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
`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.
`
`Reference ID: 3787290
`
`1
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`
`207620
`Application number:
`SDN 001
`Supporting document/s:
`10/29/14
`Applicant’s letter date:
`10/29/14
`CDER stamp date:
`LCZ696 (sacubitril/valsartan) tablets
`Product:
`Heart failure
`Indication:
`Novartis
`Applicant:
`Div. Cardio-Renal Products
`Review Division:
`William T. Link, Ph.D.
`Reviewer:
`Albert De Felice, Ph. D.
`Supervisor/Team Leader:
`Norman Stockbridge, M.D., Ph.D.
`Division Director:
`Alexis Childers
`Project Manager:
`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.
`
`Reference ID: 3756893
`
`1
`
`

`

`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
`STUDIES SUBMITTED.......................................................................................... 11
`3.1
`STUDIES REVIEWED........................................................................................... 11
`3.2
`STUDIES NOT REVIEWED ................................................................................... 11
`PHARMACOLOGY................................................................................................ 12
`4.1
`PRIMARY PHARMACOLOGY................................................................................. 12
`4.2
`SECONDARY PHARMACOLOGY............................................................................ 35
`4.3
`SAFETY PHARMACOLOGY................................................................................... 38
`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
`
`3
`
`4
`
`5
`
`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
`
`Reference ID: 3756893
`
`2
`
`

`

`NDA # 207620
`
`Reviewer: William T. Link, Ph.D.
`
`10 SPECIAL TOXICOLOGY STUDIES .................................................................... 210
`
`11 INTEGRATED SUMMARY AND SAFETY EVALUATION .................................. 232
`
`Reference ID: 3756893
`
`3
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`

`

`NDA # 207620
`
`Reviewer: William T. Link, Ph.D.
`
`1
`
`Executive Summary
`
`Introduction
`1.1
`LCZ696 (sacubitril/valsartan) is a combination angiotensin receptor/neprilysin (neutral
`endopeptidase 24.11; NEP) inhibitor (ARNI) intended as an oral treatment for heart
`failure
`
`
` 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, and vascular
`function and organ protection.
`
`Pharmacology
`The pro-drug AHU377 is a poor inhibitor of human recombinant NEP enzyme activity in
`vitro (IC50 = 16,700 ± 2,300 nM), whereas its metabolite LBQ657 is a potent inhibitor
`(IC50 = 2.3 ± 0.4 nM). Both AHU377 and LBQ657 are poor inhibitors of human
`recombinant NEP-2 enzyme activity. Valsartan does not inhibit NEP or NEP-2 activity at
`concentrations up to 100,000 nM.
`
`Valsartan blocks angiotensin II binding to AT1 receptors in rat aortic smooth muscle cell
`membranes with a Ki of 2.4 nM and is more than 30,000-fold selective relative to the
`AT2 receptor subtype. Neither AHU377 nor LBQ657 inhibit binding to the human AT1
`receptor at concentrations of 30 μM.
`
`AHU377, LBQ657, and valsartan show no meaningful inhibition (>2000-fold selective) of
`a set of ten proteases that are related to NEP or enzymes associated with NP/RAAS
`pathways. AHU377 and LBQ657 were assessed for their off-target activities on a panel
`of GPCRs, transporters, ion channels, nuclear receptors, and enzymes. No significant
`inhibitory effects were found for AHU377 at 30 μM or for LBQ657 at ≥10 μM for any of
`the targets tested.
`
`Reference ID: 3756893
`
`4
`
`(b) (4)
`
`

`

`NDA # 207620
`
`Reviewer: William T. Link, Ph.D.
`
`LCZ696 lowered blood pressure in rat models of hypertension with divergent etiologies.
`A single administration of LCZ696 (60 mg/kg) reduced MAP by 73 mmHg in double-
`transgenic rats overexpressing human renin and angiotensinogen (dTGR), a high-renin
`model of hypertension. LCZ696 (68 mg/kg/day) also reduced arterial pressure for the
`duration of the two-week treatment period in a normal-renin, salt-insensitive model of
`hypertension (SHR). Likewise, LCZ696 (68 mg/kg/day) blunted or prevented the gradual
`rise in arterial pressure in two respective studies in a low-renin volume-dependent
`model of hypertension (DSS rat on high salt diet).
`
`In cell culture, concomitant exposure to LBQ657 and valsartan reduced angiotensin II-
`mediated rat cardiomyocyte hypertrophy and rat cardiac fibroblast collagen synthesis to
`a greater extent than valsartan alone. In a rat post-myocardial infarction model, LCZ696
`reduced the hypertrophy that occurs in response to injury. In stroke-prone
`spontaneously hypertensive rats (SHRSP), combined AHU377 and valsartan was more
`effective than valsartan alone in improving cardiac and vascular fibrosis and vascular
`remodeling.
`
`Safety pharmacology
`At the maximum feasible concentrations (3 mM for LCZ696; 1 mM for AHU377), no
`meaningful hERG inhibition was observed. Therefore, the risk for QT prolongation at
`anticipated exposures associated with the proposed clinical dose of 200 mg BID is
`perceived to be low.
`
`AHU377 up to 250 mg/kg had no effects on blood pressure, heart rate or ECG
`parameters in normal, conscious dogs. Slight reductions in blood pressure (systolic,
`diastolic and mean arterial blood pressures) were observed in cynomolgus monkeys at
`a dose of 100 mg/kg LCZ696, consistent with the greater blood pressure lowering effect
`of the ARNI compared to single-acting therapy.
`
`LCZ696 andAHU377 had no adverse effects on respiratory or CNS endpoints following
`single oral administration in rodents at doses which provided valsartan exposure
`multiples of ~1X, and LBQ657 exposure multiples in excess of 8X those associated with
`a 200 mg BID clinical dose.
`
`Pharmacokinetics (ADME)
`LCZ696 or AHU377 was well absorbed in all animal species (65-100%) after p.o. dose.
`In human, absorption was estimated to be at least 61%. The absorption was relatively
`rapid in rate and onset in all species (mouse, rat, dog, rabbit, monkey, and human) with
`Tmax ranging from 0.25 - 2 h.
`
`Following an oral dose, the terminal half-life for AHU377 was short (1.3-3.2 h) in all
`species. The terminal half-life of LBQ657 or valsartan was relatively short in mice, rats
`and dogs (1.1-3.1 h), but was long in monkeys (~6 h) and humans (12-21 h).
`Bioavailability of LBQ657 was moderate to high (41-100%) in animals and was
`estimated to be greater than 50% in human. Dose-normalized plasma or blood
`
`Reference ID: 3756893
`
`5
`
`

`

`NDA # 207620
`
`Reviewer: William T. Link, Ph.D.
`
`exposure values (AUC) for LCZ696-associated components (AHU377 or LBQ657) in
`monkey were higher than other species (rank order: monkey >dog >rat ≈mouse). The
`lower dose-normalized exposure seen in mouse, rat, and dog was associated with its
`high clearance (as high as hepatic blood flow).
`
`Plasma exposure (AHU377, LBQ657 and valsartan) is generally proportional to the
`dose in all tested animal species (mice, rats, rabbits, and monkeys)
`
`Uptake of AHU377, LBQ657, and valsartan into blood cells was not significant and
`therefore drug concentrations in plasma were higher than in blood. Both AHU377 and
`LBQ657 were moderately to highly bound to plasma proteins with some species
`differences (90%, 80%, 93% and 97% in rat, dog, monkey, and human, respectively for
`LBQ657 and 91% and 97% in monkey and human, respectively, for AHU377). Similarly,
`valsartan was bound to serum proteins with some species differences (82-97%). In
`human, serum albumin was found to be the primary binding protein for AHU377,
`LBQ657 and valsartan.
`
`In rats, drug-related radioactivity was widely and rapidly distributed to most tissues
`following a single i.v. or p.o. dose of radiolabelled AHU377. The highest tissue
`radioactivity (2-4 fold higher than blood) was found in kidney and liver 5 min after i.v.
`dosing. The lowest radioactivity levels were observed in brain, eye, seminal vesicles
`and spinal cord. Based on AHU377-derived radioactivity, brain and testis penetration is
`minimal (tissue: blood ratios were 0.02 and 0.05, respectively) and affinity to melanin-
`rich tissues (pigmented skin and uveal tract) is low.
`
`Uptake of AHU377, LBQ657, and valsartan into blood cells was not significant and
`therefore drug concentrations in plasma were higher than in blood. Both AHU377 and
`LBQ657 were moderately to highly bound to plasma proteins with some species
`differences (90%, 80%, 93% and 97% in rat, dog, monkey, and human, respectively for
`LBQ657 and 91% and 97% in monkey and human, respectively, for AHU377). Similarly,
`valsartan was bound to serum proteins with some species differences (82-97%). In
`human, serum albumin was found to be the primary binding protein for AHU377,
`LBQ657 and valsartan.
`
`In pregnant rats dosed with [14C]LCZ696, the extent of the transfer of AHU377-derived
`radioactivity from maternal blood into the embryo-fetal compartment was moderate
`(fetus-to maternal blood ratio at fetus Tmax: 0.509 on day 12 and 0.246 on day 17). In
`pregnant rabbits dosed with LCZ696, the fetal exposure relative to maternal plasma was
`low (~0.06 - 0.21 for LBQ657 and ~0.01 for valsartan), indicating that LCZ696 related
`materials was poorly transferred into the fetus.
`
`Following an oral dose (30 mg/kg) of [14C]LCZ696 to lactating rats, transfer of LBQ657
`into milk was observed. The overall milk:plasma concentration ratio of total radioactivity
`was 0.91 based on AUC0-∞ values.
`
`Reference ID: 3756893
`
`6
`
`

`

`NDA # 207620
`
`Reviewer: William T. Link, Ph.D.
`
`AHU377 primarily underwent ethyl ester hydrolysis to form LBQ657 in all species. The
`rate of conversion from AHU377 to LBQ657 was high in mouse, rat and human, and the
`major compound detected in plasma/blood was LBQ657 (mouse: ~73% of AUC, rat:
`~80% AUC, human: 93-98% of AUC comparing to AHU377). In contrast, the rate of
`conversion was moderate in dog and monkey where both AHU377 and LBQ657 were
`present in plasma/blood (AHU377:LBQ657 = ~34%:~46% of AUC in dogs,
`AHU377:LBQ657 = ~37%:~62% of AUC in monkeys).
`
`AHU377 and LBQ657 undergo further hydroxylation, glucuronidation, sulfation, and
`glycine/taurine conjugation to generate several minor metabolites in plasma/blood of
`various species. LBQ657 was the major component recovered in excreta from all
`species studied, accounting for ~70-100% of the oral dose. Unchanged AHU377
`recovered in excreta was minimal in all species studied, accounting for <1-14% of the
`oral dose. The metabolic profiling studies did not reveal any major unique human
`metabolite.
`
`In mice, rats and dogs, AHU377-derived radioactivity was predominantly excreted in the
`feces (~74-98% of the dose). In monkeys and humans, however, AHU377-derived
`radioactivity had higher excretion into urine (~42-65% of the dose).
`
`LCZ696 was eliminated primarily as LBQ657 and valsartan with minimal AHU377 (~3%
`of dose, except for ~13% in dog) and some minor metabolites in both animals and
`humans.
`
`CYP Inhibition/Induction
`AHU377 showed little or no inhibition (IC50 >100 μM) in in vitro assays using human
`CYP enzymes 1A2, 2C9, 2D6, 2E1, 3A4/5, and only a weak inhibition against CYP2C8
`(IC50 ~15 μM) and 2C19 (IC50 ~20 μM).
`
`LBQ657 demonstrated weak inhibition of CYP2C9 (IC50 ~40 μM) in in vitro assays. The
`potential inhibition of CYP2C9 was investigated in the clinical trial [CLCZ696B2112] in
`which no interaction occurred between LCZ696 and warfarin, a drug metabolized by
`CYP2C9. Since LBQ657 is mainly eliminated unchanged, its elimination is unlikely to be
`influenced by CYP enzyme inhibitors. Therefore, the potential for a DDI between
`LBQ657 and concomitantly administered drugs is considered to be low.
`
`AHU377, LBQ657 and valsartan at concentrations up to 100 μM did not induce the
`expression and/or catalytic activities of CYP1A2, CYP2B6, CYP2C9, or CYP3A in
`primary human hepatocytes.
`
`Transporters The in vitro inhibition studies suggested likely involvement of P-
`glycoprotein (P-gp) in AHU377 transport; however, this is not anticipated to have a
`significant effect on its oral absorption because the affinity of AHU377 for P-gp was low
`(>100 μM) and a high absorption (65-100%) was observed in animals. These data also
`imply that potential inhibition of AHU377 absorption by other P-gp inhibitors is expected
`to be low.
`
`Reference ID: 3756893
`
`7
`
`

`

`NDA # 207620
`
`Reviewer: William T. Link, Ph.D.
`
`AHU377, up to a concentration of 50 μM, did not inhibit multi-drug resistance protein
`(MRP2) or P-gp transport activity and only very weakly inhibited breast cancer
`resistance protein (BCRP)-mediated transport activity. These data suggest that AHU377
`is unlikely to significantly inhibit BCRP, P-gp or MRP2. Similarly, LBQ657 was found not
`to be an inhibitor of P-gp and BCRP activities, suggesting a low likelihood of
`pharmacokinetic interactions when co-administered with P-gp and BCRP substrates.
`The in vitro results suggest that AHU377 or LBQ657 are weak inhibitors of multidrug
`and toxin extrusion transporter 1 (MATE1) and 2-K (MATE2-K) but these effects are
`unlikely to be clinically relevant.
`
`The in vitro results suggest that active transport by hepatic organic anion-transporting
`polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) contributes to the systemic clearance
`of LBQ657 which may be altered when LBQ657 is co-administered with drugs that
`inhibit these transporters such as cyclosporine and a number of protease inhibitors..
`LBQ657 was shown to be an in vitro inhibitor of OATP1B1 (IC50 = 126 ± 26 μM) but not
`of OATP1B3. Based on the Cmax of LBQ657 (16531 ng/mL = 43 μM) observed
`therapeutically, it is unlikely that LBQ657 will increase the systemic exposure of
`OATP1B1 substrates. AHU377, LBQ657, and valsartan did not inhibit the hepatic
`organic cation transporters 1 (OCT1) or renal OCT2 in the in vitro assays
`
`Toxicokinetics
`In the toxicokinetic studies, with respect to AHU377, LBQ657 and valsartan
`concentrations, the AUC values in all tested species (mouse, rat, rabbit, and monkey
`including pregnant rat and rabbit) were generally proportional to dose. No clear
`evidence of accumulation in rats and monkeys was observed following multiple daily
`dosing for 26 or 39 weeks. There was no evidence of gender differences. Specific
`exposure and exposure multiples are discussed with the toxicology studies.
`1.2 Brief Discussion of Nonclinical Findings
`LCZ696 has been tested in a range of species including mice, rats, rabbits, and
`cynomolgus monkeys. The cynomolgus monkey was chosen as the principal non-rodent
`species for toxicity assessment of LCZ696 based on homology of NEP and NEP
`substrates to human, but AHU377 has also been evaluated in dogs and marmosets.
`Toxicology studies in the marmoset with AHU377 provided a basis for comparison to
`previous valsartan marmoset studies and helped define the specific toxicologic effects
`of these two LCZ696 components.
`
`In repeated dose general toxicity studies up to 39 weeks in duration, the NOAEL for
`LCZ696 was established at 50 mg/kg/day in mice, and 30 mg/kg/day in rats and
`cynomolgus monkeys.
`
`Targets organs for LCZ696 and/or AHU377 were kidney, red blood cells, heart, and the
`GI tract. Each is discussed in greater detail in the Integrated Summary at the end of this
`review. None of these findings are considered an impediment to safe use of LCZ696, as
`
`Reference ID: 3756893
`
`8
`
`

`

`NDA # 207620
`
`Reviewer: William T. Link, Ph.D.
`
`all represent adaptive responses or result from exaggerated pharmacodynamic
`responses to high doses.
`
`Genotoxicity assays of LCZ696, AHU377 and LBQ657 were uniformly negative. These
`studies, which were compliant with (ICH S2 (R1)), included in vivo testing and in vitro
`assays in bacterial and mammalian systems, with and without S9 metabolic activation.
`The S9 fraction enables conversion of AHU377 to LBQ657 thereby ensuring in vitro
`characterization of this in vivo active metabolite.
`
`There was no evidence of carcinogenicity when AHU377 was administered by oral
`gavage for a minimum of 104 weeks to mice at doses up to 1200 mg/kg/day (LBQ657
`exposure multiples 14x (males) and 46X (females), and to rats at doses up to 400
`mg/kg/day (LBQ657 exposure multiples 1.6x (males) and 3.6 (females), based on Cmax
`relative to 200 mg BID clinical dose).
`
`The carcinogenicity studies were evaluated with Executive CAC concurrence as to
`conduct and interpretation.
`
`LCZ696 had no effect on fertility in rats. In embryo-fetal development studies LCZ696
`treatment was associated with increased embryo lethality in both rats and rabbits.
`LCZ696 was teratogenic in rabbits at doses of 10 mg/kg and higher based on a low but
`dose-dependent increase in hydrocephaly which occurred at maternally toxic doses.
`Both AHU377 and valsartan have been associated with fetal toxicity and embryo-fetal
`lethality in rabbits.
`
`The NOAEL for embryo-fetal toxicity in studies with LCZ696 was 30 mg/kg/day in rats
`and 3 mg/kg in rabbits. As for any drug that acts directly on the RAAS, LCZ696 is
`contraindicated during pregnancy.
`
`Results of pre and postnatal development studies with AHU377 and valsartan suggest
`that LCZ696 exposure during these periods may impair fetal development and survival.
`
`Results of neonatal and juvenile toxicology studies with AHU377 and valsartan suggest
`that LCZ696 treatment may impact bone growth and mineralization and impair kidney
`development, however these effects were minor and show recovery.
`
`A theoretical risk associated with NEP inhibition relates to effects on β-amyloid (Aβ)
`metabolism, and the potential accumulation of Aβ in the brain. Elevated levels of Aβ
`were present in CSF and plasma but not brain samples of cynomolgus monkeys treated
`with LCZ696 for two weeks at a clinically relevant dose of 50 mg/kg/day, suggesting that
`the newly synthesized Aβ was eliminated from brain tissue by other (non-NEP)
`clearance pathways. The relevance to human patients is not clear.
`
`All of the above findings are discussed in the product labeling.
`
`Reference ID: 3756893
`
`9
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`

`NDA # 207620
`
`Reviewer: William T. Link, Ph.D.
`
`1.3 Recommendations
`1.3.1 Approvability
`The preclinical toxicology program was well conducted and thorough. The studies were
`well planned and employed sufficient numbers of dose groups and animals to allow
`proper interpretation and review.
`
`This reviewer agrees with the sponsor’s interpretation of the data, as presented, and
`recommends approval of LCZ696 for the indication sought.
`
`1.3.2 Additional Non Clinical Recommendations
`none
`Labeling
`1.3.3
`Labeling edits were submitted independently through SharePoint.
`2
`Drug Information
`
`2.1 Drug
`
`Generic Name: sacubitril (AHU377)/ valsartan
`
`Code Name: LCZ696
`
`Molecular Formula/Molecular Weight
`NEPi moiety, sacubitril: C24H29NO5, MW 411.49
`ARB moiety, valsartan: C24H29N5O3, MW 435.52
`Structure or Biochemical Description
`
`sacubitril (AHU377)
`
`valsartan
`
`Pharmacologic Class: 2 components
`sacubitril – neutral endopeptidase (NEP) inhibitor
`valsartan – AT1 receptor blocker (ARB)
`
`Reference ID: 3756893
`
`10
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`

`NDA # 207620
`
`Reviewer: William T. Link, PhD.
`
`2.2 Relevant INDs, NDAs, BLAs and DMFs
`
`IND
`
`"'"", IND
`
`"’"", IND 104628
`
`2.3 Drug Formulation
`
`Composition of one LCZ696 (sacubitrillvalsartan) 50 mg, 100 mg, 200 mg film-coated
`tablet (mgl tablet)
`
`.
`r tablet
`Amount m
`_
`In redlents L Funct on
`50 mg‘
`100 mg2
`'
`g
`200 mg’
`Tablet core
`
`Reference to
`standards
`
`(m4)
`
`(m4)
`
`A
`’
`.
`Delivers the active Novartls
`
`(50 mg)
`
`(100 mg)
`
`(200 mg)
`
`substances
`
`monograph
`
`Microcrystalline cellulose I
`Cellulose, microcrystalline
`Low Substituted
`Hydroxypropylcellulose
`
`Crospovidone
`
`Magnesium stearate5
`Talc
`
`2231:2151: Silicon glfi’l'del Silica,
`
`Total core tablet weight
`
`(”l“)
`
`NF] Ph‘ Eur_
`NF
`
`NF/ Ph. Eur.
`
`NF/ Ph. Eur.
`USP/ Ph. Eur.
`
`NF/ Ph. Eur.
`
`2.4 Comments on Novel Excipients
`
`none
`
`2.5 Comments on Impurities/Degradants of Concern
`
`none
`
`2.6
`
`Proposed Clinical Population and Dosing Regimen
`
`LCZ696 (sacubitril/valsartan) is an angiotensin receptor neprilysin (neutral
`endopeptidase 24.11; NEP) inhibitor (ARNI) intended as an oral treatment for heart)
`failur
`
`The target dose is 200 mg twice daily (BID).
`
`3
`
`Studies Submitted
`
`3.1
`
`Studies Reviewed
`
`The Pharmacology and Pharmacokinetics sections are presented, mostly verbatim,
`from the sponsor. General toxicology, genetic toxicology, carcinogenicity and
`reproductive toxicology studies for L02696 and AHU377 were reviewed.
`
`3.2
`
`Studies Not Reviewed
`
`Dose-.ranging and non-GLP studies were examined, but not formally reviewed.
`
`Reference ID: 3756893
`
`1 1
`
`

`

`NDA # 207620
`
`Reviewer: William T. Link, Ph.D.
`
`4
`
`Pharmacology
`
`Primary Pharmacology
`4.1
`LCZ696 is a novel combination angiotensin receptor neprilysin (neutral endopeptidase
`24.11; NEP) inhibitor (ARNI) intended as an oral treatment for heart failure
`
`. 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). Following oral administration, LCZ696
`dissociates into valsartan and the pro-drug AHU377, which is further metabolized to the
`NEP inhibitor LBQ657.
`
`LCZ696 exhibits a dual mechanism of action of an ARNI by simultaneously inhibiting
`NEP via LBQ657and by blocking the angiotensin II type-1 (AT1) receptor via valsartan.
`The resulting increase in natriuretic peptide (NP) activity due to NEP inhibition and renin
`– angiotensin - aldosterone system (RAAS) inhibition through AT1 receptor blockade
`have complementary cardiovascular and renal effects that are considered beneficial in
`heart failure.
`
`In rats and dogs, oral administration of AHU377 delivers LBQ657 systemically, which
`resulted in concentration-dependent inhibition of NEP activity, increases in circulating
`levels of the NEP substrate atrial natriuretic peptide (ANP), and consequent elevations
`in renal sodium excretion and urine volume. LCZ696 also dose-dependently increased
`circulating ANP levels in rats.
`
`In dogs, oral administration of LCZ696 elevated plasma and urinary cyclic guanosine
`monophosphate (cGMP), indicating NP receptor activation. In dogs fed a low-salt diet to
`activate the RAAS, plasma renin activity was increased less and plasma aldosterone
`concentrations were suppressed more by LCZ696 than by valsartan alone, which
`reflects the convergence of these two pathways by the dual activities of LCZ696.
`
`The in vitro binding and inhibitor potencies of AHU377, LBQ657, and valsartan were
`evaluated for the NEP enzyme and AT1 receptor. Additional data for valsartan is
`provided in the [Diovan® NDA 20-665] and the (Diovan® - US Prescribing Information).
`
`LCZ696
`LCZ696 was not tested in vitro because it readily dissociates into AHU377 and
`valsartan in aqueous media. Therefore, these compounds and the NEPi LBQ657 were
`tested individually.
`
`AHU377 and LBQ657
`The Table below summarizes the in vitro pharmacological profiles for AHU377,
`LBQ657, and valsartan as well as comparator reference compounds on NEP and NEP-
`2 protease activity. The pro-drug AHU377 was a weak inhibitor of NEP enzyme activity
`
`Reference ID: 3756893
`
`12
`
`(b) (4)
`
`

`

`NDA # 207620
`
`Reviewer: William T. Link, Ph.D.
`
`whereas LBQ657 was a potent NEP inhibitor. Both AHU377 and LBQ657 were weak
`inhibitors of human recombinant NEP-2 enzyme activity.
`
`The reference NEP inhibitors thiorphan and omapatrilat inhibited human NEP activity at
`concentrations that were >10-fold higher than that of LBQ657. Both agents also
`inhibited NEP-2, exhibiting less selectivity (<40-fold) than LBQ657 (37,000-fold).
`
`In vitro potency and selectivity of AHU377, LBQ657, valsartan, and reference compounds
`on human recombinant NEP and NEP-2 enzyme activity
`
`LBQ657 was also tested in microsome preparations isolated from rat and human renal
`cortex tissue. LBQ657 inhibited NEP activity from rat renal cortex with an IC50 of 1.4 ±
`0.02 nM and from human renal cortex with an IC50 of 7.3 ± 0.8 nM [RD-2005-50314].
`NEP activity present in human plasma or human cerebrospinal fluid was inhibited by
`LBQ657 with an IC50 of 2,500 ± 1,100 nM [RD-2013-00079] and 50 ± 20 nM [RD-2014-
`00338], respectively. The increase of IC50 in human plasma was in part due to a
`reduction of the free fraction of LBQ657 due to high protein binding (97%). Neither
`AHU377 nor LBQ657 blocked the human AT1 receptor at concentrations of 30 μM [RD-
`2012-50571], [RD-2012-50566], indicating that these two compounds have no
`valsartan-like activity.
`
`Cellular activity
`LCZ696 was not tested in cell culture models; however, the pharmacologically active
`LBQ657 and valsartan that are delivered by LCZ696 were evaluated. Studies were
`conducted to assess the interaction of NEP inhibition by LBQ657 and AT1-receptor
`blockade by valsartan on mechanisms associated with fibrosis and cardiac hypertrophy.
`The model was based on treatment of neonatal rat cardiac fibroblasts or
`cardiomyocytes with angiotensin II, which elicited increased collagen synthesis or
`hypertrophy in these two cell types, respectively.
`
`Suppressed collagen production with LBQ657 and valsartan in rat cardiac
`fibroblasts
`LBQ657 and valsartan were evaluated for anti-fibrotic effects in a cell model of
`angiotensin II-induced collagen synthesis measured with 3H-proline incorporation. To
`stimulate fibroblast collagen