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207620Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 207620Orig1s000 PHARMACOLOGY REVIEW(S) Tertiary Pharmacology Review By: Paul C. Brown, Ph.D., ODE Associate Director for Pharmacology and Toxicology, OND IO NDA: 207620 Submission date: 10/29/14 (date of submission of nonclinical module) Drug: sacubitril/valsartan Applicant: Novartis Indication: reducing the risk of cardiovascular mortality and (b) (4) hospitalization in patients with chronic heart failure Reviewing Division: Division of Cardiovascular and Renal Products, Division of Hematology Products Discussion: The primary reviewer and supervisor found the nonclinical information adequate to support the approval of sacubitril/valsartan for the indication listed above. Sacubitril is a new molecular entity whereas valsartan is in several approved drug products. The carcinogenicity of valsartan has been previously assessed. The carcinogenicity of sacubitril was assessed in 2-year rat and mouse studies. These studies were found to be acceptable by the executive carcinogenicity assessment committee and the committee concluded that there were no drug- related neoplasms in either species. The applicant provided embryofetal studies in rats and rabbits with sacubitril and with the combination of sacubitril/valsartan. These studies showed some adverse effects such as embryo-fetal lethality and hydrocephaly that appear to be attributable to angiotensin receptor antagonism. Interaction with the renin- angiotensin system in general is considered to have the potential to induce adverse fetal effects. A pre/postnatal study in rats with sacubitril showed some slight body weight effects in pups. Adverse effects in pre/postnatal studies have also been observed with valsartan. An acceptable established pharmacologic class for sacubitril could be “neprilysin inhibitor”. Valsartan is an angiotensin II receptor blocker. Conclusions: I agree that this NDA can be approved from a pharm/tox perspective for the indication listed above. I have provided comments on labeling separately. 1 Reference ID: 3787290 --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- PAUL C BROWN 07/02/2015 Reference ID: 3787290 DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH PHARMACOLOGY/TOXICOLOGY NDA/BLA REVIEW AND EVALUATION Application number: 207620 Supporting document/s: SDN 001 Applicant’s letter date: 10/29/14 CDER stamp date: 10/29/14 Product: LCZ696 (sacubitril/valsartan) tablets Indication: Heart failure Applicant: Novartis Review Division: Div. Cardio-Renal Products Reviewer: William T. Link, Ph.D. Supervisor/Team Leader: Albert De Felice, Ph. D. Division Director: Norman Stockbridge, M.D., Ph.D. Project Manager: Alexis Childers Template Version: September 1, 2010 Disclaimer Except as specifically identified, all data and information discussed below and necessary for approval of NDA 207620 are owned by Novartis or are data for which Novartis has obtained a written right of reference. Any information or data necessary for approval of NDA 207620 that Novartis does not own or have a written right to reference constitutes one of the following: (1) published literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug, as reflected in the drug’s approved labeling. Any data or information described or referenced below from reviews or publicly available summaries of a previously approved application is for descriptive purposes only and is not relied upon for approval of NDA 207620. 1 Reference ID: 3756893 NDA # 207620 Reviewer: William T. Link, Ph.D. TABLE OF CONTENTS 1 EXECUTIVE SUMMARY ......................................................................................... 4 1.1 INTRODUCTION .................................................................................................... 4 1.2 BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 8 1.3 RECOMMENDATIONS .......................................................................................... 10 2 DRUG INFORMATION .......................................................................................... 10 2.1 DRUG ............................................................................................................... 10 2.2 RELEVANT INDS, NDAS, BLAS AND DMFS......................................................... 11 2.3 DRUG FORMULATION ......................................................................................... 11 2.4 COMMENTS ON NOVEL EXCIPIENTS..................................................................... 11 2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 11 2.6 PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .................................... 11 3 STUDIES SUBMITTED.......................................................................................... 11 3.1 STUDIES REVIEWED........................................................................................... 11 3.2 STUDIES NOT REVIEWED ................................................................................... 11 4 PHARMACOLOGY................................................................................................ 12 4.1 PRIMARY PHARMACOLOGY ................................................................................. 12 4.2 SECONDARY PHARMACOLOGY ............................................................................ 35 4.3 SAFETY PHARMACOLOGY................................................................................... 38 5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 45 5.1 ADME ............................................................................................................. 45 5.2 TOXICOKINETICS ............................................................................................... 66 6 GENERAL TOXICOLOGY..................................................................................... 67 6.1 SINGLE-DOSE TOXICITY ..................................................................................... 67 6.2 REPEAT-DOSE TOXICITY .................................................................................... 68 6.2.1 STUDIES WITH LCZ696.................................................................................. 68 6.2.2 STUDIES WITH AHU377 ................................................................................. 95 7 GENETIC TOXICOLOGY .................................................................................... 113 7.1 IN VITRO REVERSE MUTATION ASSAY IN BACTERIAL CELLS (AMES)..................... 113 7.2 IN VITRO ASSAYS IN MAMMALIAN CELLS............................................................ 118 7.3 IN VIVO CLASTOGENICITY ASSAY IN RODENT (MICRONUCLEUS ASSAY)................ 139 7.4 OTHER GENETIC TOXICITY STUDIES.................................................................. 142 8 CARCINOGENICITY ........................................................................................... 143 9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY .............................. 177 9.1 FERTILITY AND EARLY EMBRYONIC DEVELOPMENT............................................. 177 9.2 EMBRYONIC FETAL DEVELOPMENT ................................................................... 188 9.3 PRENATAL AND POSTNATAL DEVELOPMENT....................................................... 203 2 Reference ID: 3756893 NDA # 207620 Reviewer: William T. Link, Ph.D. 10 SPECIAL TOXICOLOGY STUDIES .................................................................... 210 11 INTEGRATED SUMMARY AND SAFETY EVALUATION .................................. 232 3 Reference ID: 3756893 NDA # 207620 Reviewer: William T. Link, Ph.D. 1 Executive Summary 1.1 Introduction LCZ696 (sacubitril/valsartan) is a combination angiotensin receptor/neprilysin (neutral endopeptidase 24.11; NEP) inhibitor (ARNI) intended as an oral treatment for heart failure (b) (4) The target dose is 200 mg twice daily (BID). LCZ696 is a salt complex comprising sacubitril (AHU377, a new-molecular entity) and valsartan, sodium cations, and water molecules in the molar ratio of 1:1:3:2.5 (ratio of 6:6:18:15 in the asymmetric unit cell of the solid-state crystal). Each 200-mg dose of LCZ696 contains approximately 97 mg of AHU377 and 103 mg of valsartan. Dosage forms of 50 mg LCZ696 and 100 mg LCZ696 are also available for initiation of treatment and/or down-titration. Following oral administration, LCZ696 dissociates into valsartan and the pro-drug AHU377, which is further metabolized to the NEP inhibitor LBQ657. Exposures to both LBQ657 and valsartan are dose-proportional and predictable. LCZ696 doses of 50, 100, and 200 mg deliver valsartan exposures which are similar to those delivered from the Diovan® dose strengths of 40, 80, and 160 mg, respectively. The pharmacodynamic activity and selectivity of LCZ696 was characterized in a number of in vitro and in vivo pharmacological studies conducted with LCZ696, AHU377, LBQ657, or valsartan. The animal studies were conducted in cardiorenal disease models and demonstrate a beneficial effect of LCZ696 on cardiac, renal,
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