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211616Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 211616Orig1s000 INTEGRATED REVIEW Executive Summary Interdisciplinary Assessment Appendices NDA211616 Nexletol (bempedoic acid) tablets Integrated Review Table 1. Administrative Application Information Category Application Information Application type NDA Application number 211616 Priority or standard Standard Submit date 2/20/2019 Received date(s) 2/21/2019 PDUFA goal date 2/20/2020 Division/office Division of Metabolism and Endocrinology Products (DMEP) Review completion date 2/19/2020 Established/proper name Bempedoic acid (Proposed) proprietary name Nexletol Pharmacologic class adenosine triphosphate-citrate lyase (ACL) inhibitor Code name ETC-I 002 Applicant Esperion Therapeutics, Inc. Dosage form/formulation(s) Tablets, 180 mg DosiI1 re imen One tablet dail Applicant proposed (bl(ilJ)-- indication(s)/population(s) who require additional lowering of low­ aens1ty hpoprotein cholesterol (LDL-C) Proposed SNOMED indication 55822004 (hyperlipidemia) Regulatory action Approval Approved indication(s)/ as an adjunct to diet and maximally tolerated statin therapy for the population(s) (if applicable) treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering ofLDL-C Approved SNOMED term for 55822004 (hyperlipidemia) indication Integrated Review Template, version date 2019/06/14 NDA 211616 Nexletol (bempedoic acid) tablets Table of Contents Table of Tables .................................................................................................................. vi Table of Figures ................................................................................................................ xii Glossary ............................................................................................................................1 I. Executive Summary ..........................................................................................................4 1. Summary of Regulatory Action ...................................................................................4 2. Benefit-Risk Assessment ..............................................................................................8 II. Interdisciplinary Assessment.........................................................................................12 3. Introduction ................................................................................................................12 3.1. Approach to Review ............................................................................................14 4. Patient Experience Data .............................................................................................18 5. Pharmacologic Activity, Pharmacokinetics, and Clinical Pharmacology ..................19 5.1. Nonclinical Assessment of Potential Effectiveness .............................................22 6. Evidence of Benefit (Assessment of Efficacy) ..........................................................24 6.1. Assessment of Dose and Potential Effectiveness ................................................24 6.2. Design of Clinical Trials Intended to Demonstrate Benefit to Patients ...............33 6.2.1. Trial Design ...................................................................................................33 6.2.2. Eligibility Criteria .........................................................................................34 6.2.3. Statistical Analysis Plan ................................................................................37 6.3. Results of Analyses of Clinical Trials/Studies Intended to Demonstrate Benefit to Patients ...........................................................................................40 6.4. Review Issues Relevant to Evaluation of Benefit ................................................51 6.4.1. Demonstration of Efficacy ............................................................................51 (b) (4) 6.4.4. Changes to Other Biomarkers .......................................................................53 7. Risk and Risk Management ........................................................................................55 7.1. Potential Risks or Safety Concerns Based on Nonclinical Data ..........................55 7.2. Potential Risks or Safety Concerns Based on Drug Class or Other Drug- Specific Factors ..............................................................................................58 7.3. Potential Safety Concerns Identified Through Postmarket Experience ..............62 7.4. FDA Approach to Safety Review ........................................................................62 7.5. Adequacy of Clinical Safety Database ................................................................63 7.6. Safety Findings and Safety Concerns Based on Review of the Clinical Safety Database ..............................................................................................64 7.6.1. Overall Adverse Event Summary..................................................................64 7.6.2. Deaths ............................................................................................................65 7.6.3. Serious Adverse Events.................................................................................66 ii Integrated Review Template, version date 2019/06/14 NDA 211616 Nexletol (bempedoic acid) tablets 7.6.4. Dropouts and/or Discontinuations Due to Adverse Events...........................68 7.6.5. Treatment-Emergent Adverse Events ...........................................................70 7.6.6. Laboratory Findings ......................................................................................74 7.7. Review Issues Relevant to Evaluation of Risk ....................................................77 7.7.1. Death Imbalance............................................................................................77 7.7.1.1. All-Cause Death Imbalance ....................................................................77 7.7.1.2. Cardiovascular Death Imbalance ............................................................78 7.7.1.3. Malignancy Death Imbalance .................................................................82 7.7.2. Tendon Rupture .............................................................................................86 7.7.3. Increases in Uric Acid ...................................................................................87 7.7.4. New-Onset Benign Prostatic Hyperplasia .....................................................88 7.7.5. Decreased Hemoglobin .................................................................................88 7.7.6. Decreased White Blood Cell Count ..............................................................89 7.7.7. Changes in Renal Lab Parameters.................................................................90 7.7.8. Thrombocytosis .............................................................................................91 7.7.9. Decreased Alkaline Phosphatase...................................................................92 7.7.10. Imbalance in Pancreatic Tumors in the Rat Carcinogenicity Study ...........92 7.7.11. Toxicological Interactions Between Bempedoic Acid and Statins .............93 8. Therapeutic Individualization ....................................................................................97 8.1. Intrinsic Factors ...................................................................................................97 8.2. Drug Interactions .................................................................................................97 8.3. Plans for Pediatric Drug Development ................................................................99 8.4. Pregnancy and Lactation....................................................................................100 9. Product Quality ........................................................................................................103 9.1. Device or Combination Product Considerations ...............................................103 10. Human Subjects Protections/Clinical Site and Other GCP Inspections/Financial Disclosure .........................................................................103 11. Advisory Committee Summary ..............................................................................103 III. Appendices .................................................................................................................104 12. Summary of Regulatory History ............................................................................104 13. Pharmacology Toxicology: Additional Information and Assessment ...................107 13.1. Summary Review of Studies Submitted Under IND .......................................107 13.1.1. Pharmacology ............................................................................................107 13.1.1.1. Primary Pharmacology .......................................................................107 13.1.1.2. Secondary Pharmacology ...................................................................108 13.1.1.3. Safety Pharmacology ..........................................................................109 13.1.1.4. ADME/PK ..........................................................................................110 13.1.1.5. Toxicokinetic Data .............................................................................113 iii Integrated
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