..................................................................................................................................... ix LIST OF PUBLICATIONS INCLUDED IN THE THESIS ............................................................................ xi ACRONYMS, ABBREVIATIONS AND SYMBOLS ............................................................................... xiii CHAPTER I | INTRODUCTION 1. FOREWORD ........................................................................................................................... 3 2. BACKGROUND ....................................................................................................................... 4 2.1. ATTR amyloidoses: definition and subdivision ............................................................ 4 2.2. Historical background .................................................................................................. 4 2.3. TTR ............................................................................................................................... 6 2.4. Pathogenesis ................................................................................................................ 7 2.5 Genetics ...................................................................................................................... 10 2.6. Clinical presentation .................................................................................................. 14 2.7. Disease modifying treatments ................................................................................... 16 3. OBJECTIVES ......................................................................................................................... 17 CHAPTER II | METHODS METHODS ........................................................................................................................... 21 CHAPTER III | RESULTS 1. TRIAL DESIGN AND OUTCOME MEASURES DEVELOPMENT ARTICLE 1. Norfolk QOL-DN: validation of a patient reported outcome measure in transthyretin familial amyloid polyneuropathy ......................................................... 25 ARTICLE 2. Clinical measures in transthyretin familial amyloid polyneuropathy. .............. 41 ARTICLE 3. Trial design and rationale for APOLLO, a Phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy .......... 53 2. CLINICAL DEVELOPMENT OF NEW DRUGS