CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`207620Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`Final Risk Evaluation and Mitigation Strategy (REMS) Review
`
`May 22, 2015
`
`Somya Dunn, M.D.
`Division of Risk Management (DRISK)
`
`Kimberly Lehrfeld, Pharm.D., DRISK
`
`Date:
`
`Reviewer(s):
`
`Team Leader:
`Acting Deputy
`Division Director
`Drug Name(s):
`Therapeutic Class:
`Dosage and Route:
`
`Reema Mehta Pharm.D., M.P.H., DRISK
`LCZ696 (sacubitril and valsartan)
`Angiotensin Receptor Neprilysin Inhibitor (ARNI)
`97 mg of sacubitril and 103 mg of valsartan twice daily
`orally
`Application Type/Number: NDA 207-620
`Submission Number:
`Supporting Document 5
`Applicant/sponsor:
`Novartis Pharmaceuticals Corporation
`OSE RCM #:
`2014-2615
`
`*** This document contains proprietary and confidential information that should not be
`released to the public. ***
`
`Reference ID: 3763350
`
`

`

`1
`
`INTRODUCTION
`
`The purpose of this review is to document DRISK‘s evaluation of the need for a risk
`evaluation and mitigation strategy (REMS) for LCZ696 (sacubitril/valsartan) oral tablets,
`NDA 207-620. It was submitted by Novartis Pharmaceuticals Corporation (Novartis) and
`received in a three part submission due to the Sponsor being granted Fast Track Rolling
`Submission status; the submissions were received September 30, 2014, October 29, 2014
`and December 17, 2014. The application is currently under review in the Division of
`Cardiovascular and Renal Products (DCRP). The Sponsor did not include a proposed
`REMS with the submission.
`
`1.1
`
`PRODUCT BACKGROUND
`
`LCZ696 is a novel therapy that dissociates into valsartan and the pro-drug sacubitril
`(AHU377). Sacubitril is further metabolized to LBQ656. The LBQ656 component acts as
`an angiotensin receptor neprilysin inhibitor (ARNI) by inhibiting neprilysin (neutral
`endopeptidase enzyme: NEP). NEP is a zinc metalloendopeptidase that plays a role in
`turning off peptide signaling events at the cell surface.l The valsartan component blocks
`the angiotensin II type-1 (AT1) receptor (angiotensin II receptor blocker or ARB).
`Valsartan (Diovan) is an approved product (NDA 20—665, approved 1996) indicated for
`treatment of hypertension and heart failure.
`
`The Sponsor formulated and studied three film-coated tablets of LCZ696 in strengths of
`50 mg (24 mg of sacubitril / 26 mg of valsartan), 100 mg (49 mg of sacubitril / 51 mg of
`valsartan) and 200 mg (97 mg of sacubitril/ 103 mg of valsartan).The proposed starting
`dose is
`(m4) twice a day and the dose should be doubled every two to four weeks as
`tolerated to reach the proposed target dose of 200 mg twice—daily.
`
`LCZ696 is proposed to be indicated for the treatment of heart failure New York Heart
`Association (NYHA) class lI—IV
`M“)
`
`1.2 DISEASE BACKGROUND
`
`Chronic heart failure (HF) is a common syndrome affecting approximately 2 to 3% of
`the population in many industrialized countries. Coronary artery disease (CAD) is the
`cause of approximately tvvo—thirds of cases of systolic HF, although hypertension and
`diabetes are probable contributing factors in many cases. There are many other causes
`of systolic HF, which include previous viral infection, alcohol abuse, chemotherapy
`(e.g. doxorubicin or trastuzumab), and "idiopathic" dilated cardiomyopathy.
`
`HF due to left ventricular dysfunction, also referred to as HF with reduced Ejection
`Fraction (HFrEF), is substantial and growing medical problem that effects millions of
`adults in the United states. Class I recommendations in the 2013 American College
`of Cardiology Foundation (ACCF)/American Heart_Association (AHA) guidelines
`for the pharmacologic treatment of HFrEF include:u
`
`Reference ID: 3763350
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`

`

` Angiotensin-converting enzyme inhibitors (ACE-I), or ARB if ACE
`inhibitors are not tolerated, to reduce morbidity and mortality
` Beta-blockers (bisoprolol, carvedilol, or controlled release/extended
`release metoprolol succinate) to reduce morbidity and mortality
` Diuretics and a low-sodium diet, if there is evidence of fluid retention to
`improve symptoms
` Aldosterone antagonists (provided estimated creatinine > 30 mL/min and K+ <
`5.0
` Hydralazine/isosorbide dinitrate (for African Americans with persistently
`symptomatic NYHA class III-IV heart failure) receiving optimal therapy
`with ACE inhibitors and beta blockers, to reduce morbidity and mortality.
`
`In addition to the indicated pharmacotherapies for HFrEF (i.e., digoxin, ACE
`inhibitors, beta-blockers, etc.), Class I recommendations for the device treatment of
`HFrEF, including the implantable cardioverter-defibrillator (ICD) and cardiac
`resynchronization therapy (CRT), are as follows:
`ICD therapy for primary prevention of sudden cardiac death (SCD) to reduce
`
`total mortality in selected patients with nonischemic dilated cardiomyopathy
`(DCM) or ischemic heart disease at least 40 days post-myocardial infarction (MI)
`with left ischemic heart disease at least 40 days post-myocardial infarction (MI)
`with left ventricular ejection fraction (LVEF) of 35% or less and NYHA class II
`or III symptoms on chronic guideline-directed medical therapy (GDMT), who
`have reasonable expectation of meaningful survival for more than 1 year
` CRT for patients who have LVEF of 35% or less, sinus rhythm, left bundle-
`branch block (LBBB) with a QRS duration of 150 ms or greater, and NYHA
`class II, III, or ambulatory IV symptoms on GDMT
`ICD therapy is for primary prevention of SCD to reduce total mortality in
`selected patients at least 40 days post-MI with LVEF of 30% or less, and NYHA
`class I symptoms while receiving GDMT, who have reasonable expectation of
`meaningful survival for more than 1 year.
`
`
`
`Despite these treatments, which have substantially improved outcomes in the past two
`decades, HF can severely affect the patient’s quality of life and the prognosis continues
`to be poor. New therapies are continuously sought.
`
`1.3 REGULATORY HISTORY
`February 5, 2009: The IND for LCZ696 was submitted
`April 22, 2009: Pre-IND Meeting--no major safety issues discussed. Carcinogenicity
`assessments were discussed.
`June 2, 2009: Pre-IND meeting--to discuss the Sponsor’s proposed non-clinical and
`clinical development plan for the HF indication using LCZ696.
`May 23, 2014: Novartis requests Fast Track Designation because an independent Data
`Monitoring Committee unanimously recommended early closure of the PARADIGM-HF
`study due to observed superior efficacy of LCZ696 versus enalapril.
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`June 23, 2014: Novartis is granted Fast Track Designation, allowing a rolling submission
`of the NDA.
`
`June 25, 2014: Pre NDA meeting. Discussion of REMS was postponed. The Agency
`requested that the Sponsor address the potential for theoretical safety concerns such as
`neurological diseases (from amyloid accumulation) and cancer promotion. They also
`requested an analysis for neurological Adverse Events (AEs) of interest.
`
`September 22, 2014: Type C meeting--Novartis proposed the following labeling:
`.
`.
`.
`Contramdrcatron:
`
`4
`W ’
`
`Warnings & Precautions: T0 include risk ofangioedema
`
`The Agency declined to give advice without specifics of cases for angioedema but did
`agree to the idea of a
`ma DRISK cemented that a REMS would likely
`not be needed.
`
`September 30, October 29 and December 17, 2014: The NDA is submitted in three
`parts. The initial submission, 9/30/14 requests Priority Review.
`
`February 10, 2015: DCRP and DRISK discuss the need for a REMS at an internal
`meeting to discuss known safety issues. A preliminary decision was that a REMS would
`likely not be needed.
`
`February 12, 2015: Submission is filed; Priority Review status is granted.
`
`March 11, 2015: DCRP and DRISK met internally and determined that a REMS would
`not be needed.
`
`2 MATERIALS REVIEWED
`
`2.1 DATA AND INFORMATION SOURCES
`
`The materials that informed this review were:
`
`0 Novartis Pharmaceuticals Corporation Clinical Overviewfor LCZ686 received
`12/17/14, Seq 0002
`
`o Novartis Pharmaceuticals Corporation Summary of Clinical Safetyfor LCZ686
`received 12/17/14, Seq 0002
`
`o Novartis Pharmaceuticals Corporation Draft Labelingfor LCZ686 received
`12/17/14, Seq 0002
`
`o Novartis Pharmaceuticals Corporation Summary of Clinical Safely Amendment
`120 day updatefor LCZ686 received 4/15/15, Seq 0029
`
`0 Dr. Tzu—Yun McDowell FDA DCRP Safety Review, submitted May 15, 2015.
`
`0 Dr. John Lawrence and Dr. Norman Stockbridge, FDA DCRP NDA 21-188
`Review for omapatrilat, 6/5/2002.
`
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`

`

`3 REVIEW OF SAFETY CONCERNS
`
`3.1 OVERVIEW OF CLINICAL PROGRAM
`The clinical program evaluated safety of LCZ696 at doses up to the target dose of 200 mg
`twice daily in HF patients treated for up to 4.3 years. The safety data came primarily on
`PARADIGM-HF (study CLCZ696B2314) which had 8442 randomized patients with
`chronic HF, NYHA functional class II – IV, and systolic dysfunction HFrEF. From this
`study, a total of 10,513 patients were exposed to enalapril and 9419 patients were
`exposed to LCZ696 during the run-in period. After the run-in period, a total of 8442
`patients were randomized to either LCZ696 or enalapril during the double-blind phase in
`a 1:1 ratio.
`Additional safety data was compiled from two phase 2 studies, CLCZ696B2214
`(PARAMOUNT-HF) and CLCZ696B2228 (TITRATION). Six supportive studies in
`patients with hypertension were also used to give additional safety data.
`The consolidated safety database for LCZ696 includes approximately 15,000 patients
`(10106 (pivotal study) + 3874 (phase 2 studies) + 1117 (supportive studies)). All these
`patients have been exposed to LCZ696 at varying doses and for varying treatment
`durations.
`Heart failure is the most common cause of hospital admission in this patient population.
`Cardiovascular death and HF hospitalization are both closely related to progressive
`worsening of HF and both are thought to be modifiable by treatments that improve HF.
`This rationale led to the disease-specific composite efficacy endpoint of time to CV death
`or HF hospitalization used in the pivotal trial in this clinical program.
`
`3.2 EFFICACY
`
`PARADIGM-HF was terminated early based on efficacy results evaluated at the third
`interim analysis. This was due to a recommendation of the trial’s independent data
`monitoring committee. LCZ696 reduced the risk of the primary composite endpoint
`based on a time-to-event analysis (HR 0.80; 95% CI 0.73, 0.87; 1-sided p=0.0000002).
`LCZ696 treated subjects experienced both fewer first heart failure hospitalizations (537
`[12.8%] vs. 658 [15.6%]) and fewer cardiovascular deaths as the first event (377 [9.0%]
`vs. 459 [10.9%]) compared with enalapril subjects.iii
`
`SAFETY CONCERNS
`3.3
`PARADIGM-HF served as the main safety database. The Sponsor's analysis showed that
`the incidence of AEs by system organ class (SOC) was comparable between the LCZ696
`and enalapril groups (81.4% vs. 82.8%, respectively). Some of the most frequently
`occurring primary SOC events (occurring in ≥10% of patients in either treatment group)
`were cardiac disorders, infections and infestations, metabolism and nutrition disorders.
`During the randomization phase of PARADIGM-HF, there were more deaths over all in
`the enalapril arm. Of the deaths, the most common was fatal myocardial infarction (3.5%
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`Reference ID: 3763350
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`4
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`of cardiovascular deaths in the LCZ696 group versus 3.94% in the enalapril group).
`Additionally, serious adverse events (SAEs) during the double blind period were lower in
`the LCZ696 group compared to the enalapril group (46.1% vs. 50.7%, respectively).
`SAEs were predominantly cardiac disorder events. Overall the two treatment arms in the
`pivotal study had similar patterns for drop outs and discontinuations. Cardiac failure was
`the most common AE leading to study discontinuation in both groups (2.6% in enalapril
`group and 2.4% in the LCZ696 group).
`AEs of Special Interest
`The AE of special interest with LCZ696 are hypotension, renal impairment,
`hyperkalemia, angioedema, accumulation of amyloid and teratogenicity.
`Hypotension, renal impairment and hyperkalemia
`These concerns are due to class effects associated with renin–angiotensin–aldosterone
`system (RAAS) inhibitors. The Sponsor has proposed that these AEs be addressed with
`labeling for LCZ696. Hypotension, renal impairment and hyperkalemia are proposed for
`the AE and Warnings and Precautions section of the label. DCRP reports that these rates
`in the clinical trial for LCZ696 compared to enalapril during the treatment period were
`hypotension 24.4% vs. 18.6%, renal impairment 11.9% vs. 14.3% and hyperkalemia
`16.2% vs. 17.6% respectively.iii These labeling proposals are acceptable to the Agency.
`Of note, in the Diovan label, hypotension is also a Warning and Precaution; and
`hyperkalemia is listed as an AE.
`Angioedema
`Another class effect associated with renin–angiotensin–aldosterone system (RAAS)
`inhibitors is angioedema. This risk is of concern with LCZ696 due to the Agency history
`of omapatrilat, a vasopeptidase inhibitor that inhibits ACE and neutral endopeptidase
`(NEP) that was under review from 2000-2002. Omapatrilat could not be approved due to
`the unacceptable high rate of angioedema (in the clinical program the rate was 2.2%
`versus 0.7% in patients in the comparator--enalapril). In the case of omapatrilat, there
`were two mechanisms of action that cause significant angioedema contributing to the
`high rates. LCZ696 contains one component known to cause angioedema, NEP. Of note,
`although, angioedema has been seen in patients treated with ARBs, it was not an AE
`significant enough to be classified as a Warning and Precaution. For example, for
`Diovan, it is mentioned in the label only as a hypersensitivity reaction seen
`postmarketing.
`In the PARADIGM-HF trial double-blind period, the incidence of angioedema was low
`in the overall population (19 events, rate of 0.2%), and compared to an enalapril rate of
`0.5%. None of these events involved airway compromise or death. Most events were non-
`serious and did not require treatment or were treated with antihistamines. Most
`angioedema cases occurred within 180 days after randomization. The incidence of
`angioedema was higher in black patients treated with LCZ696 than enalapril in the
`double-blind period (2.4% and 0.5%, respectively); however the number of black patients
`overall in the trial was very low (54 patients) limiting the interpretation of this finding.
`The higher rate of angioedema in black patients is seen as part of the class effect of ACE-
`I and currently in labeling for ACE-I. The Sponsor proposes to include this information
`
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`5
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`in the label in the Warnings and Precautions as well as Adverse Reactions sections. The
`Agency is discussing a post marketing study to better characterize this risk.
`
`Drug-Drug Interaction and Angioedema
`
`There were three confinned cases of angioedema in PARADIGM—HF that occ1ured in
`subjects given ACE inhibitor within < 36 horns of discontinuing LCZ696 or Vice versa.
`The Sponsor proposed a labeling contraindication to address this, stating not to
`coadminister LC Z696 with AC E-I.
`
`The Sponsor proposed a
`
`(NW
`
`(D) (4)
`
`(b) (4)
`
`(b) (4)
`
`(”(4) The risk of this ding-drug interaction will best be
`mitigated tln'ough labeling (Waming and Contraindications) to inf01m prescribers and
`through ding-drug interaction screening at pharmacies for contraindicated medications.
`
`DCRP requested that the Sponsor include a Patient Package Insert (PPI) with labeling to
`address this dlug-diug interaction risk. There are PPIs for ARBS for the risk of
`teratogenicity; Diovan has a PPI for this (the risk of teratogenicity is discussed below).
`For LCZ696, the risk of the ding-drug interaction will be stated in the PPI, followed by
`the risk of teratogenicity. DRISK does not have any issues with the inclusion of a PPI for
`labeling.
`
`Reference ID: 3763350
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`

`

`Teratogenicitv
`
`LCZ696 is considered a teratogen due to a class effect of diugs that act directly on the
`renin—angiotensin system Valsartan carries a boxed warning for potential injury or death
`to a developing fetus. The proposed label for LCZ696 also carries this warning.
`
`Patient labeling for other medications that treat HF that are in the same class as valsartan
`with a teratogenicity risk include a PPI, i.e. Edarbi (an angiotensin II receptor blocker
`with a PPI for risk to unborn baby). However, the Sponsor proposed
`M")
`. For
`
`LCZ696, this risk can be mitigated sufficiently with a PPI, as it is for ACE-Iand ARBs.
`The expected patient population (chronic HF patients) would include few females of
`reproductive potential as this condition is not commonly seen in patients younger than
`age 50.1v Additionally, likely prescribers (cardiologists and internists managing HF) are
`aware of the risk as a class effect and would be expected to counsel FRP patients.
`Therefore, the Sponsor was asked to submit a PPI to align with labeling of other products
`in the same class. The Sponsor submitted the requested labeling, which is under review
`by DCRP.
`
`Accumulation ofAmyloid
`
`DCRP selected cognitive impairment as an AB of interest based the theory that inhibition
`of NEP could accentuate accumulation of beta amyloid in the brain increasing the risk of
`Alzheimer’s disease. NEP is believed to be a major beta amyloid-degrading enzyme in
`the brain. Therefore, inhibition of NEP could accentuate accumulation of beta amyloid
`and theoretically increase the risk of Alzheimer’s disease. In preclinical studies with
`
`LCZ696, monkeys had an increased accumulation of beta amyloid (B—Amyloid 1-38, 1—
`40 & 1-41) in the cerebrospinal fluid (CSF), but not in the brain tissue. In addition,
`administration of LCZ696 400 mg daily for two weeks in healthy subjects was associated
`with a 42% increase in CSF B—Amyloid 1-38 and a 50% increase in plasma B-Amyloid 1—
`40. DCRP asserts that the clinical significance of these findings is not known. In the
`clinical program, there were very few cognitive impairment related AEs. At this time the
`Sponsor proposes labeling in the Clinical Pharmacology section of the label that
`addresses this data and mentions that the clinical significance is unknown. The Division
`acknowledges that they will be working with the Sponsor on how to better assess this risk
`in the development program.
`
`4 DISCUSSION
`
`LCZ696 is a novel therapy with two active components: valsartan, an approved ARB,
`and sacubitn'l, an ARNI which inhibits NEP. It is proposed to be indicated for the
`treatment of heart failure NYHA class II—IV
`M")
`
`. Based on the currently available data, no AEs of concern were identified that
`would warrant a REMS. AEs that are consistent with other inhibitors of the RAAS were
`
`seen. The Sponsor has included a boxed warning and a PPI to address teratogenicity and
`appropriate labeling to address angioedema, hypotension, renal impairment,
`hyperkalemia and elevated amyloid levels that were identified during the drug
`
`Reference ID: 3763350
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`

`

`development program. They have also addressed the need to discontinue ACE-I at least
`36 hours prior to starting LCZ696 in the label as well as the PPI.
`
`5 CONCLUSION/RECOMMENDATIONS
`In conclusion, risk mitigation measures beyond professional labeling and a PPI are not
`warranted for LCZ696. Based on currently available data, no safety concerns have been
`identified that cannot be discussed and communicated in the label.
`Should DCRP raise concerns with risks discussed in this review, or identify additional
`risks associated with LCZ696 warranting more extensive risk mitigation or a formal
`REMS please send a consult to DRISK.
`This serves as the primary DRISK review for LCZ696 under NDA 207-620. Please
`notify DRISK if you have any questions.
`
`
`i Turner, A.J. et al The neprilysin (NEP) family of zinc metalloendopeptidases: genomics and function.
`Bioessays. 2001 Mar;23(3):261-9.
`ii Yancy et al, Circulation. 2013;128:e240-e327
`iii Smith, Kimberly. LCZ696 Clinical Efficacy Review, DCRP, FDA submitted May 15, 2015.
`iv Redfield M. et al. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating
`the scope of the heart failure epidemic. JAMA: 2003; 289,194–202.
`
`Reference ID: 3763350
`
`8
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`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SOMYA V DUNN
`05/22/2015
`
`REEMA J MEHTA
`05/22/2015
`I concur.
`
`Reference ID: 3763350
`
`