12 Sep 2014

A therapy developed by the Swiss-based pharmaceutical company Novartis could be the next big thing for congestive heart failure, a serious disease that afflicts about 5 million Americans. Called LCZ696, this drug prevented cardiovascular-related deaths and hospitalizations when compared with a current standard treatment, report John McMurray of the University of Glasgow, Scotland, Milton Packer of the University of Texas Southwestern Medical Center, Dallas, and others in the September 11 New England Journal of Medicine. Indeed, the results were so profoundly positive that the trial was stopped early. LCZ696 contains an inhibitor of neprilysin, an enzyme that breaks down the Aβ peptide that forms amyloid plaques in the brain. While cardiologists are looking forward to having a new drug in their toolbox, some neurologists are asking if LCZ696 could potentially increase Aβ levels and, if taken long-term, increase the risk of AD.

“It’s a worthwhile question,” said Costantino Iadecola of Weill Cornell Medical College, New York. “Patients with cardiovascular problems are at a heightened risk of Alzheimer’s disease already,” he told Alzforum. In theory, reducing an enzyme that degrades Aβ could further raise the chances, but Iadecola emphasized that the vascular benefits of the drug may, at the same time, protect against Alzheimer’s (see below). “It’s a complex situation,” he said.

Congestive heart failure is typically treated with compounds that block the renin–angiotensin–aldosterone system. These include angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARB), both of which limit the effects of hormones that cause the body to retain sodium and constrict the blood vessels. Vasoactive substances, such as bradykinin and adrenomedullin, dilate blood vessels, counteracting vasoconstriction. Both are broken down by neprilysin. Scientists hypothesized that inhibiting neprilysin could elevate levels of those peptides and counteract systemic overreactions to heart failure.

In the early 2000s, scientists developed omapatrilat, a combination of an ACE inhibitor and a neprilysin inhibitor. Omapatrilat was no more effective at treating heart failure than ACE inhibitors alone, and caused swelling of the deep layers of the skin (see Packer et al., 2002). More recently, researchers developed LCZ696, which combines the neprilysin inhibitor sacubitril and the ARB valsartan, and designed it to avoid swelling. Clinicaltrials.gov lists 27 studies with this combination drug. The PARADIGM-HF trial tested if LCZ696 was more effective than the ACE inhibitor enalapril, one of the standard treatments for heart failure.

In this Phase 3 trial, funded by Novartis, researchers enrolled about 8,400 patients who had congestive heart failure and reduced ejection fraction, also known as systolic heart failure. This is when the heart contracts poorly and pumps out a smaller amount of blood than normal on each beat. Roughly half the patients, 4,187, took 200 mg of LCZ696 twice daily, while the others received two 10 mg doses of enalapril per day (the maximum approved dose for congestive heart failure is 20 mg twice daily). Patients underwent follow-up for a median 27 months, after which the executive committee halted the study because the trial’s data and safety monitoring committee informed the investigators that “the prespecified stopping boundary for an overwhelming benefit had been crossed,” the authors wrote.

The primary outcome was a composite measure based on death from cardiovascular causes and/or hospitalization for heart failure. Compared with enalapril, LCZ696 reduced this score by 20 percent. Overall mortality, the secondary outcome, dropped 16 percent in the LCZ696 group compared with those taking enalapril. Those on LCZ696 also reported fewer symptoms and physical limitations of heart failure on the Kansas City Cardiomyopathy Questionnaire. “PARADIGM-HF may well represent a new threshold of hope for patients with heart failure,” wrote Mariell Jessup of the University of Pennsylvania, Philadelphia, in an accompanying editorial.

Given that neprilysin in the brain degrades Aβ, some Alzheimer clinicians are wondering whether LCZ696 could raise the risk of the disease. The LCZ696 trials did not formally measure cognition, but did include reports of dementia as adverse events and saw no difference between treatment groups, McMurray and Packer told Alzforum. “Data from the PARADIGM-HF development program does not indicate any adverse effects related to Alzheimer's disease with LCZ696,” wrote a representative from Novartis in an email to Alzforum. “The external data safety monitoring board regularly reviewed the data and saw no cause for concern. Now that we also have access to the full data set, we have also looked closely for signals of cognitive impairment and see none.” The researchers also found no difference in dementia among the treatment and placebo arms of a previous trial of omapatrilat.

McMurray and Packer will explore the question more fully in an upcoming Phase 3 trial of LCZ696 in some 4,300 people who have congestive heart failure with preserved ejection fraction, also known as diastolic heart failure. They will assess cognitive function as an exploratory outcome measure. This is prompted by both a theoretical concern about neprilysin inhibition and Alzheimer’s risk, and by the hypothesis that, on the contrary, reducing vascular risk factors may help the brain, McMurray said. “By improving cardiac and vascular function, we might improve cognitive function,” he wrote to Alzforum in an email. McMurray is not yet sure which cognitive test this new trial will use, but said it might employ a relatively simple tool appropriate for a large population, such as the Mini-Mental State Examination.

Other researchers remained cautious about LCZ696’s potential implications for Alzheimer’s. In an email to Alzforum, Jeffrey Greenwald of Massachusetts General Hospital, Boston, wondered whether the treatment period of PARADIGM-HF was too brief to see a cognitive effect. Packer noted that the life expectancy for people who have congestive heart failure is short, even with medication, so few would likely live long enough to manifest any potential long-term effects on Aβ. For those patients, short-term benefits would outweigh any long-term risks, agreed Pieter Jelle Visser, VU University Medical Center, the Netherlands.

Besides heart failure, LCZ696 is also in trials for treating essential hypertension in adults of all ages. Visser speculated that treatment for high blood pressure could last longer than two years. He and Malcolm Leissring, University of California, Irvine, said that chronic neprilysin inhibition could potentially pose problems down the road. “I would be concerned about taking this drug for decades,” said Leissring, adding, “It appears the relevant processes for Alzheimer’s disease take place around middle age.”

Leissring and most other scientists interviewed for this article emphasized that any concern about dementia risk hinges on whether sacubitril (AHU377) crosses the blood-brain barrier. Alzforum put that question to Novartis but received no answer before this article posted. “It is difficult to comment more at this time before discussions with the health authorities, including FDA,” wrote another Novartis representative to Alzforum. Tools available online that predict whether a chemical will cross the barrier hint that this one might, speculated Leissring, but proof would come from measuring the drug in the cerebrospinal fluid. “If it does not cross into the brain, it probably would have no unanticipated effects on brain Aβ, ” Leissring told Alzforum. Several studies in animal models suggest that modifying neprilysin in the periphery does not modify brain Aβ levels (see Walker et al., 2013, and Henderson et al., 2014).

If LCZ696 did enter the brain, perhaps via a compromised blood-brain barrier, then it could inhibit Aβ clearance mechanisms that depend on neprilysin, said Iadecola. Mice having no or little neprilysin do accumulate Aβ in the brain and show other AD-like phenotypes (see Madani et al., 2006; Farris et al., 2007; Mohajeri and Wolfer, 2009). Brian Spencer of the University of California, San Diego, said the drug could also impair the processing of neuropeptide Y, which promotes neurogenesis.

Neprilysin is not the only Aβ-degrading enzyme in the human brain. Besides insulin-degrading enzyme, endothelin-converting enzyme and other proteases also subserve this function, plus there are other, non-proteolytic clearance mechanisms. Some scientists noted that there may well be sufficient redundancy to ensure that a small amount of brain neprilysin inhibition would not increase Aβ levels.

On the plus side, Iadecola said that better vascular health could help reduce the risk of Alzheimer’s in people with congestive heart failure. “If the ejection fraction improves and the heart pumps better, LCZ696 may lessen the vascular contributions to the process of Alzheimer’s disease,” he told Alzforum. Greater blood flow could speed the clearance of Aβ from the brain, he said. One study also hints that the drug’s ARB component, valsartan, reduces brain Aβ levels (see Wang et al., 2007), which could further reduce Alzheimer’s risk.

Only data can tell whether LCZ696 influences Aβ levels in the brain, and whether that, in turn, affects cognition, researchers said. Scientists suggested studies monitoring both CSF drug exposure and Aβ levels while people were on the drug, or pre- and post-treatment PET scans to see if LCZ696 leads to changes in brain Aβ. They suspect that Novartis scientists may well be gathering such data already, and will release them eventually.

According to a company press release, Novartis plans to file an application for marketing authorization with the U.S. Food and Drug Administration by the end of 2014 and in the European Union in early 2015.—Gwyneth Dickey Zakaib

Comments

- Rebecca Gottesman
  Johns Hopkins University School of Medicine
- Posted: 16 Sep 2014
- Paper: Angiotensin-neprilysin inhibition versus enalapril in heart failure.
I think that certainly the PARADIGM results are very promising, and heart failure is likely an important contributor to cognitive decline, perhaps even independently of the underlying vascular disease that it represents. Some small studies suggest that patients with heart failure, and especially those with lower blood pressures, seem to have worse cognition (I’m actually leading some ongoing studies now, evaluating the cognitive deficits in heart failure). In PARADIGM, the heart failure patients treated with the angiotensin-neprilysin inhibitor did better overall than did participants treated with an ACE-inhibitor, although they actually had lower blood pressures. However, since neprilysin is a major enzyme responsible for the degradation of Aβ, and animal studies have shown that inhibiting neprilyin increases amyloid levels in the brain, this is certainly something that needs to be evaluated for this new heart failure drug. The PARADIGM study was not long enough to detect any differences in cognitive outcomes, nor was it designed to evaluate cognitive outcomes, but I think it will be important to evaluate surrogate outcomes, which might evaluate Aβ levels, as well as longer-term cognitive outcomes, before knowing the true potential utility of this new drug. Any studies taking these outcomes into account may be difficult to interpret since controlling heart failure has the potential to improve cognition, so they will need to be carefully designed.

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References

Paper Citations

Packer M, Califf RM, Konstam MA, Krum H, McMurray JJ, Rouleau JL, Swedberg K. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation. 2002 Aug 20;106(8):920-6. PubMed.
Walker JR, Pacoma R, Watson J, Ou W, Alves J, Mason DE, Peters EC, Urbina HD, Welzel G, Althage A, Liu B, Tuntland T, Jacobson LH, Harris JL, Schumacher AM. Enhanced proteolytic clearance of plasma Aβ by peripherally administered neprilysin does not result in reduced levels of brain Aβ in mice. J Neurosci. 2013 Feb 6;33(6):2457-64. PubMed.
Henderson SJ, Andersson C, Narwal R, Janson J, Goldschmidt TJ, Appelkvist P, Bogstedt A, Steffen AC, Haupts U, Tebbe J, Freskgård PO, Jermutus L, Burrell M, Fowler SB, Webster CI. Sustained peripheral depletion of amyloid-β with a novel form of neprilysin does not affect central levels of amyloid-β. Brain. 2014 Feb;137(Pt 2):553-64. Epub 2013 Nov 20 PubMed.
Madani R, Poirier R, Wolfer DP, Welzl H, Groscurth P, Lipp HP, Lu B, El Mouedden M, Mercken M, Nitsch RM, Mohajeri MH. Lack of neprilysin suffices to generate murine amyloid-like deposits in the brain and behavioral deficit in vivo. J Neurosci Res. 2006 Dec;84(8):1871-8. PubMed.
Farris W, Schütz SG, Cirrito JR, Shankar GM, Sun X, George A, Leissring MA, Walsh DM, Qiu WQ, Holtzman DM, Selkoe DJ. Loss of neprilysin function promotes amyloid plaque formation and causes cerebral amyloid angiopathy. Am J Pathol. 2007 Jul;171(1):241-51. PubMed.
Mohajeri MH, Wolfer DP. Neprilysin deficiency-dependent impairment of cognitive functions in a mouse model of amyloidosis. Neurochem Res. 2009 Apr;34(4):717-26. PubMed.
Wang J, Ho L, Chen L, Zhao Z, Zhao W, Qian X, Humala N, Seror I, Bartholomew S, Rosendorff C, Pasinetti GM. Valsartan lowers brain beta-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease. J Clin Invest. 2007 Nov;117(11):3393-402. PubMed.

Inhibiting Neprilysin Is Good for the Heart: What About the Brain?

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