10 July 2020 EMA/385871/2020 Rev.1 Committee for Medicinal Products for Human Use (CHMP) Assessment report Kaftrio International non-proprietary name: ivacaftor / tezacaftor / elexacaftor Procedure No. EMEA/H/C/005269/0000 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 for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us An agency of the European Union Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 © European Medicines Agency, 2020. 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. Epidemiology .................................................................................................. 10 2.1.2. Aetiology and pathogenesis .............................................................................. 10 2.1.3. Clinical presentation and diagnosis. ................................................................... 11 2.1.4. Management ................................................................................................... 12 2.2. Quality aspects .................................................................................................. 13 2.2.1. Introduction .................................................................................................... 13 2.2.2. Active Substance ............................................................................................. 14 2.2.3. Finished Medicinal Product ................................................................................ 24 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 31 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 32 2.2.6. Recommendation for future quality development ................................................. 32 2.3. Non-clinical aspects ............................................................................................ 32 2.3.1. Introduction .................................................................................................... 32 2.3.2. Pharmacology ................................................................................................. 33 2.3.3. Pharmacokinetics............................................................................................. 36 2.3.4. Toxicology ...................................................................................................... 41 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 46 2.3.6. Discussion on non-clinical aspects...................................................................... 49 2.3.7. Conclusion on non-clinical aspects ..................................................................... 57 2.4. Clinical aspects .................................................................................................. 57 2.4.1. Introduction .................................................................................................... 57 2.4.2. Pharmacokinetics............................................................................................. 58 2.4.3. Pharmacodynamics .......................................................................................... 63 2.4.4. Discussion on clinical pharmacology ................................................................... 64 2.4.5. Conclusions on clinical pharmacology ................................................................. 66 2.5. Clinical efficacy .................................................................................................. 66 2.5.1. Dose-response studies ..................................................................................... 69 2.5.2. Main studies ................................................................................................... 72 2.5.3. Discussion on clinical efficacy .......................................................................... 112 2.5.4. Conclusions on clinical efficacy ........................................................................ 124 2.6. Clinical safety .................................................................................................. 124 2.6.1. Discussion on clinical safety ............................................................................ 154 2.6.2. Conclusions on clinical safety .......................................................................... 158 2.7. Risk Management Plan ...................................................................................... 158 2.8. Pharmacovigilance ............................................................................................ 162 2.9. New Active Substance ....................................................................................... 162 2.10. Product information ........................................................................................ 162 Assessment report EMA/385871/2020 Page 2/3 2.10.1. User consultation ......................................................................................... 162 2.10.2. Additional monitoring ................................................................................... 162 3. Benefit-Risk Balance............................................................................ 162 3.1. Therapeutic Context ......................................................................................... 162 3.1.1. Disease or condition ....................................................................................... 162 3.1.2. Available therapies and unmet medical need ..................................................... 163 3.1.3. Main clinical studies ....................................................................................... 163 3.2. Favourable effects ............................................................................................ 164 3.3. Uncertainties and limitations about favourable effects ........................................... 166 3.4. Unfavourable effects ......................................................................................... 167 3.5. Uncertainties and limitations about unfavourable effects ....................................... 169 3.6. Effects Table .................................................................................................... 170 3.7. Benefit-risk assessment and discussion ............................................................... 172 3.7.1. Importance of favourable and unfavourable effects ............................................ 172 3.7.2. Balance of benefits and risks ........................................................................... 175 3.7.3. Additional considerations on the benefit-risk balance ......................................... 177 3.8. Conclusions ..................................................................................................... 177 4. Recommendations ............................................................................... 177 Assessment report EMA/385871/2020 Page 3/4 List of abbreviations ADR adverse drug reaction AE adverse event ALT alanine transaminase ARAUC accumulation ratio of AUC AST aspartate transaminase AUC area under the concentration versus time curve AUCτ AUC during a dosing interval BA bioavailability BL baseline BMI body mass index BP blood pressure bpm beats per minute Cavg average concentration during a dosing interval at steady-state CF cystic fibrosis CFF-TDN Cystic Fibrosis Foundation Therapeutics Development Network CFQ-R Cystic Fibrosis Questionnaire-Revised CFQ-R RD Cystic Fibrosis Questionnaire-Revised Respiratory Domain CFTR cystic fibrosis transmembrane conductance regulator gene CFTR cystic fibrosis transmembrane conductance regulator protein CI confidence interval CK creatine kinase Cmax maximum observed concentration Cmin minimum observed concentration CSR clinical study report CYP cytochrome P450 C-QTc concentration-QTc DBP diastolic blood pressure DDI drug-drug interaction ECFS-CTN European Cystic Fibrosis Society Clinical Trials Network ECG electrocardiogram EE ethinyl estradiol eGFR estimated glomerular filtration rate EMA European Medicines Agency EOP2 End-of-Phase 2 E-R exposure-response EU European Union F/F homozygous for F508del F/G heterozygous for F508del and a gating mutation F/MF heterozygous for F508del and an MF mutation F/RF heterozygous for F508del and a residual function mutation Assessment report EMA/385871/2020 Page 4/5 F508del CFTR gene mutation with an in-frame deletion of a phenylalanine codon corresponding to position 508 of the wild-type protein FAS Full Analysis Set FDA Food and Drug Administration FDC fixed-dose combination FEV1 forced expiratory volume in 1 second G gating GCP Good Clinical Practice GGT gamma-glutamyl transferase HBE human bronchial epithelial HR heart rate IA interim analysis