4. Discussion
Hypertension is a chronic
cardiovascular disease characterized by elevated systolic and/or
diastolic blood pressure. It is a major risk factor for various
cardiovascular diseases. A high-salt diet is closely associated with
hypertension, and its mechanism of action is complex. ARNi is a novel
type of antihypertensive medication with a unique mechanism of action.
The first ARNi drug, LCZ696, has been reported to have significant
antihypertensive effects, particularly in patients with salt-sensitive
hypertension, and its clinical efficacy in reducing blood pressure is
significantly better than that of olmesartan, an angiotensin receptor
blocker (ARB) [12]. S086, a new generation of ARNi product developed
by Salubris, has validated anti-heart failure effects in preclinical
MI chronic heart failure models and
completed phase 1 clinical trial [17-18]. We investigated the
antihypertensive effect of S086 compared to LCZ696 using the DSS rat
model of hypertension and explored the diuretic and natriuretic effects
of ARNi drugs. Additionally, we used real-time telemetry system for
blood pressure measuring, providing a more accurate reflection of rats’
real-time blood pressure status and avoiding blood pressure fluctuations
caused by traditional animal manipulation methods.
Our study found that peak blood pressure values for both DSS rats and
normal rats occurred between 9:00 PM and 2:00 AM, and trough values
occurred between 1:00 PM and 6:00 PM. This indicates a significant
difference from the circadian rhythm of human blood pressure, which
peaks between 12:00 PM and 6:00 PM and has trough values between 1:00 AM
and 4:00 AM according to clinical research [20-21]. Differences in
blood pressure rhythms between rats and humans may be due to differences
in their circadian activity rhythms. Rodents are typically active and
eat at night and rest during the day, while humans are generally active
and eat during the day and rest at night. Our administration of
compounds to DSS rats at 11:00 AM is equivalent to humans taking
medication before bedtime at 11:00 PM, which has certain guiding
significance for the timing of administration in future rodent models of
hypertension. If we aim to fully simulate human clinical medication
habits (taking medication in the morning), we suggest administering
animals during 5:00-6:00 PM [22-23].
The new generation of ARNi drug-S086 demonstrated significant
antihypertensive effects in the DSS rat model of hypertension,
dose-dependently reducing both systolic and diastolic blood pressure
(Figure 2, Figure 3). In the DSS hypertensive rat model, a high-salt
diet leads to sodium and water retention, resulting in increased blood
volume and elevated blood pressure. Furthermore, studies have reported
that a high-salt diet directly activates the
renin-angiotensin-aldosterone system (RAAS), which is an additional
mechanism contributing to the development of high blood pressure
[24]. S086, composed of an ARB and NEP inhibitor, can directly
inhibit the RAAS system while activating the natriuretic peptide system,
ultimately lowering blood pressure. Compared to LCZ696 (69 mpk), the
middle dose of S086 (23 mpk) demonstrated significantly superior
antihypertensive efficacy at certain time points (Figure 4). This can be
attributed to the superior activity of its ARB component, EXP3174,
against the AT1 receptor, as well as its longer half-life.
[18,25-26]. This indicates that S086 has the potential to be a more
effective ARNi antihypertensive medication than LCZ696 for patients with
hypertension. Additionally, the antihypertensive effects of S086 are
even better than those of an equimolar dose of EXP3174 for two reasons.
Firstly, S086 metabolizes into EXP3174 and sacubitril. Sacubitril
further metabolizes into LBQ657- NEP inhibitor, and both of EXP3174 and
LBQ657 reduce blood pressure through different mechanisms. Although the
antihypertensive effect of the NEP inhibitor is relatively moderate, it
is still stronger than that of the separate dose of EXP3174. Secondly,
sacubitril increases the exposure level of EXP3174, resulting in a
higher exposure after administering an equimolar dose of S086 [17].
LBQ657 as a neprilysin inhibitor has been reported significantly
increases the expression of ANP and other natriuretic peptides in the
body [27]. Upon metabolism into LBQ657, S086 activates the
natriuretic peptide system, resulting in natriuresis and diuresis
[28]. EXP3174, a high potent ARB metabolized from S086, has been
shown to have a natriuretic effect [29]. We investigated the effects
of each compound on water consumption,
natriuresis and diuresis in the DSS
model. The results indicated that each treatment group showed a slight
decrease in water consumption compared to the vehicle group. This
decrease may be attributed to the drug’s natriuretic and diuretic
effects, leading to differences in salt and water balance in the body.
With regard to the natriuresis and diuresis study, significant
natriuretic and diuretic effects were observed in all treatment groups
on the first dosing day (P<0.001, P<0.01,
P<0.05). However, over time, the intensity of these effects
gradually diminished, which aligns with the trend observed in clinical
studies of LCZ696 in patients with salt-sensitive hypertension. In that
study, compared to valsartan monotherapy, LCZ696 showed significant
increases in natriuresis and diuresis on the first day after
administration, which could not be sustained [12]. However, we
observed antihypertensive efficacy with sacubitril (pro-drug of LBQ657)
monotherapy, especially after 14-28 days of treatment, when its effect
was stronger than after 7 days. This suggests that the antihypertensive
effect of NEPi may not be solely due to natriuresis and diuresis, but
rather from vasodilation. ANP and BNP can activate receptors expressed
in peripheral blood vessels, leading to vasodilation. ANP and BNP can
also inhibit aldosterone release, blocking the downstream signaling
pathway of the RAAS system, which finally lead to antihypertensive
effect [30]. However, the inhibitory effect of NEPi on the
downstream signaling of the RAAS system activates the body’s negative
feedback regulation mechanism, promoting the activity of upstream
signals of the RAAS system, thereby activating the RAAS system.
Therefore, NEPi’s antihypertensive effect alone is slight and must be
used in combination with RAAS system blockers. The first-generation
NEPi-omapatrilat simultaneously inhibited both NEP and ACE to activate
the natriuretic peptide system and inhibit the RAAS system. However, due
to the accumulation of bradykinin (a substrate of NEP and ACE) in the
body, causing severe vascular edema, the drug was ultimately withdrawn
from the market [31-32].
NEPi and ARB combine to form a cocrystal, which reduces the risk of
vascular edema caused by omapatrilat (NEPi and ACE). The cocrystal form
has better drug properties than physical mixtures since it improves
solubility, enhances compound PK properties, and increases absorption
[33-34]. We developed S086-a novel ARNi cocrystal, which improved
EXP3174’s poor PK profile. Preclinical studies validated its significant
blood pressure-reduction effect, superior to LCZ696. Completed phase 1
clinical trial demonstrated that S086 is well-absorbed in the human
body, exhibits linear absorption, and can significantly affect
target-related biomarkers. These provide solid foundation for conducting
further clinical studies. We will explore S086’s
antihypertensive effect in future
phase 2 and phase 3 clinical trials, providing better treatment options
for hypertension patients.