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1 First in Class Angiotensin Receptor Neprilysin Inhibitor in Heart Failure Orly Vardeny, PharmD, MS, Travis Tacheny, Scott D. Solomon, MD Cite this article as: Orly Vardeny, PharmD, MS, Travis Tacheny, Scott D. Solomon, MD, First in Class Angiotensin Receptor Neprilysin Inhibitor in Heart Failure, Clinical Pharmacology & Therapeutics accepted article preview online 19 July 2013; doi: /clpt This is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication. NPG is providing this early version of the manuscript as a service to our customers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply. Received 13 June 2013; accepted 11 July 2013; Accepted article preview online 19 July 2013
2 First in Class Angiotensin Receptor Neprilysin Inhibitor in Heart Failure Orly Vardeny, PharmD, MS, Travis Tacheny, Scott D. Solomon, MD From University of Wisconsin School of Pharmacy (O.V., T.T.) and Brigham and Women s Hospital, Harvard Medical School (S.D.S.) Address Correspondence to: Scott D. Solomon, MD Cardiovascular Division Brigham and Women s Hospital 75 Francis St Boston, MA ssolomon@rics.bwh.harvard.edu
3 Introduction Neprilysin inhibitors augment the natriuretic peptide system by preventing breakdown of ANP and BNP. LCZ696, an angiotensin receptor neprilysin inhibitor (ARNI) comprised of a neprilysin inhibitor pro-drug and the angiotensin receptor antagonist valsartan, has proven effective in hypertension, shown promise in a pilot trial of heart failure with preserved ejection fraction, and is being tested in a large outcomes trial of heart failure with reduced ejection fraction. A preserved ejection fraction outcomes trial is beginning.
4 Heart failure (HF) affects nearly 6 million individuals in the United States and its prevalence is increasing due to an aging population. Current treatment options for heart failure with reduced ejection fraction (HFrEF) target up-regulated neurohormonal pathways such as the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system. However, pharmacologic therapies that have proven beneficial for HFrEF have not resulted in improved clinical outcomes in patients with heart failure and preserved ejection fraction (HFpEF), for which no evidenced-based recommended therapies exist. HFpEF occurs in up to 50% of patients with HF and the etiology and pathophysiology may be distinct from HFrEF. Development of novel treatment options are necessary for further targeting pathophysiologic contributors to HF and are crucial for improving patient outcomes. Neprilysin inhibitors as a class of drugs were developed to harness the benefits of the endogenous natriuretic peptide system. Natriuretic peptides are a group of hormones that play a role in fluid homeostasis. In the setting of volume or pressure overload, natriuretic peptides are released; The natriuretic peptides that play a predominant role in cardiovascular physiology are atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP). ANP is predominantly synthesized and secreted in the atria, and BNP is secreted from the ventricles. C-type natriuretic peptide (CNP) is predominantly present in the central nervous system and vasculature, and plasma concentrations are very low. Natriuretic peptides stimulate natriuresis and diuresis, promote vasodilation, and oppose acute effects of volume overload by inhibiting the RAAS and the sympathetic nervous system. They have also been shown to attenuate development of cardiac hypertrophy and fibrosis and enhance endothelial function. These peptides exert their effect through membrane-bound natriuretic peptide receptors which in turn work through the guanylate
5 cyclase signaling cascade, resulting in increased production of cgmp which is ultimately responsible for the physiologic effects. Elevation of BNP or NT-proBNP have both been used as markers of heart failure severity, and although natriuretic peptide levels rise significantly during acute heart failure, studies suggest that patients with heart failure have reduced levels of biologically active BNP and are resistant to its effects. Both exogenous administration of natriuretic peptides and augmentation of the endogenous natriuretic peptide system have been considered as potential therapeutic strategies in heart failure. The former has been limited by the need for parenteral administration; while it can be effective in the acute setting, the long-term benefits have not been proven. An alternative approach has been to augment the endogenous natriuretic peptides by blocking its breakdown. Neprilysin is a neutral endopeptidase which catalyzes the degradation of a number of vasodilator peptides including ANP and BNP, in addition to bradykinin, substance P, adrenomedullin, and contributes to the breakdown of angiotensin II. 1 Thus, inhibiting this enzyme will augment the naturally occurring natriuretic peptides. Neprilysin plays no role in the breakdown of NT-proBNP. Because neprilysin also contributes to the breakdown of angiotensin II, neprilysin inhibitors could potentially increase circulating Angiotensin II levels, thus providing a rationale for compounds that dually block this enzyme and the RAAS. One such compound was the ill-fated drug omapatrilat, a dual acting neprilysin inhibitor and ACE inhibitor. Originally developed for, and quite effective in, hypertension, this drug was also studied in heart failure. In a 24 week study comparing omapatrilat 40mg to lisinopril 20mg, omapatrilat was associated with a reduction in the composite of death, hospitalization, or discontinuation of study treatment for worsening heart failure. Subsequently, an outcomes trial
6 comparing omapatrilat 40mg to enalapril 10mg bid, did not demonstrate benefit of omapatrilat on reducing the combined risk of death or hospitalization for heart failure requiring intravenous treatment. 2 However, while the primary endpoint of death or heart failure hospitalization was not met, although several secondary endpoints were met. However, the increased frequency of angioedema observed in the hypertension studies prompted withdrawal of omapatrilat from regulatory consideration. Omapatrilat was thought to predispose to angioedema because it inhibited angiotensin converting enzyme, aminopeptidase, and to a lesser degree neprilysin, enzymes that contribute to the breakdown of bradykinin, which promotes vasodilation and vascular permeability and is considered one of the predominant mediators of angiodedema. The investigational drug LCZ696 is an angiotensin receptor neprilysin inhibitor (ARNI) comprised of two distinct pharmacologic moieties, a neprilysin inhibitor pro-drug and the angiotensin receptor antagonist valsartan. By pairing the neprilysin inhibitor with an angiotensin receptor blocker (ARB) component, the risk of angioedema is reduced, while the benefits of neprilysin and RAAS inhibition remain. After ingestion, LCZ696 is broken down into the component neprilysin pro-drug AHU377 and valsartan (Figure 1). AHU377 is subsequently converted to the active neprilysin inhibitor LBQ657. From a pharmacokinetic standpoint LCZ696 does not differ much from valsartan. In a study comparing these two agents in a cohort of healthy volunteers, the half-lives of therapeutically similar doses were nearly identical, with LCZ696 averaging 17.7 hours and valsartan averaging 17.5 hours. 1 The neprilysin pro-drug moiety, AHU377 has a relatively short half-life averaging 1.7 hours. Its rapid conversion to the active LBQ657 moiety helps explain LCZ696 s prompt onset of activity. Drug clearance rates were also similar between valsartan and LCZ696, estimated at 10.2 L/hr and 7.2 L/hr, respectively.
7 LCZ696 has proven effective in blood pressure lowering trials. In an eight week comparison of LCZ696 to an equivalent dose of valsartan, Ruilope et al. showed that LCZ696 was significantly more effective at reducing blood pressure. 3 The potential benefit of augmenting the endogenous natriuretic peptide system in heart failure has provided the rationale for two studies in this population. PARADIGM-HF is an ongoing phase III trial of LCZ696 compared with enalapril in heart failure with reduced ejection fraction with a primary endpoint of cardiovascular death or heart failure hospitalization. 4 In order to acquire substantial safety data, this trial was designed with an active run-in phase in which all participants received both agents in an open-label fashion. PARADIGM-HF has randomized over 8400 patients. The results of PARADIGM-HF, which should be reported in 2015, will aid in determining if ARNI therapy has superior outcomes compared to ACE-I, currently the standard of therapy for patients diagnosed with HFrEF. The efficacy of LCZ696 as a treatment for HFpEF was assessed in PARAMOUNT, a phase II clinical trial. 5 This trial enrolled patients with ejection fractions 45% who were classified as NYHA class II-III with an NT-proBNP greater than 400 pg/ml. The primary endpoint was change in NT-proBNP levels, a measure of ventricular wall stress, at baseline and 12 weeks, compared between LCZ696 and valsartan. NT-proBNP is not a substrate for neprilysin degradation and therefore changes in NT-proBNP still represent a marker of the severity of heart failure even in the setting of neprilysin inhibition. After randomization, 152 patients received 160 mg of valsartan twice daily and 149 patients received LCZ mg twice daily. A reduction in blood pressure was observed after 12 weeks in both treatment arms, however LCZ696 patients had significantly lower systolic blood pressures compared to the valsartan group (9.3 ± 14 vs. 2.9 ± 17 mm Hg, p = 0.001). LCZ696 was superior to valsartan in
8 reduction of NT-proBNP at 12 weeks (p = 0.005). After 36 weeks, NT-proBNP levels remained reduced in the LCZ696 arm, although reduction was also observed in the valsartan arm, so that between-group treatment differences were no longer significant (496 [ ] pg/ml vs. 607[ ] pg/ml). However, patients receiving LCZ696 did have significant improvement in NYHA class and left atrial size compared to those receiving valsartan at 36 weeks. Importantly, these benefits were independent of the blood pressure lowering effect of the drug. Moreover, LCZ696 was well tolerated with an adverse effect profile that was similar to the comparator valsartan. These hypothesis generating findings have prompted initiation of an outcomes trial, PARAGON-HF, which will determine whether LCZ696 can reduce morbidity and mortality in HFpEF patients. PARAGON-HF, which will begin in late 2013, will enroll approximately 4300 patients with signs and symptoms of HF, ejection fraction of 45% or greater, history of heart failure hospitalization within 9 months or an elevated NT-proBNP at entry, and evidence of structural heart disease. The primary outcome measure will be cardiovascular death and total heart failure hospitalizations. Due to the considerable morbidity from HFrEF and HFpEF, novel new therapies are needed beyond what is currently available to improve clinical outcomes, prolong survival, and reduce societal burden from heart failure. LCZ696, a first in class dual acting angiotensin receptor neprilysin inhibitor has already proven an effective antihypertensive and was well tolerated. While the potential benefit of LCZ696 in heart failure is still speculative, joint inhibition of the renin-angiotensin system along with augmentation of the endogenous natriuretic peptide system may have benefits that go beyond lowering blood pressure. Ongoing prospective, randomized, controlled studies will help elucidate the role of LCZ696 in the context of available pharmacotherapy.
9 Disclosures: Dr. Solomon has received research support in the form of grants to Brigham and Women s Hospital (> $10,000) and has consulted for Novartis (<$10,000).
10 Figure Legends Figure 1. Pharmacologic activation and mechanism of action of the angiotensin receptor neprilysin inhibitor LCZ696. LCZ696 is comprised of two molecular moieties, valsartan and the neprilysin inhibitor AHU377. AHU377 is converted to the active neprilysin inhibitor LBQ657 which inhibitors the neprilysin enzyme, responsible for the breakdown of the biologically active natriuretic peptides, including BNP, ANP, bradykinin, substance P, adrenomedullin, and angiotensin II. BNPcontributes to natriuresis, diuresis and vasodilation. The valsartan component blocks the AT1 receptor, thus negating the effects of angiotensin II. Figure 2. Primary results of the PARAMOUNT trial. Left panel, reduction in NT-proBNP at 12 weeks (primary endpoint); Middle panel, reduction in left atrial size over 36 weeks; Right panel, improvement in NYHA class.
11 REFERENCES 1. Gu J, Noe A, Chandra P, Al-Fayoumi S, Ligueros-Saylan M, Sarangapani R, Maahs S, Ksander G, Rigel DF, Jeng AY, Lin TH, Zheng W, Dole WP. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). Journal of clinical pharmacology. Apr 2010;50(4): 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. Aug ;106(8): Ruilope LM, Dukat A, Bohm M, Lacourciere Y, Gong J, Lefkowitz MP. Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active comparator study. Lancet. Apr ;375(9722): McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau J, Shi VC, Solomon SD, Swedberg K, Zile MR. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail. Apr Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, Shi V, Bransford T, Takeuchi M, Gong J, Lefkowitz M, Packer M, McMurray JJ. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet. Oct ;380(9851):
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