25 January 2018 EMA/88321/2018 Committee for Medicinal Products for Human Use (CHMP) Assessment report EnCyzix International non-proprietary name: enclomifene Procedure No. EMEA/H/C/004198/0000 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. Administrative information Name of the medicinal product: EnCyzix Applicant: Renable Pharma Limited 20-22 Bedford Row WC1R 4JS UNITED KINGDOM Active substance: ENCLOMIFENE CITRATE International Non-proprietary Name/Common Enclomifene Name: Not assigned Pharmaco-therapeutic group (ATC Code): Treatment of hypogonadotropic hypogonadism (secondary hypogonadism) in Therapeutic indication(s): adult men aged ≤60 years with a body mass index (BMI) ≥25 kg/m2 which has been confirmed by clinical features and biochemical tests in patients which have not responded to diet and exercise Pharmaceutical form(s): Capsule, hard Strength(s): 8.5 mg and 17 mg Route(s) of administration: Oral use Packaging: bottle (HDPE) Package size(s): 30 capsules EMA/88321/2018 Page 2/111 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 ........................................................ 8 2. Scientific discussion ................................................................................ 9 2.1. Problem statement ............................................................................................... 9 2.1.1. Disease or condition .......................................................................................... 9 2.1.2. Epidemiology .................................................................................................... 9 2.1.3. Aetiology and pathogenesis ................................................................................ 9 2.1.4. Clinical presentation and diagnosis .................................................................... 10 2.1.5. Management ................................................................................................... 10 2.2. Quality aspects .................................................................................................. 11 2.2.1. Introduction.................................................................................................... 11 2.2.2. Active Substance ............................................................................................. 11 General information .................................................................................................. 11 Manufacture, characterisation and process controls ....................................................... 12 Specification ............................................................................................................ 13 Stability................................................................................................................... 13 2.2.3. Finished Medicinal Product ................................................................................ 14 Description of the product and Pharmaceutical development .......................................... 14 Manufacture of the product and process controls .......................................................... 15 Product specification ................................................................................................. 15 Stability of the product .............................................................................................. 15 Adventitious agents .................................................................................................. 16 2.2.4. Discussion on chemical, pharmaceutical and biological aspects.............................. 16 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 16 2.2.6. Recommendations for future quality development ............................................... 16 2.3. Non-clinical aspects ............................................................................................ 17 2.3.1. Introduction.................................................................................................... 17 2.3.2. Pharmacology ................................................................................................. 17 2.3.3. Pharmacokinetics ............................................................................................ 19 2.3.4. Toxicology ...................................................................................................... 22 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 29 2.3.6. Discussion on non-clinical aspects ..................................................................... 30 2.3.7. Conclusion on the non-clinical aspects ............................................................... 33 2.4. Clinical aspects .................................................................................................. 33 2.4.1. Introduction.................................................................................................... 33 2.4.2. Pharmacokinetics ............................................................................................ 36 2.4.3. Pharmacodynamics .......................................................................................... 44 2.4.4. Discussion on clinical pharmacology ................................................................... 48 EMA/88321/2018 Page 3/111 2.4.5. Conclusions on clinical pharmacology ................................................................. 50 2.5. Clinical efficacy .................................................................................................. 50 2.5.1. Dose response studies ..................................................................................... 50 2.5.2. Main studies ................................................................................................... 50 2.5.3. Discussion on clinical efficacy ............................................................................ 87 2.5.4. Conclusions on the clinical efficacy .................................................................... 90 2.6. Clinical safety .................................................................................................... 90 2.6.1. Discussion on clinical safety .............................................................................. 99 2.7. Risk Management Plan ...................................................................................... 101 2.8. Pharmacovigilance ........................................................................................... 101 2.9. New Active Substance ...................................................................................... 101 2.10. Product information ........................................................................................ 101 2.10.1. User consultation ......................................................................................... 101 3. Benefit-Risk Balance ........................................................................... 102 3.1. Therapeutic Context ......................................................................................... 102 3.1.1. Disease or condition ...................................................................................... 102 3.1.2. Available therapies and unmet medical need ..................................................... 102 3.1.3. Main clinical studies ....................................................................................... 102 3.2. Favourable effects ............................................................................................ 103 3.3. Uncertainties and limitations about favourable effects ........................................... 104 3.4. Unfavourable effects ......................................................................................... 105 3.5. Uncertainties and limitations about unfavourable effects ....................................... 105 3.6. Effects Table .................................................................................................... 105 3.7. Benefit-risk assessment and discussion ............................................................... 107 3.7.1. Importance of favourable and unfavourable effects ............................................ 107 3.7.2. Balance of benefits and risks .......................................................................... 107 3.8. Conclusions ..................................................................................................... 107 4. Recommendations ............................................................................... 107 Divergent position – Encyzix (EMEA/H/C/004198) ................................ 110 EMA/88321/2018 Page 4/111 List of abbreviations ACTH Adrenocorticotropic Hormone AE Adverse Event ALT Alanine Transaminase AST Aspartate Transaminase AUC Area Under the Curve BCS Biopharmaceutics Classification System b.i.d bis in die (twice a day) BMI Body Mass Index