Comparative efficacy of AHU-377, a potent neprilysin inhibitor, in two rat models of volume-dependent hypertension

Hegde, Laxminarayan G.; Yu, Cecile; Cheruvu, Madhavi; Araki, Russell; Villarreal, Jennifer; Obedencio, Glenmar P.; Kanta, Anne; Sandvick, Erik; Hill, Craig; DeMent, Kevin; Klein, Uwe; McConn, Donavon J.; Martin, William J.; Hegde, Sharath S.

doi:10.1186/1471-2210-11-s1-p33

Cited by 5 publications

(5 citation statements)

References 2 publications

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“…25 Clinical and laboratory data from preclinical investigations of this novel combination suggested simultaneous NEP inhibition and angiotensin receptor blockade while also providing evidence on its safety and tolerability. 25,26 Favorable findings from these early studies paved way for the evaluation of sacubitril/valsartan in various CV disorders, largely in hypertensive and HF patients. Actions of LCZ696 on the CV system are briefly outlined in Figure 1.…”

Section: Sacubitril/valsartanmentioning

confidence: 99%

Sacubitril/valsartan in cardiovascular disease: evidence to date and place in therapy

Yandrapalli

Khan

Rochlani

et al. 2018

Therapeutic Advances in Cardiovascular Disease

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Cardiovascular (CV) disease is a major cause of morbidity and mortality in the developing and the developed world. Mortality from CV disease had plateaued in the recent years raising concerning alarms about the sustained efficacy of available preventive and treatment options. Heart failure (HF) is among the major contributors to the CV-related health care burden, a persisting concern despite the use of clinically proven guideline-directed therapies. A requirement for more efficient medical therapies coupled with recent advances in bio-innovation led to the creation of sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), which demonstrated substantial CV benefit when compared with the standard of care, enalapril, in patients with HF and reduced ejection fraction. Further investigations of this novel combination ARNI at the tissue level shed light into the anti-remodeling and cardioprotective effects of sacubitril/valsartan, while clinical studies in the phenotypes of HF with preserved ejection fraction, hypertension and subsets, coronary outcomes, postmyocardial infarction, and renal disease suggested that this combination could be beneficial across a wide spectrum of CV disease. Sacubitril/valsartan is a much-needed therapeutic advance in the avenue of CV disease.

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Section: Sacubitril/valsartanmentioning

confidence: 99%

Sacubitril/valsartan in cardiovascular disease: evidence to date and place in therapy

Yandrapalli

Khan

Rochlani

et al. 2018

Therapeutic Advances in Cardiovascular Disease

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“…Phase I and II studies of LCZ696 showed that after oral administration of LCZ696, peak plasma concentrations were reached rapidly for valsartan (1.6–4.9 h), sacubitril (0.5–1.1 h), and its active moiety LBQ657 (1.8–3.5 h), followed by an acute blood pressure reduction [ 61 ]. LCZ696 treatment was associated with increases in plasma ANP and cGMP, diuresis, blood pressure reduction, increased renin concentration and activity, and increased angiotensin II levels, providing evidence for NEP inhibition and angiotensin receptor blockade [ 61 , 62 ]. LCZ696 was considered safe and well tolerated, and data from these studies supported its further clinical development for hypertension and HF.…”

Section: Lcz696 and The Early Clinical Trialsmentioning

confidence: 99%

The evolution of natriuretic peptide augmentation in management of heart failure and the role of sacubitril/valsartan

Yandrapalli¹,

Aronow²,

Mondal³

et al. 2017

aoms

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Heart failure (HF) is one of the leading causes of morbidity, mortality, and health care expenditures in the US and worldwide. For three decades, the pillars of treatment of HF with reduced ejection fraction (HFrEF) were medications that targeted the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS). Prior attempts to augment the natriuretic peptide system (NPS) for the management of HF failed either due to lack of significant clinical benefit or due to the unacceptable side effect profile. This review article will discuss the NPS, the failure of early drugs which targeted the NPS as therapies for HF, and the sequence of events which led to the development of sacubitril plus valsartan (Entresto; LCZ696; Novartis). LCZ696 has been shown to be superior to the standard of care available for treatment of HFrEF in several substantial hard endpoints including heart failure hospitalizations, cardiovascular mortality, and all-cause mortality.

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“…64 Preclinical studies of AHU377 versus placebo confirmed an increase in cGMP, natriuresis, and diuresis in response to exogenous ANP administration. 65 Other preclinical work confirmed a rapid increase in plasma concentrations of both valsartan (peak 1.6e4.9 h) and LBQ657 (peak 1.8e2.7 h) after oral administration of LCZ696, followed by an acute decrease in blood pressure and dosedependent increase in ANP levels. 63 Healthy human volunteers receiving escalating doses of LCZ696 were noted to have significant acute increases in plasma cGMP levels that returned to baseline by 24 hours as well as dosedependent increases in plasma renin concentration, renin activity, and Ang II that were sustained after 12 days.…”

Section: Lcz696mentioning

confidence: 79%

Angiotensin Receptor Neprilysin Inhibition in Heart Failure: Mechanistic Action and Clinical Impact

Buggey

Mentz

DeVore

et al. 2015

Journal of Cardiac Failure

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Heart failure (HF) is an increasingly common syndrome associated with high mortality and economic burden, and there has been a paucity over the past decade of new pharmacotherapies that improve outcomes. However, recent data from a large randomized controlled trial compared the novel agent LCZ696, a dual-acting angiotensin receptor blocker and neprilysin inhibitor (ARNi), with the well established angiotensin-converting enzyme (ACE) inhibitor enalapril and found significant reduction in mortality among the chronic reduced ejection fraction HF population. Preclinical and clinical data suggest that neprilysin inhibition provides beneficial outcomes in HF patients by preventing the degradation of natriuretic peptides and thereby promoting natriuresis and vasodilatation and counteracting the negative cardiorenal effects of the up-regulated renin-angiotensin-aldosterone system. Agents such as omapatrilat combined neprilysin and ACE inhibition but had increased rates of angioedema. Goals of an improved safety profile provided the rationale for the development of the ARNi LCZ696. Along with significant reductions in mortality and hospitalizations, clinical trials suggest that LCZ696 may improve surrogate markers of HF severity. In this paper, we review the preclinical and clinical data that led to the development of LCZ696, the understanding of the underlying mechanistic action, and the robust clinical impact that LCZ696 may have in the near future. (J Cardiac Fail 2015;21:741e750)

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Comparative efficacy of AHU-377, a potent neprilysin inhibitor, in two rat models of volume-dependent hypertension

Cited by 5 publications

References 2 publications

Sacubitril/valsartan in cardiovascular disease: evidence to date and place in therapy

Sacubitril/valsartan in cardiovascular disease: evidence to date and place in therapy

The evolution of natriuretic peptide augmentation in management of heart failure and the role of sacubitril/valsartan

Angiotensin Receptor Neprilysin Inhibition in Heart Failure: Mechanistic Action and Clinical Impact

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