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

`

`DIVISION OF CARDIOVASCULAR AND RENAL PRODUCTS
`
`Regulatory Project Manager Overview
`
`NDA:
`
`207620
`
`Drug:
`Class:
`
`Entrsto (sacubitril/valsartan) 24/26 mg: 49/51 mg: 97/103 mg Tablets
`a combination of sacubitn'l. a neprilysisn inhibitor. and valsartan, an angiotensin receptor
`neprilysin inhibitor
`Novartis Phannaceuticals Corp.
`Applicant:
`Proposed Indication:
`o
`
`The treatment of heart failure (NYHA class II—IV)
`
`M (4)
`
`(b) (4)
`
`Final indication:
`
`ENTRESTO is indicated to reduce the risk of cardiovascular death and hospitalization for
`heart failure in patients with chronic heart failure (NYHA Class H—IW and reduced
`ejection fraction.
`
`ENTRESTO is usually administered in conjunction with other heart failure therapies. in
`place of an ACE inhibitor or other ARB.
`Date of submission: 17 December 2015
`
`PDUFA date: 17 August 2015
`Action date: 7 July 2015
`
`0:0 REVIEW TEAM
`
`0 Office of New Drugs. Office of Drug Evaluation 1. Division of Cardiovascular & Renal Products
`0 Cross Discipline Team Leader (CDTL)
`o Aliza Thompson
`0 Medical Reviewer
`
`0 Kimberly Smith (Eflicacy). Tzu-Yun McDowell (Safety)
`0 Pharmacology & Toxicology
`0 William Link
`
`0 Regulatory Health Project Manager
`0 Alexis Childers
`
`0 Office of Pharmaceutical Quality (OPQ)
`o — CMC & Biopharmaceutics
`0 Wendy Wilson (Application Technical Lead)
`0 Anamitro Banerjee (Drug Substance), Sherita McLamore-Hines (Drug Product)
`0
`Salaheldin Hamed (Biopharmaceutics)
`0 Robert Mello (Microbiology)
`0 Office of Clinical Pharmacology
`0
`Sreedharan Sabarinath (Clinical Pharmacology)
`0
`Liming Zhuang (Pharmacometrics)
`
`Reference ID: 37891 64
`
`

`

`NDA 207620 – RPM Overview
`
` Office of Biostatistics, Division of Biometrics I
`John Lawrence
`
` Office of Surveillance and Epidemiology
`o – DMEPA
`Janine Stewart
`
`o DRISK
`Somya Dunn
`
`
` BACKGROUND
`LCZ696, developed by Novartis is a novel combination of sacubitril and valsartan for the treatment of
`heart failure (NYHA class II-IV)
`. The Phase 3 trial, CLCZ696B2314
`(PARADIGM-HF) was a randomized, double-blind pivotal outcome study comparing the efficacy and
`safety of LCZ696 to enalapril in patients with heart failure and reduced ejection fraction (HFrEF). In
`March 2014, the Data Monitoring Committee recommended early closure of the trial because of
`compelling efficacy after the third interim analysis.
`
`In addition to the Phase 3 trial, there are two supportive phase 2 studies in patients with heart failure,
`CLZ696B2214 (PARAMOUNT) and CLCZ696B2228 (TITRATION). Safety data is provided from
`completed studies in patients with hypertension as well.
`
`The applicant submitted a SPA in June 2009 for the phase 3 trial. The Division issued a No Agreement
`letter on 16 July 2009. There were subsequent discussions with the applicant but a new SPA was never
`submitted. The applicant opened the IND with the phase 3 trial.
`
`The NDA had fast track designation with a rolling review. The NDA was given a priority review with a
`PDUFA date of 17 August 2015. An early action is being taken.
`
`The proposed doses are 24/26 mg; 49/51 mg; 97/103 mg (sacubitril/valsartan) tablets for the treatment of
`heart failure.
`
`The review of the application in general met all of the 21st century review guidelines through primary
`reviews. The CDTL, Division Director and Signatory memos were all accelerated as an early action was
`taken.
`
`User Fee
`The user fee for this application was paid in full on 22 September 2014. User Fee ID 3014514.
`
`Pediatric Review Committee (PeRC)
`The applicant submitted a waiver request in Pediatrics. The PeRC meeting to discuss this application was
`held on 24 June 2015. The committee agreed to grant a full waiver in pediatric patients because studies
`are impossible or highly impractical as there are too few patients with disease/condition to study. The
`causes and mechanisms of heart failure in children and adults are different.
`
`Advisory Committee
`There was no Advisory Committee meeting for this NDA because this drug does not raise significant
`safety or efficacy issues.
`
`Trade name
`The applicant originally submitted the proposed name Entresto to IND 104628 on 19 June 2014. The
`name was approved on 17 November 2014. Novartis submitted the same name request on 15 January
`2015 to the NDA. The name was still considered acceptable. Novartis was asked to resubmit the name
`
`Reference ID: 3789164
`
`(b) (4)
`
`

`

`NDA 207620 — RPM Overview
`
`request due to a change in strength presentation. The request was submitted on 24 April 2015 and found
`acceptable on 11 ere 2015. A grant letter was issued on 19 June 2015.
`
`Facilities Inspection
`The Office of Compliance provided an overall recommendation of acceptability for the manufacturing
`sites on 30 June 2015.
`
`Division of Scientific Investigations: Four foreign clinical investigator inspections were conducted in
`support of NDA 207620. for audit of Study CLCZ696B2314 (PARADIGM-HF). A site inspection also
`occurred at Novartis New Jersey. No regulatory violations were found druing 3 of the inspections. Minor
`regulatory violations were found druing the inspections of 2 of the sites: one for failure to follow the
`investigational plan and one for failure to prepare or maintain accurate records. These issues did not
`significantly impact the quality or the integrity of the data submitted in support of this NDA.
`
`02° REGULATORY TINIELINE
`
`Top-Line Results Meeting: 22 September 2014 (minutes dated 22 October 2014)
`Pre-NDA Meeting: 25 ere 2014 (minutes dated 14 July 2014)
`CMC Pre-NDA : 14 August 2014 (minutes dated 18 September 2014)
`NDA Received Date: 17 December 2014
`
`Filing Day 60: 15 February 2015
`Filing/74 Day Letter: 12 February 2015
`Mid-cycle Communication Meeting: 19 March 2015 (minutes dated 7 April 2015)
`Late-Cycle Meeting: 3 June 2015 (minutes dated 24 June 2015)
`Advisory Committee: N/A
`PDUFA Date: 17 August 2015
`
`°2° REVIEWS
`
`Below are the conclusions reached by the Entresto team members. organized by role or discipline.
`
`ODE I Memorandum (dated 7 July 2015)
`Dr. Unger provided a thorough synopsis of each disciplines review. (see full memo for details). He states
`that the following factors make the theoretical risk of cognitive impairment acceptable: if the risk exists. it
`could take a long time to develop. life expectancy of heart failure patients is short. there are proven effects
`on meaningful outcomes. and the risk is based on mechanistic theory without supportive data.
`
`He explains that although all-cause mortality was statistically significantly lower in the LCZ696 arm. it
`was driven entirely by cardiovascular mortality
`(”1 (4)
`
`(b) (4)
`
`(5) (‘0
`(”I “I
`
`He agrees with the angioedema PMR.
`
`Dr. Unger does not agree with Dr. Marciniak‘s cancer assessment.
`
`The Division was generally not in favor of ordering a post-marketing requirement to assess longer term
`cognitive effects. The Division had major concerns around publicizing this potential risk — a purely
`theoretical issue — because publicity will discourage patients from using the drug. Moreover. the Division
`questioned whether this theoretical concern meets the threshold for a PMR. and whether. in light of the
`
`Reference ID: 37891 64
`
`

`

`NDA 207620 – RPM Overview
`
`data from the Phase 3 trial and literature, the potential PMR study would lay the question to rest. Though
`Dr. Unger certainly shared the Division’s concerns, (FDAAA) states that post-marketing studies and
`clinical trials may be required to identify an unexpected serious risk when available data indicates the
`potential for a serious risk. Based on its mechanism of action, sacubitril poses a potential risk for serious
`CNS toxicity, and Dr. Unger reached the conclusion that the company’s proposed CNS study will be
`appropriate as a post-marketing requirement.
`
`Overall, Dr. Unger agrees with the review team’s recommendation for approval.
`
`Divisional Memorandum (dated 22 June 2015)
`Dr. Stockbridge’s memo recommends approval. The memo provides a brief overview of the program and
`results. He finds available pharm/tox data regarding reassuring in regards to the potential for Entresto to
`cause cognitive decline. He concurs with the reviewers’ assessment regarding KCCQ and symptom
`assessment in that the effect is smaller than what is generally regarded as clinically relevant
`. He does not agree with the reviewers’ recommendation for a PMR for
`angioedema. He states the risk is well known and feels our pharmacovigilance tools are better than what
`Novartis can obtain. He mentions a review conducted by Dr. Marciniak, who was not part of the review
`team. While Dr. Marciniak feels there are flaws in the case report forms and the validity of the data can be
`questioned, he states it was not severe enough to reject the trial. Dr. Stockbridge agrees that the data
`should not be rejected. Dr. Stockbridge does not agree with Dr. Marciniak’s assessment regarding cancer
`findings.
`
`
`
`Cross-Discipline Team Leader (CDTL) Review (dated 12 June 2015)
`Dr. Thompson recommends approval. Her review summarizes each disciplines findings including consult
`review. She also provided a detailed regulatory history. She notes that Dr. Lawrence did not recommend
`approval for the combination policy. She did not agree with his assessment stating that the trial provides a
`mortality benefit; there were no safety signals that would lead one needing to determine the contributions
`of each component, nor would it be ethical to conduct such a trial; there is a benefit over an active
`comparator.
`
`Dr. Thompson’s review discusses the applicant’s
` as well as the clinical reviewers’ assessments. She agrees with the clinical reviewers.
`
`
`
`She discusses a theoretical safety concern that inhibition of neprilysin by LCZ696 could accentuate
`accumulation of beta amyloid in the brain causing an increased risk of Alzheimer’s disease. There has
`been a lot of internal discussion including whether the information should be included in the label.
`Findings have been included in the label. She notes that at the point of her review, there have been no
`discussions to discuss next steps. The clinical reviewers did not recommend a PMR and she agreed as the
`
`.
`
`Medical (dated 15 May 2015)
`Dr.’s Smith and McDowell provided a combined review discussing safety and efficacy. They both
`recommended approval stating that the benefits outweigh the risks. They state that LCZ696 reduced the
`risk of the primary composite endpoint based on a time-to-event analysis with patients having fewer first
`heart failure hospitalizations and cardiovascular deaths as first event compared to enalapril. The most
`important risks identified in the review were angioedema, hypotension, renal impairment, and
`hyperkalemia. Although, the over-all incidence was low, the most concerning of the risks is angioedema.
`The incidence of angioedema was higher in black subjects but only 5% of the test subjects were black in
`PARADIGM. It is therefore difficult to assess the true risk. A PMR to assess the risk of angioedema in
`black patients is recommended by the reviewers. A PMR has been created and agreed upon with the
`sponsor (see action letter for details).
`
`Reference ID: 3789164
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 207620 – RPM Overview
`
`The review also points out that LCZ696 is a fixed-dose combination. Per the regulations, each component
`must contribute to the effect. With the design of PARADIGM, one could not establish the individual
`contributions of each component. The reviewers used other available data to make an assessment,
`including the VAL-HeFT trial. Based on the assessment and the fact that no studies have directly
`compared valsartan to enalapril, they feel that both therapies are at least equivalent therapies, and
`sacubitril alone contributed to the treatment effect. They believe the risks they identified can be managed
`through clinical monitoring and dose titration.
`
`Dr. Marciniak, who was not part of the review team, also wrote a review regarding flaws in case report
`forms that can bring into question the validity of the data. He did not feel that is was severe enough to
`reject trial data. He also pointed out concerns regarding cancer.
`
`Biostatistics Review (dated 20 May 2015)
`Dr. Lawrence’s review stated that the combination should not be approved. Due to limitations in the study
`design, he states that it is not possible to know whether both components contribute to the effects. If the
`drug is approved, he feels that this should be clearly stated in the label.
`
`He suggests that sacubitril should be approved as a monotherapy for reducing CV mortality only. He
`explains that it is unknown whether valsartan alone could explain the heart failure hospitalization benefit.
`Dr. Lawrence’s review also notes that:
`
` One-sided p-values were used sometimes in the report
`p-values.
`Primary endpoint and all-cause mortality endpoints had significant p-values.
`
`
`
`. The label should show 2-sided
`
`Clinical Pharmacology Review (dated 15 May 2015 & 26 June 2015)
`Dr.’s Sabarinath (clinical pharmacology) and Zhuang (pharmacometrics) provided a combined review.
`They find the information submitted to the NDA to be supportive of approval with the following dose
`recommendations: Use a lower starting dose of 50 mg BID in patients with (1) severe renal function
`impairment or (2) moderate hepatic impairment.
`
`
`
`The most noteworthy findings were (for a complete list, see review):
` 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.
` The LCZ696 analytes have high plasma protein binding (97 % for sacubitril and LBQ657 and 94
`% for valsartan)
` 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.
`
`They also provided an addendum to compare the mean daily dose of enalapril to that in the SOLVD-
`Treatment (SOLVD-T) study. They determined that based on limited information from publications for
`SOLVD-T, it can be concluded that the daily dose of enalapril in PARADIGM-HF is numerically higher.
`
`Reference ID: 3789164
`
`(b) (4)
`
`

`

`NDA 207620 — RPM Overview
`
`They also documented revised estimates for apparent volume of distribution of sacubitril and valsartan in
`the addendum and label.
`
`Pharmacology & Toxicology Review (dated 15 May 2015)
`Dr. Link‘s review states that the LCZ696 was tested in a several different species including mice. rats.
`rabbits. marmosets and cynomolgus monkeys. Target organs were kidney. red blood cells. heart and GI
`tract. He didn’t consider any of the findings detrimental to the safe use of LCZ.
`
`The genotoxicity studies included in vivo and in vitro bacterial and mammalian systems.
`
`The carcinogenicity studies were evaluated with Executive CAC concurrence. There was no effect on
`fertility in rats. LCZ696 did show teratogenicity in rabbits and increased embryo lethality in rats and
`rabbits.LCZ696 is contraindicated during pregnancy.
`
`Dr. Link’s review mentions the theoretical risk associated with NEP inhibition as it relates to effects on
`
`B—amyloid (All) metabolism. and the potential accumulation of AB in the brain. Elevated levels of B—
`amyloid were present in the CSF and plasma but not brain in monkeys. He states the relevance to humans
`is not clear.
`
`Dr. Link stated the preclinical program was thorough and well conducted. He agrees with the applicant’s
`interpretations of the data and recommends approval.
`
`Ter‘tiarl Pharmacology Review (2 July 2015)
`Dr. Brown summarized the phannacologists review and agrees with the primary reviewers assessments.
`
`Office of Pharmaceutical Qualig' Review (dated 15 May 2015. 30 June 2015)
`An integrated summary was written for product quality. Approval is recommended from a quality
`perspective. LCZ696 is a
`m“) comprised of two active ingredients. sacubitril and valsartan. OPQ
`prefers the term
`mm to describe the active moiety: whereas the applicant preferred
`mu)
`. It was agreed during labeling negotiations that the active moiety will be called complex.
`
`There were several discussions throughout the review regarding expression of strength. Novartis
`originally wanted a single strength expressed for each dose level. OPQ stated that each component needed
`to be shown. While the review team and the applicant agreed that the dose strengths can be separated by a
`”I OPQ feels that “and” is more appropriate. Ultimately. they agreed with using “and”.
`
`A 24 month expiry has been assigned when stored at room temperature.
`
`From a Biopharmaceutics perspective it was determined that the dissolution data submitted for clinical
`and registration batches did not support the dissolution acceptance criteria proposed by the applicant. A
`post-marketing commitment was agreed upon regarding dissolution (see full review and action letter for
`details).
`
`Regarding drug substance. the applicant did not propose any BCS Classification. It was determined that
`the BCS classification is BCS IV.
`
`From a microbiology perspective. the tests and proposed acceptance criteria for microbial burden are
`adequate.
`
`Reference ID: 37891 64
`
`

`

`NDA 207620 – RPM Overview
`
`CONSULTS
`
`Office of Surveillance and Epidemiology Reviews
`DMEPA (1 Jun 2015), (16 Jun 2015)
`Dr. Stewart reviewed that carton and container labels and labeling insert using a Failure Mode
`and Effects Analysis. The risk assessment performed on the PI and container labels identified
`deficiencies that may lead to medication errors and areas for improvement.
`
`Full details on recommendations can be found in the review. Comments regarding the container
`labels were sent to the applicant via email. The applicant revised the container labels per
`DMEPA’s recommendations. DMEPA found them acceptable. Final agreed upon cartons were
`submitted June 11, 2015.
`
`DRISK (22 May 2015)
`Dr. Dunn evaluated the need for a risk evaluation and mitigation strategy (REMS). She concludes
`that no risk mitigations measures other than professional labeling and a PPI are needed as no
`safety concerns have been identified. Of note, the applicant originally
`.
`
`
`
`DEPI (5 June 2015)
`Dr. Eworuke reviewed the applicant’s proposed post marketing study plan. She concludes that
`that the applicant’s approach to evaluating the risk of angioedema is reasonable and provided
`recommendations to the Division and applicant. See full review.
`
`Office of Medical Policy Initiatives, Division of Medical Policy Programs (4 June 2015)
`Ms. Dowdy did a combined review with Dr. Patel evaluating the PPI. See full review for comments
`regarding the PPI. They concluded that the document is acceptable pending proposed corrections.
`
`Office of Prescription Drug Promotions, Division of Professional Drug Promotion (8 June 2015)
`Dr. Patel provided comments on the draft prescribing information and carton container. See full review
`for details
`
`Division of Pediatric and Maternal Health (26 May 2015)
`Dr. Dinatale provided comments regarding the applicant’s submission of PLLR. They provided
`comments on draft prescribing information. See full review for details.
`
`Labeling
`Labeling discussions occurred with the applicant. The final agreed upon labeling will be attached to the
`approval letter.
`
`CONCLUSION
`The review team recommended approval.
`
`An approval letter was drafted and signed by Dr. Unger on 7 July 2015.
`
`Reference ID: 3789164
`
`(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/
`----------------------------------------------------
`
`ALISON L BLAUS
`07/08/2015
`Signing on behalf of Alexis Childers
`
`Reference ID: 3789164
`
`

`

`PMR/PMC Development Template
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`NDA #
`
`207-620
`
`Product Name:
`
`EntrestoTM (sacubitril/valsartan) Tablets. 97/ 103. 49/51. and 24/26 mg
`
`PMR/PMC Description:
`
`1) Optimization of the dissolution method for EntrestoTM (sacubitril/valsartan)
`Tablets. and
`
`2) Setting of the final acceptance criterion for the dissolution test, based on
`data from a minimum of 12 commercial batches per strength (using the
`optimized dissolution method).
`
`PMR/PMC Schedule Milestones: Dissolution Method Development Report
`Submission:
`
`February 2016
`
`Study/Trial Completion:
`Final Report Submission:
`Other:
`
`NA
`July 2016
`NA
`
`1. During application review. explain why this issue is appropriate for a PMR/PMC instead of a pre-approval
`requirement. Check type below and describe.
`
`g Unmet need
`X Life-threatening condition
`XI Long-term data needed
`[:I Only feasible to conduct post-approval
`D Prior clinical experience indicates safety
`El Small subpopulation affected
`|:| Theoretical concern
`l:l Other
`
`During the review cycle it was determined that the dissolution acceptance criterion proposed by
`the Applicant
`(m4) (Q = 33% at 8} minutes) was not supported by the
`dissolution data submitted.for the clinical and the registration batches. The FDA recommended Q
`(I!) (4)
`= 33% at :2} minutes;
`
`
`
`The FDA recommended that
`(m4)
`the Applicantfurther optimize the dissolution method
`Therefore, a PMC is necessary to allowfor the optimization ofthe dissolution method and
`acceptance criterion, which would require time beyond the remaining review clock time. It is
`noted that the control strategvfor the currentproduct (e.g., operating closely to the normal
`o’eratin
`es or the clinical trial batch) ensures the Iualitv o the dru :roduct.
`
`PMR/PMC Development Template
`
`Last Updated 7/7/2015
`
`Page 1 of 4
`
`Reference ID: 3788828
`
`

`

`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a
`FDAAA PMR. describe the risk. If the FDAAA PMR is created post-approval. describe the “new safety
`information.”
`
`The currentlyproposed dissolution method
`
`n=12 batches/each strength).
`
`The currentlyproposed acceptance criterion (Q = 93% at 33
`(we)
`minutes)
`. In the absence ofan adequate in vitro to in vivo relation andproper exposure response
`(b)
`data, a release specification at Q = (0% should be established to ensure complete release ofthe
`drug substance. The goals ofthe in vitro dissolution studv under the PMC are: I) to optimize the
`dissolution methodparameters to
`(m4)
`and 2) to set an adequate dissolution acceptance criterionfor the drug product using
`thefull dissolution profile data collectedfrom an adequate number ofcommercial batches (i. e.,
`
`3.
`
`If the study/clinical trial is a PMR. check the applicable regulation.
`Ifnot a PMR, skip to 4.
`
`— Which regulation?
`
`|:| Accelerated Approval (subpart H/E)
`|:l Animal Efficacy Rule
`|:| Pediauic Research Equity Act
`l:l FDAAA required safety study/clinical trial
`
`—
`
`If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
`l:l Assess a known serious risk related to the use of the drug?
`l:| Assess signals of serious risk related to the use of the drug?
`[3 Identify an unexpected serious risk when available data indicate the potential for a serious risk?
`
`—
`
`If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
`
`|:| Analysis of spontaneous p_ostmarketing adverse events?
`Do not select the above study/clinical trial Me if. such an analysis will not be sufficient to assess
`or identify a serious risk
`
`[:| Analysis using pharmacovigjlance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA
`is required to establish under section 505(k)(3) has not yet been established and is thus not sufficient
`to assess this known serious risk or has been established but is nevertheless not sufficient to assess
`
`or identify a serious risk
`
`|:| Study: all other investigations. such as investigations in humans that are not clinical trials as defined
`below (e.g.. observational epidemiologic studies). animal studies. and laboratory experiments?
`Do not select the above study type if: a study will not be suflicient to identify or assess a serious
`risk
`
`|:| Clinical trial: any prospective investigation in which the sponsor or investigator determines the
`method of assigning investigational product or other interventions to one or more hmnan subjects?
`
`PMR/PMC Development Template
`
`Last Updated 7t“7.u"201 5
`
`Page 2 of 4
`
`Reference ID: 3788828
`
`

`

`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study
`or trial will be performed in a subpopulation. list here.
`
`This Post-Marketing Commitment should befulfilled within 12 monthsfrom action date
`for:
`1) Development ofa new dissolution methodfor all the strengths with demonstrated
`.
`.
`.
`.
`.
`.
`4
`discriminating ability,
`on )
`
`I
`
`
`
`
`2) Setting ofthefinal dissolution acceptance criterionfor EntrestoTM (sacubitril/
`valsartan) Tablets, 97/103, 49/51, and 24/26 mg using the new method and the overall
`nmltipoint dissolution profile datafrom a minimum of 12 commercial batches per
`strength, manufactured under the same conditions as those usedfor the manufactured of
`the batches used in pivotal clinical trials. The FDA will be open to providingfeedback
`during the method ’s developmentprocess as needed.
`
`Required
`
`:l Observational pharmacoepidemiologic study
`:| Registry studies
`:| Primary safety study or clinical trial
`:I Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
`:I Thorough Q-T clinical trial
`:I Nonclinical (animal) safety study (e.g., carcinogenicity. reproductive toxicology)
`:I Nonclinical study (laboratory resistance, receptor affinity. quality study related to safety)
`:I Pharmacokinetic studies or clinical trials
`:| Drug interaction or bioavailability studies or clinical trials
`:l Dosing trials
`Continuation o
`estion 4
`
`:l Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
`:I Meta-analysis or pooled analysis ofprevious studies/clinical trials
`:I Immunogenicity as a marker of safety
`:| Other (provide explanation)
`
`Agreed upon:
`
`XI Quality study without a safety endpoint (e.g.. development of a discriminating dissolution method)
`[:I Pharmacoepidemiologic study not related to safe drug use (e.g.r natural history of disease, background
`rates of adverse events)
`[:I Clinical trials primarily designed to further define efficacy (e.g. in another condition, different disease
`severity. or subgroup) that are NOT required under Subpart H/E
`|:l Dose-response study or clinical trial performed for effectiveness
`l:l Nonclinical study. not safety-related (specify)
`
`[:I Other
`
`PMR/PMC Development Template
`
`Last Updated 7l‘7l201 5
`
`Page 3 of 4
`
`Reference ID: 3788828
`
`

`

`5.
`
`Is the PMR/PMC clear, feasible, and appropriate?
`Do the study/clinical trial meet criteria for PMRs or PMCs?
`Are the objectives clear from the description of the PMR/PMC?
`Has the applicant adequately justified the choice of schedule milestone dates?
`Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility,
`and contribute to the development process?
`
`Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial
`
`If so, does the clinical trial meet the following criteria?
`
`There is a significant question about the public health risks of an approved drug
`There is not enough existing information to assess these risks
`Information cannot be gained through a different kind of investigation
`The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and
`The trial will emphasize risk minimization for participants as the protocol is developed
`
`PMR/PMC Development Coordinator:
`This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the
`safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality.
`_______________________________________
`(Signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 7/7/2015
`
`Page 4 of 4
`
`Reference ID: 3788828
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`Lori A WACHTER
`07/07/2015
`
`Reference ID: 3788828
`
`

`

`PMR/PMC Development Template
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`NDA/BLA #
`Product Name:
`
`NDA 207620
`Sacubitril/valsartan (Entresto®)
`
`PMR/PMC Description: Conduct a randomized controlled study to evaluate the effects of Entresto
`compared to valsartan on cognitive function and PET imaging in patients with
`chronic heart failure with preserved ejection fraction.
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`Trial Completion:
`Final Report Submission:
`
`April 2016
`October 2021
`March 2022
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval
`requirement. Check type below and describe.
`Unmet need
`Life-threatening condition
`Long-term data needed
`Only feasible to conduct post-approval
`Prior clinical experience indicates safety
`Small subpopulation affected
`Theoretical concern
`Other
`
`Neprilysin (NEP) is a major beta amyloid (β-amyloid) degrading enzyme in the brain and sacubatril is a
`NEP inhibitor. Hence, there is a theoretical risk that NEP inhibition by Entresto could lead to
`accumulation of β-amyloid in the brain, causing cognitive dysfunction and/or increasing the risk of
`Alzheimer’s disease.
`In non-clinical studies, sacubitril/valsartan increased β-amyloid levels in the CSF, without corresponding
`increases in the brain. In a study in healthy subjects, sacubitril/valsartan is associated with increases in
`CSF β-amyloid 1-38 and plasma β-amyloid 1-40 concentrations, though the clinical significance of these
`findings is unclear. Analyses of adverse event data from the phase 3 trial-PARADIGM-HF did not reveal
`an obvious signal. The incidence of potential dementia-related adverse events was similar in the two
`treatment groups in the double-blind period: 2% in both groups for adverse events; 0.5% in both groups
`for serious adverse events.
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a
`FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety
`information.”
`
`PMR/PMC Development Template
`
`Last Updated 7/7/2015
`
`Page 1 of 4
`
`Reference ID: 3788823
`
`

`

`Review Issue: There is a theoretical risk that NEP inhibition by Entresto could lead to accumulation of B-
`amyloid in the brain. causing cognitive dysfimction and/or increasing the risk of Alzheimer’s disease.
`
`The primary objective of the study is to evaluate the effects of Entresto compared to valsartan on cognitive
`function
`
`mm in patients with heart failure with preserved ejection fraction.
`
`3.
`
`If the study/clinical trial is a PMR. check the applicable regulation.
`Ifnot a PMR, skip to 4.
`
`— Which regulation?
`El Accelerated Approval (subpart H/E)
`|:l Animal Efficacy Rule
`|:l Pediatric Research Equity Act
`X FDAAA required safety study/clinical trial
`
`—
`
`If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
`l:l Assess a known serious risk related to the use of the drug?
`l:l Assess signals of serious risk related to the use of the drug?
`X Identify an unexpected serious risk when available data indicate the potential for a serious risk?
`
`—
`
`If the PMR is a FDAAA safety study/clinical tr