Assessment report - European Medicines Agency

1 18 September 2012 EMA/689976/2012 Committee for Medicinal Products for Human Use (CHMP) Assessment report Forxiga dapagliflozin Procedure No.: EMEA/H/C/002322 Note 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 An Agency of the European Union Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8613 E-mail Website Table of contents 1. Background information on the procedure .. 6 Submission of the dossier .. 6 Manufacturers .. 7 Steps taken for the Assessment of the product .. 7 2. Scientific discussion .. 9 9 Quality aspects .. 10 Introduction .. 10 Active Substance .. 10 Finished Medicinal Product .. 13 Discussion on chemical, pharmaceutical and biological aspects.

2 18 Conclusions on the chemical, pharmaceutical and biological aspects .. 18 Non-clinical aspects .. 18 Introduction .. 18 Pharmacology .. 18 21 Toxicology .. 24 Ecotoxicity/environmental risk Assessment .. 30 Discussion on non-clinical 32 Conclusion on the non-clinical aspects .. 33 Clinical aspects .. 34 Introduction .. 34 36 Pharmacodynamics .. 45 Discussion on clinical pharmacology .. 49 Conclusions on clinical pharmacology .. 51 Clinical efficacy .. 51 Dose response 51 Main studies .. 54 Discussion on clinical efficacy .. 117 Conclusions on the clinical efficacy .. 120 Clinical safety .. 120 Discussion on clinical safety .. 137 Conclusions on the clinical safety .. 144 Pharmacovigilance .. 145 User consultation .. 162 3. Benefit-Risk Balance.

3 163 4. Recommendations .. 170 Forxiga Assessment report EMA/689976/2012 Page 2/170 List of abbreviations ABP Ambulatory blood pressure ADME Absorption, distribution, metabolism, elimination AE Adverse event ALT/ALAT Alanine transaminase ANOVA Analysis of variance AST/ASAT Aspartat transaminase AUC Area under the analyte plasma concentration-time curve AUEC Area under the effect curve AUCinf Area under the analyte plasma concentration-time curve from time point zero extrapolated to infinity AUC ,ss(,norm) Area under the analyte plasma concentration-time curve over a dosing interval at steady-state (dose normalized) AUC(tau) Area under the analyte plasma concentration-time curve in one dosing interval BA Bioavailability BCS Biopharmaceutical Classification Syste BE Bioequivalence BMS-512148 Dapagliflozin [DAPA] BMS-511926 Minor, pharmacologically-active, hydroxylated metabolite of DAPA BMS-801576 DAPA- 3-O- glucuronide (major but inactive metabolite towards the SGLT2 transporter) BMI Body mass index BMS Bristol-Myers Squibb C Concentration C-G Cockroft-Gault CI Confidence interval CL Clearance CrCl Creatinine clearance CL/F,(ss) Apparent clearance of the analyte in plasma following extravascular administration Cler / CLR Renal clearance of the analyte CLi Iohexol plasma clearance Cmax Maxmum observed concentration Cmax,ss(,norm) Maximum analyte plasma concentration at steady-state (dose-normalized)

4 Cpre,ss Predose concentration at steady state CV Coefficient of variation DAPA Dapagliflozin DDI Drug-drug interaction Forxiga Assessment report EMA/689976/2012 Page 3/170 DPP-4 Dipeptidyl peptidase-4 E24(,ss) Effect at time point 24 hours after dosing (at steady state) eCLR / e CLer Estimated renal clearance EC50 Half maximal effective concentration eCcr Estimated creatinine clearance ECG Electrocardiogram eGFR Estimated glomerular filtration rate Emax(,ss) Maximum effect at steady state) E-R Exposure- response ESRD End-stage renal-disease F Absolute bioavailability factor FPG Fasting plasma glucose gCV Geometric coefficient of variation GFR Glomerular filtration rate GIP Glucose-dependent insulinotropic peptide GLP-1 (-2) Glucagon-like peptide-1 (-2) gMean Geometric mean GMR Geometric mean ratio HbA1c Glycosylated haemoglobin A1 HOMA Homeostasis Model Assessment HPLC-MS/MS High-performance liquid chromatography-tandem mass spectrometry HPLC High-performance liquid chromatography IC50 Half maximal inhibitory concentration LLOQ Lower limit of quantitation Max Maximum MD Multiple dose MRD Multiple rising dose MTT Meal tolerance test N/A.

5 Not available; not applicable OGTT Oral glucose tolerance test PD Pharmacodynamics p-gp Permeability glycoprotein PK Pharmacokinetics PPK Population PK QD Once per day QTcX Population based frequency correctec QT interval RA Accumulation ratio of the analyte in plasma after multiple dose administration over a uniform dosing interval Forxiga Assessment report EMA/689976/2012 Page 4/170 SD Standard deviation SD Single dose SGLT2 Sodium glucose co-transporter type 2 ss Steady state SRD Single rising dose SU Sulfonylurea T-HALF Terminal elimination half-life t1/2(,ss) Terminal elimination half-life (at steady-state) T2DM Type 2 diabetes mellitus Tmax(,ss); tmax Time of maximum analyte plasma concentration after administration (at steady-state) T/R Ratio test/reference TRA Total radioactivity tz(,ss) Time of last measurable concentration of the analyte in plasma (at steady state) U Units UGT1A9 uridine diphosphate glucuronosyltransferase V Volume of distribution Vs.

6 Versus Vss / V(ss) Apparent volume of distribution under steady state conditions Vz/F(,ss) Apparent volume of distribution during the terminal phase z following an extravascular administration (at steady state) Forxiga Assessment report EMA/689976/2012 Page 5/170 1. Background information on the procedure Submission of the dossier The applicant Bristol-Myers Squibb/AstraZeneca EEIG submitted on 16 December 2010 an application for Marketing Authorisation to the European Medicines Agency (EMA) for Forxiga, 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 22 April 2010. The applicant applied for the following indication: Monotherapy Forxiga is indicated in adults aged 18 years and older with type 2 diabetes mellitus to improve glycaemic control: when diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance.

7 Combination therapy Add-on combination Forxiga is indicated in adults aged 18 years and older with type 2 diabetes mellitus to improve glycaemic control: in combination with metformin, when metformin alone with diet and exercise does not provide adequate glycaemic control; in combination with a sulfonylurea, when the sulfonylurea alone with diet and exercise does not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance; in combination with a thiazolidinedione, when the thiazolidinedione alone with diet and exercise does not provide adequate glycaemic control in patients for whom use of a thiazolidinedione is considered appropriate; in combination with insulin (alone or with up to two oral glucose-lowering agents), when the underlying treatment regimen with diet and exercise does not provide adequate glycaemic control.

8 The legal basis for this application refers to Article of Directive 2001/83/EC, as amended - 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/or bibliographic literature substituting/supporting certain test(s) or study(ies). Forxiga Assessment report EMA/689976/2012 Page 6/170 Information on Paediatric requirements Pursuant to Article 7 of Regulation (EC) No 1901/2006, the application included an EMA Decision (P/100/2010) on the agreement of a paediatric investigation plan (PIP). At the time of submission of the application, the PIP was not yet completed as some measures were deferred. Information relating to orphan market exclusivity Similarity Not applicable.

9 Market Exclusivity Not applicable. Applicant s request(s) for consideration New active Substance status The applicant requested the active substance dapagliflozin contained in the above medicinal product to be considered as a new active substance in itself. Scientific Advice/Protocol Assistance The applicant received Scientific Advice from the CHMP on 18-21 February 2008. The Scientific Advice pertained to clinical aspects of the dossier. Licensing status The product was not licensed in any country at the time of submission of the application. Manufacturers Manufacturer responsible for batch release Bristol-Myers Squibb Loc. Fontana del Ceraso, 03012 Anagni (FR) Italy Steps taken for the Assessment of the product The Rapporteur and Co-Rapporteur appointed by the CHMP and the evaluation teams were: Rapporteur: Kristina Dunder Co-Rapporteur: Martina Weise The application was received by the EMA on 16 December 2010.

10 The procedure started on 19 January 2011. The Rapporteur's first Assessment report was circulated to all CHMP members on 8 April 2011. The Co-Rapporteur's first Assessment report was circulated to all CHMP members on 18 April 2011. Forxiga Assessment report EMA/689976/2012 Page 7/170 During the meeting on 16-19 May 2011, the CHMP agreed on the consolidated List of Questions to be sent to the applicant. The final consolidated List of Questions was sent to the applicant on 20 May 2011. The applicant submitted the responses to the CHMP consolidated List of Questions on 16 August 2011. The Rapporteurs circulated the Joint Assessment report on the applicant s responses to the List of Questions to all CHMP members on 30 September 2011. During the CHMP meeting on 17-20 October 2011, the CHMP agreed on a list of outstanding issues to be addressed in writing and/or in an oral explanation by the applicant.