CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 207620Orig1s000 MEDICAL REVIEW(S) DNP Clinical Consult Memo NOA 207620 Sponsor: Novartis Drug: LCZ696 (Entresto) Proposed Indication: Heart Failure (NYHA class 11-IV) Material Submitted: NOA submission Consult Request Date: 6/29/15 Date Review Completed: 6/30/15 Clinical Reviewer: Teresa Buracchio, M.D. Nonclinical Reviewer: David B. Hawver, Ph.D. Clinical Team Lead: Nick Kozauer, M.D. Nonclinical Supervisor: Lois M. Freed, Ph.D. Division Director: 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 (NOA) 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 1 States. It is estimated that over half of HF patients die within 5 years of diagnosis. .. 4 Novartis has studied LCZ696 for the treatment of heart failure (NYHA class II-IV) <b>< > (b)(4 . LCZ696 is a dual angiotensm receptor neprilysin Inhibitor (A~l\l i ) 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 LBQ657. 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 (Al3) 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 Al3 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 4 Tzu-Yun McDowell; a synopsis of Study <b>< I (focusing on cognitive 4 outcomes (bJ< >) submitted by the Sponsor. Study A2126, Phase 1 study AP in CSF: As stated in the Clinical Pharmacology review by Ors. Zhuang and Sabarinath, this was a placebo-controlled study in healthy subjects that examined the PK and PD effects of 400mg LCZ696 once daily for 14 days. At Day 14, there was about 50% increase in plasma Al3 1-40 (AUEC0_36h) with LCZ696 relative to placebo but there was no difference from placebo in the CSF. However, Al3 1-38 1 Go et al. Circulation. 2013;127:e6-e245 Reference ID: 3786906 Teresa Buracchio, MD, HFD-120 Medical Review Page 2 of 6 NDA 207620, LCZ696 (Entresto), Novartis 6/30/15 AUEC0_36h increased from baseline with LCZ696 by about 42% relative to placebo in the CSF. There was no significant difference with LCZ696 for amyloid-13 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 LCZ696 compared to enalapril in patients with HF (NYHA class 11- IV) and reduced ejection fraction (LVEF::535%). 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 LCZ696. Approximately 50% of the patients were age 2:65 years with 20% of all patients ;::75 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 MEDORA 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 LCZ696 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 ~ . rellminary d1scuss1ons have occurred oelveen the Sponsor andlJCRP w 1t h'-re_s_p_e-ct·~t· _..o the design and goals of this trial. 4 4 The Sponsor is planning to conduct a l study, <bH r that will assess the r n ' impact of LCZ696 on cognitive testingL <bH4l as measured by positron emission tomography (PET) imaging. (b)(4~ \U/\'t/ While neprilysin inhibitors such as sacubitril can potentially increase Aj3 levels in the CNS, the impact of increasing Aj3 in the CNS and subsequent risks of AD are unknown. Although animal models of neprilysin deficiency have shown increased Aj3 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 Teresa Buracchio, MD, HFD-120 Medical Review Page 3 of 6 NDA 207620, LCZ696 (Entresto), Novartis 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 Al3 and it is possible that these alternate ....__ pathways may be able to compensate for any loss in neprilysin. (bH-0' __ The effect of a neprilysin inhibitor on Al3 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 Al3 in the CNS. The Phase 1 PK/PD study suggests that LCZ696 may elevate some forms of Al3 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 Al3 in the CNS are unknown. However, it should be stressed that even if elevations of Al3 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 LCZ696 could have a positive benefit on the vascular contributions to dementia that may balance or outweigh the potential risk of increasing Aj3. 4 A signal for dementia risk was not identified for the <bH I study; however, the study was not designed to assess dementia or cognitive ou comes. 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 ~65 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 LCZ696. At this point there is no cl inical evidence to suggest that there is a risk for increasing development of AD or cognitive impairment with use of LCZ696 in this population of HF 4 patients with low ejection fraction. The Sponsor's plan to further evaluate the >1 ! study and a cognitive test battery and <1>mr PET imaging 4 (b>< study are reasonable as additional steps for assessing any impact of LGZ696--- on cognition and amyloid pathology. 2Vodovar et al. Eur Heart J. 2015;36:902-5. 3 http://www.alzforum.org/news/research-news/inhibiting-neprilysin-good-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 Page 4 of 6 NDA 207620, LCZ696 (Entresto), Novartis 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.