25 July 2013 EMA/CHMP/208477/2013 Committee for Medicinal Products for Human Use (CHMP) CHMP assessment report Incresync International non-proprietary name: alogliptin / pioglitazone Procedure No. EMEA/H/C/002178/0000 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 Table of contents 1. Background information on the procedure .............................................. 7 1.1. Submission of the dossier ...................................................................................... 7 1.2. Manufacturers ...................................................................................................... 8 1.3. Steps taken for the assessment of the product ......................................................... 8 2. Scientific discussion ................................................................................ 9 2.1. Introduction......................................................................................................... 9 2.2. Quality aspects .................................................................................................. 10 2.2.1. Introduction .................................................................................................... 10 2.2.2. Active Substance Pioglitazone ........................................................................... 11 2.2.3. Active Substance Alogliptin ............................................................................... 12 2.2.4. Finished Medicinal Product ................................................................................ 15 2.2.5. Discussion on chemical, pharmaceutical and biological aspects .............................. 18 2.2.6. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 18 2.2.7. Recommendation 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............................................................................................. 25 2.3.4. Toxicology ...................................................................................................... 34 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 45 2.3.6. Discussion on non-clinical aspects...................................................................... 48 2.3.7. Conclusion on the non-clinical aspects ................................................................ 54 2.4. Clinical aspects .................................................................................................. 54 2.4.1. Introduction .................................................................................................... 54 2.4.2. Pharmacokinetics............................................................................................. 57 2.4.3. Pharmacodynamics .......................................................................................... 65 2.4.4. Discussion on clinical pharmacology ................................................................... 67 2.4.5. Conclusions on clinical pharmacology ................................................................. 70 2.5. Clinical efficacy .................................................................................................. 70 2.5.1. Dose response study ........................................................................................ 73 2.5.2. Main studies ................................................................................................... 74 2.5.3. Discussion on clinical efficacy ............................................................................ 88 2.5.4. Conclusions on the clinical efficacy ..................................................................... 90 2.6. Clinical safety .................................................................................................... 90 2.6.1. Discussion on clinical safety ............................................................................ 115 2.6.2. Conclusions on the clinical safety ..................................................................... 120 2.7. Pharmacovigilance ............................................................................................ 120 2.8. Risk Management Plan ...................................................................................... 120 2.9. User consultation ............................................................................................. 126 CHMP assessment report EMA/CHMP/208477/2013 Page 2/136 3. Benefit-Risk Balance ........................................................................... 126 4. Recommendations ............................................................................... 131 CHMP assessment report EMA/CHMP/208477/2013 Page 3/136 List of abbreviations ADME absorption, distribution, metabolism, and excretion ADR adverse drug reaction Ae total amount of drug excreted A/G albumin/globulin ALB albumin ALP alkaline phosphatase ALT alanine aminotransferase ANCOVA analysis of covariance ANOVA analysis of variance API Active Pharmaceutical Ingredient ADR adverse drug reactions AR Assessment Report ASM Active Substance Manufacturer AST aspartate aminotransferase AUC area under the plasma concentration-time curve AUC(0-inf) area under the plasma concentration-time curve from time 0 to time infinity BA bioavailability BID twice per day %CV percent coefficient of variation Caco-2 human colonic adenocarcinoma CHO Chinese hamster ovary CI confidence interval CK creatine kinase Cl chloride CL clearance CLr renal clearance Cmax maximum observed plasma concentration CNS central nervous system Cr serum creatinine CrCl creatinine clearance CRP C-reactive protein CYP cytochrome P-450 DASH DASH DPP-4 activity and/or structure homologues DPP-2,-4… dipeptidyl peptidase-2, 4, … E2 estradiol EC50 half-maximal effective concentration ECG electrocardiogram FDC fixed-dose combination GC Gas Chromatography GD Gestation Day GFR glomerular filtration rate GGT γ-glutamyl transferase GHb glycosylated hemoglobin GI gastrointestinal GIP glucose-dependent insulinotropic peptide GLP Good Laboratory Practice GLP-1 glucagon-like peptide-1 Glut2 glucose transporter 2 GMP Good Manufacturing Practice HbA1c glycosylated hemoglobin HCl Hydrochloric acid HCT hematocrit HDL high-density lipoprotein HDL-C high-density lipoprotein cholesterol CHMP assessment report EMA/CHMP/208477/2013 Page 4/136 HGB haemoglobin HPLC high-performance liquid chromatography ICH International Conference on Harmonisation IC50 50% inhibitory concentration IDL intermediate-density lipoprotein IP intraperitoneal IPC In-process control IR Infrared IR immunoreactivity ITT intent to treat IV intravenously ka absorption constant KF Karl Fischer LD Lactation Day LDH lactate dehydrogenase LDL low-density lipoprotein LDL-C Low-density lipoprotein cholesterol LDPE Low Density Polyethylene LH luteinizing hormone LS least squares M-I, M-II, … metabolite I, I … LYM lymphocytes MAA Marketing Authorisation Application MET metformin MON monocytes MS Mass Spectrometry MTD maximum tolerated dose N/A not applicable ND Not detected NOAEL no-observed-adverse-effect level NT Not tested OGTT oral glucose tolerance test OAT organic anion transporters PCTFE Polychlorotrifluoroethylene pdx-1 insulin promoter transcription factor PE Polyethylene Ph.Eur. European Pharmacopoeia PIP Paediatric Investigation Plan PK Pharmacokinetic PO by mouth PPARγ peroxisome proliferator–activated receptorγ Ppg postprandial glucose PSUR Periodic Safety Update Report PT prothrombin time PVC Polyvinylchloride QTc QT interval corrected for heart rate RBC red blood cell RET reticulocytes RH Relative Humidity RV residual variability SAE serious adverse event SC subcutaneous SCr serum creatinine %SEM standard error of the parameter estimate divided by the parameter estimate 100% STZ streptozotocin SU sulfonylurea T1/2 or T1/2, z terminal elimination half-life T2DM type 2 diabetes mellitus TFA triflouroacetate salt CHMP assessment report EMA/CHMP/208477/2013 Page 5/136 TG triglycerides TLC Thin Layer Chromatography Tmax time to reach Cmax TS tosylate salt TZD thiazolidinedione ULN upper limit of normal UN urea nitrogen USP United States Pharmacopoeia UV Ultraviolet WBC white blood cells CHMP assessment report EMA/CHMP/208477/2013 Page 6/136 1. Background information on the procedure 1.1. Submission of the dossier The applicant Takeda Global Research and Development Centre (Europe) Limited submitted on 30 May 2012 an application for Marketing Authorisation to the European Medicines Agency (EMA) for Incresync, through the centralised procedure falling within the Article 3(1) and point 3 of Annex of Regulation (EC) No 726/2004 . The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 20 October 2011. During the procedure the applicant has changed to Takeda Pharma A/S. The applicant applied for the following indication: Incresync is indicated to improve glycaemic control in adult patients (≥ 18 years old) with type