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OCALIVA, INN-Obeticholic Acid

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OCALIVA, INN-Obeticholic Acid 13 October 2016 EMA/725757/2016 Committee for Medicinal Products for Human Use (CHMP) Assessment report OCALIVA International non-proprietary name: obeticholic acid Procedure No. EMEA/H/C/004093/0000 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, 2016. Reproduction is authorised provided the source is acknowledged. Administrative information Name of the medicinal product: OCALIVA Applicant: Intercept Pharma Ltd. 2 Pancras Square London N1C 4AG UNITED KINGDOM Active substance: obeticholic acid International Non-proprietary Name: obeticholic acid Pharmaco-therapeutic group bile therapy, bile acid preparations (ATC Code): (A05AA04) Therapeutic indication(s): OCALIVA is indicated for the treatment of primary biliary cholangitis (also known as primary biliary cirrhosis) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA or as monotherapy in adults unable to tolerate UDCA. Pharmaceutical form(s): Film-coated tablet Strength(s): 5 mg and 10 mg Route(s) of administration: Oral use Packaging: bottle (HDPE) Package size(s): 30 tablets Assessment report EMA/725757/2016 Page 2/129 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 and risk factors .............................................................................. 9 2.1.3. Aetiology and pathogenesis ................................................................................ 9 2.1.4. Clinical presentation, diagnosis and stage/prognosis ............................................ 10 2.1.5. Management ................................................................................................... 11 2.2. Quality aspects .................................................................................................. 14 2.2.1. Introduction .................................................................................................... 14 2.2.2. Active Substance ............................................................................................. 14 2.2.3. Finished Medicinal Product ................................................................................ 17 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 19 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 19 2.2.6. Recommendation(s) for future quality development ............................................. 19 2.3. - A second identification method for OCA should be developed and validated as TLC is an outdated and inaccurate method. Non-clinical aspects ................................................... 20 2.3.1. Introduction .................................................................................................... 20 2.3.2. Pharmacology ................................................................................................. 20 2.3.3. Pharmacokinetics............................................................................................. 21 2.3.4. Toxicology ...................................................................................................... 23 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 25 2.3.6. Discussion on non-clinical aspects...................................................................... 25 2.3.7. Conclusion on the non-clinical aspects ................................................................ 26 2.4. Clinical aspects .................................................................................................. 27 2.4.1. Introduction .................................................................................................... 27 2.4.2. Pharmacokinetics............................................................................................. 31 2.4.3. Pharmacodynamics .......................................................................................... 46 2.4.4. Discussion on clinical pharmacology ................................................................... 49 2.4.5. Conclusions on clinical pharmacology ................................................................. 51 2.5. Clinical efficacy .................................................................................................. 51 2.5.1. Dose response studies...................................................................................... 51 2.5.2. Main study ...................................................................................................... 53 2.5.3. Discussion on clinical efficacy ............................................................................ 95 2.5.4. Conclusions on the clinical efficacy ................................................................... 100 2.6. Clinical safety .................................................................................................. 101 2.6.1. Discussion on clinical safety ............................................................................ 113 2.6.2. Conclusions on the clinical safety ..................................................................... 118 2.7. Risk Management Plan ...................................................................................... 119 Assessment report EMA/725757/2016 Page 3/129 2.8. Pharmacovigilance ............................................................................................ 120 2.9. New Active Substance ....................................................................................... 120 2.10. Product information ........................................................................................ 121 2.10.1. User consultation ......................................................................................... 121 2.10.2. Additional monitoring ................................................................................... 121 3. Benefit-Risk Balance............................................................................ 121 3.1. Therapeutic Context ......................................................................................... 121 3.1.1. Disease or condition ....................................................................................... 121 3.1.2. Available therapies and unmet medical need ..................................................... 121 3.1.3. Main clinical studies ....................................................................................... 122 3.2. Favourable effects ............................................................................................ 123 3.3. Uncertainties and limitations about favourable effects ........................................... 123 3.4. Unfavourable effects ......................................................................................... 124 3.5. Uncertainties and limitations about unfavourable effects ....................................... 124 3.6. Effects Table .................................................................................................... 125 3.7. Benefit-risk assessment and discussion ............................................................... 126 3.7.1. Importance of favourable and unfavourable effects ............................................ 126 3.7.2. Balance of benefits and risks ........................................................................... 126 3.7.3. Additional considerations on the benefit-risk balance ......................................... 127 3.8. Conclusions ..................................................................................................... 128 4. Recommendations ............................................................................... 128 Assessment report EMA/725757/2016 Page 4/129 List of abbreviations AASLD American Association for the Study of Liver Diseases AE adverse event AMA antimitochondrial antibody ALT alanine aminotransferase ALP alkaline phosphatase AMA antimitochondrial antibodies ANCOVA analysis of covariance aPTT activated partial thromboplastin time AST aspartate aminotransferase ATC Anatomical/Therapeutic/Chemical AUC area under the curve BA bioavailability BAS bile acid sequestrants BE bioequivalence BMD bone mineral density BMI body mass index BP blood pressure CA cholic acid CDCA chenodeoxycholic acid Clcr creatinine clearance Cmax Maximum observed concentration CRA clinical research associate CRF case report form CRP C-reactive protein CSR clinical study report DB double-blind DCA deoxycholic acid DDI drug-drug interaction DEXA dual-emission x-ray absorptiometry DSMC Data Safety Monitoring Committee EASL European Association for
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