14 September 2017 EMA/692068/2017 Committee for Medicinal Products for Human Use (CHMP) Assessment report Tremfya International non-proprietary name: guselkumab Procedure No. EMEA/H/C/004271/0000 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 Administrative information Name of the medicinal product: Tremfya Applicant: Janssen-Cilag International N.V. Turnhoutseweg 30 B-2340 Beerse BELGIUM Active substance: GUSELKUMAB International Non-proprietary Name/Common guselkumab Name: Pharmaco-therapeutic group immunosuppressants, interleukin inhibitors (ATC Code): (not yet assigned) Therapeutic indication(s): Tremfya is indicated for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy. Pharmaceutical form(s): Solution for injection (injection) Strength(s): 100 mg Route(s) of administration: Subcutaneous use Packaging: pre-filled syringe (glass) Package size(s): 1 pre-filled syringe Assessment report EMA/692068/2017 Page 2/148 Table of contents 1. Background information on the procedure .............................................. 8 1.1. Submission of the dossier ...................................................................................... 8 2. Scientific discussion .............................................................................. 10 2.1. Problem statement ............................................................................................. 10 2.1.1. Disease or condition ......................................................................................... 10 2.1.2. Epidemiology .................................................................................................. 10 2.1.3. Aetiology and pathogenesis .............................................................................. 10 2.1.4. Clinical presentation ......................................................................................... 11 2.1.5. Management ................................................................................................... 11 2.2. Quality aspects .................................................................................................. 13 2.2.1. Introduction ................................................................................................. 13 2.2.2. Active Substance .......................................................................................... 13 2.2.3. Discussion and conclusions on the chemical, pharmaceutical and biological aspects .................................................................................................................. 20 2.3. Non-clinical aspects ............................................................................................ 20 2.3.1. Introduction .................................................................................................... 20 2.3.2. Pharmacology ................................................................................................. 20 2.3.3. Pharmacokinetics............................................................................................. 22 2.3.4. Toxicology ...................................................................................................... 24 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 31 2.3.6. Discussion on non-clinical aspects...................................................................... 31 2.3.7. Conclusion on the non-clinical aspects ................................................................ 33 2.4. Clinical aspects .................................................................................................. 34 2.4.1. Introduction .................................................................................................... 34 2.4.2. Pharmacokinetics............................................................................................. 35 2.4.3. Pharmacodynamics .......................................................................................... 40 2.4.4. Discussion on clinical pharmacology ................................................................... 45 2.4.5. Conclusions on clinical pharmacology ................................................................. 47 2.5. Clinical efficacy .................................................................................................. 47 2.5.1. Dose response studies...................................................................................... 47 2.5.2. Main studies ................................................................................................... 50 Study CNTO1959PSO3003 (NAVIGATE) ....................................................................... 53 Study CNTO1959PSO3003 (NAVIGATE) ....................................................................... 57 Study CNTO1959PSO3003 (NAVIGATE) ....................................................................... 58 2.5.3. Discussion on clinical efficacy .......................................................................... 104 2.5.4. Conclusions on the clinical efficacy ................................................................... 111 2.6. Clinical safety .................................................................................................. 111 2.6.1. Discussion on clinical safety ............................................................................ 126 2.6.2. Conclusions on the clinical safety ..................................................................... 131 2.7. Risk Management Plan ...................................................................................... 132 2.8. Pharmacovigilance ............................................................................................ 137 Assessment report EMA/692068/2017 Page 3/148 2.9. New Active Substance ....................................................................................... 137 2.10. Product information ........................................................................................ 137 2.10.1. User consultation ......................................................................................... 137 2.10.2. Additional monitoring ................................................................................... 138 3. Benefit-Risk Balance............................................................................ 138 3.1. Therapeutic Context ......................................................................................... 138 3.1.1. Disease or condition ....................................................................................... 138 3.1.2. Available therapies and unmet medical need ..................................................... 138 3.1.3. Main clinical studies ....................................................................................... 139 3.2. Favourable effects ............................................................................................ 139 3.3. Uncertainties and limitations about favourable effects ........................................... 140 3.4. Unfavourable effects ......................................................................................... 141 3.5. Uncertainties and limitations about unfavourable effects ....................................... 142 3.6. Effects Table .................................................................................................... 144 3.7. Benefit-risk assessment and discussion ............................................................... 145 3.7.1. Importance of favourable and unfavourable effects ............................................ 145 3.7.2. Balance of benefits and risks ........................................................................... 147 3.8. Conclusions ..................................................................................................... 147 4. Recommendations ............................................................................... 147 Assessment report EMA/692068/2017 Page 4/148 List of abbreviations ADA anti-drug antibodies ADR adverse drug reaction AE adverse event AUC area under the concentration versus time curve AUC0-28week cumulative area under the concentration time curve up to Week 28 BSA body surface area Cave average daily serum guselkumab concentration C-CASA Columbia Classification Algorithm of Suicide Assessment CHMP Committee for Medicinal Products for Human Use CI confidence interval CL systemic clearance CL/F apparent total systemic clearance of drug after extravascular administration Cmax maximum observed concentration CSR clinical study report CTCAE Common Terminology Criteria for Adverse Events CV cardiovascular DBL database lock DELFIA dissociation-enhanced lanthanide fluorescent immunoassay DLQI Dermatology Life Quality Index ECLIA electrochemiluminescence immunoassay EP erythromdermic psoriasis FDA Food and Drug Administration f-PGA fingernail Physician’s Global Assessment HADS Hospital Anxiety and Depression Scale hf-PGA Physician’s Global Assessment of hands and/or feet HPRA Health Products Regulatory Authority GPP generalized pustular psoriasis IBD inflammatory bowel disease IGA Investigator’s Global Assessment IgG1λ immunoglobulin G1 lambda Assessment report EMA/692068/2017 Page