CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`207620Orig1s000
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`

`

`ADDENDUM to CLINICAL PHARMACOLOGY REVIEW
`
`207620
`December 17, 2014
`Priority
`ENTRESTO
`LCZ696 (sacubitril/valsartan)
`Angiotensin receptor-Neprilysin Inhibitor
`Film-coated Tablets/Oral
`50 mg, 100 mg and 200 mg
`Treatment of heart failure (NYHA class II – IV)
`
`Target dose is 200 mg twice daily (BID). The starting dose is 100
`mg BID. Double dose every 2-4 weeks as tolerated.
`Novartis Pharmaceuticals
`DCP1
`Division of Cardiovascular and Renal Products (DCRP)
`Luning Zhuang, PhD & Sreedharan Sabarinath, PhD
`Jeffry Florian, PhD & Rajanikanth Madabushi, PhD
`
`
`
`NDA Number:
`Submission Dates:
`Submission Type:
`Brand Name:
`Generic Name:
`Drug Class:
`Dosage Form/Route:
`Dosage Strengths:
`Proposed Indication:
`
`Proposed Dose:
`
`Applicant:
`OCP Division:
`OND Division:
`Reviewers:
`Team Leaders:
`
`
`INTRODUCTION:
`
`The objectives of this review addendum are:
`
`(1) To compare the mean daily dose of enalapril, the active comparator used in PARADIGM-
`HF Phase III study, to that in SOLVD-Treatment study (SOLVD-T), and
`
`(2) To document revised estimates for apparent volume of distribution of sacubitril and
`valsartan.
`
`
`
`Reference ID: 3784800
`
`1
`
`(b) (4)
`
`

`

`
`
`(1) Mean Daily Dose of Enalapril in PARADIDGM-HF versus SOLVD-T
`
`Background:
`
`In the PRADIGM-HF study, the target dose for enalapril, the active comparator, was 10 mg
`twice daily (BID). The applicant stated that this target dose was selected because enalapril
`demonstrated a significant reduction of mortality in SOLVD-Treatment study (SOLVD-T) in
`patients with NYHA Class II-IV . The reported mean daily dose in all randomized patients for
`enalapril was 11.2 mg in SOLVD-T. The mean daily dose, among patients on the study
`medication at final visit, was 16.6 mg in SOLVD-T. In an attempt to compare the dose of
`enalapril across the two trials, the Applicant computed mean enalapril daily dose from
`PARADIGM-HF. The mean enalapril daily dose was calculated to be 15.7 mg and 18.9 mg,
`respectively, in patients who survived to the final visit (i.e., patients who died before their final
`visits were excluded) and in those patients taking study medication.
`
`The applicant also submitted mean daily dose calculations for enalapril from SOLVD-T. The main
`assumption for this calculation method was that all mean doses described in the publication
`were based on the final dose of patients who survived to the final study visit (i.e., patients who
`died before their final visits were excluded).
`
`The calculations provided by the applicant are listed below:
`
`Methodology of how final mean enalapril doses were calculated in SOLVD-T (From Applicant)
`Number of patients randomized to enalapril: 1285
`Number of enalapril patients who died before the study final visit: 452
`Number of enalapril patients who survived to the final visit: 1285 – 452 = 833
`Number of patients who were on enalapril 2.5 mg/d at the final visit: 1.8% × 833 = 15
`Number of patients who were on enalapril 5 mg/d at the final visit: 6.7% × 833 = 56
`Number of patients who were on enalapril 10 mg/d at the final visit: 9.5% × 833 = 79
`Number of patients who were on enalapril 20 mg/d at the final visit: 49.3% × 833 = 411
`Number of enalapril patients on study medication at the final visit: 15 + 56 + 79 + 411 = 561
`Number of enalapril patients who stopped blinded medication by end of study: 833 – 561 =
`272
`Final mean daily dose of enalapril:
`
`2
`
`
`
`
`
`Reference ID: 3784800
`
`

`

`Mean enalapril daily dose among patients taking study medication:
`(15 x 2.5mm) + {56 x Smald) + (79 x 10min!) + (411 x 2mm) = 9327.5
`[15 + 5.5 + 79 + 411)
`.561
`
`= 16.6 mg/d
`
`Review Team’s Comments:
`
`We agree that the proposed calculation method was able to reproduce the reported mean daily
`
`dose of enalapril. However, it should be noted that the SOLVD-T publication provided only the
`
`percentage of patients at each dose level at the final visit, total number of deaths and the total
`
`number of patients who were randomized. It is not clear from the publication whether the
`
`percentages of patients at each dose level are based on the overall population or those patients
`
`who were alive at the final visit (as proposed by the applicant). The review team tested the
`
`alternative assumption i.e.,
`
`'all
`
`randomized patients’ as referring to the overall study
`
`population and not just those patients who were alive at the end of the study (See Figure 1
`
`below for a snapshot of the publication). The ”final visit” is interpreted as the visit prior to the
`
`study end date or the visit prior to an event.
`
`Tubs. maTanum-Iyuu
`FMNWUMTm
`
`WWW'
`
`Figure 1. Relevant section of SOLVD-T publication showing mean daily dose of enalapril
`
`Reference ID: 3784800
`
`

`

`Using the same information available from the publication, we can reproduce the reported
`mean daily dose of enalapril even if we use all patients that are randomized in the SOLVD-T
`(i.e., using N=1258, without excluding patients who died before final study visit). This is because
`both calculation methods rely only on the reported percentage of patients at each dose level.
`Our calculations are illustrated below:
`
`Methodology of how final mean enalapril doses were calculated in SOLVD-T (From FDA)
`Number of patients randomized to enalapril: 1285
`Number of patients who were on enalapril 2.5 mg/d at the final visit: 1.8% × 1285 = 23
`Number of patients who were on enalapril 5 mg/d at the final visit: 6.7% × 1285 = 86
`Number of patients who were on enalapril 10 mg/d at the final visit: 9.5% × 1285 = 122
`Number of patients who were on enalapril 20 mg/d at the final visit: 49.3% × 1285 =634
`Number of enalapril patients on study medication at the final visit: 23 + 86 + 122 + 634 = 865
`Number of enalapril patients who stopped blinded medication by end of study: 1285 – 865
`= 420
`Final mean daily dose of enalapril:
`
`Mean enalapril daily dose among patients taking study medication:
`
`
`
`This suggests that the actual method applied in SOLVD-T publication could be either as
`proposed by the applicant or as illustrated above, without excluding patients who died before
`final study visit. The same calculation methodologies can be used for PARADIGM-HF and the
`results are summarized in Table 2.
`
`
`
`
`
`
`
`Reference ID: 3784800
`
`4
`
`

`

`Table 2. Mean daily dose of enalapril from SOLVD-T and PARADIGM-HF
`
`Study
`
`Approach Used
`
`Mean daily dose
`
`Mean daily dose for
`_
`.
`_
`those taking medication
`
`SOLVD-T
`
`PARADIGM-
`
`HF
`
`All Randomized Patients
`_
`_
`(FDA’s Interpretation)
`_
`Excluding deaths*
`.
`_
`.
`(Applicant’s Interpretation)
`
`All Randomized Patients
`,
`_
`_
`(FDA 5 Interpretation)
`
`Excludin deaths**
`g
`(Applicant’s interpretation)
`
`11.2 mg/d
`
`16.6 mg/d
`
`11.2 mg/d
`
`16.6 mg/d
`
`14.2 mg/d
`
`18.9 mg/d
`
`15.6 mg/d
`
`18.9 mg/d
`
`*Excluded 452 patients who died before final study visit
`
`** Excluded 848 patients who died before final study visit
`
`Summary/Conclusion:
`
`Both calculation approaches were able to reproduce the reported enalapril daily dose for
`
`SOLVD-T. This is because of the limited information from the publication. PARADIGM-HF study
`
`had average daily dose of 14.2 mg of enalapril in all randomized patients and 15.6 mg in
`
`survivors (patients who died were excluded from the calculation), respectively. When
`
`compared to the best available mean enalapril daily dose from SOLVD-T, i.e., 11.2 mg, the mean
`
`enalapril daily dose in PARADIGM-HF (calculated either way) is numerically higher. Hence, it can
`
`be concluded that the daily dose of enalapril in PARADIGM-HF is no less than that reported
`
`from SOLVD-T.
`
`(2)
`
`Apparent volume of distribution of sacubitril and valsartan
`
`In the NDA, the average apparent volume of distribution (Vz/F) parameter was reported as
`
`M“) L and M“) L, respectively, for sacubitril and valsartan. This was based on the data
`
`obtained from 82 healthy subjects following single dose administration of 200 mg LCZ696 from
`
`Clinical studies LC2696A1101 (N=8), LC2696A2102 (N=8), LC269632115 (N=10), LC269632203
`
`(N=16, matching healthy subjects), LC269632126 (N=40). The clinical pharmacology review
`
`(DARRTS dated 5/15/2015) also reported these values on page 19.
`
`However, it was later determined that the dose used for the calculation of Vz/F for the study
`
`LC269632126 was not correct.
`
`M“)
`
`Reference ID: 3784800
`
`

`

`
` Therefore, correction to the dose for study LCZ696B2126 was required and
`Vz/F was recalculated (Reference: Labeling communication with the applicant, dated
`6/22/2015). Based on these revised estimates, average Vz/F value is corrected to 103.4 L for
`sacubitril and 75.4 L for valsartan. These changes are implemented in Section 12.3 of the label.
`
`
`
`
`
`Reference ID: 3784800
`
`6
`
`(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/
`----------------------------------------------------
`
`SREEDHARAN N SABARINATH
`06/26/2015
`
`LUNING ZHUANG
`06/26/2015
`
`JEFFRY FLORIAN
`06/26/2015
`
`RAJANIKANTH MADABUSHI
`06/26/2015
`
`Reference ID: 3784800
`
`

`

`CLINICAL PHARMACOLOGY REVIEW
`
`207620
`December 17, 2014
`Priority
`ENTRESTO
`LCZ696 (sacubitril/valsartan)
`Angiotensin receptor-Neprilysin Inhibitor
`Film-coated Tablets/Oral
`50 mg, 100 mg and 200 mg
`Treatment of heart failure (NYHA class II – IV)
`
`Target dose is 200 mg twice daily (BID). The starting dose is 100
`mg BID. Double dose every 2-4 weeks as tolerated.
`Novartis Pharmaceuticals
`DCP1
`Division of Cardiovascular and Renal Products (DCRP)
`Luning Zhuang, PhD & Sreedharan Sabarinath, PhD
`Jeffry Florian, PhD & Rajanikanth Madabushi, PhD
`
`
`
`NDA Number:
`Submission Dates:
`Submission Type:
`Brand Name:
`Generic Name:
`Drug Class:
`Dosage Form/Route:
`Dosage Strengths:
`Proposed Indication:
`
`Proposed Dose:
`
`Applicant:
`OCP Division:
`OND Division:
`Reviewers:
`Team Leaders:
`
`
`
`
`Reference ID: 3755835
`
`1
`
`(b) (4)
`
`

`

`Table of Contents
`TABLE OF CONTENTS .............................................................................................................................................. 2
`1. EXECUTIVE SUMMARY ................................................................................................................................... 4
`1.1
`RECOMMENDATIONS ................................................................................................................................ 4
`1.2
`PHASE 4 STUDY COMMITMENTS ............................................................................................................... 4
`1.3
`SUMMARY OF OCP FINDINGS .................................................................................................................... 5
`1.3.1 Pharmacokinetics ...................................................................................................................................... 5
`1.3.2
`Exposure-Response Relationships ............................................................................................................ 5
`1.3.3
`Intrinsic Factors ........................................................................................................................................ 5
`1.3.4
`Extrinsic Factors ....................................................................................................................................... 7
`1.3.5 Biopharmaceutics .................................................................................................................................... 7
`2. QUESTION BASED REVIEW (QBR)................................................................................................................... 8
`2.1
`GENERAL ATTRIBUTES ........................................................................................................................................ 8
`2.1.2 What are the proposed therapeutic indication and mechanism of action?............................................. 9
`2.1.3 What are the current treatments available for the proposed indication? ............................................. 10
`2.1.4 What are the proposed dosages and route of administration? ............................................................. 11
`2.2
`GENERAL CLINICAL PHARMACOLOGY ................................................................................................................... 11
`2.2.1 What are the design features of the clinical pharmacology and clinical studies used to support dosing
`or claims? ............................................................................................................................................................ 11
`2.2.2 What is the basis for selecting response endpoints in clinical studies? ................................................. 11
`2.2.3 Were correct moieties identified and properly measured to access clinical pharmacology? ................ 12
`2.2.4 What are the key features of the Phase III trial of LCZ696? ................................................................... 12
`2.2.5 How was the Phase III dose and regimen selected? .............................................................................. 13
`2.2.5 Was any alternate dose titration scheme evaluated for LCZ696? ......................................................... 15
`2.2.6
`Is the washout period between stopping ACE inhibitors and starting LCZ696 justified? ....................... 17
`2.2.7 What are the characteristics of the exposure or dose-response relationships for efficacy or safety? ... 18
`2.2.8 Does LCZ696 prolog QT or QTc interval? ............................................................................................... 18
`2.3
`PHARMACOKINETICS OF DRUG AND METABOLITE(S) .............................................................................................. 19
`2.3.1 What are the single and multiple dose PK parameters? ........................................................................ 19
`2.3.2 What are the characteristics of drug absorption? ................................................................................. 19
`2.3.3 What are the characteristics of drug distribution, including plasma protein binding? ......................... 19
`2.3.4 What are the characteristics of drug metabolism? ............................................................................... 20
`2.3.5 What are the characteristics of drug excretion? .................................................................................... 20
`2.3.6 Does the mass balance study suggest renal or hepatic as the major route of elimination for LCZ696? 20
`2.3.7 How does the PK of the drug and metabolite(s) in healthy volunteers compare to that in patients? ... 21
`2.3.8 Based on the PK parameters, what is the degree of linearity or non-linearity in dose-concentration
`relationship? ....................................................................................................................................................... 21
`2.3.9 What is the variability of PK parameters and what are the major causes of variability? ...................... 22
`2.4
`Intrinsic Factors ...................................................................................................................................... 22
`
`
`
`Reference ID: 3755835
`
`2
`
`

`

`2.4.1 What intrinsic factors (age, sex, race, weight, height, disease, genetic polymorphism, pregnancy, and
`organ dysfunction) influence exposure (PK usually) and/or response, and what is the impact of any differences
`in exposure on efficacy or safety responses? ...................................................................................................... 22
`2.5
`Extrinsic Factors ..................................................................................................................................... 27
`2.5.1 What is the drug-drug interaction (DDI) potential for LCZ696? ............................................................. 27
`2.6
`OTHER RELEVANT ISSUES .................................................................................................................................. 32
`2.7
`BIOPHARMACEUTICS ........................................................................................................................................ 36
`2.7.1 What are the characteristics of the bioanalytical method(s) used in the clinical pharmacology studies?
`36
`
`2.7.2 How is the final marketing image formulation bridged to the Phase III formulation? .......................... 37
`
`
`
`
`
`Reference ID: 3755835
`
`3
`
`

`

`1. EXECUTIVE SUMMARY
`Novartis Pharmaceuticals has submitted an original new drug application (NDA 207620) for
`LCZ696 (sacubitril/valsartan). The applicant is seeking approval for the indication: treatment of
`heart failure (NYHA Class II-IV)
`.
`LCZ696 is a
` which dissociates to a prodrug sacubitril and valsartan up on oral
`administration. Sacubitril is further metabolized by esterases to form an active moiety called
`LBQ657, which is a neprilysin inhibitor. Valsartan is an angiotensin II receptor blocker, approved
`in the US for the treatment of hypertension and heart failure. The proposed mechanism of
`action of LCZ696 is simultaneous blockade of neprilysin and angiotensin II receptors.
`
`The primary evidence of efficacy and safety are based on a single phase III study (PARADIGM-
`HF), comparing LCZ696 200 mg twice daily (BID) with an active comparator, enalapril 10 mg BID.
`The study was stopped early by the recommendation of the Data Monitoring Committee (DMC)
`at a pre-specified interim analysis due to compelling evidence for efficacy. LCZ696 was superior
`to enalapril in reducing the risk of the composite primary endpoint with a 20 % relative risk
`reduction (HR 0.8, 95 % CI 0.73-0.87, P<0.0001). LCZ696 was also superior to enalapril in
`delaying time to cardiovascular (CV) death, with a relative risk reduction of 20 %.
`
`The submission also includes two phase II studies in patients with heart failure and supportive
`clinical pharmacology studies, including intrinsic and extrinsic factor studies. The pivotal
`efficacy study used final marketing image (FMI) formulations, except for the 50 mg strength. A
`pivotal bioequivalence study bridges the 50 mg clinical service formulation to the 50 mg FMI
`tablet.
`
`1.1 Recommendations
`The new drug application (NDA 207620) for LCZ696 (sacubitril/valsartan) is acceptable and can
`be approved from a clinical pharmacology perspective.
`
`We have the following dosing recommendations:
`
`Use a lower starting dose of 50 mg BID in patients with (1) severe renal function impairment or
`(2) moderate hepatic impairment.
`
`1.2 Phase 4 Study Commitments
`None.
`
`
`
`Reference ID: 3755835
`
`4
`
`(b) (4)
`
`(b) (4)
`
`

`

`1.3 Summary of OCP Findings
`
`1.3.1 Pharmacokinetics
`• On oral administration, LCZ696 dissociates into sacubitril and valsartan and these
`moieties are absorbed rapidly.
`
`• Sacubitril undergoes metabolism via esterases to form the active moiety LBQ657, which
`inhibits neprilysin.
`
`• Absolute bioavailability of sacubitril from LCZ696 is at least 60 %. The bioavailability of
`valsartan from LCZ696 is at least 50 % higher than valsartan administered alone.
`Valsartan from 400 mg LCZ696 (containing ~ 203 mg valsartan) is equivalent to 320 mg
`valsartan marketed formulation.
`
`• LCZ696 tablets can be administered with no regard to food.
`
`• The LCZ696 analytes have high plasma protein binding (97 % for sacubitril and LBQ657
`and 94 % for valsartan)
`
`• No significant CYP isozyme involvement in the metabolism of LCZ696 analytes. LBQ657,
`formed from sacubitril by esterases, is not metabolized further into any major
`metabolites. CYP2C9 plays a minor role for valsartan (~ 9 %). Drug interaction potential
`for LCZ696 as a victim drug is low.
`
`• Approximately 52-68 % of sacubitril is excreted in urine (as LBQ657) and 37-48 % was
`recovered in feces in a mass balance study. Approximately 83 % of valsartan was
`excreted in feces and about 13 % in urine.
`
`• The average elimination half-life is about 1.4 h, 11.5 h and 9.9 h respectively for
`sacubitril, LBQ657 and valsartan in healthy subjects.
`
`1.3.2 Exposure-Response Relationships
`There was limited pharmacokinetic (PK) data collected from the Phase III study PRADIGM-HF (~
`7 %). Moreover, the study employed a dose titration scheme based on tolerability to attain the
`target dose (200 mg BID) of LCZ696. No dose/exposure response analysis was feasible.
`
`1.3.3 Intrinsic Factors
`Age, race, gender or body weight did not have any significant impact on the exposure of LCZ696
`analytes. Pre-specified sub-group analyses on primary efficacy endpoint of cardiovascular death
`or hospitalization for worsening heart failure also showed consistent treatment effect across all
`5
`
`
`
`Reference ID: 3755835
`
`

`

`subpopulations for LCZ696 relative to enalapril, the active comparator. No dose adjustments
`are required for age, race, gender or as per body weight.
`
`Renal impairment
`1.3.3.1
`In subjects with mild (CrCL 50 to ≤ 80 mL/min) and moderate (CrCL 30 to ≤ 50 mL/min) renal
`impairment, exposure to LQB657 increased by about 2X. Subjects with severe renal impairment
`(CrCL<30 mL/min) showed a 2.7X increase in exposure to LBQ657. However, the exposure to
`sacubitril and valsartan were not significantly altered in renal function impairment. Patients
`with mild to moderate renal impairment were enrolled in the pivotal efficacy study and there
`were no increase in adverse events associated with the increased exposure to LQB657 in those
`patients. Therefore, no dose adjustments are proposed for mild and moderate renal
`impairment.
`
`LCZ696 is a fixed dose combination of sacubitril (prodrug for LBQ657) and valsartan. Therefore
`adjusting dose levels for LBQ657 alone without affecting the dose of valsartan is not feasible.
`Moreover, LCZ696 is titrated to the target dose based on tolerability in each patient. The
`incremental increase in exposure seen in severe renal impairment is 2.7X relative to healthy
`subjects and is closer to the 2.2X increase seen in patients with moderate renal impairment.
`There is clinical experience with LCZ696 in patients with moderate renal impairment in Phase
`III, where no dose adjustments were employed. Therefore, no change to the target dose is
`proposed in patients with severe renal impairment. However a lower starting dose of 50 mg BID
`should be used in patients with severe renal impairment. A lower starting dose and slower
`titration to target may reduce tolerability issues.
`
`Hepatic impairment
`1.3.3.2
`Subjects with mild hepatic impairment (Child-Pugh Class A) showed increased exposure to
`sacubitril, LBQ657 and valsartan by about 53 %, 48 % and 19 % respectively. The increase in
`exposure seen in moderate hepatic impairment (Child-Pugh Class B) was about 245 %, 90 % and
`109 % for sacubitril, LBQ657 and valsartan respectively. No studies were conducted in subjects
`with severe hepatic impairment (Child-Pugh Class C). Sacubitril is an inactive pro-drug and has
`no significant safety issues identified. No dose adjustments are proposed for mild hepatic
`impairment. Use of a lower starting dose of 50 mg BID is recommended in patients with
`moderate hepatic impairment. Use of LCZ696 in patients with severe hepatic impairment is not
`recommended.
`
`
`
`Reference ID: 3755835
`
`6
`
`

`

`1.3.4 Extrinsic Factors
`
`Drug-Drug Interactions
`1.3.4.1
`The involvement of CYPs for the biotransformation of sacubitril, LBQ657 and valsartan is
`considered minimal. Therefore, the DDI potential of LCZ696 as a victim when co-administered
`with drugs that may affect the CYP system is considered to be low.
`
`No clinically relevant interaction was observed when LCZ696 was co-administered with
`carvedilol, furosemide, nitroglycerine, digoxin, warfarin, metformin, omeprazole,
`hydrochlorothiazide, amlodipine, and oral contraceptives. Co-administration of sildenafil and
`LCZ696 resulted in additional reduction in blood pressure (BP), possibly due to additive
`pharmacodynamic effects (~4-5 mmHg additional reduction in SBP/DBP). Patients should be
`advised about potential adverse effects due to BP lowering effects when sildenafil or other
`phosphodiesterase-5 inhibitors are to be initiated while on treatment with LCZ696.
`
`Co-administration of LCZ696 increased the Cmax of atorvastatin and its metabolites by up to 2X
`and AUC by 1.3X. These effects may potentially be due to the OATP1B1 and OATP1B3 inhibitory
`effects of sacubitril. However, atorvastatin was used as a co-medication in the Phase III study
`for LCZ696 (~31 % of patients in LCZ696 and enalapril treatment groups) and no significant
`adverse events related to atorvastatin were reported in them. No dose adjustments are
`proposed for atorvastatin when co-administered with LCZ696.
`
`1.3.5 Biopharmaceutics
`The pivotal efficacy study PARADIGM-HF used final marketing image (FMI) formulations for 100
`mg and 200 mg tablet strengths. The 50 mg strength clinical service form tablet used in Phase III
`was bridged to FMI 50 mg tablet with a pivotal bioequivalence study.
`
`
`
`Reference ID: 3755835
`
`7
`
`

`

`2. QUESTION BASED REVIEW (QBR)
`
`2.1 General Attributes
`LCZ696 is a
` of a pro-drug sacubitril, which forms the active moiety LBQ657, and
`valsartan. LBQ657 is a neprilysin inhibitor. There are no approved neprilysin inhibitors in the US.
`Valsartan is an angiotensin II receptor Type 1 blocker (ARB) and is approved in the US for the
`treatment of hypertension and heart failure. The clinical pharmacology information on
`valsartan is available in the USPI1 and in its approval package2. Hence, this review does not
`discuss the clinical pharmacology aspects of valsartan in detail.
`
`2.1.1 What are the highlights of the chemistry and physical-chemical properties
`of the drug substance and the formulation of the drug product?
`
`Drug Substance:
`Appearance:
`Molecular Formula
`(hemipentahydrate):
`Molecular Weight
`(hemipentahydrate):
`Structural Formula:
`
`C48H55N6O8Na3.2.5H2O
`
`
`
`957.99
`
`
`Source: Quality overview summary- Drug substance, Section 2.3
`Conc. of sacubitril (mg/mL)
`Conc. of valsartan (mg/mL)
`Solubility:
`0.052
`0.032
`0.1 N HCl
`>100
`>100
`Water
`Phosphate buffer, pH 6.8 >50
`>50
`Partition coefficients:
`Log D o/w at pH 6.8 =1.29 for sacubitril,
`
`
`1 DIOVAN® (valsartan) USPI: http://www.accessdata.fda.gov/drugsatfda docs/label/2014/021283s044lbl.pdf
`
` 2
`
` NDA 21283 (Diovan®) Approval Package:
`http://www.accessdata.fda.gov/drugsatfda docs/nda/2001/021283 ORIGINAL APPROVAL PACKAGE.PDF
`
`
`
`
`Reference ID: 3755835
`
`8
`
`(b) (4)
`
`(b) (4)
`
`

`

` -1.49 at pH 7.4 for valsartan
`4.6 for sacubitril, 3.9 and 4.7 for valsartan
`pKa
`Source: Quality overview summary- Drug substance, Section 2.3
`
`Drug Product:
`LCZ696 (sacubitril/valsartan) is formulated as immediate release, film-coated tablets for oral
`administration in 50 mg, 100 mg and 200 mg strengths (differentiated by debossing and color).
`The excipients included microcrystalline cellulose, low substituted hydroxypropylcellulose
`crospovidone, magnesium stearate, talc and colloidal silicone dioxide.
`
`2.1.2 What are the proposed therapeutic indication and mechanism of action?
`The proposed indication for LCZ696 is the treatment of heart failure (NYHA class II-IV)
`
`. The proposed label claims include
`
`
`
`
`
`
`
`LCZ696 contains sacubitril, a pro-drug for a neprilysin inhibitor LBQ657, and valsartan. The
`proposed mechanism of action of LCZ696 involves simultaneously inhibiting neprilysin via
`LBQ657 and angiotensin II Type-1 (AT-1) receptors via valsartan. The mechanism of action for
`valsartan is well understood and is depicted in the schematic below (Figure 1). LBQ657 is
`believed to enhance the effects of natriuretic peptides, including atrial natriuretic peptide
`(ANP), brain natriuretic peptide (BNP), and C-Type natriuretic peptide (CNP). ANP and BNP are
`released into circulation by the heart in response to myocardial stress. CNP is synthesized by
`endothelial and renal epithelial cells. These peptides are cleared from circulation by neprilysin
`dependent proteolytic degradation and through natriuretic peptide clearance receptors. The
`natriuretic peptides act by activating membrane bound guanylyl cyclase-coupled receptors and
`by increasing concentrations of cyclic guanosine monophosphate (cGMP). The cGMP is thus
`considered as an indirect marker for neprilysin inhibition.
`
`The proposed mechanism of action of LCZ696 and potential beneficial effects in patients with
`heart failure (HF) are illustrated in Figure 1:
`
`
`
`Reference ID: 3755835
`
`9
`
`(b)
`(4)
`
`(b) (4)
`
`

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`
`Figure 1 Proposed mechanism of action of LC2696. Source: Applicant’s slides - Topline results
`
`meeting PARADIGM-HF
`
`2.1.3 What are the current treatments available for the proposed indication?
`
`The guideline recommended treatments available for the proposed indication includes:
`
`0 Angiotensin converting enzyme (ACE) inhibitors, Angiotensin II receptor blockers (ARBs),
`
`if ACE inhibitors are not tolerated (Class I, Level A)
`
`AND
`
`0 Beta blockers (Class I, Level A) - carvedilol, bisoprolol or extended release metoprolol
`
`o Diuretics, if there is evidence of fluid retention (Class I , Level C)
`
`o Spironolactone, provided estimated creatinine clearance is >30 mL/min and K“ < 5
`mEq/L (Class I, Level A)
`
`o Hydralazine/isosorbide dinitrate for self-identified African Americans with symptomatic
`
`NYHA class Ill-IV heart failure receiving optimal therapy with ACE inhibitors and beta
`
`blockers (Class I, Level A)
`
`o Digoxin (Class Ila, Level B)
`
`3 ACCF/AHA Guideline for the management of heart failure, 2013
`
`10
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`Reference ID: 3755835
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`

`

`•
`
`Ivabradine, approved in April 2015 to reduce risk of hospitalizations for worsening heart
`failure in patients with symptomatic heart failure with left ventricular ejection fraction
`<35%, who are on sinus rhythm with resting heart rate >70 bpm and either on
`maximally tolerated doses of beta blockers or have a contra indication to beta blocker
`use. Ivabradine is thought to act by reducing heart rate in these patients.
`In addition to the pharmacotherapies listed above, implantable cardioverter-defibrillators
`(ICDs) and cardiac resynchronization therapy (CRT) are also used in patients with heart failure
`with reduced ejection fraction3.
`
`2.1.4 What are the proposed dosages and route of administration?
`LCZ696 is available as film coated tablets for oral administration in 50 mg (24 mg of sacubitril/
`26 mg of valsartan), 100 mg (49 mg of sacubitril/ 51 mg of valsartan) or 200 mg (97 mg of
`sacubitril/ 103 mg of valsartan) strengths.
`
`The proposed target dose is 200 mg twice daily (BID). The starting dose is 100 mg BID. A lower
`starting dose of 50 mg BID is recommended in patients not currently taking an angiotensin
`converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), and for patients
`previously taking low doses of these drugs. The dose should be doubled every 2-4 weeks, as
`tolerated by the patient, to the target dose of 200 mg BID.
`
`2.2 General Clinical Pharmacology
`
`2.2.1 What are the design features of the clinical pharmacology and clinical
`studies used to support dosing or claims?
`The efficacy and safety claims of LCZ696 are primarily based on a single, pivotal Phase III study,
`PARADIGM-HF in heart failure patients with systolic dysfunction (See Section 2.2.4).
`
`There were two Phase II studies, PARAMOUNT-HF and TITRATION (See Section 2.2.5). The
`PARAMOUNT-HF study compared the