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(CRDAC) Meeting Date: 13 September 2012 FDA Briefing Document for the Cardiovascular and Renal Drugs Advisory (CRDAC) Meeting Date: 13 September 2012 NDA: 203009 Sponsor: Cardiokine Biopharma, LLC Drug: Lixivaptan Proposed Indication for Use: The treatment of symptomatic hypervolemic and euvolemic hyponatremia associated with heart failure and syndrome of inappropriate antidiuretic hormone (SIADH), respectively. Important Limitations Patients requiring intervention to raise sodium concentration urgently to prevent or to treat serious neurological symptoms should not be treated with lixivaptan. DISCLAIMER STATEMENT The attached package contains background information prepared by the Food and Drug Administration (FDA) for the panel members of the advisory committee. The FDA background package often contains assessments and/or conclusions and recommendations written by individual FDA reviewers. Such conclusions and recommendations do not necessarily represent the final position of the individual reviewers, nor do they necessarily represent the final position of the Review Division or Office. We have brought the Lixivaptan NDA to this Advisory Committee in order to gain the Committee’s insights and opinions, and the background package may not include all issues relevant to the final regulatory recommendation and instead is intended to focus on issues identified by the Agency for discussion by the advisory committee. The FDA will not issue a final determination on the issues at hand until input from the advisory committee process has been considered and all reviews have been finalized. The final determination may be affected by issues not discussed at the advisory committee meeting. CLINICAL REVIEW Application Type NDA 203,009 Application Number(s) 000-000 Priority or Standard Standard Submit Date(s) December 29, 2011 Received Date(s) December 29, 2011 PDUFA Goal Date October 29, 2012 Division / Office Cardiovascular and Renal Products/ ODE1 Reviewer Name(s) Nancy N. Xu, M.D. Review Completion Date August 16, 2012 Established Name Lixivaptan (Proposed) Trade Name LIXAR® Therapeutic Class Vasopressin 2 receptor antagonist Applicant Cornerstone Therapeutics Formulation(s) Oral 25 mg and 50 mg capsules Dosing Regimen Start at 25 mg QD (outpatient) or 50 mg QD (inpatient), titrate to 100 mg QD (SIADH) or 100 mg BID (Heart Failure and Hyponatremia) Indication(s) Treatment of hyponatremia Intended Population(s) Adult subjects with hyponatremia associated with SIADH or heart failure Clinical Review {Nancy N. Xu} {NDA 203,009 Submission #000} {LIXAR (lixivaptan)} Table of Contents 1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 8 1.1 Recommendation on Regulatory Action ............................................................. 8 1.2 Risk Benefit Assessment.................................................................................... 8 1.2.1 Assessment of Efficacy................................................................................ 8 1.2.2 Assessment of Safety ................................................................................ 10 1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies . 12 1.4 Recommendations for Postmarket Requirements and Commitments .............. 12 2 INTRODUCTION AND REGULATORY BACKGROUND ...................................... 12 2.1 Product Information .......................................................................................... 12 2.2 Tables of Currently Available Treatments for Proposed Indications ................. 13 2.3 Availability of Proposed Active Ingredient in the United States ........................ 14 2.4 Important Safety Issues With Consideration to Related Drugs......................... 15 2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 15 2.6 Other Relevant Background Information .......................................................... 17 3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 17 3.1 Submission Quality and Integrity ...................................................................... 17 3.2 Compliance with Good Clinical Practices ......................................................... 17 3.3 Financial Disclosures........................................................................................ 18 4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES ......................................................................................................... 18 4.1 Chemistry Manufacturing and Controls ............................................................ 18 4.2 Clinical Microbiology......................................................................................... 18 4.3 Preclinical Pharmacology/Toxicology ............................................................... 19 4.4 Clinical Pharmacology...................................................................................... 19 4.4.1 Mechanism of Action.................................................................................. 20 Pharmacodynamics................................................................................................ 20 4.4.3 Pharmacokinetics....................................................................................... 21 5 SOURCES OF CLINICAL DATA............................................................................ 22 5.1 Tables of Studies/Clinical Trials ....................................................................... 22 5.2 Review Strategy ............................................................................................... 26 5.3 Discussion of Individual Studies/Clinical Trials................................................. 26 5.3.1 An Overview of the BALANCE Trial: ............................................................. 27 5.3.2 An Overview of the LIBRA Trial, 3405:.......................................................... 31 5.3.3 An Overview of the HARMONY Trial, 3430:.................................................. 33 6 REVIEW OF EFFICACY......................................................................................... 35 6.1 Indication .......................................................................................................... 36 6.1.1 Methods ..................................................................................................... 36 2 Clinical Review {Nancy N. Xu} {NDA 203,009 Submission #000} {LIXAR (lixivaptan)} 6.2 The BALANCE trial in the congestive heart failure and hyponatremia population ......................................................................................................................... 37 6.2.1 Demographics in the BALANCE trial.......................................................... 37 6.2.2 Subject Disposition in the BALANCE Trial ................................................. 43 6.2.3 Analysis of Primary Endpoint(s) in the BALANCE trial............................... 45 6.2.4 Analysis of Secondary Endpoints(s) in the BALANCE trial ........................ 46 6.3 The SIADH population (the LIBRA trial, in-patient dose titration) ..................... 48 6.3.1 Demographics of the LIBRA trial................................................................ 48 6.3.2 Subject Disposition-the LIBRA Trial ........................................................... 51 6.3.3 Analysis of Primary Endpoint(s) for the LIBRA trial.................................... 52 6.3.4 Analysis of Secondary Endpoints(s) for the LIBRA trial ............................. 53 6.4 The SIADH population (the HARMONY trial, monitored out-patient dose titration) ............................................................................................................ 55 6.4.1 Demographics: the HARMONY trial, SIADH population............................. 55 6.4.2 Subject Disposition (HARMONY)............................................................... 57 6.4.3 Analysis of Primary Endpoint(s) ................................................................. 60 6.4.4 Analysis of Secondary Endpoints(s) .......................................................... 60 6.5 Other Endpoints ............................................................................................... 62 6.6 Subpopulations................................................................................................... 62 6.7 Analysis of Clinical Information Relevant to Dosing Recommendations ............. 64 6.8 Discussion of Persistence of Efficacy and/or Tolerance Effects ....................... 64 7 REVIEW OF SAFETY............................................................................................. 64 7.1 Methods............................................................................................................ 64 Studies/Clinical Trials Used to Evaluate Safety ..................................................... 65 7.1.2 Categorization of Adverse Events.............................................................. 66 7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare Incidence.................................................................................................... 66 7.2 Adequacy of Safety Assessments .................................................................... 66 7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of Target Populations..................................................................................... 66 7.2.2 Explorations for Dose Response...............................................................
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