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

`

`DNP Clinical Consult Memo
`
`NDA
`
`Sponsor:
`Drug:
`Proposed Indication:
`Material Submitted:
`
`Consult Request Date:
`Date Review Completed:
`Clinical Reviewer:
`Nonclinical Reviewer:
`Clinical Team Lead:
`Nonclinical Supervisor:
`Division Director:
`
`207620
`
`Novartis
`LCZ696 (Entresto)
`Heart Failure (NYHA class ll-IV)
`NDA submission
`
`6/29/15
`6I30I15
`Teresa Buracchio, M.D.
`David B. Hawver, Ph.D.
`Nick Kozauer, M.D.
`Lois M. Freed, Ph.D.
`Billy Dunn, M.D.
`
`DCRP has requested a consult from DNP to provide assistance in evaluating the
`theoretical potential for LCZ696 (Entresto) to increase the risk of developing Alzheimer’s
`disease (AD). This memo will briefly summarize the relevant data discussed in the
`DCRP New Drug Application (NDA) reviews and will focus primarily on responding to the
`consult questions provided to DNP.
`
`Background: Heart failure (HF) is a major cause of morbidity and mortality in the United
`States. It is estimated that over half of HF patients die within 5 years of diagnosis.1
`Novartis has studied LCZ696 for the treatment of heart failure (NYHA class ll—IV) mm)
`(mm
`
`. LCZ696 is a dual angiotensin receptor neprilysin inhibitor (ARNi)
`that dissociates into valsartan, an angiotensin receptor (AT1) blocker (ARB), and the
`pro-drug sacubitril (AHU377) following oral administration. Sacubitril is rapidly
`hydrolyzed in vivo to the active neprilysin inhibitor LBQG57.
`
`Neprilysin is an enzyme that degrades natriuretic peptides and vasoactive peptides.
`Neprilysin is also one of the major enzymes that breaks down the amyloid beta (AB)
`peptide, a pathological marker of Alzheimer’s disease, in the central nervous system.
`While showing benefit in the treatment of heart failure, it is theorized that inhibition of
`neprilysin could potentially increase levels of AB in the brain and CSF and increase the
`risk of developing AD.
`
`The following documents were reviewed for this consult: Clinical Pharmacology review
`by Luning Zhuang and Sreedharan Sabarinath; Clinical review by Kimberly Smith and
`Tzu-Yun McDowell; a synopsis of Study
`“M" (focusing on cognitive
`outcomes
`M") submitted by the Sponsor.
`
`Study A2126, Phase 1 study AB in CSF: As stated in the Clinical Pharmacology review
`by Drs. Zhuang and Sabarinath, this was a placebo-controlled study in healthy subjects
`that examined the PK and PD effects of 400mg LCZGQG once daily for 14 days. At Day
`14, there was about 50% increase in plasma AB 1-40 (AUECMSh) with L02696 relative
`to placebo but there was no difference from placebo in the CSF. However, AB 1-38
`
`1 Go et al. Circulation. 2013;127ze6—e245
`
`Reference ID: 3786906
`
`

`

`Teresa Buracchio, MD, HFD—120 Medical Review
`NDA 207620, LCZ696 (Entresto), Novartis
`
`Page 2 of 6
`6/30/15
`
`AUECMQ. increased from baseline with L02696 by about 42% relative to placebo in the
`CSF. There was no significant difference with L02696 for amyloid-B 1-42 in CSF. It was
`estimated that blood brain barrier (BBB) penetrance for LZC696 was approximately
`0.3%.
`
`PARADIGM-HF, Phase 3 study pivotal study: This was a multicenter, randomized,
`double-blind, double-dummy, parallel group, active-controlled study to evaluate the
`efficacy and safety of LCZBQG compared to enalapril in patients with HF (NYHA class II-
`IV) and reduced ejection fraction (LVEFS35%). The study was stopped early after a
`median of 27 months of follow—up after the third interim analysis showed benefit on the
`primary endpoint, a composite of cardiovascular death or first heart failure
`hospitalization. From the clinical reviews by Dr. McDowell and Smith, the study enrolled
`8442 patients age 18 years and older. The mean age of the study subjects was 64 years
`with a range of 18-96 years, 4229 patients in the enalapril arm and 4203 patients in the
`LCZG96. Approximately 50% of the patients were age 265 years with 20% of all patients
`275 years of age. Patients were evenly distributed between the two treatment arms with
`regard to age. Dementia and cognitive function were not prospectively assessed in the
`study or identified as adverse events of special interest. Dementia-related events were
`captured through standard adverse event (AE) collection. Dementia-related events using
`the broad Standard MEDDRA Query (SMQ) were seen equally in only 2% of patients in
`each treatment arm (Table 77 in the Clinical Review). This analysis used a broad search
`strategy which included preferred terms (PTs) such as “feeling abnormal” or “initial
`insomnia" that do not necessarily indicate dementia or cognitive impairment. For the
`narrow dementia SMQ which focuses on dementia diagnostic PTs, there were a total of
`15/4229 (0.004%) dementia adverse events in the enalapril arm and 12/4203 (0.003%)
`in the LC2696 arm. Of note, there were only 2 reports of Dementia Alzheimer's Type in
`each treatment arm.
`
`Planned studies to assess cognition and amyloid
`The Sponsor plans to further investigate the effects of LCZ696 on cognitive testing and
`amyloid by including
`“m"
`
`. Preliminary discussions have occurred between
`the Sponsor and DCRP with respect to the design and goals of this trial.
`
`The Sponsor is planning to conduct a
`impact of LC2696 on cognitive testing
`positron emission tomography (PET) imaging.
`
`a“) study,
`
`“m", that will assess the
`"’"" as measured by
`"9‘"
`
`l”! 1"!
`
`While neprilysin inhibitors such as sacubitril can potentially increase AB levels in the
`CNS, the impact of increasing AB in the CNS and subsequent risks of AD are unknown.
`Although animal models of neprilysin deficiency have shown increased AB brain
`accumulation, to date, neprolysin deficiency has not been identified as a significant
`causative factor in the pathophysiology of AD in humans and there have not been
`
`Reference ID: 3786906
`
`

`

`Tema Buracchio, MD, HFD—120 Medical Review
`NDA 207620, LCZ696 (Entresto), Novartis
`
`Page 3 of 6
`6/30/15
`
`consistent findings in the association between single nucleotide polymorphisms in
`neprolysin genes and risk of AD.234 There are alternate clearance pathways and
`enzymes that participate in the breakdown of AB and it is possible that these alternate
`pathways may be able to compensate for any loss in neprilysin.
`“M"
`
`The effect of a neprilysin inhibitor on AB in the CNS will depend on its ability to cross the
`BBB and it appears that a very small amount (0.3%) of LCZ696 crosses the BBB. It is
`unclear if this is sufficient to significantly elevate AB in the CNS. The Phase 1 PK/PD
`study suggests that LCZGQG may elevate some forms of AB in the CSF and plasma in
`the short—term, but the clinical significance of these findings is unclear. The effects of
`chronic administration of LCZ696 on AB in the CNS are unknown. However, it should be
`stressed that even if elevations of AB should occur with LCZ696, it is not known if these
`elevations would impact the risk of developing AD. It has become increasingly evident
`that disturbances in amyloid regulation are but one of a number of complex
`pathophysiologic changes that occur in AD. Co—morbidities such as cardiovascular
`disease can also contribute significantly to the onset of dementia in patients with AD
`pathology. As patients with HF frequently have some degree of cognitive impairment, it
`is even theoretically possible that L02696 could have a positive benefit on the vascular
`contributions to dementia that may balance or outweigh the potential risk of increasing
`AB.
`
`"’"4’ study; however, the
`A signal for dementia risk was not identified for the
`study was not designed to assess dementia or cognitive outcomes. As noted in the
`Clinical review, dementia and cognitive impairment were captured as adverse events but
`were not identified as Adverse Events of Special Interest so there is a possibility that
`these events may be underreported. Additionally, a median follow-up of 27 months
`would not be long enough to capture a significant number of incident cases of AD which
`can have a long latency period. Although there were limitations in the study design for
`ascertainment of dementia, this was a large study with approximately half of the patients
`age 265 years who are at risk of developing dementia by virtue of age. There was not an
`imbalance in events seen between the treatment groups in either narrow or broad SMQ
`analyses for dementia to suggest a signal for increased risk of dementia or cognitive
`impairment with L02696.
`
`At this point there is no clinical evidence to suggest that there is a risk for increasing
`development of AD or cognitive impairment with use of LCZGQG in this population of HF
`patients with low ejection fraction. The Sponsor’s plan to further evaluate the
`(m4)
`study and a cognitive test battery and
`W" PET imaging
`(m4) study are reasonable as additional steps for assessing any impact of
`L02696 on cognition and amyloid pathology.
`
`2Vodovar et al. Eur Heart J. 2015;36:902-5.
`3 http://wwwalzforum.org/news/research-newsfinhibiting-neprilysingood-heart-what-about-brain.
`Accessed June 30, 2015
`4 Xingzhi et al. J Neurol Sci 2014; 346:6-10.
`
`Reference ID: 3786906
`
`

`

`Teresa Buracchio, MD, HFD-120 Medical Review
`NDA 207620, LCZ696 (Entresto), Novartis
`
`
`
`Page 4 of 6
`6/30/15
`
`DCRP Questions
`
`
`1. Dr. Link (DCRP pharmacology-toxicology reviewer) reviewed the evidence
`that neprilysin breaks down beta amyloid (see attached). Do you agree with
`his assessment of the evidence that neprilysin breaks down beta amyloid?
`
`We agree with Dr. Link’s view that the evidence supports a role for neprilysin as
`one of the primary Aβ degrading enzymes (of more than a dozen enzymes
`identified to date) that are involved in clearance of Aβ from the brain. However,
`other important Aβ clearance mechanisms include phagocytosis, transport
`across the blood-brain barrier, and transport into the CSF. One recent report
`estimated that these latter two mechanisms may each account for about 25% of
`Aβ clearance out of the CNS (Roberts KF et al., 2014, Annals of Neurology
`76(6):837-844).
`
`2. How strong is the science supporting the amyloid hypothesis in the
`etiology of Alzheimer's disease?
`
`The veracity of the amyloid cascade hypothesis in Alzheimer’s disease (AD),
`which posits that accumulation of the beta-amyloid peptide (specifically the
`abnormal Aβ42 form) in brain parenchyma initiates a sequence of events that
`ultimately leads to dementia, is the subject of a great deal of scientific uncertainty
`and debate. Disruptions of amyloid processing are commonly involved in some
`manner in the pathophysiology of AD. However, the exact nature of their role in
`the development of clinical disease has yet to be determined. It has also become
`increasingly evident that disturbances in amyloid regulation are but one of a
`number of complex pathophysiologic changes that occur in AD. In addition, over
`the past decade a series of development programs have evaluated drugs that
`have sought to lower levels of amyloid in the brain. While many of these drugs
`have demonstrated target engagement, they have all uniformly failed to confer
`any clinical benefit to patients with dementia. The reasons for these seemingly
`discordant results are uncertain and, no doubt, complicated. However, they
`further highlight the lack of understanding as to the part that amyloid plays in the
`disease process.
`
`
`The fact that the rare early-onset autosomal-dominant forms of AD involve
`mutations in genes that are directly involved in amyloid processing lends support
`to the amyloid hypothesis. However, the relevance to the far more common
`sporadic forms of the disease is not immediately obvious. For example, evidence
`suggests that the autosomal dominant forms of AD may result from amyloid over-
`production, while the sporadic forms potentially involve disruptions in clearance.
`Timing of pathology may also be important as some authors propose that
`amyloid may trigger a downstream series of events, but then become less
`directly relevant over time. It must be stressed that this view is also highly
`theoretical at the present time. The past decade of scientific research and clinical
`trials in AD have revealed our substantial lack of understanding as to how the
`commonly observed pathophysiologic changes in AD ultimately manifest in
`clinical disease. It is clear, however, that the processes involved are complex. As
`a result, the clinical impact of the disruption of a single aspect of this environment
`in isolation would be extremely uncertain.
`
`
`
`Reference ID: 3786906
`
`

`

`Teresa Buracchio, MD, HFD-120 Medical Review
`NDA 207620, LCZ696 (Entresto), Novartis
`
`
`
`Page 5 of 6
`6/30/15
`
`3. How do you interpret the CSF findings in the preclinical and clinical
`studies? What is the likely clinical significance of these findings?
`
`Young female cynomolgus monkeys (2.5-4 years old) given oral LCZ696 50
`mg/kg once daily for 16 days showed significant increases in CSF exposures to
`newly generated Aβ38, Aβ40, Aβ42, and total Aβ (Day 14/15 AUC) compared to
`vehicle controls; however, no changes were observed in cortex or hippocampus
`levels of Aβ40 or Aβ42 (Study 1270586; Aβ38 levels were below the limit of
`quantitation). These observations suggest that sufficient levels of LBQ657 (the
`active moiety produced by esterase metabolism of the sacubitril component of
`LCZ696 after oral administration) reached the CNS to inhibit neprilysin, but that
`other Aβ clearance mechanisms, including transport into the CSF, compensated
`such that no net increase in brain Aβ was apparent at steady state.
`
`The dose of 50 mg/kg was described as “clinically relevant,” since the mean
`LBQ657 CSF Day 15 Cmax (19.8 ng/mL) was similar to the mean LBQ657 CSF
`Day 14 Cmax (19.2 ng/mL) observed in healthy volunteers given LCZ696 400 mg
`QD (Study A2126; the target dose for LCZ696 is 200 mg BID); however, the
`mean LBQ657 CSF AUC0-24 hr was 387 ng*hr/mL in humans vs. 128 ng*hr/mL in
`monkeys. Higher doses should have been explored to allow assessment of CNS
`exposures several-fold greater than those expected in humans at the maximum
`recommended dose.
`
`These results suggest that drug-induced changes in Aβ CSF levels may not
`reliably reflect steady state changes in Aβ brain levels because of the complex
`and potentially compensatory mechanisms involved in Aβ clearance from the
`CNS. Furthermore, these effects observed in 2.5-4 year old monkeys may not
`accurately predict effects that might occur in elderly humans, since cynomolgus
`monkeys do not typically have measurable cerebral amyloid pathology until
`middle age. Diffuse amyloid plaques were observed in cynomolgus monkeys
`aged 18-19 years in one study (Kodama et al., 2010, Toxicologic Pathology
`38:303-311), while classic dense core senile plaques were observed in another
`study in cynomolgus monkeys aged 29-30 years (Darusman et al., 2014,
`Frontiers in Aging 6:313). Humans typically accumulate amyloid pathology
`starting at age 45-65 years (depending on ApoE genotype).
`
`Study A2126, which analyzed the PD effects of LCZ696 on CSF Aβ,
`demonstrated BBB penetration of approximately 0.3%. Over a two week period
`there was an increase in Aβ1-38 in the CSF and Aβ1-40 in the plasma, but no
`increases were seen in the more pathologic Aβ1-42 in either CSF or plasma. The
`clinical significance of these findings is not known. This was also a short study
`and it is not known how LCZ696 may impact Aβ levels with chronic use.
`Moreover, it is unknown whether increasing levels of any form of Aβ in the CSF
`may ultimately increase the risk of developing Alzheimer’s disease.
`
` study that will include neurocognitive tests and
`The Sponsor’s plan for a
` PET imaging is reasonable as an additional step for assessing any
`impact of LCZ696 on cognition
`. However, there is no a
`priori basis at the present time to conclude that the pattern of results observed in
`the CSF would necessarily suggest that LCZ696 would convey a high likelihood
`of an increased risk for Alzheimer’s disease.
`
`Reference ID: 3786906
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Teresa Buracchio, MD, HFD-120 Medical Review
`NDA 207620, LCZ696 (Entresto), Novartis
`
`
`
`Page 6 of 6
`6/30/15
`
`
`
`4. How do you interpret the brain tissue findings in the 39-week monkey study
`as relates to the risk of LCZ696 causing Alzheimer’s disease?
`
`In Study 0670621, 2-4 year old cynomolgus monkeys given 300 mg/kg LCZ696
`once daily via oral gavage for 39 weeks showed no changes in Aβ42
`immunostaining in brain (parenchymal or vascular) compared to vehicle controls.
`Plasma LBQ657 exposures were approximately 2-fold (Cmax) and 9-fold (AUC)
`those observed in humans given LCZ696 200 mg BID. These results are not very
`informative about the risk of AD, since amyloid deposition does not occur
`spontaneously in non-human primates until at least middle age, as noted above
`(see response to Question 3). A study in aged monkeys, measuring levels of
`soluble and insoluble Aβ in brain homogenates as well as immunoreactive Aβ,
`may have provided more relevant information.
`
`5. See Table 77 of the FDA Clinical Review. Do you think the approach that
`was taken to analyze the AE data in PARADIGM-HF was reasonable? If not,
`how do you think the data should be analyzed?
`
`The analyses that were performed using broad and narrow range SMQs for
`dementia appear to be appropriate. The incidence of dementia AEs under the
`dementia narrow SMQ are quite low. As noted in the Clinical review by Dr.
`McDowell and Smith, there was no prospective assessment of dementia or
`cognitive impairment in the PARADIGM-HF study so there may be
`underreporting of dementia and cognitive impairment. Despite this limitation,
`there does not appear to be any imbalance of dementia adverse events between
`the two treatment arms. Given the low reported rates of dementia AEs, additional
`analyses are not likely to be informative.
`
`
`
`
`
`
`
`
`
`6. Are you aware of any PMRs to assess the risk of Alzheimer’s disease? If
`so, can you provide additional information on the design of these studies?
`
`We are not aware of any PMRs to assess the risk of AD.
`
`
`
`Summary Comment: As expressed in our responses to the consult questions above,
`certain aspects of the studies in the monkey limit the extent to which they could fully
`investigate the effect of LCZ696 on amyloid pathology. However, these limitations must
`also be viewed in the context of the sponsor’s overall development program as well as
`the current scientific understanding of the pathophysiology of AD. Based on the totality
`of the data available at this time, we do not believe that they suggest a high likelihood of
`an increased risk of developing AD with the use of LCZ696.
`
`
`Reference ID: 3786906
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`NICHOLAS A KOZAUER
`07/01/2015
`
`TERESA J BURACCHIO
`07/01/2015
`
`DAVID B HAWVER
`07/01/2015
`
`LOIS M FREED
`07/01/2015
`
`WILLIAM H Dunn
`07/02/2015
`
`Reference ID: 3786906
`
`

`

`
`
`DIVISION OF CARDIOVASCULAR AND RENAL PRODUCTS
`Divisional Memo
`
`
`NDA:
`207620 Sacubitril plus valsartan (Entresto) for
`reducing the risk of cardiovascular mortality and
`hospitalization in patients with chronic heart failure.
`Sponsor:
`Novartis
`Review date: 22 June 2015
`
`
`
`
`Reviewer:
`N. Stockbridge, M.D., Ph.D., HFD-110
`This memo conveys the Division’s recommendation to issue an “Approval” letter for this
`application.
`This application has been the subject of reviews of CMC (Banerjee, McLamore-Hines,
`Kurtyka, Mello, Li, Bloom, Wilson-Lee; 15 May 2015), pharmacology/toxicology (Link;
`15 May 2015), clinical pharmacology (Sabarinath, Zhuang; 15 May 2015), clinical
`effectiveness and safety (Marciniak; 29 December 2014, Smith; 15 May 2015, and
`McDowell; 15 May 2015), and statistics (Lawrence; 20 May 2015). There is also a CDTL
`memo (Thompson; 12 June 2015), with which I am in agreement.
`Entresto is the 1:1 combination of valsartan, an angiotensin receptor blocker, and
`sacubitril, which would be the first approved neprilysin inhibitor. The latter’s effects
`include vasodilation, natreuresis, aldosterone antagonism, and elevation of CSF levels
`of beta-amyloid in cynomogus monkeys and man.
`Entresto would be marketed as tablets of (sacubitril/valsartan) 24/26 mg, 49/51 mg,
`and 97/103 mg.
`
`
`
` There is a 24-month expiry. Facility inspections are
`
`not complete.
`There are no unresolved issues with pharmacology/toxicology. Hydrocephalus and
`reduced survival were seen in rabbit pups. CSF levels of beta-amyloid are elevated
`short-term, but, in a 2-year study in monkeys, beta-amyloid levels were not elevated in
`brain parenchyma. Given the typical lifespan of a patient with heart failure, I find the
`available data adequately reassuring with regard to the potential of Entresto to cause
`cognitive decline.
`Sacubitril is at least 60% bioavailable. Valsartan is somewhat more bioavailable from
`Entresto than as monotherapy. Sacubitril is subject to esterase activity, but neither
`sacubitril nor valsartan is subject to other metabolism. Entresto inhibits transporters
`OATP1B1 and B3.
`Entresto was
`
`
` Although the review team is not unanimous in
`the policy decision we made, we did say that one did not need to satisfy the
`combination policy if one could demonstrate an effect on mortality or irreversible
`morbidity, and this decision led to the heart failure development program.
`The sole study supporting approval for heart failure is PARADIGM, a randomized,
`double-blind study comparing enalapril to a single regimen of Entresto. Subjects with
`stable NYHA Class II-IV heart failure and reduced ejection fraction (HFrEF) underwent
`sequential several-week run-in phases on enalapril and Entresto before being
`randomized, resulting in about 10% withdrawal rates in each run-in phase, a feature
`that complicates description of study results.
`
`Last saved
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`
`1
`10:56 Monday, June 22, 2015
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`Reference ID: 3782466
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Divisional memo
`Entresto (sacubitril + valsartan)
`
`
`
`
`NDA 207620
`Heart failure
`
`PARADIGM was stopped after the third of three planned interim analyses. Results are
`summarized in the table below:
`Endpoint
`Enalapril
`Entresto
`N=4212
`N=4187
`26.5%
`21.8%
`
`RR
`(95% CI)
`0.80
`(0.73, 0.87)
`
`Alpha
`
`P-value
`
`0.002 0.0000002
`
`Primary: Heart
`failure
`hospitalization or CV
`death
`HF Hospitalization
`
`15.6%
`
`12.8%
`
`CV death
`
`16.5%
`
`13.3%
`
`All-cause mortality
`
`19.8%
`
`17.0%
`
`0.79
`(0.71, 0.89)
`0.80
`(0.71, 0.89)
`0.84
`(0.76, 0.93)
`
`--
`
`--
`
`--
`
`--
`
`0.0016
`
`0.0009
`
`
`All of the effect on all-cause mortality appears to be the effect on cardiovascular
`mortality; this finding merely reassures me that there are not other, important adverse
`mortal effects of Entresto. Inclusion of all-cause mortality as a formal end point was
`probably harmless in this study, but I do not think its inclusion is ever smart.
`There was a second secondary end point attributed 20% of the alpha: the Kansas City
`Cardiomyopathy Questionnaire (KCCQ), a widely used 23-item patient-reported,
`
`symptom assessment. Although there was an effect,
` the review team notes and I concur that the effect is much smaller
`than is generally regarded as clinically relevant,
`
`
`Subsequent secondaries for time to new onset atrial fibrillation or a 50% reduction in
`eGFR showed no nominally statistically significant effects.
`Expected adverse effects were hypotension, which was generally adequately managed
`without study drug discontinuation, and hyperkalemia, which was nominally worse on
`enalapril.
`Angioedema was a major problem with omapatrilat, a drug with ACE inhibitor and
`neprilysin inhibitor properties. As with ACE inhibitors alone, rates of angioedema were
`several-fold higher in Blacks. Several severe cases with airway compromise occurred in
`the omapatrilat development program, and it was never approved. In the Entresto heart
`failure program, no cases with airway compromise were reported. Rates were 0.1% in
`each run-in period, but then showed the expected amplification in the randomized
`period: 0.2% on enalapril and 0.5% on Entresto. The program also showed the expected
`increased risk in Blacks, few though there were in the study—0.5% on enalapril and
`2.4% on Entresto. There is discussion of a post-marketing requirement to obtain further
`data on angioedema, particularly in US Blacks, but I do not recommend a PMR, in part
`because I believe we already know the risk well enough and in part because our
`pharmacovigilance tools are likely better than anything we could get Novartis to do.
`There is a third clinical review, by Dr. Marciniak, not mentioned in the CDTL memo. Dr.
`Marciniak was not part of the review team. He cites “flaws” in the case report forms for
`PARADIGM “that challenge the validity of its data”, but then he concludes the issues
`“are not severe enough to reject outright the trial results”, and in that conclusion I
`certainly concur. Dr. Marciniak describes the 27 lung cancers in the Entresto group vs.
`22 on enalapril as a “modest increased risk”, but makes little of other trends—all solid
`
`Last saved
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`
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`Reference ID: 3782466
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`(b) (4)
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`(b) (4)
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`

`

`Divisional memo
`Entresto (sacubitril + valsartan)
`
`
`
`
`NDA 207620
`Heart failure
`
`tumors 122 vs 1181, all brain 6 vs 7, all hematologic 10 vs 10—and he dismisses as
`unreliable the biggest observed difference, in non-melanoma skin—11 vs 29. In my
`view, there is no cancer finding here of the least concern.
`I concur with the entire review team in recommending approval. I also want to
`acknowledge the entire review team’s diligence in producing their reviews well in
`advance of user fee goal dates for a priority review. I particularly wish to acknowledge
`leadership by Drs. Wilson-Lee and Thompson.
`
`
`1 Entresto vs enalapril
`Last saved
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`
`
`
`Reference ID: 3782466
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
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`----------------------------------------------------
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`NORMAN L STOCKBRIDGE
`06/22/2015
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`Reference ID: 3782466
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`

`

`CLINICAL REVIEW
`
`
`Reviewer Name(s)
`
`Application Type NDA
`Application Number(s)
`207620
`Priority or Standard
`Priority
`
`
`Submit Date(s) December 17, 2014
`Received Date(s) December 17, 2014
`PDUFA Goal Date
`August 26, 2015
`Division / Office Division of Cardiovascular and Renal
`Products/ODEI
`
`Tzu-Yun McDowell (safety)
`Kimberly Smith (efficacy)
`Review Completion Date May 15, 2015
`
`
`Established Name
`Sacubitril/valsartan
`(Proposed) Trade Name
`Entresto
`Therapeutic Class
`Angiotensin receptor neprilysin inhibitor
`Applicant Novartis Pharmaceuticals Corporation
`
`
`Formulation(s)
`50, 100, and 200 mg film-coated tablets
`Dosing Regimen
`Initial dose of 100 mg twice daily with titration to a
`target dose of 200 mg twice daily. Initial dose of
`50 mg daily for patients not currently taking an
`angiotensin-converting enzyme inhibitor or an
`angiotensin II receptor blocker, or on low doses.
`Treatment of heart failure (NYHA class II–IV)
`
`Indication(s)
`
`Intended Population(s)
`
`
`
`Template Version: March 6, 2009
`
`Adults
`
`
`
`Reference ID: 3756838
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review
`Tzu-Yun McDowell and Kimberly Smith
`NDA 207620
`Entresto (sacubitril/valsartan)
`
`
`Table of Contents
`
`2
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ....................................... 10
`1.1 Recommendation on Regulatory Action ........................................................... 10
`1.2 Risk Benefit Assessment .................................................................................. 10
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies . 12
`1.4 Recommendations for Postmarket Requirements and Commitments .............. 12
`INTRODUCTION AND REGULATORY BACKGROUND ...................................... 13
`2.1 Product Information .......................................................................................... 13
`2.2 Tables of Currently Available Treatments for Proposed Indications ................. 13
`2.3 Availability of Proposed Active Ingredient in the United States ........................ 16
`2.4
`Important Safety Issues with Consideration to Related Drugs .......................... 17
`2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 17
`2.6 Other Relevant Background Information .......................................................... 20
`3 ETHICS AND GOOD CLINICAL PRACTICES ....................................................... 20
`3.1 Submission Quality and Integrity ...................................................................... 20
`3.2 Compliance with Good Clinical Practices ......................................................... 20
`3.3 Financial Disclosures ........................................................................................ 21
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 23
`4.1 Chemistry Manufacturing and Controls ............................................................ 23
`4.2 Clinical Microbiology ......................................................................................... 23
`4.3 Preclinical Pharmacology/Toxicology ............................................................... 24
`4.3.1 Preclinical Pharmacology .............................................................................. 24
`4.3.2 Preclinical Toxicology .................................................................................... 24
`4.4 Clinical Pharmacology ...................................................................................... 26
`4.4.1 Mechanism of Action .................................................................................. 26
`4.4.2 Pharmacodynamics.................................................................................... 26
`4.4.3 Pharmacokinetics ....................................................................................... 26
`5 SOURCES OF CLINICAL DATA............................................................................ 27
`5.1 Tables of Studies/Clinical Trials ....................................................................... 27
`5.2 Review Strategy ............................................................................................... 27
`5.3 Discussion of Individual Studies/Clinical Trials ................................................. 28
`6 REVIEW OF EFFICACY ......................................................................................... 43
`Efficacy Summary ...................................................................................................... 43
`6.1
`Indication .......................................................................................................... 46
`6.1.1 Methods ..................................................................................................... 47
`6.1.2 Demographics ............................................................................................ 47
`6.1.3 Subject Disposition .................................................................................... 51
`
`Reference ID: 3756838
`
`2
`
`

`

`Clinical Review
`Tzu-Yun McDowell and Kimberly Smith
`NDA 207620
`Entresto (sacubitril/valsartan)
`
`
`6.1.4 Analysis of Primary Endpoint(s) ................................................................. 56
`6.1.5 Analysis of Secondary Endpoints(s)........................................................... 59
`6.1.6 Other Endpoints ......................................................................................... 62
`6.1.7 Subpopulations .................................................................