Prucalopride for the Treatment of Chronic Idiopathic Constipation FDA Advisory Committee Meeting Briefing Document Gastrointestinal Drugs Advisory Committee Meeting Date: 18 October 2018 Shire Page 2 Gastrointestinal Drugs Advisory Committee Briefing Document Prucalopride for Chronic Idiopathic Constipation 18 Oct 2018 Meeting TABLE OF CONTENTS 1. EXECUTIVE SUMMARY ....................................................................................................15 1.1 Unmet Need..............................................................................................................16 1.2 Mechanism of Action...............................................................................................17 1.3 Clinical Pharmacology .............................................................................................17 1.4 Efficacy ....................................................................................................................18 1.4.1 Efficacy Results .....................................................................................................21 1.4.2 Efficacy Conclusions .............................................................................................33 1.5 Safety........................................................................................................................35 1.5.1 Safety in Randomized Double-blind Placebo-controlled Studies..........................37 1.5.2 Cardiovascular Safety Assessment ........................................................................44 1.5.2.1 In Vitro and In Vivo Nonclinical Cardiovascular Testing .....................45 1.5.2.2 Studies with Intense Cardiovascular Monitoring (Thorough QT and Phase 1 Cardiovascular Monitoring)......................................................46 1.5.2.3 Events from Randomized Double-Blind Placebo-Controlled Studies and Open-Label Extensions with QT Prolongation, Arrhythmia, and Ischemia .................................................................................................46 1.5.2.4 Independent Blinded Adjudication for MACE of the Randomized Double-Blind Placebo-Controlled Studies.............................................47 1.5.2.5 Pharmacoepidemiology Study 802 (EUPAS9200) ................................49 1.6 Conclusions ..............................................................................................................50 2. BACKGROUND ON CHRONIC IDIOPATHIC CONSTIPATION ....................................51 2.1 Overview of Chronic Idiopathic Constipation .........................................................51 2.1.1 Clinical Diagnosis..................................................................................................52 2.1.2 Types of Bowel Movements ..................................................................................53 2.1.3 Goal of Treatment..................................................................................................53 2.2 Treatment for Chronic Idiopathic Constipation .......................................................53 2.2.1 Non-prescription Treatment...................................................................................53 2.2.2 Prosecretory Agents...............................................................................................53 2.2.3 Prokinetic Agents...................................................................................................54 2.3 Patient Medical Need ...............................................................................................54 3. PRODUCT DESCRIPTION...................................................................................................55 3.1 Proposed Indication..................................................................................................55 3.2 Dosing Regimen.......................................................................................................55 3.3 Mechanism of Action...............................................................................................55 3.3.1 Selective vs. Non-selective 5-HT4 Agonists..........................................................55 4. REGULATORY AND DEVELOPMENT HISTORY...........................................................61 4.1 Regulatory Milestones..............................................................................................61 ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE Shire Page 3 Gastrointestinal Drugs Advisory Committee Briefing Document Prucalopride for Chronic Idiopathic Constipation 18 Oct 2018 Meeting 4.2 Clinical Development Program................................................................................61 4.3 Global Regulatory Approvals...................................................................................62 5. CLINICAL PHARMACOLOGY...........................................................................................63 5.1 Pharmacokinetics .....................................................................................................63 5.1.1 Pharmacokinetics in Renal Impairment.................................................................64 5.1.2 Population Pharmacokinetics.................................................................................64 5.2 Drug-Drug Interactions ............................................................................................65 5.3 Pharmacodynamics...................................................................................................65 5.4 Dose Selection..........................................................................................................67 6. CLINICAL EFFICACY .........................................................................................................68 6.1 Clinical Study Design...............................................................................................68 6.1.1 Inclusion and Exclusion Criteria............................................................................70 6.1.2 Endpoints ...............................................................................................................70 6.1.3 Statistical Analyses ................................................................................................71 6.2 Demographic and Baseline Characteristics..............................................................72 6.3 Patient Disposition ...................................................................................................77 6.4 Primary Endpoint Results: Proportion of Patients with an Average of ≥3 CSBMs/week Over 12 Weeks of Treatment ............................................................79 6.4.1 Alternative Endpoint A: Proportion of Patients with an Average of ≥3 CSBMs/week and ≥1 CSBM/week for ≥9/12 Weeks including 3/4 of the Last Weeks of Treatment.......................................................................................82 6.4.2 Study 401 Investigation .........................................................................................85 6.5 Secondary Endpoint Results.....................................................................................85 6.5.1 Proportion of Patients with an Average Increase of ≥1 CSBM/Week...................85 6.5.2 Time to First CSBM and SBM ..............................................................................87 6.5.3 Average Number of CSBMs..................................................................................89 6.5.4 Use of Rescue Medication (Bisacodyl)..................................................................92 6.5.5 Patient Assessment of Constipation – Symptoms (PAC-SYM) ............................95 6.5.6 Patient Assessment of Constipation – Quality of Life (PAC-QOL)....................101 6.6 Subgroup Analyses.................................................................................................107 6.6.1 Subgroup Analysis by Age ..................................................................................107 6.6.2 Subgroup Analysis by Sex...................................................................................108 6.6.3 Subgroup Analysis by Race.................................................................................109 6.6.4 Subgroup Analysis by Region .............................................................................110 6.7 Efficacy Conclusions..............................................................................................113 7. CLINICAL SAFETY............................................................................................................116 7.1 Treatment Exposure ...............................................................................................117 7.2 Safety Pooling Strategy..........................................................................................119 ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE Shire Page 4 Gastrointestinal Drugs Advisory Committee Briefing Document Prucalopride for Chronic Idiopathic Constipation 18 Oct 2018 Meeting 7.3 Overview of Adverse Events in Pooled Randomized Double-blind Placebo- controlled Studies ≥4 Weeks..................................................................................119 7.3.1 Common Adverse Events (≥2%) .........................................................................120 7.3.2 Onset and Duration of Adverse Events................................................................122 7.4 Serious Adverse Events in Pooled Randomized Double-blind Placebo-