CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 209939Orig1s000 209940Orig1s000 CLINICAL REVIEW(S) Clinical Review Aimee Hodowanec NDAs 209939 and 209940 Letermovir (PREVYMIS) CLINICAL REVIEW Application Type New Drug Application (NDA) Application Number(s) 209939 and 209940 Priority or Standard Priority Submit Date(s) March 8, 2017 Received Date(s) March 8, 2017 PDUFA Goal Date November 8, 2017 Division/Office DAVP/OAP Reviewer Name(s) Aimee Hodowanec Review Completion Date August 7, 2017 Established Name Letermovir (Proposed) Trade Name Prevymis Applicant Merck Formulation(s) 240 mg tablets, 480 mg tablets, 240 mg/12 mL vial, and 480 mg/24 mL vial Dosing Regimen 480 mg PO or IV once daily until 100 days post-transplantation Applicant Proposed Prophylaxis of cytomegalovirus (CMV) infection or disease in adult Indication(s)/Population(s) CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). Recommendation on Approval Regulatory Action Recommended Prophylaxis of cytomegalovirus (CMV) infection or disease in adult Indication(s)/Population(s) CMV-seropositive recipients [R+] of an allogeneic hematopoietic (if applicable) stem cell transplant (HSCT). CDER Clinical Review Template 2015 Edition 1 Version date: November 5, 2015 for initial rollout (NME/original BLA reviews) Reference ID: 4135996 Clinical Review Aimee Hodowanec NDAs 209939 and 209940 Letermovir (PREVYMIS) Table of Contents Glossary ........................................................................................................................................... 9 1 Executive Summary ............................................................................................................... 11 1.1. Product Introduction ...................................................................................................... 11 1.2. Conclusions on the Substantial Evidence of Effectiveness ............................................ 11 1.3. Benefit-Risk Assessment ................................................................................................ 11 2 Therapeutic Context .............................................................................................................. 19 2.1. Analysis of Condition ...................................................................................................... 19 2.2. Analysis of Current Treatment Options ......................................................................... 19 3 Regulatory Background ......................................................................................................... 22 3.1. U.S. Regulatory Actions and Marketing History ............................................................. 22 3.2. Summary of Presubmission/Submission Regulatory Activity ........................................ 22 3.3. Foreign Regulatory Actions and Marketing History ....................................................... 25 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety................................................................................................................. 25 4.1. Office of Scientific Investigations (OSI) .......................................................................... 25 4.2. Product Quality .............................................................................................................. 25 4.3. Clinical Microbiology ...................................................................................................... 26 4.4. Nonclinical Pharmacology/Toxicology ........................................................................... 27 4.5. Clinical Pharmacology .................................................................................................... 28 4.5.1. Mechanism of Action .............................................................................................. 28 4.5.2. Pharmacodynamics ................................................................................................. 29 4.5.3. Pharmacokinetics .................................................................................................... 29 4.6. Devices and Companion Diagnostic Issues .................................................................... 32 4.7. Consumer Study Reviews ............................................................................................... 32 5 Sources of Clinical Data and Review Strategy ....................................................................... 32 5.1. Table of Clinical Studies .................................................................................................. 32 5.2. Review Strategy .............................................................................................................. 34 6 Review of Relevant Individual Trials Used to Support Efficacy ............................................. 34 CDER Clinical Review Template 2015 Edition 2 Version date: November 5, 2015 for initial rollout (NME/original BLA reviews) Reference ID: 4135996 Clinical Review Aimee Hodowanec NDAs 209939 and 209940 Letermovir (PREVYMIS) 6.1. Trial P001 ........................................................................................................................ 34 6.1.1. Study Design............................................................................................................ 34 6.1.2. Study Results ........................................................................................................... 38 6.2. Trial P020 ........................................................................................................................ 62 6.2.1. Study Design............................................................................................................ 62 6.2.2. Study Results ........................................................................................................... 63 7 Integrated Review of Effectiveness ....................................................................................... 67 7.1. Assessment of Efficacy Across Trials .............................................................................. 67 7.1.1. Primary Endpoints ................................................................................................... 67 7.1.2. Secondary and Other Endpoints ............................................................................. 68 7.1.3. Subpopulations ....................................................................................................... 68 7.1.4. Dose and Dose-Response: Trial P020 ..................................................................... 69 7.1.5. Onset, Duration, and Durability of Efficacy Effects ................................................ 69 7.2. Additional Efficacy Considerations ................................................................................. 70 7.2.1. Considerations on Benefit in the Postmarket Setting ............................................ 70 7.2.2. Other Relevant Benefits .......................................................................................... 70 7.3. Integrated Assessment of Effectiveness ........................................................................ 70 8 Review of Safety .................................................................................................................... 71 8.1. Safety Review Approach ................................................................................................ 71 8.2. Review of the Safety Database ...................................................................................... 72 8.2.1. Overall Exposure ..................................................................................................... 72 8.2.2. Relevant characteristics of the safety population: ................................................. 73 8.2.3. Adequacy of the safety database: .......................................................................... 74 8.3. Adequacy of Applicant’s Clinical Safety Assessments .................................................... 74 8.3.1. Issues Regarding Data Integrity and Submission Quality ....................................... 74 8.3.2. Categorization of Adverse Events ........................................................................... 74 8.3.3. Routine Clinical Tests .............................................................................................. 75 8.4. Safety Results ................................................................................................................. 75 8.4.1. Deaths ..................................................................................................................... 77 8.4.2. Serious Adverse Events ........................................................................................... 81 CDER Clinical Review Template 2015 Edition 3 Version date: November 5, 2015 for initial rollout (NME/original BLA reviews) Reference ID: 4135996 Clinical Review Aimee Hodowanec NDAs 209939 and 209940 Letermovir (PREVYMIS) 8.4.3. Dropouts and/or Discontinuations Due to Adverse Effects ................................... 85 8.4.4. Significant Adverse Events ...................................................................................... 86 8.4.5. Treatment Emergent Adverse Events and Adverse Reactions ............................... 87 8.4.6. Laboratory Findings ...............................................................................................