25 April 2013 EMA/CHMP/383457/2013 Committee for Medicinal Products for Human Use (CHMP) CHMP assessment report Xtandi enzalutamide Procedure No EMEA/H/C/002639 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7455 E -mail [email protected] Website www.ema.europa.eu An agency of the European Union Product information Name of the medicinal product: Xtandi Applicant: Astellas Pharma Europe B.V. Sylviusweg 62 2333 BE Leiden The Netherlands Active substance: enzalutamide International Nonproprietary Name/Common Name: enzalutamide Pharmaco-therapeutic group (ATC Code): Not yet assigned Therapeutic indication: Treatment of adult men with metastatic castration-resistant prostate cancer whose disease has progressed on or after docetaxel therapy. Pharmaceutical form: Capsule, soft Strength: 40 mg Route of administration: Oral use Packaging: blister (PVC/PCTFE/Alu) Package size: 112 capsules Xtandi CHMP assessment report EMA/CHMP/383457/2013 Page 2/86 Table of contents 1. Background information on the procedure ............................................ 10 1.1. Submission of the dossier .................................................................................... 10 Information on Paediatric requirements ....................................................................... 10 Information relating to orphan market exclusivity ......................................................... 10 Applicant’s request for consideration ........................................................................... 10 New active Substance status ...................................................................................... 10 Scientific Advice........................................................................................................ 10 Licensing status ........................................................................................................ 10 2. Scientific discussion .............................................................................. 11 2.1. Introduction....................................................................................................... 11 2.2. Quality aspects .................................................................................................. 13 2.2.1. Introduction .................................................................................................... 13 2.2.2. Active substance ............................................................................................ 14 Manufacture ............................................................................................................. 14 Specification............................................................................................................. 14 Stability ................................................................................................................... 15 2.2.3. Finished medicinal product ................................................................................ 15 Pharmaceutical development ...................................................................................... 15 Adventitious agents ................................................................................................... 16 Manufacture of the product ........................................................................................ 16 Product specification ................................................................................................. 16 Stability of the product .............................................................................................. 17 2.2.4. Discussion on chemical, and pharmaceutical aspects ............................................ 17 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 17 2.2.6. Recommendation(s) for future quality development ............................................. 17 2.3. Non-clinical aspects ............................................................................................ 18 2.3.1. Introduction .................................................................................................... 18 2.3.2. Pharmacology ................................................................................................. 18 Pharmacodynamic drug interactions ............................................................................ 22 2.3.3. Pharmacokinetics............................................................................................. 22 2.3.4. Toxicology ...................................................................................................... 23 Single dose toxicity ................................................................................................... 23 Repeat dose toxicity .................................................................................................. 24 Genotoxicity ............................................................................................................. 26 Carcinogenicity ......................................................................................................... 26 Reproduction Toxicity ................................................................................................ 26 Toxicokinetic data ..................................................................................................... 27 Local Tolerance ......................................................................................................... 27 Other toxicity studies ................................................................................................ 27 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 28 2.3.6. Discussion on non-clinical aspects...................................................................... 29 2.3.7. Conclusion on the non-clinical aspects ................................................................ 32 2.4. Clinical aspects .................................................................................................. 32 Xtandi CHMP assessment report EMA/CHMP/383457/2013 Page 3/86 2.4.1. Introduction .................................................................................................... 32 GCP ........................................................................................................................ 32 2.4.2. Pharmacokinetics............................................................................................. 34 Absorption ............................................................................................................... 34 Distribution .............................................................................................................. 34 Elimination ............................................................................................................... 35 Dose proportionality and time dependencies ................................................................. 36 Special populations ................................................................................................... 36 Pharmacokinetic interaction studies ............................................................................. 37 Pharmacokinetics using human biomaterials ................................................................. 39 2.4.3. Pharmacodynamics .......................................................................................... 39 Mechanism of action .................................................................................................. 39 Primary and Secondary pharmacology ......................................................................... 40 2.4.4. Discussion on clinical pharmacology ................................................................... 40 2.4.5. Conclusions on clinical pharmacology ................................................................. 43 2.5. Clinical efficacy .................................................................................................. 43 2.5.1. Dose response study ........................................................................................ 43 2.5.2. Main study(ies) ............................................................................................... 45 Methods .................................................................................................................. 45 Study Participants ..................................................................................................... 45 Treatments .............................................................................................................. 46 Objectives ................................................................................................................ 47 Outcomes/endpoints ................................................................................................. 47 Sample size ............................................................................................................. 49 Randomisation.......................................................................................................... 49 Blinding (masking) .................................................................................................... 49 Statistical methods ..................................................................................................