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Kolbam, INN-Cholic Acid 24 September 2015 EMA/689761/2015 Committee for Medicinal Products for Human Use (CHMP) Assessment report Kolbam Medicinal International non-proprietary name: cholic acid Procedure No. EMEA/H/C/002081/0000product Note no Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. longer authorised 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, 2015. Reproduction is authorised provided the source is acknowledged. Table of contents 1.1. Submission of the dossier ...................................................................................... 5 1.2. Manufacturers ...................................................................................................... 7 1.3. Steps taken for the assessment of the product ......................................................... 7 2. Scientific discussion ................................................................................ 9 2.1. Introduction......................................................................................................... 9 2.2. Quality aspects .................................................................................................. 11 2.2.1. Introduction .................................................................................................... 11 2.2.2. Active Substance ............................................................................................. 11 2.2.3. Finished Medicinal Product ................................................................................ 14 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 16 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 16 2.3. Non-clinical aspects ............................................................................................ 17 2.3.1. IntroductionMedicinal.................................................................................................... product n 17 2.3.2. Pharmacology ................................................................................................. 17 2.3.3. Pharmacokinetics............................................................................................. 19 2.3.4. Toxicology ...................................................................................................... 21 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................................................................ 27 2.4. Clinical aspects .................................................................................................. 28 2.4.1. Introduction.................................................................................................... 28 2.4.2. Pharmacokinetics.............................................................................................o longer authorised 29 2.4.3. Pharmacodynamics .......................................................................................... 34 2.4.4. Discussion on clinical pharmacology................................................................... 35 2.4.5. Conclusions on clinical pharmacology ................................................................. 37 2.5. Clinical efficacy .................................................................................................. 37 2.5.1. Dose response study........................................................................................ 37 2.5.2. Main study...................................................................................................... 38 2.5.3. Discussion on clinical efficacy............................................................................ 63 2.5.4. Conclusions on the clinical efficacy..................................................................... 71 2.6. Clinical safety .................................................................................................... 73 2.6.1. Discussion on clinical safety .............................................................................. 81 2.6.2. Conclusions on the clinical safety ....................................................................... 82 2.7. Pharmacovigilance .............................................................................................. 83 2.8. Risk Management Plan ........................................................................................ 83 2.9. Significance of paediatric studies .......................................................................... 86 2.10. User consultation .............................................................................................. 86 3. Benefit-Risk Balance ............................................................................ 86 4. Recommendations ............................................................................... 89 Assessment report EMA/689761/2015 Page 2/97 List of abbreviations 3β-HSD 3β-hydroxy-Δ5-C27-steroid oxidoreductase ∆4-3-oxo-R Δ4-3-oxosteroid 5β-reductase AE Adverse Event ALT Alanine Aminotransferase AKR1D1 Δ4-3-oxosteroid 5β-reductase AMACR 2- (or α-) methylacyl-CoA racemase AST Aspartate Aminotransferase ATC Anatomical Therapeutic Classification AUC MedicinalArea Under the Concentration Curve CA cholic acid CCHMC Cincinnati Children’s Hospital Medical Center CDCA Chenodeoxycholic acid CI Confidence Intervalproduct Cmax Maximum Plasma Concentration CNS Central Nervous System CSR Clinical Study Report no CTX Cerebrotendinous Xanthomatosislonger CYP7A1 Cholesterol 7α-Hydroxylase CYP7B1 Oxysterol 7α-Hydroxylase GGT Gamma Glutamyl Transferase authorised DHCA Dihydroxycholestanoic acid EMA European Medicines Agency EU European Union FAB-MS Fast Atomic Bombardment-Mass Spectroscopy FXR Faresoid X Receptor GC Gas Chromatography GC-MS Gas Chromatography-Mass Spectrometry GCP Good Clinical Practice HPLC High Pressure Liquid Chromatography HSD3ß7 3β-hydroxy-Δ5-C27-steroid oxidoreductase ICH International Conference on Harmonization IRB Institutional Review Board ITT Intent To Treat Assessment report EMA/689761/2015 Page 3/97 LC-MS Liquid Chromatography-Mass Spectrometry LFT Liver Function Test mITT Modified Intent To Treat MS Mass Spectroscopy NALD Neonatal Adrenoleukodystrophy PK Pharmacokinetic SAE Serious Adverse Event SmPC Summary of Product Characteristics SOC System Organ Class TBM To Be Marketed THCA Trihydroxycholestanoic acid THCA-CoA MedicinalTrihydroxycholestanoic acid Coenzyme A ULN Upper Limit Normal URSO Ursodeoxycholic acid product no longer authorised Assessment report EMA/689761/2015 Page 4/97 1. Background information on the procedure 1.1. Submission of the dossier The applicant FGK Representative Service GmbH submitted on 29 February 2012 an application for Marketing Authorisation to the European Medicines Agency (EMA) for cholic acid FGK, 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 29 May 2009. Cholic acid FGK, was designated as an orphan medicinal product EU/3/09/683 on 9 December 2011 in the following indication: Treatment of inborn errors of primary bile acid synthesis responsive to treatment with cholic acid. At the time of designation, inborn errors in primary bile acid synthesis responsive to treatment with cholic acid affected approximately 0.07 in 10,000 people in the European Union (EU). Following the CHMP positiveMedicinal opinion on this marketing authorisation, the Committee for Orphan Medicinal Products (COMP) reviewed the designation of Kolbam 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 applicant applied for the followingproduct indications: Cholic acid FGK is indicated for the treatment of inborn errors of primary bile acid synthesis, responsive to treatment with cholic acid, in infants from one month of age for continuous lifelong treatment through adulthood. no Inborn errors of primary bile acid synthesis involve congenital defects in the primary enzymes responsible for catalysing key reactions in the synthesislonger of cholic and chenodeoxycholic acids. The primary enzyme defects include but are not limited to: 5 5 • 3β-hydroxy-∆ -C27-steroid oxidoreductase (also known as 3β-hydroxy-∆ -C27-steroid dehydrogenase/isomerase or 3β-HSD or HSD3β7) deficiencyauthorised • ∆4-3-oxosteroid 5β-reductase (∆4-3-oxo-R or AKR1D1) deficiency • Sterol 27-hydroxylase (presenting as cerebrotendinous xanthomatosis, CTX) deficiency • Defective bile acid amidation due to failure to conjugate with glycine and/or taurine • 2- (or α-) methylacyl-CoA racemase (AMACR) deficiency • Oxysterol 7α-hydroxylase (CYP7B1) deficiency • Cholesterol 7α-hydroxylase (CYP7A1) deficiency • Trihydroxycholestanoic acid (THCA) CoA oxidase deficiency • Side-chain oxidation defect in the sterol 25-hydroxylation pathway The legal basis for this application refers to: Article 8.3 of Directive 2001/83/EC, as amended - complete and independent application.
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