Plivensia, INN-Sirukumab
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14 September 2017 EMA/CHMP/576037/2017 Committee for Medicinal Products for Human Use (CHMP) Withdrawal assessment report Plivensia International non-proprietary name: sirukumab Procedure No. EMEA/H/C/004165/0000 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, 2018. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Recommendation ..................................................................................... 5 2. Executive summary ................................................................................. 6 2.1. Problem statement ............................................................................................... 6 2.1.1. Disease or condition ........................................................................................... 6 2.1.2. Epidemiology .................................................................................................... 6 2.1.3. Biologic features; aetiology and pathogenesis ....................................................... 6 2.1.4. Clinical presentation, diagnosis and prognosis ....................................................... 6 2.1.5. Management ..................................................................................................... 6 2.2. About the product ................................................................................................ 7 2.3. The development programme, compliance with CHMP guidance and scientific advice .... 7 2.4. General comments on compliance with GMP, GLP, GCP ............................................. 8 2.5. Type of application and other comments on the submitted dossier.............................. 8 3. Scientific overview and discussion .......................................................... 8 3.1. Introduction......................................................................................................... 8 3.2. Quality aspects .................................................................................................... 9 3.2.1. Introduction ...................................................................................................... 9 3.2.2. Active Substance ............................................................................................... 9 3.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 16 3.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 16 3.3. Non clinical aspects ............................................................................................ 17 3.3.1. Pharmacokinetics............................................................................................. 18 3.3.2. Toxicology ...................................................................................................... 20 3.3.3. Ecotoxicity/environmental risk assessment ......................................................... 21 3.3.4. Discussion on non-clinical aspects...................................................................... 21 3.3.5. Conclusion on non-clinical aspects ..................................................................... 24 3.4. Clinical aspects .................................................................................................. 24 3.4.1. Pharmacokinetics............................................................................................. 28 3.4.2. Pharmacodynamics .......................................................................................... 33 3.4.3. Discussion on clinical pharmacology ................................................................... 33 3.4.4. Conclusions on clinical pharmacology ................................................................. 34 3.4.5. Clinical efficacy ............................................................................................... 35 3.4.6. Conclusions on clinical efficacy .......................................................................... 56 3.4.7. Clinical safety .................................................................................................. 57 3.4.8. Discussion on clinical safety ............................................................................ 112 3.4.9. Conclusions on clinical safety .......................................................................... 123 3.5. Risk management plan ...................................................................................... 123 3.6. Pharmacovigilance system ................................................................................. 129 4. Orphan medicinal products .................................................................. 130 5. Benefit risk assessment ....................................................................... 130 5.1. Therapeutic Context ......................................................................................... 130 5.1.1. Disease or condition ....................................................................................... 130 Withdrawal assessment report EMA/CHMP/576037/2017 Page 2/150 5.2. Available therapies and unmet medical need ........................................................ 130 5.3. Main clinical studies .......................................................................................... 131 5.4. Favourable effects ............................................................................................ 132 5.5. Uncertainties and limitations about favourable effects ........................................... 134 5.6. Unfavourable effects ......................................................................................... 137 5.7. Uncertainties and limitations about unfavourable effects ....................................... 138 5.8. Effects Table .................................................................................................... 139 5.9. Benefit-risk assessment and discussion ............................................................... 143 5.9.1. Importance of favourable and unfavourable effects ............................................ 143 5.9.2. Balance of benefits and risks ........................................................................... 145 5.9.3. Additional considerations on the benefit-risk balance ......................................... 145 6. CHMP list of outstanding issues to be addressed in an oral explanation and/or in writing ..................................................................................... 146 6.1. Quality aspects ................................................................................................ 146 6.2. Non clinical aspects .......................................................................................... 146 6.3. Clinical aspects ................................................................................................ 146 6.4. Pharmacovigilance system ................................................................................. 149 7. Recommended conditions for marketing authorisation and product information in case of a positive benefit risk assessment ........................ 149 7.1. Other conditions ............................................................................................... 149 7.2. Summary of product characteristics (SmPC) ........................................................ 149 7.3. Labelling ......................................................................................................... 149 7.4. Package leaflet (PL) .......................................................................................... 149 Withdrawal assessment report EMA/CHMP/576037/2017 Page 3/150 List of abbreviations ACR American College of Rheumatology ADR Adverse drug reaction AE adverse event ANCOVA analysis of covariance ANOVA analysis of variance anti-TNF-IR anti-tumor-necrosis-factor- agent-inadequate responder(s) CCP cyclic citrullinated peptide CDAI Clinical Disease Activity Index CI confidence interval CMH Cochran-Mantel-Haenszel (test) CO Crossover CQ chloroquine CRP C-reactive protein DAS28 Disease Activity Index Score 28 DBL database lock DMARD disease modifying antirheumatic drugs EE early escape ESR erythrocyte sedimentation rate ER exposure-response EULAR European League Against Rheumatism FACIT-fatigue Functional Assessment of Chronic Illness Therapy-fatigue HAQ-DI Health Assessment Questionnaire-Disability Index HCQ hydroxychloroquine IL interleukin ITT Intention to treat JSN joint space narrowing LDA Low Disease Activity LE late escape LOCF last observation carried forward LoQ list of questions LS means Least-squares means LTE long-term extension mAb monoclonal antibody MCR Major Clinical Response MCS Mental Component Score MTX methotrexate NSAIDs nonsteroidal anti-inflammatory drugs PK pharmacokinetics PTY patient-years PD pharmacodynamics q1w every week q2w every 2 weeks q4w every 4 weeks PCS Physical Component Score RA rheumatoid arthritis RF rheumatoid factor SC subcutaneous SD standard deviation SCS Summary of clinical safety SDAI Simplified Disease Activity Index SF-36 36-item short form health survey SmPC Summary of product information SSZ sulfasalazine TF Treatment Failure TNF tumor necrosis factor alpha