15 October 2020 EMA/582495/2020 Committee for Medicinal Products for Human Use (CHMP) Assessment report Trixeo Aerosphere International non-proprietary name: Formoterol / glycopyrronium bromide/ budesonide Procedure No. EMEA/H/C/004983/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address[Type here] for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2021. Reproduction is authorised provided the source is acknowledged. 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, screening tools/prevention ......................................9 2.1.3. Aetiology and pathogenesis................................................................................9 2.1.4. Clinical presentation, diagnosis and stage/prognosis ............................................10 2.1.5. Management ..................................................................................................10 2.2. Quality aspects..................................................................................................13 Introduction ............................................................................................................13 2.2.1. Active substances ...........................................................................................13 Budesonide – micronised- .........................................................................................13 General information..................................................................................................13 Manufacture, characterisation and process controls.......................................................14 Specification............................................................................................................14 Stability ..................................................................................................................15 Glycopyrronium bromide – micronised- .......................................................................15 General information..................................................................................................15 Manufacture, characterisation and process controls.......................................................16 Specification............................................................................................................16 Stability ..................................................................................................................16 Formoterol fumarate dihydrate-micronised ..................................................................17 General information..................................................................................................17 Manufacture, characterisation and process controls.......................................................17 Specification............................................................................................................18 Stability ..................................................................................................................18 2.2.2. Finished medicinal product ...............................................................................18 Description of the product and Pharmaceutical development ..........................................18 Manufacture of the product and process controls ..........................................................20 Product specification.................................................................................................20 Stability of the product .............................................................................................21 Adventitious agents ..................................................................................................22 2.2.3. Discussion on chemical, and pharmaceutical aspects............................................22 Conclusions on the chemical, pharmaceutical and biological aspects................................22 2.2.4. Recommendations for future quality development ...............................................22 2.3. Non-clinical aspects ...........................................................................................23 2.3.1. Introduction ...................................................................................................23 2.3.2. Pharmacology.................................................................................................23 Primary pharmacodynamics.......................................................................................25 Assessment report EMA/582495/2020 Page 2/238 Secondary pharmacodynamics ...................................................................................27 Safety pharmacology programme ...............................................................................27 Pharmacodynamic drug interactions............................................................................28 2.3.3. Pharmacokinetics ............................................................................................28 Methods of analysis ..................................................................................................28 Absorption ..............................................................................................................29 Distribution .............................................................................................................38 Metabolism..............................................................................................................41 Excretion ................................................................................................................43 Pharmacokinetic drug interactions ..............................................................................44 Other pharmacokinetic studies ...................................................................................46 2.3.4. Toxicology .....................................................................................................47 Long-term studies ....................................................................................................59 Antigenicity .............................................................................................................68 Immunotoxicity........................................................................................................68 Studies on impurities ................................................................................................68 Other studies...........................................................................................................74 2.3.5. .....................................................................................................................77 2.3.6. Ecotoxicity/environmental risk assessment .........................................................77 2.3.7. Discussion on non-clinical aspects .....................................................................79 2.3.8. Conclusion on the non-clinical aspects ...............................................................80 2.4. Clinical aspects..................................................................................................81 2.4.1. Introduction ...................................................................................................81 human pharmacodynamic studies..............................................................85 Efficacy and safety studies ........................................................................87 2.4.2. Pharmacokinetics ............................................................................................89 2.4.3. Pharmacodynamics........................................................................................104 2.4.4. Discussion on clinical pharmacology.................................................................104 2.4.5. Conclusions on clinical pharmacology ...............................................................107 2.5. Clinical efficacy................................................................................................108 2.5.1. Dose response studies ...................................................................................108 2.5.2. Main studies .................................................................................................109 2.5.3. Discussion on clinical efficacy..........................................................................189 2.5.4. Conclusions on the clinical efficacy...................................................................197 2.6. Clinical safety ..................................................................................................198