23 April 2015 EMA/CHMP/601383/2014 Committee for Medicinal Products for Human Use (CHMP) Assessment report Hetlioz International non-proprietary name: tasimelteon Procedure No. EMEA/H/C/003870/0000 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: Hetlioz Applicant: Vanda Pharmaceuticals Ltd. Liberty House 222 Regent Street London, W1B 5TR United Kingdom Active substance: tasimelteon International Nonproprietary Name/Common tasimelteon Name: Pharmaco-therapeutic group Psycholeptics, melatonin receptor agonists (ATC Code): (N05CH03) Therapeutic indication: Hetlioz is indicated for the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24) in totally blind adults. Pharmaceutical form: Capsule, hard Strength: 20 mg Route of administration: Oral use Packaging: bottle (HDPE) Package size: 30 capsules EMA/CHMP/601383/2014 Page 2/79 Table of contents 1. Background information on the procedure .............................................. 7 1.1. Submission of the dossier ..................................................................................... 7 1.2. Manufacturers ..................................................................................................... 8 1.3. Steps taken for the assessment of the product ........................................................ 8 2. Scientific discussion ................................................................................ 9 2.1. Introduction ........................................................................................................ 9 2.2. Problem statement ............................................................................................... 9 2.3. About the product .............................................................................................. 10 2.4. Quality aspects .................................................................................................. 10 2.4.1. Introduction.................................................................................................... 10 2.4.2. Active Substance ............................................................................................. 10 2.4.3. Finished Medicinal Product ................................................................................ 12 2.4.4. Discussion on chemical, pharmaceutical and biological aspects.............................. 14 2.4.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 14 2.5. Non-clinical aspects ............................................................................................ 15 2.5.1. Introduction.................................................................................................... 15 2.5.2. Pharmacology ................................................................................................. 15 2.5.3. Pharmacokinetics ............................................................................................ 17 2.5.4. Toxicology ...................................................................................................... 19 2.5.5. Ecotoxicity/environmental risk assessment ......................................................... 29 2.5.6. Discussion on non-clinical aspects ..................................................................... 30 2.5.7. Conclusion on the non-clinical aspects ............................................................... 32 2.6. Clinical aspects .................................................................................................. 32 2.6.1. Introduction.................................................................................................... 32 2.6.2. Pharmacokinetics ............................................................................................ 34 2.6.3. Pharmacodynamics .......................................................................................... 39 2.6.4. Discussion on clinical pharmacology ................................................................... 39 2.6.5. Conclusions on clinical pharmacology ................................................................. 40 2.7. Clinical efficacy .................................................................................................. 41 2.7.1. Dose response studies ..................................................................................... 41 2.7.2. Main studies ................................................................................................... 42 2.7.3. Discussion on clinical efficacy ............................................................................ 61 2.7.4. Conclusions on the clinical efficacy .................................................................... 63 2.8. Clinical safety .................................................................................................... 63 2.8.1. Discussion on clinical safety .............................................................................. 68 2.8.2. Conclusions on the clinical safety ...................................................................... 69 2.9. Pharmacovigilance ............................................................................................. 69 EMA/CHMP/601383/2014 Page 3/79 2.10. Risk Management Plan ...................................................................................... 70 2.11. Product information .......................................................................................... 76 2.11.1. User consultation ........................................................................................... 76 3. Benefit-Risk Balance ............................................................................. 76 4. Recommendations ................................................................................. 78 EMA/CHMP/601383/2014 Page 4/79 List of abbreviations ADR Adverse Drug Reaction AE Adverse Event ALT Alanine aminotransferase aMT6s urinary 6-sulfatoxymelatonin ANCOVA analysis of covariance AST aspartate aminotransferase AUS area under the plasma concentration-time curve AUC0-24 AUC from time 0 to 24 hours AUC0-inf AUC from time 0 extrapolated to infinity BCS Biopharmaceutical Classification System BMI Body Mass Index CEP Certificate of Suitability CGI-C Clinical Global Impression of Change CHMP Committee for Medicinal Products for Human Use Cmax maximum observed plasma concentration Cmin minimum observed serum concentration CYP cytochrome P-450 DSC Differential scanning calorimetry dTSD Day time Total Sleep Duration EC European Commission EEA European Economic Area EU European Union GC Gas chromatography GCP Good Clinical Practice GMP Good Manufacturing Practice HDPE High Density Polyethylene HPLC High-performance liquid chromatography ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ICP-MS Inductively coupled plasma mass spectrometry ITT Intent to treat IR Infrared KF Karl Fischer titration LC-MS Liquid Chromatography coupled with Mass Spectrometry LDPE Low Density Polyethylene LOD Limit of Detection LOQ Limit of Quantification LQ-nTST Lower Quartile of nTST MoST Midpoint of Sleep Timing n/a not applicable Non-24 Non-24-Hour Sleep-Wake Disorder N24CRS Non-24 Clinical Response Scale nTST Night-time Total Sleep Time PhEur European Pharmacopoeia PIL Patient Information LeafletPIP Paediatric Investigation Plan EMA/CHMP/601383/2014 Page 5/79 PK Pharmacokinetic PP polypropylene Pre-SQ Pre-Sleep Questionnaire PVC polyvinyl chloride RH relative humidity SAE Serious Adverse Event SCN suprachiasmatic nucleus SmPC Summary of Product Characteristics TSE Transmissible Spongiform Encephalopathy Tmax time at maximum concentration UQ-dTSD Upper Quartile of dTSD UV Ultraviolet XRPD X-ray powder diffraction EMA/CHMP/601383/2014 Page 6/79 1. Background information on the procedure 1.1. Submission of the dossier The applicant Vanda Pharmaceuticals Ltd. submitted on 1 May 2014 an application for Marketing Authorisation to the European Medicines Agency (EMA) for Hetlioz, through the centralised procedure falling within the Article 3(1) and point 4 of Annex of Regulation (EC) No 726/2004. The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 24 October 2013. Hetlioz was designated as an orphan medicinal product EU/3/10/841 on 23 February 2011. Hetlioz was designated as an orphan medicinal product in the following indication: treatment of Non-24-Hour Sleep-Wake Disorders in blind people with no light perception. The applicant applied for the following indication: treatment of Non-24-Hour Sleep-Wake Disorder (Non-24) in the totally blind. Following the CHMP positive opinion on this marketing authorisation, the Committee for Orphan Medicinal Products (COMP) reviewed the designation of Hetlioz as an orphan medicinal product in the approved indication. The outcome of the COMP review can be found on the Agency's website: ema.europa.eu/Find medicine/Rare disease designations. The legal basis for this application refers to: Article 8.3 of Directive 2001/83/EC - complete and independent application. The applicant indicated that tasimelteon was considered to be a new active substance. The application submitted is composed of administrative