Lixisenatide and Insulin Glargine/Lixisenatide Briefing Document EMDAC Advisory Committee Meeting LIXISENATIDE and iGlarLixi (insulin glargine/lixisenatide fixed-ratio combination) FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS BRIEFING DOCUMENT FOR THE ENDOCRINOLOGIC AND METABOLIC DRUGS ADVISORY COMMITTEE MEETING DATE: 25 May 2016 ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE Available for Public Release Page 1 of 217 Lixisenatide and Insulin Glargine/Lixisenatide Briefing Document EMDAC Advisory Committee Meeting TABLE OF CONTENTS TABLE OF CONTENTS .................................................................................................................................. 2 LISTING OF TABLES ..................................................................................................................................... 7 LISTING OF FIGURES ................................................................................................................................. 11 ABBREVIATIONS ......................................................................................................................................... 14 1 READERS GUIDE TO THE BRIEFING BOOK ............................................................................. 16 2 EXECUTIVE SUMMARY ............................................................................................................... 17 2.1 MANAGEMENT OF T2DM IN 2016 ............................................................................................... 17 2.2 INTRODUCTION TO LIXISENATIDE AND IGLARLIXI ................................................................. 18 2.2.1 Lixisenatide .................................................................................................................................... 18 2.2.2 Insulin glargine (100 U/mL) ............................................................................................................ 18 2.2.3 iGlarLixi .......................................................................................................................................... 19 2.3 REGULATORY HISTORY ............................................................................................................. 20 2.4 UNMET NEED IN T2DM - RELATIVE ROLES OF FPG AND PPG .............................................. 20 2.5 MECHANISM OF ACTION ............................................................................................................ 23 2.5.1 Mechanism of action: lixisenatide .................................................................................................. 23 2.5.2 Complementary actions of iGlarLixi ............................................................................................... 31 2.6 CLINICAL PHARMACOLOGY ....................................................................................................... 31 2.6.1 Lixisenatide .................................................................................................................................... 31 2.6.2 iGlarLixi .......................................................................................................................................... 32 2.7 DOSING AND ADMINISTRATION ................................................................................................ 33 2.7.1 Lixisenatide .................................................................................................................................... 33 2.7.2 iGlarLixi .......................................................................................................................................... 33 2.8 OVERVIEW OF EFFICACY IN THE LIXISENATIDE PROGRAM ................................................. 36 Available for Public Release Page 2 of 217 Lixisenatide and Insulin Glargine/Lixisenatide Briefing Document EMDAC Advisory Committee Meeting 2.8.1 Introduction .................................................................................................................................... 36 2.8.2 Efficacy in placebo-controlled trials ................................................................................................ 36 2.8.3 Efficacy of lixisenatide versus placebo added on to basal insulin ................................................. 38 2.8.4 Efficacy of lixisenatide versus prandial insulin added on to insulin glargine.................................. 38 2.8.5 Anti-lixisenatide antibodies and efficacy ........................................................................................ 41 2.8.6 Efficacy conclusions for lixisenatide ............................................................................................... 42 2.9 OVERVIEW OF EFFICACY IN THE IGLARLIXI DEVELOPMENT PROGRAM ............................ 42 2.9.1 Study EFC12404 (insulin-naïve) .................................................................................................... 42 2.9.2 Study EFC12405 (previously insulin-treated) ................................................................................ 45 2.9.3 iGlarLixi: Consistency of findings across subgroups ..................................................................... 48 2.9.4 Efficacy of iGlarLixi by daily insulin glargine dose levels ............................................................... 50 2.9.5 Robustness of efficacy findings ..................................................................................................... 55 2.10 OVERVIEW OF SAFETY ............................................................................................................... 57 2.10.1 Safety findings: lixisenatide ............................................................................................................ 57 2.10.2 Safety findings: iGlarLixi ................................................................................................................ 63 2.11 BENEFIT/RISK: LIXISENATIDE AND IGLARLIXI ......................................................................... 65 3 LIXISENATIDE EFFICACY IN 9 PHASE 3 PLACEBO-CONTROLLED STUDIES ..................... 69 3.1 STUDY DESIGN ............................................................................................................................ 69 3.1.1 Inclusion and exclusion criteria ...................................................................................................... 71 3.1.2 Endpoints ....................................................................................................................................... 71 3.1.3 Statistical methodology .................................................................................................................. 72 3.2 RESULTS ....................................................................................................................................... 73 3.2.1 Patient disposition .......................................................................................................................... 73 3.2.2 Baseline demographics and disease characteristics ..................................................................... 73 3.2.3 Change in HbA1c from baseline to the primary efficacy time point ............................................... 74 3.2.4 HbA1c responder analysis ............................................................................................................. 79 3.2.5 Mean change from baseline in 2-hour postprandial glucose ......................................................... 81 3.2.6 Mean change from baseline in fasting plasma glucose ................................................................. 82 3.2.7 Mean change from baseline in body weight .................................................................................. 83 3.3 DURABILITY OF EFFECT ............................................................................................................. 86 3.4 STUDY EFC12626: EFFICACY OF LIXISENATIDE VERSUS PRANDIAL INSULIN ADDED ON TO INSULIN GLARGINE ........................................................................................... 86 3.4.1 Study design and methods ............................................................................................................ 86 3.4.2 Patient disposition .......................................................................................................................... 87 Available for Public Release Page 3 of 217 Lixisenatide and Insulin Glargine/Lixisenatide Briefing Document EMDAC Advisory Committee Meeting 3.4.3 Demographics and baseline characteristics .................................................................................. 88 3.4.4 Primary endpoint: change from baseline in HbA1c ........................................................................ 89 3.4.5 Secondary endpoints ..................................................................................................................... 91 3.5 LIXISENATIDE EFFICACY CONCLUSIONS ................................................................................ 92 4 EFFICACY OF IGLARLIXI – STUDIES EFC12404 AND EFC12405 ........................................... 94 4.1 OVERVIEW OF STUDY DESIGN .................................................................................................. 94 4.1.1 Endpoints ....................................................................................................................................... 95 4.1.2 Statistical methodology .................................................................................................................