25 September 2014 EMA/CHMP/738815/2014 Committee for Medicinal Products for Human Use (CHMP) Assessment report Moventig International non-proprietary name: naloxegol Procedure No. EMEA/H/C/002810/0000 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 © European Medicines Agency, 2014. Reproduction is authorised provided the source is acknowledged. Administrative information Name of the medicinal product: Moventig Applicant: AstraZeneca AB SE-151 85 Södertälje Sweden Active substance: naloxegol oxalate International Nonproprietary Name/Common naloxegol Name: Pharmaco-therapeutic group Drugs for constipation (ATC Code): (A06AH03) Therapeutic indication(s): Moventig is indicated for the treatment of opioid-induced constipation (OIC) in adult patients who have had an inadequate response to laxative(s). Pharmaceutical form: Film-coated tablet Strengths: 12.5 mg and 25 mg Route of administration: Oral use Packaging: Blister 12.5 mg: Package sizes: 30 (3x10) tablets, 90 (9x10) tablets and 90 x 1 tablets (unit dose) 25mg: 10 (1x10) tablets, 30 (3x10) tablets, 90 (9x10) tablets and 90 x 1 tablets (unit dose) Assessment report EMA/CHMP/738815/2014 Page 2/120 Table of contents 1. Background information on the procedure .............................................. 9 1.1. Submission of the dossier ...................................................................................... 9 1.2. Manufacturers .................................................................................................... 10 1.3. Steps taken for the assessment of the product ....................................................... 10 2. Scientific discussion .............................................................................. 12 2.1. Introduction....................................................................................................... 12 2.2. Quality aspects .................................................................................................. 13 2.2.1. Introduction .................................................................................................... 13 2.2.2. Active Substance ............................................................................................. 13 2.2.3. Finished Medicinal Product ................................................................................ 15 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 18 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 18 2.2.6. Recommendation(s) for future quality development ............................................. 18 2.3. Non-clinical aspects ............................................................................................ 18 2.3.1. Introduction .................................................................................................... 18 2.3.2. Pharmacology ................................................................................................. 19 2.3.3. Pharmacokinetics............................................................................................. 21 2.3.4. Toxicology ...................................................................................................... 22 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 26 2.3.6. Discussion on non-clinical aspects...................................................................... 27 2.3.7. Conclusion on the non-clinical aspects ................................................................ 28 2.4. Clinical aspects .................................................................................................. 28 2.4.1. Introduction .................................................................................................... 28 2.4.2. Pharmacokinetics............................................................................................. 31 2.4.3. Pharmacodynamics .......................................................................................... 39 2.4.4. Discussion on clinical pharmacology ................................................................... 41 2.4.5. Conclusions on clinical pharmacology ................................................................. 41 2.5. Clinical efficacy .................................................................................................. 42 2.5.1. Dose response study ........................................................................................ 46 2.5.3. Discussion on clinical efficacy ............................................................................ 89 2.5.4. Conclusions on the clinical efficacy ..................................................................... 92 2.6. Clinical safety .................................................................................................... 93 2.6.1. Discussion on clinical safety ............................................................................ 102 2.6.2. Conclusions on the clinical safety ..................................................................... 104 2.7. Pharmacovigilance ............................................................................................ 104 2.8. Risk Management Plan ...................................................................................... 104 2.9. Product information .......................................................................................... 114 2.9.1. User consultation ........................................................................................... 114 Assessment report EMA/CHMP/738815/2014 Page 3/120 3. Benefit-Risk Balance............................................................................ 114 4. Recommendations ............................................................................... 119 Assessment report EMA/CHMP/738815/2014 Page 4/120 List of abbreviations ADME Absorption, distribution, metabolism and excretion ADR Adverse Drug Reaction AE Adverse event ALMP Abuse Liability Monitoring Plan AUC Area under the concentration time curve BA Bioavailability BBB Blood-brain barrier BCS Biopharmaceutics Classification System BE Bioequivalence BLRSQ Baseline Laxative Response Status Questionnaire BMI Body mass index BP Blood pressure CEP Certification of suitability to the monographs of the European Pharmacopoeia CHMP Committee for Medicinal Products for Human Use CI Confidence interval CL Clearance Cmax Maximum plasma drug concentration CMH Cochran-Mantel-Haenszel CNS Central nervous system CQA Critical quality attribute CSP Clinical study protocol CSR Clinical study report C-SSRS Columbia-Suicide Severity Rating Scale CYP3A4 Cytochrome P450 3A4 CV Cardiovascular CV-EAC Cardiovascular event adjudication committee DAE Discontinuation of investigational product due to an AE DEA US Drug Enforcement Administration DAMGO [D-Ala2, N-MePhe4, Gly-ol]-enkephalin EC European Commission Assessment report EMA/CHMP/738815/2014 Page 5/120 ECG Electrocardiogram eDiary Electronic diary EDQM European Directorate for the Quality of Medicines & Healthcare EFD Embryo-fetal development EMA European Medicines Agency EU European Union FDA US Food and Drug Administration GC Gas chromatography GI Gastrointestinal GI-EAC Gastrointestinal event adjudication committee HPLC High performance liquid chromatography ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use IP Investigational Product IPC In-process control IR Immediate release IR Infrared spectroscopy ISR incurred sample reproducibility ITT Intent-to-treat KF Karl-Fischer titration LAR Laxative Adequate Responder/Response LCMS Liquid chromatograpy mass spectrometry LIR Laxative Inadequate Responder/Response LS Mean Least-Squares Mean LUR Laxative Unknown Responder/Response MACE Major adverse cardiovascular event MedDRA Medical Dictionary for Regulatory Activities meu Morphine equivalent units mHS Modified Himmelsbach scale MI Myocardial infarction MMRM Mixed model for Repeated Measures MTP Multiple Testing Procedure Naloxegol Also known as NKTR-118, PEG-naloxol, NKT-10018, as naloxol 6α- Assessment report EMA/CHMP/738815/2014 Page 6/120 methoxyhepta(ethylene glycol) ether, also known as α-6-mPEG7-O-naloxol. Naloxegol oxalate salt International Union of Pure and Applied Chemistry (IUPAC) name is (5a,6a)-17-allyl-6-(2,5,8,11,14,17,20-heptaoxadocosan-22-yloxy)-4,5- epoxymorphinan-3,14-diol oxalate NMR Nuclear magnetic resonance NRS Numeric rating scale OCTT Oral cecal transit time OIC Opioid induced constipation PAC-QOL Patient Assessment of Constipation Quality of Life PAC-SYM Patient Assessment of Constipation Symptoms questionnaire PAMORA Peripherally acting μ-opioid receptor antagonist PBPK Physiologically-based pharmacokinetic modeling PCI Potentially clinically important PDCO Paediatric Committee PEG Polyethylene glycol P-gp P-glycoprotein Ph. Eur. European Pharmacopoeia PIP Paediatric Investigation Plan PK Pharmacokinetic(s) PPI Proton Pump Inhibitors PRO Patient reported outcome PRMP Patient Risk Management Plan PT Preferred Term QD Every day/once daily QoL Quality of Life QTcF Fridericia corrected QT interval QWBA quantitative whole body autoradiography