MAKENA® Advisory Committee Briefing Document NDA 021945 / S-023 Page 1 ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE Bone, Reproductive, and Urologic Drugs Advisory Committee Meeting October 29, 2019 MAKENA® (hydroxyprogesterone caproate injection) NDA 021945 / S-023 AMAG Pharmaceuticals, Inc. 1100 Winter Street Waltham, MA 02451 MAKENA® Advisory Committee Briefing Document NDA 021945 / S-023 Page 2 TABLE OF CONTENTS TABLE OF CONTENTS .................................................................................................................2 LIST OF TABLES ...........................................................................................................................5 LIST OF FIGURES .........................................................................................................................7 LIST OF ABBREVIATIONS AND ACRONYMS ........................................................................8 1. EXECUTIVE SUMMARY ..........................................................................................9 1.1. Overview .......................................................................................................................9 1.2. Preterm Birth Prevalence and Prevention .....................................................................9 1.3. Makena .......................................................................................................................10 1.3.1. Approval .....................................................................................................................11 1.3.2. Availability of 17P ......................................................................................................12 1.4. Overview of Clinical Studies ......................................................................................12 1.5. Meis: Pivotal Trial Results .........................................................................................13 1.5.1. Efficacy .......................................................................................................................13 1.5.2. Safety ..........................................................................................................................16 1.6. PROLONG: Trial Results ...........................................................................................16 1.6.1. Efficacy .......................................................................................................................17 1.6.2. Safety ..........................................................................................................................20 1.7. Exploratory Analyses ..................................................................................................22 1.7.1. Comparison of Demographics ....................................................................................22 1.7.2. Comparison of Efficacy Outcomes .............................................................................24 1.8. Discussion ...................................................................................................................25 1.8.1. Conclusions.................................................................................................................26 2. PRETERM BIRTH .....................................................................................................28 2.1. Preterm Birth: Definitions and Complications ...........................................................28 2.2. Prevalence ...................................................................................................................29 3. PREVENTION OF PRETERM BIRTH .....................................................................32 3.1. Prophylactic Methods .................................................................................................32 3.1.1. Hydroxyprogesterone Caproate ..................................................................................32 3.1.2. Vaginal Progesterone ..................................................................................................33 3.1.3. Treatment Guidelines ..................................................................................................34 3.2. Compounding of 17P ..................................................................................................34 MAKENA® Advisory Committee Briefing Document NDA 021945 / S-023 Page 3 3.3. Continued Medical Need ............................................................................................36 4. HYDROXYPROGESTERONE CAPROATE ...........................................................37 4.1. Makena (HPC Injection) .............................................................................................37 4.1.1. Product Description ....................................................................................................37 4.1.2. Mechanism of Action .................................................................................................37 4.1.3. Indication ....................................................................................................................38 4.2. Generic HPC ...............................................................................................................38 5. REGULATORY HISTORY .......................................................................................39 5.1. FDA Advisory Committee Meeting (2006) ................................................................39 5.2. FDA Review of NDA Submission .............................................................................40 5.3. Orphan Drug Designation ...........................................................................................40 5.4. Confirmatory Study Requirement for Makena ...........................................................40 5.4.1. Postmarketing Commitments ......................................................................................41 6. CLINICAL DEVELOPMENT PROGRAM ..............................................................43 6.1. Meis: Pivotal Trial Design and Results ......................................................................44 6.1.1. Study Design ...............................................................................................................44 6.1.2. Study Enrollment ........................................................................................................46 6.1.3. Demographics and Baseline Characteristics ...............................................................46 6.1.4. Efficacy .......................................................................................................................48 6.1.5. Safety ..........................................................................................................................51 6.2. PROLONG: Trial Design and Results ........................................................................51 6.2.1. Study Design ...............................................................................................................52 6.2.2. Study Enrollment ........................................................................................................56 6.2.3. Disposition ..................................................................................................................58 6.2.4. Demographics and Baseline Characteristics ...............................................................58 6.2.5. Exposure to Study Treatment .....................................................................................61 6.2.6. Efficacy .......................................................................................................................61 6.2.7. Safety ..........................................................................................................................70 6.2.8. Pharmacokinetics ........................................................................................................76 7. EXPLORATORY POST HOC ANALYSES .............................................................77 7.1. Comparison of Study Demographics ..........................................................................77 7.2. Comparison of Efficacy Outcomes .............................................................................80 7.3. Integrated Safety (PROLONG and Meis) ...................................................................81 MAKENA® Advisory Committee Briefing Document NDA 021945 / S-023 Page 4 7.3.1. Common Adverse Events ...........................................................................................81 7.3.2. Serious Adverse Events ..............................................................................................83 8. DISCUSSION .............................................................................................................86 8.1. Conclusions.................................................................................................................87 9. REFERENCES ...........................................................................................................88 MAKENA® Advisory Committee Briefing Document NDA 021945 / S-023 Page 5 LIST OF TABLES Table 1: Overview of Key Clinical Studies ..............................................................................12 Table 2: Percentage of Patients with Delivery <370 Weeks of Gestation (Meis) .....................14 Table 3: Percentage of Patients with Delivery <350 and <320 Weeks of Gestation (Meis) ..........................................................................................................................14