1 August 2012 EMA/CHMP/508338/2012 Committee for Medicinal Products for Human Use (CHMP) Assessment report Enurev Breezhaler International non-proprietary name: glycopyrronium bromide Procedure No.: EMEA/H/C/002430 Assessment Report as adopted by the CHMP with all information of a commercially confidential nature deleted 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7455 E-mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2012. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 5 1.1. Submission of the dossier.................................................................................... 5 1.2. Steps taken for the assessment of the product ....................................................... 5 2. Scientific discussion ................................................................................ 6 2.1. Introduction ...................................................................................................... 6 2.2. Quality aspects .................................................................................................. 8 2.2.1. Introduction ................................................................................................... 8 2.2.2. Active Substance............................................................................................. 8 2.2.3. Finished Medicinal Product .............................................................................. 10 2.2.4. Discussion on chemical, pharmaceutical and biological aspects............................. 12 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ..................... 12 2.3. Non-clinical aspects .......................................................................................... 13 2.3.1. Introduction ................................................................................................. 13 2.3.2. Pharmacology ............................................................................................... 13 2.3.3. Pharmacokinetics .......................................................................................... 16 2.3.4. Toxicology.................................................................................................... 21 2.3.5. Ecotoxicity/environmental risk assessment........................................................ 31 2.3.6. Discussion on non-clinical aspects.................................................................... 32 2.3.7. Conclusion on the non-clinical aspects .............................................................. 32 2.4. Clinical aspects ................................................................................................ 32 2.4.1. Introduction ................................................................................................. 32 2.4.2. Pharmacokinetics .......................................................................................... 35 2.4.3. Pharmacodynamics........................................................................................ 39 2.4.4. Discussion on clinical pharmacology ................................................................. 41 2.4.5. Conclusions on clinical pharmacology ............................................................... 42 2.5. Clinical efficacy ................................................................................................ 43 2.5.1. Dose response studies.................................................................................... 44 2.5.2. Main studies ................................................................................................. 47 2.5.3. Discussion on clinical efficacy .......................................................................... 66 2.5.4. Conclusions on the clinical efficacy ................................................................... 67 2.6. Clinical safety .................................................................................................. 68 2.6.1. Discussion on clinical safety ............................................................................ 76 2.6.2. Conclusions on the clinical safety ..................................................................... 77 2.7. Pharmacovigilance............................................................................................ 78 2.8. User consultation ............................................................................................. 80 3. Benefit-Risk Balance............................................................................ 81 4. Recommendations ............................................................................... 83 Enurev Breezhaler CHMP assessment report EMA/CHMP/508338/2012 Page 2/84 List of abbreviations ABC ATP-binding cassette ADR Adverse drug reaction AE Adverse event ALT Alanine aminotransferase ANCOVA Analysis of covariance AST Aspartate aminotransferase ATP Adenosine triphosphate AUC Area under the curve b.i.d. Bis in diem/twice daily BDI Baseline dyspnea index BMI Body mass index BP Blood pressure bpm Beats per minute CCV Cardio- and cerebro-vascular CHO Chinese hamster ovary CI Confidence interval CL Clearance Cmax Maximum peak concentration Cmax,ss Maximum plasma concentration at steady-state CNS Central nervous system COPD Chronic obstructive pulmonary disease CTD Common Technical Document CV Cardiovascular CYP Cytochrome DBP Diastolic blood pressure DRF Dose-range finding ECG Electrocardiogram eCRF Electronic Case Report Form EMEA/EMA European Medicines Evaluation Agency FAS Full analysis set FDA Food and Drug Administration FEV1 Forced expiratory volume in 1 second FMO Flavin-containing monooxygenase enzyme FVC Forced vital capacity GD Gestation day GI Gastro-intestinal GLP Good laboratory practice GOLD Global Initiative for Chronic Obstructive Lung Disease GP Glycopyrronium bromide hERG human ether-a-go-go-related gene HPLC High performance liquid chromatography HR Heart rate HLT High level term IC Inspiratory capacity IC50 Inhibitor concentration producing 50% inhibition of enzyme or transporter activity ICS Inhaled corticosteroid IT Intratracheal i.v. Intravenous Ki Inhibitor binding constant LABA Long-acting β2-agonist LAMA Long-acting muscarinic-antagonist LC-MS Liquid chromatography coupled with mass spectrometry LC-MS/MS Liquid chromatography coupled with tandem mass spectrometry LOQ Limit of quantification LOAEL Lowest observed adverse effect level LS Least square means MACE Major adverse cardiovascular event MAP Mean arterial blood pressure Enurev Breezhaler CHMP assessment report EMA/CHMP/508338/2012 Page 3/84 MATE1 Multi-drug and toxin extrusion protein MCID Minimal clinically important difference MDR Multidrug-resistant protein efflux transporter MedDRA Medical Dictionary for Regulatory Affairs MMAD Mass median aerodynamic diameter MRP Multidrug resistance-associated protein efflux transporter MS Mass spectrometry MXR Breast cancer resistant protein or mitoxantrone resistant protein efflux transporter NOAEL No observed adverse effect level NOEL No observed effect level NVA/NVA237 glycopyrronium bromide OCT Organic cation transporter o.d. omnie die/every day OL Open label OR Odds ratio Pbo Placebo PD Pharmacodynamic(s) PEC Predicted environmental concentration Ph.Eur European Pharmacopoeia PK Pharmacokinetic(s) pKi Apparent binding affinity constant PO Oral PY Patient-years QBA608 ([3S,2R]-threo-isomer) of NVA237 QBA609 ([3R,2S]-threo-isomer) of NVA 237 q.d. quaque die/every day QTcF QTc (Fridericia correction) RI Renal impairment RTI Respiratory tract infection SAE Serious adverse event SBP Systolic blood pressure SC Subcutaneous SD Standard deviation SDDPI Single dose dry powder inhaler SLC Solute carrier uptake transporters SMQ Standardized MedDRA query SOC System organ class SGRQ St Gorge Respiratory Questionnaire SMETT Sub-max constant-load cycle ergometry test ss Steady state T½ Apparent elimination half-life TDI Transition dyspnea index Tg Transgenic Tmax Time to reach maximum concentration Tio Tiotropium ULN Upper limit normal URTI Upper respiratory tract infection V Volume of distribution WBC White blood cell Enurev Breezhaler CHMP assessment report EMA/CHMP/508338/2012 Page 4/84 1. Background information on the procedure 1.1. Submission of the dossier The applicant Novartis Europharm Ltd. submitted on 1 September 2011 an application for Marketing Authorisation to the European Medicines Agency (EMA) for Enurev Breezhaler, through the centralised procedure under Article 3 (2) (b) of Regulation (EC) No 726/2004. The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 16 December 2010. The eligibility to the centralised procedure under Article 3(2)(b) of Regulation (EC) No 726/2004 was based on demonstration of significant therapeutic innovation. The applicant applied for the following indication: Enurev Breezhaler is indicated as a once-daily maintenance bronchodilator treatment to relieve symptoms of patients with chronic obstructive pulmonary disease (COPD). The legal basis for this application refers to: Article 8.3 of Directive 2001/83/EC - complete and independent application. The application submitted is composed of administrative information, complete quality data, non- clinical and clinical data based on applicants’ own tests and studies and bibliographic literature