Amikacin Liposome Inhalation Suspension Antimicrobial Drugs Advisory Committee Briefing Document 07 August 2018 Meeting AMIKACIN LIPOSOME INHALATION SUSPENSION ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE ANTIMICROBIAL DRUGS ADVISORY COMMITTEE MEETING DATE: 07 AUGUST 2018 1 Amikacin Liposome Inhalation Suspension Antimicrobial Drugs Advisory Committee Briefing Document 07 August 2018 Meeting TABLE OF CONTENTS TABLE OF CONTENTS .................................................................................................................2 List of Tables ...................................................................................................................................7 List of Figures ................................................................................................................................10 LIST OF ABBREVIATIONS ........................................................................................................11 1 EXECUTIVE SUMMARY ........................................................................................13 1.1 Background and Unmet Need .....................................................................................14 1.2 Regulatory ...................................................................................................................17 1.2.1 Indication Statement ...................................................................................................17 1.2.2 Regulatory History ......................................................................................................17 1.3 Efficacy .......................................................................................................................18 1.3.1 Study 212 ....................................................................................................................18 1.3.2 Study 312 ....................................................................................................................25 1.3.3 Study 112 ....................................................................................................................29 1.3.4 Efficacy Summary ......................................................................................................32 1.4 Safety ..........................................................................................................................33 1.4.1 Adverse Events of Special Interest .............................................................................37 1.5 Conclusions.................................................................................................................38 2 BACKGROUND ON NONTUBERCULULOUS MYCOBACTERIAL LUNG INFECTIONS .................................................................................................40 2.1 Overview of Nontuberculous Mycobacterial Lung Infections ...................................40 2.1.1 Epidemiology ..............................................................................................................40 2.1.2 Morbidity and Mortality in Nontuberculous Mycobacterial Lung Infections ............41 2.2 Current Treatment Options .........................................................................................42 2.3 Patient Medical Need ..................................................................................................44 3 PRODUCT DESCRIPTION .......................................................................................45 3.1 ALIS Description ........................................................................................................45 3.2 Lamira Nebulizer System ...........................................................................................45 3.3 Mechanism of Action .................................................................................................46 3.4 In Vitro and In Vivo Studies .......................................................................................47 3.4.1 Biodistribution ............................................................................................................47 3.4.2 Intracellular Accumulation of Amikacin in Macrophages .........................................47 2 Amikacin Liposome Inhalation Suspension Antimicrobial Drugs Advisory Committee Briefing Document 07 August 2018 Meeting 3.4.3 Effect of Residual Amikacin in Sputum Samples ......................................................48 4 REGULATORY AND DEVELOPMENT HISTORY ...............................................49 4.1 Regulatory History ......................................................................................................49 4.2 Clinical Development Program ..................................................................................50 5 CLINICAL PHARMACOLOGY ...............................................................................53 5.1 Dose Rationale ............................................................................................................53 5.2 Pharmacokinetics ........................................................................................................55 5.3 Population Pharmacokinetics ......................................................................................57 6 CLINICAL EFFICACY .............................................................................................58 6.1 Efficacy Overview ......................................................................................................58 6.1.1 Endpoint Definitions ...................................................................................................58 6.1.1.1 Culture Conversion .....................................................................................................58 6.1.1.2 Semi-Quantitative Scale for Mycobacterial Culture ...................................................59 6.1.1.3 6 Minute Walk Test (6MWT) .....................................................................................60 6.1.1.4 St. George’s Respiratory Questionnaire (SGRQ) .......................................................60 6.2 Study 212 ....................................................................................................................60 6.2.1 Study Design ...............................................................................................................60 6.2.1.1 Inclusion and Exclusion Criteria ................................................................................61 6.2.1.2 Statistical Analyses .....................................................................................................62 6.2.2 Demographic and Baseline Characteristics ................................................................62 6.2.3 Patient Disposition ......................................................................................................65 6.2.4 Primary Endpoint – Proportion of Patients Achieving Culture Conversion by Month 6 .......................................................................................................................66 6.2.5 Secondary Endpoints ..................................................................................................67 6.2.5.1 Change from Baseline in 6 Minute Walk Test (6MWT) Distance at Month 6 ..........67 6.2.5.2 Time from Baseline to Culture Conversion ................................................................69 6.2.5.3 Change from Baseline in St. George’s Respiratory Questionnaire (SGRQ) at Month 6 .......................................................................................................................69 6.2.6 Exploratory Endpoints ................................................................................................70 6.2.6.1 Change from Baseline in 6 Minute Walk Test (6MWT) at Month 6 for Converters vs Non-converters for All Patients ...........................................................70 6.2.6.2 Change from Baseline in 6 Minute Walk Test (6MWT) at Month 6 for Converters vs Non- converters in the ALIS + Multidrug Regimen Arm ...................71 3 Amikacin Liposome Inhalation Suspension Antimicrobial Drugs Advisory Committee Briefing Document 07 August 2018 Meeting 6.2.6.3 Change from Baseline in 6 Minute Walk Test (6MWT) at Month 6 for Converters vs Non-converters in the Multidrug Regimen Alone Arm .......................72 6.2.7 Amikacin Resistance ..................................................................................................73 6.3 Study 312 ....................................................................................................................74 6.3.1 Overview .....................................................................................................................74 6.3.2 Demographic and Baseline Characteristics ................................................................75 6.3.3 Patient Disposition ......................................................................................................76 6.3.4 Secondary Endpoints ..................................................................................................77 6.3.4.1 Proportion of Patients Achieving Culture Conversion by Month 6 ...........................77 6.3.4.2 Time from Baseline to Culture Conversion ................................................................77 6.3.4.3 Change from Baseline in St. George’s Respiratory Questionnaire at Month 6 ..........78 6.4 Study 112 ....................................................................................................................78