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