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Alunbrig, INN-Brigatinib 20 September 2018 EMA/696925/2018 Committee for Medicinal Products for Human Use (CHMP) Assessment report Alunbrig International non-proprietary name: brigatinib Procedure No. EMEA/H/C/004248/0000 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. Background information on the procedure .............................................. 7 1.1. Submission of the dossier ...................................................................................... 7 1.2. Steps taken for the assessment of the product ......................................................... 7 2. Scientific discussion ................................................................................ 9 2.1. Problem statement ............................................................................................... 9 2.1.1. Disease or condition ........................................................................................... 9 2.1.2. Epidemiology and risk factors, screening tools/prevention ...................................... 9 2.1.3. Biologic features/Aetiology and pathogenesis ........................................................ 9 2.1.4. Clinical presentation, diagnosis and stage/prognosis ............................................ 10 2.1.5. Management ................................................................................................... 10 2.2. Quality aspects .................................................................................................. 17 2.2.1. Introduction .................................................................................................... 17 2.2.2. Active Substance ............................................................................................. 17 General information .................................................................................................. 17 Manufacture, characterisation and process controls ....................................................... 18 Specification............................................................................................................. 19 Stability ................................................................................................................... 19 2.2.3. Finished Medicinal Product ................................................................................ 20 Description of the product and Pharmaceutical development .......................................... 20 Manufacture of the product and process controls .......................................................... 22 Product specification ................................................................................................. 22 Stability of the product .............................................................................................. 23 Adventitious agents ................................................................................................... 24 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 24 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 24 2.2.6. Recommendations for future quality development................................................ 24 2.3. Non-clinical aspects ............................................................................................ 24 2.3.1. Introduction .................................................................................................... 24 2.3.2. Pharmacology ................................................................................................. 24 2.3.3. Pharmacokinetics............................................................................................. 35 2.3.4. Toxicology ...................................................................................................... 38 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 47 2.3.6. Discussion on non-clinical aspects...................................................................... 48 2.3.7. Conclusion on the non-clinical aspects ................................................................ 49 2.4. Clinical aspects .................................................................................................. 49 2.5. Clinical aspects .................................................................................................. 49 2.5.1. Introduction .................................................................................................... 49 2.5.2. Pharmacokinetics............................................................................................. 51 2.5.3. Pharmacodynamics .......................................................................................... 60 2.5.4. Discussion on clinical pharmacology ................................................................... 64 2.5.5. Conclusions on clinical pharmacology ................................................................. 66 2.1. Clinical efficacy .................................................................................................. 66 2.2. Dose response study ........................................................................................... 66 2.2.1. Main study ................................................................................................... 68 Assessment Report - Alunbrig EMA/696925/2018 Page 2/132 2.2.2. Discussion on clinical efficacy ............................................................................ 96 2.2.3. Conclusions on the clinical efficacy ..................................................................... 99 2.3. Clinical safety .................................................................................................... 99 2.3.1. Discussion on clinical safety ............................................................................ 118 2.3.2. Conclusions on the clinical safety ..................................................................... 122 2.4. Risk Management Plan ...................................................................................... 122 2.5. Pharmacovigilance ............................................................................................ 125 2.6. New Active Substance ....................................................................................... 126 2.7. Product information .......................................................................................... 126 2.7.1. User consultation ........................................................................................... 126 2.7.2. Additional monitoring ..................................................................................... 126 3. Benefit-Risk Balance............................................................................ 126 3.1. Therapeutic Context ......................................................................................... 126 3.1.1. Disease or condition ....................................................................................... 126 3.1.2. Available therapies and unmet medical need ..................................................... 126 3.1.3. Main clinical studies ....................................................................................... 126 3.2. Favourable effects ............................................................................................ 127 3.3. Uncertainties and limitations about favourable effects ........................................... 127 3.4. Unfavourable effects ......................................................................................... 127 3.5. Uncertainties and limitations about unfavourable effects ....................................... 128 3.6. Effects Table .................................................................................................... 128 3.7. Benefit-risk assessment and discussion ............................................................... 129 3.7.1. Importance of favourable and unfavourable effects ............................................ 129 3.7.2. Balance of benefits and risks ........................................................................... 130 3.7.3. Additional considerations on the benefit-risk balance ......................................... 130 3.8. Conclusions ..................................................................................................... 130 4. Recommendations ............................................................................... 130 Assessment Report - Alunbrig EMA/696925/2018 Page 3/132 List of abbreviations ADME absorption, distribution, metabolism, and excretion AE adverse event ALK anaplastic lymphoma kinase ALK+ ALK-positive ALT alanine aminotransferase ANC absolute neutrophil count ANSM Agence Nationale de Sécurité du Médicament et des Produits de Santé (France) aPTT activated partial thromboplastin time ARIAD ARIAD Pharmaceuticals, Inc. AST aspartate aminotransferase AUC area under the curve AUC0–120 area under the curve from time 0 to 120 hours postdose AUC0-24 area under the curve between 0 to 24 hours postdose at steady state AUC0–∞ area under
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