Oliceridine Briefing Document: October 11, 2018 FDA Advisory Committee Meeting FDA ADVISORY COMMITTEE BRIEFING DOCUMENT Oliceridine MEETING OF THE ANESTHETIC AND ANALGESIC DRUG PRODUCTS ADVISORY COMMITTEE MEETING DATE: October 11, 2018 Page 1 of 123 Oliceridine Briefing Document: October 11, 2018 FDA Advisory Committee Meeting Table of Contents 1 Executive Summary ..................................................................................................12 Introduction .................................................................................................................12 Current Pain Management Paradigm ..........................................................................13 Goals of Development Program .................................................................................15 Dosing and Administration .........................................................................................15 Efficacy .......................................................................................................................15 Opioid-Related Adverse Events .................................................................................20 1.6.1 Respiratory Effects ..............................................................................................20 1.6.2 Nausea and Vomiting ..........................................................................................25 Other Safety Findings .................................................................................................27 Conclusions.................................................................................................................28 2 Product Description and Development Program ...................................................30 G Protein-Coupled Receptors .....................................................................................30 Product Characteristics and Mechanism of Action ....................................................32 Proposed Indication and Dosing .................................................................................33 2.3.1 Dosing Paradigms Evaluated During Development ............................................33 2.3.2 Proposed Dosing ..................................................................................................34 Regulatory Milestones ................................................................................................34 Clinical Development Program ..................................................................................35 Treatment Exposures ..................................................................................................37 3 Nonclinical Pharmacology .......................................................................................38 Nonclinical Pharmacology ..........................................................................................38 3.1.1 G Protein-Biased Signaling with Oliceridine ......................................................38 3.1.2 Analgesic Efficacy and Gastrointestinal and Respiratory Effects in Nonclinical Studies ..............................................................................................39 3.1.3 Oliceridine Binding and Reversibility with Naloxone ........................................40 3.1.4 Metabolism and Excretion ...................................................................................40 3.1.5 Oliceridine Metabolites .......................................................................................41 Nonclinical Toxicology ..............................................................................................41 4 Clinical Pharmacology .............................................................................................43 Relevant Background and CYP2D6 Pharmacogenomics ...........................................43 Oliceridine Pharmacokinetics .....................................................................................44 Page 2 of 123 Oliceridine Briefing Document: October 11, 2018 FDA Advisory Committee Meeting 4.2.1 Population Pharmacokinetics/Pharmacodynamics ..............................................45 4.2.2 Drug Interactions .................................................................................................46 4.2.3 Hepatic Impairment .............................................................................................47 4.2.4 Renal Impairment ................................................................................................48 4.2.5 Comparison to Other IV Opioids ........................................................................48 4.2.6 Conclusions .........................................................................................................49 5 Human Pharmacodynamics .....................................................................................50 Pharmacologic Proof-of-Concept Study .....................................................................50 Human Abuse Liability ...............................................................................................51 6 Phase 2 Studies ..........................................................................................................53 Study 2001: Phase 2a, Fixed-Dose Bunionectomy Study ..........................................53 6.1.1 Study Design .......................................................................................................53 6.1.2 Results .................................................................................................................54 Study 2002: Phase 2b, PRN-Dosing Abdominoplasty Study .....................................55 6.2.1 Design ..................................................................................................................55 6.2.2 Efficacy Results ...................................................................................................56 6.2.3 Safety Results ......................................................................................................56 6.2.4 Conclusions from Phase 2 Studies ......................................................................58 7 Phase 3 Studies ..........................................................................................................59 APOLLO 1 and APOLLO 2 Study Designs ...............................................................59 7.1.1 PRN Dosing Regimens ........................................................................................60 7.1.2 Enrollment Criteria ..............................................................................................61 7.1.3 Clinical Endpoints ...............................................................................................61 7.1.4 Patient Disposition ...............................................................................................64 7.1.5 Demographics and Baseline Characteristics .......................................................65 APOLLO 1 and APOLLO 2 Efficacy Results ............................................................66 7.2.1 Exposure to Active Study Medication .................................................................66 7.2.2 Primary Endpoint Results: Responder Analysis Versus Placebo ........................67 7.2.3 Key Secondary Endpoint Results ........................................................................69 7.2.4 Use of Rescue Pain Medication ...........................................................................69 7.2.5 Efficacy in Subgroups .........................................................................................70 7.2.6 Efficacy Conclusions ...........................................................................................70 APOLLO 1 and APOLLO 2 Safety Results ...............................................................71 7.3.1 Overview of Adverse Events (AEs) ....................................................................71 7.3.2 Common Adverse Events ....................................................................................72 Page 3 of 123 Oliceridine Briefing Document: October 11, 2018 FDA Advisory Committee Meeting 7.3.3 Adverse Events Leading to Early Discontinuation of Study Medication ............73 7.3.4 Serious Adverse Events .......................................................................................73 7.3.5 Respiratory Safety ...............................................................................................74 7.3.6 Postoperative Nausea and Vomiting ...................................................................76 Phase 3 Open-label Safety Study (ATHENA) ............................................................79 7.4.1 Study Design .......................................................................................................79 7.4.2 Patient Disposition ...............................................................................................79 7.4.3 Patient Characteristics and Exposure to Study Medication .................................79 7.4.4 ATHENA Safety Results .....................................................................................82 7.4.5 ATHENA Conclusions ........................................................................................83 Safety Topics of Special Interest ................................................................................84 7.5.1 Hepatic Safety .....................................................................................................84 7.5.2