................................... 11 2.1.5. Introduction.................................................................................................... 15 2.1.6. Active Substance ............................................................................................. 16 2.1.7. Finished Medicinal Product ................................................................................ 19 2.1.8. Discussion on chemical, pharmaceutical and biological aspects.............................. 22 2.1.9. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 22 2.1.10. Recommendations for future quality development.............................................. 22 2.2. Non-clinical aspects ............................................................................................ 22 2.2.1. Introduction.................................................................................................... 22 2.2.2. Pharmacology ................................................................................................. 22 2.2.3. Pharmacokinetics ............................................................................................ 24 2.2.4. Toxicology ...................................................................................................... 28 2.2.5. Ecotoxicity/environmental risk assessment ......................................................... 41 2.2.6. Discussion on non-clinical aspects ..................................................................... 42 2.2.7. Conclusion on the non-clinical aspects ............................................................... 44 2.3. Clinical aspects .................................................................................................. 44 2.3.1. Introduction.................................................................................................... 44 2.3.2. Pharmacokinetics ............................................................................................ 48 2.3.3. Pharmacodynamics .......................................................................................... 53 2.3.4. Discussion on clinical pharmacology ................................................................... 57 2.3.5. Conclusions on clinical pharmacology ................................................................. 59 2.4. Clinical efficacy .................................................................................................. 60 2.4.1. Dose response studies ..................................................................................... 60 2.4.2. Main studies ................................................................................................... 60 Clinical studies in special populations ....................................................... 82 2.4.3. Discussion on clinical efficacy ............................................................................ 82 2.4.4. Conclusions on the clinical efficacy .................................................................... 85 2.5. Clinical safety .................................................................................................... 85 2.5.1. Discussion on clinical safety ............................................................................ 108 2.5.2. Conclusions on the clinical safety .................................................................... 111 2.6. Risk Management Plan ...................................................................................... 112 2.7. Pharmacovigilance ........................................................................................... 118 EMA/13493/2017 Page 2/132 2.8. New Active Substance ...................................................................................... 118 2.9. Product information .......................................................................................... 119 2.9.1. User consultation .......................................................................................... 119 2.9.2. Quick Response (QR) code ............................................................................. 119 2.9.3. Additional monitoring ..................................................................................... 119 3. Benefit-Risk Balance ........................................................................... 120 3.1. Therapeutic Context ......................................................................................... 120 3.1.1. Disease or condition ...................................................................................... 120 3.1.2. Available therapies and unmet medical need ..................................................... 120 3.1.3. Main clinical studies ....................................................................................... 120 3.2. Favourable effects ............................................................................................ 121 3.3. Uncertainties and limitations about favourable effects ........................................... 122 3.4. Unfavourable effects ......................................................................................... 122 3.5. Uncertainties and limitations about unfavourable effects ....................................... 124 3.6. Effects Table .................................................................................................... 125 3.7. Benefit-risk assessment and discussion ............................................................... 127 3.7.1. Importance of favourable and unfavourable effects ............................................ 127 3.7.2. Balance of benefits and risks .......................................................................... 128 3.7.3. Additional considerations on the benefit-risk balance ......................................... 130 3.8. Conclusions ..................................................................................................... 130 4. Recommendations ............................................................................... 130 EMA/13493/2017 Page 3/132 List of abbreviations Term Definition ACPA anti-citrullinated protein antibody ACR American College of Rheumatology ACR20/50/70 20%, 50%, or 70% improvement in American College of Rheumatology criteria ADA adalimumab ADR adverse drug reaction AE adverse event ALP alkaline phosphatase ALT alanine aminotransferase ANC absolute neutrophil count Apo-A1 apolipoprotein A1 Apo-B apolipoprotein B AST aspartate aminotransferase AUC area under the concentration versus time curve AUC(0-∞) area under the concentration versus time curve from zero to infinity AUCτ,ss area under the concentration versus time curve during one dosing interval at steady state BARI baricitinib BCS Biopharmaceutics Classification System bDMARD biologic disease-modifying antirheumatic drug BID twice daily BMI body mass index Cav,ss model-estimated average drug concentration under steady state conditions during multiple dosing cDMARD conventional disease-modifying antirheumatic drug CDAI Clinical Disease Activity Index CHMP Committee for Medicinal Products for Human Use EMA/13493/2017 Page 4/132 CI confidence interval CHMP Committee for Medicinal Products for Human Use Cmax,ss mean maximum plasma baricitinib concentration at steady state CPK creatine phosphokinase CTCAE Common Terminology Criteria for Adverse Events CPP critical process parameter CQA critical quality attribute CYP cytochrome DAS28 Disease Activity Score based on 28 joints. Higher scores indicate increased disease activity. DMARD disease-modifying antirheumatic drug DNA deoxyribonucleic acid DoE design of experiments DSC differential scanning calorimetry EAIR exposure adjusted incidence rate eGFR estimated glomerular filtration rate EPO erythropoietin EQ-5D-5L European Quality of Life–5 Dimensions–5 Level ESR erythrocyte sedimentation rate ESRD end-stage renal disease Ext extended EU European Union EULAR European League Against Rheumatism FACIT-F Functional Assessment of Chronic Illness