CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 209776Orig1s000 CLINICAL REVIEW(S) Clinical Review Rama Kapoor, MD NDA 209776 (Meropenem-vaborbactam) CLINICAL REVIEW Application Type 505(b)(2) Application Number NDA 209776 Priority or Standard Priority Submit Date 12/29/2016 Received Date 12/29/2016 PDUFA Goal Date 08/29/2017 Division/Office DAIP/OAP Reviewer Name Rama Kapoor, M.D. Established Name Meropenem-vaborbactam Proposed Trade Name Vabomere (Proposed name) Applicant Rempex Pharmaceuticals a wholly owned subsidiary of The Medicines Company Formulation Powder for intravenous injection /meropenem 1000mg and vaborbactam 1000mg per vial Dosing Regimen 4 g (meropenem 2 g-vaborbactam 2 g) every 8 hours by IV infusion over 3 hours. Dosage Duration (b) (4)14 days Applicant Proposed Complicated urinary tract infections (cUTI), including Indication/Population pyelonephritis in patients 18 years and older Recommendation on Approval Regulatory Action Recommended Complicated urinary tract infections (cUTI), including Indication/Population pyelonephritis in patients 18 years and older CDER Clinical Review Template 2015 Edition 1 Version date: November 5, 2015 for initial rollout (NME/original BLA reviews) Reference ID: 4108970 Clinical Review Rama Kapoor, MD NDA 209776 (Meropenem-vaborbactam) Table of Contents Glossary ......................................................................................................................................... 12 1 Executive Summary ............................................................................................................... 14 1.1. Product Introduction ...................................................................................................... 14 1.2. Conclusions on the Substantial Evidence of Effectiveness ............................................ 15 1.3. Benefit-Risk Assessment Summary ................................................................................ 16 1.3.1. Benefit-Risk Assessment ......................................................................................... 19 2 Therapeutic Context .............................................................................................................. 30 2.1. Analysis of Condition ...................................................................................................... 30 2.2. Analysis of Current Treatment Options ......................................................................... 35 3 Regulatory Background ......................................................................................................... 40 3.1. U.S. Regulatory Actions and Marketing History ............................................................. 40 3.2. Summary of Presubmission/Submission Regulatory Activity ........................................ 40 3.3. Foreign Regulatory Actions and Marketing History ....................................................... 42 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety................................................................................................................. 42 4.1. Office of Scientific Investigations (OSI) .......................................................................... 42 4.2. Product Quality .............................................................................................................. 43 4.3. Clinical Microbiology ...................................................................................................... 43 4.4. Nonclinical Pharmacology/Toxicology ........................................................................... 46 4.5. Clinical Pharmacology .................................................................................................... 47 4.5.1. Mechanism of Action .............................................................................................. 48 4.5.2. Pharmacokinetics .................................................................................................... 48 4.5.3. Pharmacodynamics ................................................................................................. 50 4.5.4. Population PK and PK-PD Analyses ......................................................................... 50 4.5.5. Exposure-Safety Relationships ................................................................................ 52 4.6. Devices and Companion Diagnostic Issues .................................................................... 53 4.7. Consumer Study Reviews ............................................................................................... 53 5 Sources of Clinical Data and Review Strategy ....................................................................... 54 CDER Clinical Review Template 2015 Edition 2 Version date: November 5, 2015 for initial rollout (NME/original BLA reviews) Reference ID: 4108970 Clinical Review Rama Kapoor, MD NDA 209776 (Meropenem-vaborbactam) 5.1. Table of Clinical Studies .................................................................................................. 54 5.2. Review Strategy .............................................................................................................. 60 6 Review of Relevant Individual Trials Used to Support Efficacy ............................................. 61 6.1. Study 505 ........................................................................................................................ 61 6.1.1. Study Design............................................................................................................ 61 6.1.2. Study Results ........................................................................................................... 79 6.1.3. Patient Disposition .................................................................................................. 80 6.1.4. Analysis Population ................................................................................................. 83 6.1.5. Protocol Violations/Deviations ............................................................................... 85 6.1.6. Demographic Characteristics .................................................................................. 86 6.1.7. Other Baseline Characteristics ................................................................................ 88 6.1.8. Baseline Pathogen Characteristics .......................................................................... 93 6.1.9. Treatment Compliance, Concomitant Medications, and Rescue Medication Use . 97 6.1.10. Efficacy Results .............................................................................................. 100 6.1.11. Data Quality and Integrity – Reviewers’ Assessment .................................... 133 6.1.12. Onset, Duration, and Durability of Efficacy Effects ....................................... 138 6.1.13. Reviewers’ Conclusion ................................................................................... 138 6.2. Study 506 ...................................................................................................................... 139 6.2.1. Study Design.......................................................................................................... 139 6.2.2. Study Results ......................................................................................................... 150 6.2.3. Study 506- Efficacy Results ................................................................................... 156 7 Integrated Assessment of Effectiveness .............................................................................. 161 8 Review of Safety .................................................................................................................. 164 8.1. Safety Review Approach .............................................................................................. 164 8.2. Review of the Safety Database .................................................................................... 165 8.2.1. Overall Exposure ................................................................................................... 165 8.2.2. Relevant characteristics of the safety population: ............................................... 168 8.2.3. Adequacy of the safety database: ........................................................................ 172 8.3. Adequacy of Applicant’s Clinical Safety Assessments .................................................. 172 8.3.1. Issues Regarding Data Integrity and Submission Quality ..................................... 172 CDER Clinical Review Template 2015 Edition 3 Version date: November 5, 2015 for initial rollout (NME/original BLA reviews) Reference ID: 4108970 Clinical Review Rama Kapoor, MD NDA 209776 (Meropenem-vaborbactam) 8.3.2. Categorization of Adverse Events ......................................................................... 172 8.3.3. Routine Clinical Tests ............................................................................................ 174 8.4. Safety Results ............................................................................................................... 174 8.4.1. Deaths ................................................................................................................... 175 8.4.2. Serious Adverse Events ......................................................................................... 181 8.4.3. Dropouts and/or Discontinuations Due to Adverse Effects