Abstract
Background: Angiotensin receptor- neprilysin (NEP) inhibitor (ARNi), which is consisting of an angiotensin receptor blocker (ARB) and a neprilysin inhibitor (NEPi), has been proven safe and effective for treating hypertension. S086 is a novel ARNi cocrystal developed by Salubris for the treatment of heart failure and hypertension. Rat hypertension model and telemetry system were employed in this study to investigate circadian rhythm of rat blood pressure and evaluate the anti-hypertensive efficacy of S086.
Methods: Dahl Salt Sensitive (DSS) hypertensive rat model and telemetry system were used in this research.
Results: Our findings showed that oral administration of S086 dose-dependently reduced blood pressure (P<0.001) and demonstrated superior efficacy compared to LCZ696 (P<0.05). Additionally, water consumption slightly decreased after treatment compared to the vehicle group. Natriuresis and diuresis significantly increased on the first day of treatment (P<0.001, P<0.01, P<0.05). However, as the treatment duration progressed, the effects of all treatment groups gradually diminished.
Conclusion: This study demonstrates the anti-hypertensive efficacy of S086 to support the further clinical study.
Keywords: Angiotensin receptor-NEP inhibitor (ARNi), hypertension, Neprilysin inhibitor, angiotensin receptor blocker (ARB)
Abbreviations: Dahl salt-sensitive (DSS); Angiotensin receptor-NEP inhibitor (ARNi); left ventricular hypertrophy (LVH); angiotensin receptor blocker (ARB); neprilysin inhibitor (NEPi); renin-angiotensin-aldosterone system (RAAS); atrial-type natriuretic peptide (ANP); brain-type natriuretic peptide (BNP); angiotensin-converting enzyme (ACE); systolic blood pressure (SBP); diastolic blood pressure (DBP); mean arterial pressure (MAP); heart rate (HR); pharmacokinetics (PK); Myocardial ischemia (MI); milligram per kilogram (mpk)
Introduction
Hypertension is a worldwide chronic cardiovascular disease (CVD) and the leading cause for premature death. Over the past few decades, the population of hypertension patients has surged due to the aging of society [1]. According to data from the NCD (non-communicable diseases) Risk Factor Collaboration, there were more than 1.2 billion people aged 30-79 with hypertension worldwide in 2019, double the number from 1990 [2]. Notably, the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) Hypertension Guidelines have lowered the threshold for hypertension diagnosis from a systolic blood pressure (BP)/diastolic BP of ≥140/90 mm Hg to ≥130/80 mm Hg, indicating an increase in patients needing medical treatment in the future [3]. High salt dietary consumption is one of the predominant risk factors for the essential pathogenesis of hypertension and strongly correlated with BP-independent organ damage. It has been reported that 30-50% of hypertensive patients are associated with high salt intake [4]. Studies suggest that high salt intake can lead to increased blood pressure by decreasing glomerular filtration membrane permeability, reducing filtration area and the number of glomeruli, and producing excess reactive oxygen species. As sodium load increases, endothelial function decreases, resulting in impaired vascular relaxation and elevated blood pressure [5-6]. Diuretics are effective in lowering blood pressure caused by a high-salt diet, but their adverse effects, such as low potassium and high uric acid, also require attention in clinic [7].
ARNi, which is a co-crystal comprising an angiotensin receptor II blocker (ARB) and a neprilysin inhibitor (NEPi), is a novel therapy for cardiovascular disease [8]. Its most common use in clinical practice is for heart failure patients, particularly those with reduced ejection fraction (HF-REF), and is recommended as the first-line therapy for HF-REF treatment by ACC (American College of Cardiology) /AHA (American Heart Association) /HFSA (American Heart Association) and ESC (European Society of Cardiology ) guidelines [9-10]. Additionally, ARNi has shown efficacy in hypertensive patients due to NEPi’s mechanism of inhibiting ANP (Atrial natriuretic peptide) and BNP (Brain natriuretic peptide) degradation which leads to natriuresis and diuresis, potentially reducing blood pressure in salt-sensitive patients [11]. LCZ696 (Entresto) is the first ARNi product launched globally and has shown profound efficacy in controlling BP in Asian patients with salt-sensitive hypertension [12]. In several clinical trials, LCZ696 had a significantly superior effect on BP control compared with current first-line antihypertensive agents, Valsartan, and Olmesartan [13-16].
S086, a new generation ARNi, has demonstrated superior profiles compared to LCZ696. It is a co-crystal containing ARB, NEPi, calcium, and hydrate. EXP3174, which is a higher potency and longer t1/2 ARB in S086 than valsartan in LCZ696. The NEPi ingredient in S086 is the same as that in LCZ696, which is a prodrug of LBQ657-Sacubitril. S086 has been proven to have comparable efficacy to LCZ696 in rat and dog myocardial infarction models. Both S086 and LCZ696 improved the left ventricular ejection fraction and myocardial fibrosis, and do not have a significant impact on hemodynamics [17]. The phase I clinical trial for S086 in healthy volunteers indicated a dose-dependent pharmacokinetic profile (Cmax and AUC) and pharmacodynamic effect (mean diastolic and systolic blood pressure). No severe adverse events occurred during the trial, and the most common side effects were hypotension and hypokalemia, which were expected pharmacology effect of S086 [18].
To further advance the clinical applications of S086, we conducted a study utilizing an implantable telemetry system to observe real-time blood pressure. We investigated the antihypertensive effects of the new generation of ARNi in a rat model of Dahl Salt Sensitive (DSS) hypertension and measured natriuresis and diuresis. In this study, we found that S086 demonstrates a dose-dependent antihypertensive effect and greater potency in controlling blood pressure compared to LCZ696, EXP3174, and Sacubitril. These results are promising and open up opportunities for further clinical development of S086 as a potential hypertension treatment.
2. Materials and Methods