15 November 2012 EMA/CHMP/27767/2013 Committee for Medicinal Products for Human Use (CHMP) Assessment report Istodax International non-proprietary name: romidepsin Procedure No. EMEA/H/C/002122 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 Telep one +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: Istodax Applicant: Celgene Europe Ltd. 1 Longwalk Road Stockley Park UB11 1DB United Kingdom Active substance: romidepsin International Nonproprietary Name/Common Name: romidepsin Pharmaco-therapeutic group Other antineoplastic agents (ATC Code): (L01XX39) Treatment of adult patients with peripheral T-cell Therapeutic indication: lymphoma (PTCL) that has relapsed after or become refractory to at least one prior therapy Pharmaceutical forms: Powder and solvent for concentrate for solution for infusion Strength: 5 mg/ml Route of administration: Intravenous use Packaging: powder: vial (glass); solvent: vial (glass) Package sizes: 1 vial + 1 vial Istodax CHMP assessment report Page 2/92 Table of contents 1. Background information on the procedure .............................................. 7 1.1. Submission of the dossier ...................................................................................... 7 Information on Paediatric requirements ......................................................................... 7 Information relating to orphan market exclusivity ........................................................... 7 Scientific Advice.......................................................................................................... 7 Licensing status .......................................................................................................... 7 1.2. Steps taken for the assessment of the product ......................................................... 8 1.3. Steps taken for the re-examination procedure ......................................................... 9 2. Scientific discussion .............................................................................. 10 2.1. Introduction....................................................................................................... 10 2.2. Quality aspects .................................................................................................. 12 Manufacture ............................................................................................................. 13 Specification............................................................................................................. 13 Stability ................................................................................................................... 14 Pharmaceutical Development ..................................................................................... 14 Adventitious agents ................................................................................................... 15 Manufacture of the product ........................................................................................ 15 Product specification ................................................................................................. 16 Stability of the product .............................................................................................. 16 2.3. Non-clinical aspects ............................................................................................ 19 Primary pharmacodynamic studies .............................................................................. 19 Secondary pharmacodynamic studies .......................................................................... 24 Safety pharmacology programme ............................................................................... 24 Pharmacodynamic drug interactions ............................................................................ 26 Single dose toxicity ................................................................................................... 28 Repeat dose toxicity .................................................................................................. 29 Genotoxicity ............................................................................................................. 34 Carcinogenicity ......................................................................................................... 34 Reproduction Toxicity ................................................................................................ 34 Toxicokinetic data ..................................................................................................... 35 Local Tolerance ......................................................................................................... 35 Other toxicity studies ................................................................................................ 35 2.4. Clinical aspects .................................................................................................. 43 GCP ........................................................................................................................ 43 Absorption ............................................................................................................... 45 Distribution .............................................................................................................. 45 Elimination ............................................................................................................... 46 Dose proportionality and time dependencies ................................................................. 46 Special populations ................................................................................................... 46 Pharmacokinetic interaction studies ............................................................................. 46 Pharmacokinetics using human biomaterials ................................................................. 47 Mechanism of action .................................................................................................. 47 Primary and Secondary pharmacology ......................................................................... 47 Istodax CHMP assessment report Page 3/92 2.5. Clinical efficacy .................................................................................................. 49 Methods .................................................................................................................. 49 Study Participants ..................................................................................................... 49 Treatments .............................................................................................................. 50 Objectives ................................................................................................................ 50 Outcomes/endpoints ................................................................................................. 50 Sample size ............................................................................................................. 50 Randomisation.......................................................................................................... 51 Blinding (masking) .................................................................................................... 51 Statistical methods ................................................................................................... 51 Results .................................................................................................................... 51 2.6. Clinical safety .................................................................................................... 62 2.7. Pharmacovigilance .............................................................................................. 77 2.8. User consultation ............................................................................................... 77 3. Benefit-Risk Balance.............................................................................. 77 Benefits ................................................................................................................... 77 Risks ....................................................................................................................... 78 Benefit-risk balance .................................................................................................. 81 Discussion on the benefit-risk balance ......................................................................... 81 4. Recommendations ................................................................................. 82 Outcome .................................................................................................................. 82 Re-examination of the CHMP opinion of 19 July 2012 ............................... 82 Detailed grounds for re-examination submitted by the applicant .............. 82 Overall conclusion on grounds for re-examination .................................... 87 Recommendations following re-examination ............................................. 88 Istodax CHMP assessment report Page 4/92 List of abbreviations ADR adverse drug reaction AE adverse event AITL angioimmunoblastic T cell lymphoma ALC absolute leukocyte count ALCL anaplastic large cell lymphoma ALK anaplastic