Mallinckrodt Pharmaceuticals NDA #022231 Terlipressin Advisory Committee Briefing Document CARDIOVASCULAR AND RENAL DRUGS ADVISORY COMMITTEE TERLIPRESSIN BRIEFING DOCUMENT NDA # 022231 Mallinckrodt Pharmaceuticals 1425 US 206 Bedminster, NJ 07921 AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION Page 1 of 179 Mallinckrodt Pharmaceuticals NDA #022231 Terlipressin Advisory Committee Briefing Document TABLE OF CONTENTS TABLE OF CONTENTS ............................................................................................................. 2 LIST OF TABLES ........................................................................................................................ 6 LIST OF FIGURES .................................................................................................................... 10 LIST OF ABBREVIATIONS AND ACRONYMS .................................................................. 12 1 EXECUTIVE OVERVIEW ............................................................................................ 14 1.1 Introduction ...................................................................................................................... 15 1.2 HRS-1: The Unmet Need ................................................................................................. 17 1.3 Terlipressin for HRS-1 ..................................................................................................... 19 1.4 Efficacy ............................................................................................................................ 19 1.4.1 Study Endpoints ........................................................................................................ 20 1.4.2 CONFIRM Study ...................................................................................................... 21 1.4.3 Study OT-0401 .......................................................................................................... 25 1.4.4 REVERSE Study ....................................................................................................... 25 1.4.5 Pooled Efficacy Analyses .......................................................................................... 25 1.4.6 Efficacy Conclusions ................................................................................................. 27 1.5 Safety ................................................................................................................................ 27 1.5.1 Safety in Subjects with the Most Advanced Renal Dysfunction .............................. 28 1.5.2 Respiratory Events .................................................................................................... 29 1.5.3 Sepsis and Septic Shock ............................................................................................ 30 1.5.4 Multiple Organ Dysfunction Syndrome .................................................................... 31 1.5.5 Ischemic Events ......................................................................................................... 31 1.5.6 Safety Conclusions .................................................................................................... 32 1.6 Risk Mitigation and Optimizing the Benefit-Risk of Terlipressin ................................... 32 1.6.1 Baseline SCr .............................................................................................................. 32 1.6.2 Respiratory Failure .................................................................................................... 34 1.7 Benefit-Risk ..................................................................................................................... 37 1.7.1 Demonstrated Benefits .............................................................................................. 37 1.7.2 Demonstrated Risks ................................................................................................... 38 1.7.3 Quantitative Benefit-Risk Evaluation ....................................................................... 39 1.7.4 Benefit-Risk Conclusions .......................................................................................... 41 2 TERLIPRESSIN RATIONALE AND DEVELOPMENTAL HISTORY .................. 42 2.1 Pathophysiology of HRS-1 .............................................................................................. 42 Page 2 of 179 Mallinckrodt Pharmaceuticals NDA #022231 Terlipressin Advisory Committee Briefing Document 2.2 Treatment of HRS-1 ......................................................................................................... 44 2.3 Terlipressin for HRS-1 ..................................................................................................... 45 2.4 Regulatory History of Terlipressin ................................................................................... 46 2.4.1 Orphan Therapeutics (2003 to 2010) ........................................................................ 47 2.4.2 Ikaria Therapeutics (2010 to 2015) ........................................................................... 47 2.4.3 Mallinckrodt Pharmaceuticals (2015 to Present) ...................................................... 48 2.5 Clinical Development Program ........................................................................................ 48 2.6 Dosing Regimen ............................................................................................................... 49 3 NONCLINICAL SUMMARY ........................................................................................ 52 3.1 Toxicology Studies........................................................................................................... 52 4 CLINICAL PHARMACOLOGY ................................................................................... 54 4.1 Terlipressin Pharmacology ............................................................................................... 54 4.2 Pharmacodynamics .......................................................................................................... 55 4.2.1 QTc Substudy ............................................................................................................ 55 4.3 Pharmacokinetics ............................................................................................................. 56 4.3.1 Drug-Drug Interactions and Antigenicity ................................................................. 57 4.3.1.1 Pharmacokinetic Drug-Drug Interactions .......................................................................... 57 4.3.1.2 Pharmacodynamic Drug-Drug Interactions ....................................................................... 57 4.3.1.3 Antigenicity ....................................................................................................................... 58 4.4 Clinical Pharmacology Data Relevant to Dose Recommendation ................................... 58 4.5 Clinical Pharmacology Conclusions ................................................................................ 59 5 EFFICACY ....................................................................................................................... 60 5.1 Clinical Studies of Terlipressin in HRS-1 ........................................................................ 60 5.1.1 Clinical Development ................................................................................................ 60 5.1.2 Key Study Design Features of the CONFIRM, OT-0401, and REVERSE Studies .. 61 5.1.3 Study Population ....................................................................................................... 62 5.1.4 Treatment .................................................................................................................. 64 5.2 CONFIRM Study ............................................................................................................. 65 5.2.1 CONFIRM Study Design .......................................................................................... 65 5.2.2 Study Population ....................................................................................................... 66 5.2.3 Subject Disposition and Discontinuation From Treatment ....................................... 66 5.2.4 Baseline Characteristics and Demographics ............................................................. 67 5.2.5 Statistical Analysis .................................................................................................... 70 5.2.5.1 Primary Endpoint of Verified HRS Reversal .................................................................... 70 5.2.5.2 Multiple Testing for the Final Analysis of the Secondary Endpoint Analyses.................. 70 5.2.5.3 Change from Baseline to EOT in Renal Function ............................................................. 71 Page 3 of 179 Mallinckrodt Pharmaceuticals NDA #022231 Terlipressin Advisory Committee Briefing Document 5.2.6 Efficacy Results in the ITT Population ..................................................................... 71 5.2.6.1 Verified HRS Reversal ...................................................................................................... 71 5.2.6.2 Secondary Endpoints ......................................................................................................... 72 5.2.6.3 Additional Prespecified Renal Function Endpoints ........................................................... 73 5.2.6.4 Clinical Endpoints ............................................................................................................