31 May 2018 EMA/556923/2018 Committee for Medicinal Products for Human Use (CHMP) Assessment report RXULTI International non-proprietary name: brexpiprazole Procedure No. EMEA/H/C/003841/0000 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 .............................................. 8 1.1. Submission of the dossier ..................................................................................... 8 1.2. Steps taken for the assessment of the product ........................................................ 9 2. Scientific discussion .............................................................................. 10 2.1. Problem statement ............................................................................................. 10 2.1.1. Disease or condition ........................................................................................ 10 2.1.2. Epidemiology and risk factors, screening tools/prevention .................................... 10 2.1.3. Biologic features, aetiology and pathogenesis ..................................................... 10 2.1.4. Clinical presentation, diagnosis and stage/prognosis ............................................ 11 2.1.5. Management .................................................................................................. 11 2.2. Quality aspects .................................................................................................. 15 2.2.1. Introduction ................................................................................................... 15 2.2.2. Active Substance ............................................................................................. 15 General information .................................................................................................. 15 Manufacture, characterisation and process controls ...................................................... 16 Specification ............................................................................................................ 16 Stability .................................................................................................................. 16 2.2.3. Finished Medicinal Product ................................................................................ 17 Description of the product and Pharmaceutical development .......................................... 17 Manufacture of the product and process controls .......................................................... 17 Product specification ................................................................................................. 17 Stability of the product .............................................................................................. 18 2.2.4. Discussion on chemical, pharmaceutical and biological aspects ............................. 18 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 19 2.2.6. Recommendations for future quality development ............................................... 19 2.3. Non-clinical aspects ............................................................................................ 19 2.3.1. Introduction ................................................................................................... 19 2.3.2. Pharmacology ................................................................................................. 19 2.3.3. Pharmacokinetics ............................................................................................ 28 2.3.4. Toxicology ...................................................................................................... 31 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 39 2.3.6. Discussion on non-clinical aspects ..................................................................... 42 2.3.7. Conclusion on the non-clinical aspects ............................................................... 49 2.4. Clinical aspects .................................................................................................. 50 2.4.1. Introduction ................................................................................................... 50 2.4.2. Pharmacokinetics ............................................................................................ 51 2.4.3. Pharmacodynamics .......................................................................................... 61 2.4.4. Discussion on clinical pharmacology .................................................................. 63 2.4.5. Conclusions on clinical pharmacology ................................................................. 64 2.5. Clinical efficacy .................................................................................................. 64 Assessment report EMA/556923/2018 Page 2/172 2.5.1. Dose response study(ies) ................................................................................. 64 2.5.2. Main studies ................................................................................................... 69 2.5.3. Discussion on clinical efficacy............................................................................ 84 2.5.4. Conclusions on the clinical efficacy .................................................................... 91 2.1. Clinical safety .................................................................................................... 92 2.1.1. Discussion on clinical safety ............................................................................ 144 2.1.2. Conclusions on the clinical safety .................................................................... 153 2.2. Risk Management Plan ...................................................................................... 154 Use in patients with Insulin dependent diabetes mellitus (IDDM) .................................. 157 2.3. Pharmacovigilance ........................................................................................... 157 2.4. New Active Substance ...................................................................................... 157 2.5. Product information .......................................................................................... 157 2.5.1. User consultation .......................................................................................... 157 2.5.2. Additional monitoring ..................................................................................... 158 3. Benefit-Risk Balance ........................................................................... 158 3.1. Therapeutic Context ......................................................................................... 158 3.1.1. Disease or condition ...................................................................................... 158 3.1.2. Available therapies and unmet medical need .................................................... 158 3.1.3. Main clinical studies ....................................................................................... 158 3.2. Favourable effects ............................................................................................ 159 3.3. Uncertainties and limitations about favourable effects .......................................... 160 3.4. Unfavourable effects ......................................................................................... 161 3.5. Uncertainties and limitations about unfavourable effects ....................................... 164 3.6. Effects Table ................................................................................................... 166 3.7. Benefit-risk assessment and discussion............................................................... 170 3.7.1. Importance of favourable and unfavourable effects ........................................... 170 3.7.2. Balance of benefits and risks .......................................................................... 170 3.8. Conclusions ..................................................................................................... 171 4. Recommendations ............................................................................... 171 Assessment report EMA/556923/2018 Page 3/172 List of abbreviations 5-HT Serotonin (5-hyrodoxytryptamine) 5-HT1A/1B/1D Serotonin 5-HT1A/1B/1D 5-HT2A/2B/2C(s23c)/2C(vsv) Serotonin 5-HT2A/2B/2C 5-HT3/5A/6/7/7A Serotonin 5-HT3/5A/6/7/7A ADR Adverse drug reaction AE Adverse event AIMS Abnormal Involuntary Movement Scale ALT Alanine aminotrasferase APO Apomorphine ARI Aripiprazole ASMF Active Substance Master File AST Aspartate aminotransferase AUC Area under the concentration-time curve AUC∞/AUCinf Area under the concentration-time curve from time zero to infinity (inf= ∞) AUCt Area under the concentration-time curve calculated to the last observable concentration at time t AUCtau Area under the plasma concentration-time curve during a dosing interval (tau [τ]) BARS Barnes Akathisia Rating Scale BE Bioequivalence BREX Brexpiprazole CAR Cariprazine or conditioned avoidance response CDP Clinical development program CGI Clinical