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Acute heart failure (AHF) represents a major healthcare burden with a high risk of in-hospital and post-discharge mortality, which remained almost unchanged in the last few decades, underscoring the need of new treatments. Relaxin is a naturally occurring human peptide initially identified as a reproductive hormone and has been shown to play a key role in the maternal hemodynamic and renal adjustments that accommodate pregnancy. Recently, the new molecule serelaxin, a recombinant form of the naturally occurring hormone relaxin has been studied in patients hospitalized for AHF. In addition to vasodilation, serelaxin has anti-oxidative, anti-inflammatory and connective tissue regulating properties. In preclinical studies, it reduced both systemic and renal vascular resistance and, in the clinical trials Pre-RELAX-AHF and RELAX-AHF, it improved dyspnea and signs of congestion. In addition, serelaxin was associated with a reduction of 180-day mortality. The aim of this review is to summarize the pharmacological properties of serelaxin and the results of the preclinical and clinical studies.
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Serelaxin a novel treatment
for acute heart failure
Expert Rev. Clin. Pharmacol. 8(5), 549–557 (2015)
Anna Isotta Castrini,
Valentina Carubelli,
Valentina Lazzarini,
Ivano Bonadei,
Carlo Lombardi and
Marco Metra*
Department of Medical and Surgical
Specialties, Cardiology, Radiological
Sciences, and Public Health, University
and Civil Hospital of Brescia,
Brescia, Italy
*Author for correspondence:
Tel.: +39 030 399 5572
Fax: +39 030 399 5018
metramarco@libero.it
Acute heart failure (AHF) represents a major healthcare burden with a high risk of in-hospital and
post-discharge mortality, which remained almost unchanged in the last few decades,
underscoring the need of new treatments. Relaxin is a naturally occurring human peptide initially
identified as a reproductive hormone and has been shown to play a key role in the maternal
hemodynamic and renal adjustments that accommodate pregnancy. Recently, the new molecule
serelaxin, a recombinant form of the naturally occurring hormone relaxin has been studied in
patients hospitalized for AHF. In addition to vasodilation, serelaxin has anti-oxidative, anti-
inflammatory and connective tissue regulating properties. In preclinical studies, it reduced both
systemic and renal vascular resistance and, in the clinical trials Pre-RELAX-AHF and RELAX-AHF, it
improved dyspnea and signs of congestion. In addition, serelaxin was associated with a reduction
of 180-day mortality. The aim of this review is to summarize the pharmacological properties of
serelaxin and the results of the preclinical and clinical studies.
KEYWORDS:acute heart failure .heart failure .serelaxin .treatment .vasodilator
Acute heart failure (AHF) is the major cause
of hospitalization in patients aged >65 years
with high mortality and readmission rates of
20–30% and 30–40%, respectively, in the year
after discharge [1,2]. Recent studies have
hypothesized that organ damage and persistent
or recurrent congestion during AHF admission
may be associated with poor prognosis [35].
Serelaxin, the recombinant form of the natu-
rally occurring hormone, human relaxin-2, in
the recent RELAX-AHF study (RELAXin in
AHF), reduced 180-day mortality and showed
a protective action on organ injury [6,7]. This is
the first time that favorable results were
reached in a large trial with a new drug in
patients with AHF. The aim of this review is
to explore the pharmacological actions of sere-
laxin and its beneficial effects in the contest of
AHF pathophysiology.
Chemistry of the drug
Relaxin was discovered following observation
of the reproductive endocrinology of the
gopher and later the guinea pig. It was named
relaxindue to its putative role in relaxing pel-
vic ligaments and softening the pubic symphy-
sis in pregnant guinea pigs. While three
human relaxin genes have been identified
(RLN1, RLN2 and RLN3), the peptide
encoded by the RLN2 gene is the circulating
form in humans. It is initially synthesized in
the cell as a pre-pro-peptide that is processed
to yield the mature relaxin molecule, with
a 2-chain heterodimeric (24-amino acid A
chain plus 29-amino acid B chain) covalently
bonded by two disulfide bridges. The A-chain
has an additional internal disulfide bridge.
Relaxin is synthesized in the corpus luteum
of the ovary and women are exposed to
monthly elevation of relaxin during the luteal
phase [8]. In men, relaxin is synthesized and is
present in the prostate and very low levels may
be present in the circulation although little is
known about the physiology of relaxin in male
subjects [9]. Serelaxin (RLX030, Novartis) is
the recombinant form of human relaxin-2.
The molecular formula for serelaxin is
C
256
H
408
N
74
O
74
S
8
and the molecular weight
is 5.96 kilodaltons.
Pharmacokinetics & metabolism
Serelaxin plasma steady-state concentrations
exhibit proportional increments with increasing
dosage when the drug is administered as a con-
tinuous intravenous (IV) infusion over a period
of 24–48 h, at doses of <200 mcg/kg/day. The
drug demonstrates a linear clearance in dosages
of 100 mcg/kg/day or less, while at higher dose
the clearance decreases and becomes nonlinear.
When the drug is administered at dosages of 6,
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Drug Profile
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12, 50 and 100 mcg/kg/day its half-life averages 5.28 days [10].
Serelaxin is cleared in the body via catabolism by proteases/
peptidases, which are not affected by cytochrome P450 enzyme.
No statistically significant changes were observed in the levels of
pro-inflammatory cytokines, including interleukin 6 and tumor
necrosis factor alpha, supporting the concept that no cytokine-
mediated therapeutic protein–drug interaction is expected [11].
A recent study evaluated the pharmacokinetics (PK) of serelaxin
in patients with mild, moderate or severe hepatic disease. In this
open-label, parallel group study comparing PK of serelaxin fol-
lowing a single 24-h IV infusion (30 mcg/kg/day) between
patient with Child-Pugh class A, B or C and healthy controls,
PK parameters were comparable in each group. No serious
adverse events, discontinuations due to serious adverse event or
adjustment of dose were observed [12]. An open-label, non-
randomized study to evaluate the PK, safety, immunogenicity,
tolerability and pharmacogenetics of serelaxin in patients with
severe renal impairment and end-stage renal disease has recently
closed the recruitment phase (ClinicalTrials.gov identifier
NCT1875523).
Pharmacodynamics
Serelaxin has two G-protein coupled receptors, relaxin family pep-
tide 1 (RXFP-1) and RXFP2. RXFP1 is the specific, high affinity
relaxin receptor whereas RXFP2 binds relaxin with lower affin-
ity [14]. RXFP1 distribution is widespread, having been found in
the vasculature, heart, kidney, liver, reproductive systems and
blood cells [15]. A non-clinical study, using immune-
histochemistry confirmed that RXFP1 receptors are located in
fetal/juvenile, adult human and rat tissues from heart, lung, kid-
ney, liver, brain and spleen. In the heart, they were localized in
the cardiomyocytes and the smooth cells of tunica media of blood
vessels. In the lungs, the smooth muscle cells of bronchi and
tunica media of blood vessels were posi-
tively stained. Histological analysis of kid-
ney tissue revealed the presence of
RXFP1 receptor in tubular cells of proxi-
mal convoluted tubules, mesangial cells in
glomeruli and smooth muscle cells of
tunica of blood vessels [16]. Activation of
the RXFP1 receptor requires serelaxin
binding to a high-affinity extracellular
domain, a low affinity transmembrane
domain and also requires involvement of
the low-density lipoprotein a receptor
domain. RXFP1 receptor activation can
result in the stimulation of multiple signal-
ing pathways, including those involving
cyclic adenosine monophosphate, extracel-
lular signal-related kinases, tyrosine kinase
and nitric oxide (NO) [15]. Activation of
NO synthase (NOS) appears to be central
in the vascular modulation effects of
serelaxin (FIGURE 1). The serelaxin-induced
sustained vasodilator pathway utilizes the
endogenous endothelin (ET) system, which regulates vascular
tone via a balance between vasodilation and vasoconstriction [17].
ET-1 is expressed in vascular endothelial cells and mediates vaso-
constriction upon binding to ET
A
or ET
B
receptors on smooth
muscle cells, while it mediates vasodilation upon binding to ET
B
receptors on endothelial cells [18]. Serelaxin, binding to RXFP1 on
endothelial cells, leads to rapid NOS activation via phosphoryla-
tion; sustained NOS activation via endothelial ET
B
receptors,
which also mediate ET-1 clearance. Rapid signaling occurs within
minutes following receptor binding in endothelial cells where ser-
elaxin stimulates the activation of phosphatidylinositol-3-kinase
and NOS. Serelaxin also upregulates ET
B
receptor gene expres-
sion in endothelial cells within 2 h and the ET
B
receptor density
is increased following a 6 h exposure [9].
Serelaxin: a vasodilator with pleiotropic effects
The NOS activation plays a central role in different cellular
processes that include extracellular matrix turnover [19], anti-
oxidative [20] and anti-inflammatory activities [21]. Moreover,
the serelaxin-induced sustained vasodilation utilizes a pathway
that is connected with endogenous endothelin system [17,18].
ex vivo studies, using isolated human resistance arteries or rat
thoracic aorta, mesenteric and small renal arteries, have demon-
strated that vascular serelaxin effect is endothelium-dependent
[22,23]. Serelaxin activates ET
B
receptors, which are responsible
for endothelin clearance.
The hemodynamic effects of serelaxin have been demonstrated
in preclinical studies in experimental models. Serelaxin increases
global arterial compliance by 25% with a concomitant decrease
of arterial stiffness in renal arterioles and in several other vascular
beds, including mesenteric, uterine, brain parenchymal and
carotid arteries [24,25]. In rat kidneys from both sexes, renal vascu-
lar resistance decreased by 25%, glomerular filtration rate (GFR)
Serelaxin
Vasodilation
Volume redistribution,
NO, SVR, ET-1,
RBF, GFR
Myocardial remodeling
Renal funciton
Angiogenesis
Stem cells survival
Tissue healing
Cell survival
Oxidative stress
Apoptosis
Calcium overload
Infarct size
Inflammation
Inflammatory cell
infiltration
Oxidative stress
Fibrosis
Collagen synthesis
Collagen breakdown
Matrix
metalloproteinase
Figure 1. Physiological effects of serelaxin.
ET-1: Endothelin-1; GRF: Glomerular filtration rate; NO: Nitric oxide; RBF: Renal blood
flow; SVR: Systemic vascular resistance.
Drug Profile Castrini, Carubelli, Lazzarini, Bonadei, Lombardi & Metra
550 Expert Rev. Clin. Pharmacol. 8(5), (2015)
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and renal blood flow (RBF) increased by 25% from baseline
within 1–2 h following IV administration of serelaxin [26].Asa
consequence of the improvement of kidney hemodynamics, sere-
laxin showed also a slight natriuretic effect [27]. In healthy sub-
jects, RBF, measured using inulin clearance, was increased by
45% from baseline following 4 h of IV administration of sere-
laxin at pregnancy levels [28]. In multiple non-clinical models,
and consistently with the relative insensitivity of pregnant women
to angiotensin II, serelaxin has been shown to antagonize the
effects of angiotensin II on several parameters in vivo, including
systemic blood pressure (SBP), systemic vascular resistance, car-
diac output, arterial compliance, RBF and GFR, renal oxidative
damage and fibrosis, cardiac fibrosis and hypertrophy [20,26,29].
The anti-fibrotic activity of serelaxin is mediated by its interfer-
ence with phosphorylation and smad2, the transcription factor
activated via phosphorylation following binding of the pro-
fibrotic cytokine TGF-bto its receptor [30]. Phosphorylation of
smad2 leads downstream to increased collagen synthesis and
decreases metalloproteinases expression. Serelaxin inhibits the
pro-fibrotic effects of TGF-b, blocking smad2 phosphorylation,
an event that is intensified when TGF-bis highly expressed dur-
ing the development of fibrosis [30,31].
Clinical efficacy
The clinical trials that investigated the safety and efficacy of ser-
elaxin in heart failure patients are summarized in TABLE 1. Four
Phase I studies to evaluate use of serelaxin were performed.
Three of these were PK studies and were completed in healthy
volunteers and in patients with hepatic impairment, respectively
(R006g, CRLX030A2103 and CRLX030A2101). A pilot safety
and hemodynamic study, to evaluate the effect of IV serelaxin
infusion on pulmonary capillary wedge pressure (PCWP) and
cardiac index (CI), was performed in stable chronic heart failure
(CHF) patients (RLX.CHF.001) [32]. The study had no concur-
rent control and applied an intra-subject dose escalation span-
ning serelaxin 10–960 mcg/kg/day over 8 h for each dose rate.
A maximum reduction in PCWP from baseline of 5.0 ±
2.6 mmHg (mean ±SD) at 8 h was observed at the dose of
30 mcg/kg/day. Similar results were obtained with the same
dose, on mean pulmonary artery pressure, which showed a
decrease of 4.5 ±4.2 mmHg at 8 h. There was a trend
toward increasing CI with incremental dose/duration of treat-
ment resulting in a mean change form baseline of 0.25 ±0.4 l/
min/m
2
at 8 h. At dose rates of serelaxin ranging form 10 to
960 mcg/kg/day, early decreases in serum creatinine, uric acid
and blood urea nitrogen were observed at 24 and 48 h [32].
The Pre-RELAX-AHF was designed as a dose-finding, pilot
Phase II study, examining four doses of IV serelaxin versus pla-
cebo. As an exploratory dose-finding study, Pre-RELAX-AHF
did not have one pre-specified primary end point, but rather
assessed the overall effect of IV serelaxin on: relief of dyspnea,
assessed by Likert scale and visual analogue scale; in-hospital
worsening heart failure from baseline to day 5; renal impairment
(defined as increase of 25% or more in serum creatinine from
baseline to day 5) and persistent renal impairment (defined as
creatinine increase of 26 mmol/l or above at both day 5 and
14 from randomization); length of hospital stay; days alive and
out of hospital to day 60; death due to cardiovascular causes or
readmission for heart failure or renal failure to day 60; and mor-
tality due to cardiovascular causes to day 180. The efficacy anal-
ysis population included 229 patients who received the study
drug or placebo. Among the different dose regimens, 48 h infu-
sion of serelaxin at 30 mg/kg per day provided the most notable
beneficial effects in five of seven primary treatment targets, with
some nominal improvement in dyspnea relief, cardiovascular
death or readmission at 60 days, and cardiovascular death at
180 days, as well as non-significant improvement in length of
hospital stay and days alive out of hospital at 60 days. No differ-
ences were observed in worsening heart failure to day 5 or persis-
tent renal impairment event rate. No safety concerns were noted
with serelaxin 30 mg/kg per day [33].
Two Phase II trials were designed to evaluate the central hemo-
dynamic response and the renal hemodynamic response to IV ser-
elaxin infusion. In study CRLX030A2201, a randomized, double-
blind, parallel-group Phase II study, 71 patients hospitalized for
AHF with a mean PCWP 18 mmHg, SBP 115, eGRF
30 ml/min/1.73 m
2
and treated with IV loop diuretic (40
120 mg furosemide or equivalent) prior to randomization,
received a 20-h IV infusion of serelaxin at 30 mcg/kg/day or pla-
cebo within 48 h from admission. The primary objective was to
evaluate the hemodynamic response of PCWP and CI to 30 mcg/
kg/day IV serelaxin or placebo in the first 8 h. Secondary objec-
tives included the effects of serelaxin on other hemodynamic
parameters, cardiac and renal biomarkers, urine flow rate, urinary
creatinine and creatinine clearance. Serelaxin infusion was associ-
ated with a significant decrease in peak PCWP from baseline over
the first 8 h of 6.69 ±0.59 mmHg versus 4.25 ±0.6 mmHg in
the placebo group. This result is supported by the treatment differ-
ence in the time-weighted average PCWP change from baseline
over 0–8 h of 2.70 mmHg (p =0.0001). The onset of serelaxin
effect was observed at 30 min with a significant treatment differ-
ence at 2 h after the start of the infusion. Significant differences in
PCWP change from baseline between the treatment groups were
observed at 2, 4, 6 and 8 h from the start of infusion. The effect
on PCWP was no longer statistically significant during the 4 h
wash-out phase. Serelaxin also resulted in mean pulmonary artery
pressure decrease from baseline during the first 8 h of 7.56 ±
0.72 mmHg versus 3.63 ±0.74 mmHg in the placebo group and
resulted in a treatment difference of 3.93 mmHg (p =0.0001).
Similar results were observed for the time average change from
baseline over 0–8 h (p < 0.0001), 8–20 h (p =0.028) and 0–20 h
(p =0.0002). Systemic vascular resistance decreased from baseline
in the serelaxin group versus placebo, reaching statistic significance
at some time points [34]. The study CRLX030A2202 was a ran-
domized, double-blind, parallel-group, placebo-controlled
Phase II study, which focused on renal hemodynamic effects of
30 mcg/kg/day serelaxin infusion for 24 h. The trial included
65 CHF patients with BNP 100 pg/ml or NT-proBNP
400 pg/ml, NYHA class II–III, reduced left ventricular ejection
fraction (£45%), worsening symptoms in the last 3 months, SBP
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Table 1. Summary of the main clinical trials with serelaxin in heart failure.
Study code Study design Major study objectives Study population Dose regimen (number
of patients)
Study results Ref.
Phase I
RLX.
CHF.001 (Pilot
study in CHF)
Phase I study open-label
single-center safety and
hemodynamic study
Hemodynamic effect of IV
serelaxin infusion on PCWP,
CO/CI and SVR; renal safety
(serum creatinine, BUN and uric
acid)
16 patients with stable
CHF
24-h IV infusion (8-h
intervals) with escalating
doses:10, 30, 100 mcg/kg
(n =4), 250, 480,
960 mcg/kg/day (n =6);
960 mcg/kg/day (n =6)
Significant reduction in
PCWP, SBP, SVR;
increase of CO and CI;
early decrease in
creatinine and BUN;
reduction in Nt-proBNP
values
[32]
CRLX030A2101 Phase I single- dose,
open-label, parallel group
study in subjects with
hepatic impairment
PK of serelaxin in subjects with
hepatic impairment, compared to
healthy controls
25 subjects with mild
(n =9), moderate (n =8)
and severe (n =8) hepatic
impairment versus
24 matched subjects with
normal hepatic function
24-h IV infusion:
serelaxin 30 mg/kg/day
(n =49)
No difference in PK of
serelaxin between
subjects with hepatic
impairment and healthy
subjects
[11]
CRLX030A2103 Phase I, double- blind,
placebo-controlled,
parallel group, exploratory
study in healthy subjects
Safety, tolerability, PK/PD of IV
infusion of serelaxin at three dose
levels in Japanese healthy
subjects, with an open-label
comparison to Caucasian subjects
at one dose level
32 Japanese male and
female healthy subjects
and eight Caucasian male
and female healthy
subjects
48-h IV infusion: Placebo
(n =8);
Serelaxin: 10 mg/kg/day
(n =8) 30 mg/kg/day
(n =16) 100 mg/kg/day
(n =8)
PK profiles between
Japanese and Caucasian
subjects are comparable
[11]
Phase II
RLX.CHF.003.
PRE
(PRE-RELAX-
AHF)
Phase II multi-center
randomized, double-blind,
placebo-controlled safety
and efficacy study
Dose-ranging study evaluating
effects of IV serelaxin on a
number of clinical end points,
including dyspnea improvement,
in-hospital outcomes, CV and all-
cause mortality through day 180.
234 randomized patients
hospitalized with AHF, mild
to moderate renal
impairment and normal to
elevated blood pressure
48-h IV infusion:
Placebo (n =62)
Serelaxin:
10 mcg/kg/day (n =40)
30 mcg/kg7day (n =43)
100 mcg/kg/day (n =39)
250 mcg/kg/day (n =50)
Consistent trends in
improving dyspnea and
clinical outcomes with
serelaxin 30 mcg/kg/day
[33]
CRLX030A2201 Phase II multi-center,
randomized, double-blind,
placebo-controlled,
parallel group,
hemodynamic study
Evaluate the central
hemodynamic responses to IV
serelaxin infusion
71 patients hospitalized
with AHF
20-h IV infusion:
Placebo (n =37)
Serelaxin30mcg/kg/day
(n =34)
Decrease in peak PCWP,
mean PAP and SVR from
baseline in serelaxin
group. No differences in
CI
[34]
CRLX0A2202 Phase II multi-center,
randomized, double-blind,
placebo-controlled group,
parallel group, renal
hemodynamic study
Evaluate the renal hemodynamic
responses to IV serelaxin infusion
87 CHF patients with mild
to moderate renal
impairment
24-h IV infusion:
Placebo (n =48)
Serelaxin30mcg/kg/day
(n =39)
Increase in RBF in
serelaxin group but no
changes in GFR
[35]
AE: Adverse events; AHF: Acute heart failure; BUN: Blood urea nitrogen; CHF: Chronic heart failure; CI: Cardiac index; CO: Cardiac output; GFR: Glomerular filtration rate; PAP: Pulmonary artery pressure;
PCWP: Pulmonary capillary wedge pressure; PD: Pharmacodynamic; PK: Pharmacokinetic; SAE: Serious adverse events; SBP: Systolic blood pressure.
Drug Profile Castrini, Carubelli, Lazzarini, Bonadei, Lombardi & Metra
552 Expert Rev. Clin. Pharmacol. 8(5), (2015)
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110 mmHg, eGFR 30–89 ml/min/1.73 m
2
, and treated with a
stable loop diuretic dose. The primary objective was to evaluate
the effects of serelaxin or placebo for 24 h on renal plasma flow
(RPF) and GFR over the 8–24-h interval. Secondary objectives
included filtration fraction (FF), changes in urinary flow rate,
sodium excretion and changes in systolic and diastolic blood pres-
sure. Serelaxin improved RPF from baseline over 8–24 h of infu-
sion (change 29% serelaxin versus 14% placebo; p =0.0386) and
at other time points, as from baseline over 0–24 and 24–48 h. No
significant variations of GFR were observed. The lack of effect on
GFR has been interpreted by the authors as a possible conse-
quence of the study population of stable CHF patients. In fact, it
is reasonable to assume that renal function is more seriously com-
promised during the acute decompensated heart failure. More-
over, the increase in RPF in the absence of an increase in GFR
might be explained by a direct renal vasorelaxant effect of sere-
laxin, probably by both renal afferent and efferent vasorelaxation,
leading to a reduced pressure load on the glomerulus. FF
increased at all time points in both serelaxin and placebo group.
However, the change observed with serelaxin was lower compared
with placebo (16% relative decrease with serelaxin versus placebo;
p=0.0019) [35]. This may be one of the mechanisms that explain
the renal-protective properties of serelaxin. The increase in RPF
without changes in GFR leads to a reduction in FF. In animal
models, an elevated FF is associated with elevated glomerular pres-
sure and with a higher risk of progressive renal function deteriora-
tion. On the other hand, a reduction of FF, as observed during
treatment with renin-angiotensin-aldosterone (RAA) system
inhibitors, which induces a rise in RPF with unchanged GFR,
results in protection against function loss due to lower intraglo-
merular pressure [36]. Therefore, these renal hemodynamic effects
support the pathophysiological basis of serelaxin renal protective
properties observed in clinical trials.
In the RELAX-AHF study, 1161 patients hospitalized for
AHF were randomized within 16 h from admission to receive a
48 h infusion of serelaxin (30 mcg/kg/day) or placebo. The
study showed that serelaxin significantly reduced dyspnea, as
measured by the visual analogue scale from baseline to day 5,
but did not affect dyspnea as measured using a 7-point Likert
scale, over the first 24 h (co-primary end points). Patients
treated with serelaxin received lower diuretic dose, and showed
a better improvement in clinical signs of congestion. In addi-
tion, less patients in the treatment group experienced a worsen-
ing heart failure event up to day 14 (serelaxin 11.4% vs placebo
15.7%; p =0.024) and the length of hospital stay was signifi-
cantly lower (serelaxin 9.6 days vs placebo 10.5 days;
p=0.039). Serelaxin did not affect 60-day readmission or
death, largely because of the lack of an effect on readmissions
(the secondary composite end points), but showed a significant
reduction of 180-day all-cause mortality (Hazard ratio (HR)
0.63; 95% CI 0.43 – 0.93; p =0.02) and cardiovascular mor-
tality (HR 0.63; 95% CI 0.41 – 0.96; p =0.028). Subgroup
analyses, based on pre-specified covariates, which included sev-
eral demographic and clinical characteristics, did not show any
difference in the effects of serelaxin versus placebo on dyspnea
Table 1. Summary of the main clinical trials with serelaxin in heart failure (cont.).
Study code Study design Major study objectives Study population Dose regimen (number
of patients)
Study results Ref.
Phase III
RLX.CHF.003
(RELAX-AHF)
Phase III multi-center,
randomized, double blind,
placebo-controlled
efficacy and safety study
Study to evaluate whether 48 h
serelaxin infusion is superior to
placebo in improving dyspnea;
secondary end points days alive
and out of the hospital to day
60 and CV death or readmission
to hospital for heart failure or
renal failure before day 60; time
to worsening heart failure up to
days 5 and 14; all cause and CV
death to day 180
1161 patients hospitalized
with AHF within 16 h from
admission, normal to
elevated blood pressure,
and mild to moderate
renal impairment
48-h IV infusion:
Placebo (n =580)
Serelaxin30mcg/kg/day
(n =581)
Significant improvement
of dyspnea in serelaxin
group
CV death trough day
180 was significantly
lower in the serelaxin
group
Fewer patients
experienced WHF event
or death in the serelaxin
group
No significant differences
in AE in serelaxin and
placebo group
[6]
AE: Adverse events; AHF: Acute heart failure; BUN: Blood urea nitrogen; CHF: Chronic heart failure; CI: Cardiac index; CO: Cardiac output; GFR: Glomerular filtration rate; PAP: Pulmonary artery pressure;
PCWP: Pulmonary capillary wedge pressure; PD: Pharmacodynamic; PK: Pharmacokinetic; SAE: Serious adverse events; SBP: Systolic blood pressure.
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relief or on the incidence of cardiovascular death or rehospitali-
zation for heart failure or renal failure at 60 days [37]. Moreover,
serelaxin efficacy was similar both in patients with reduced and
with preserved left ventricular ejection fraction [38]. In several
early phase clinical trials and in the Phase III RELAX-AHF trial,
serelaxin demonstrated to relieve symptoms and congestion and
was associated with better in-hospital and long-term clinical
outcomes.
Safety
Serelaxin is a vasodilator and as several other drugs of this class its
main adverse effect is hypotension. Hypotensive effects demon-
strated in preclinical and clinical studies are consistent with the sys-
temic vasodilation mediated by serelaxin. In the RELAX-AHF
trial, there was a significant major decrease of SBP in the serelaxin-
treated patients both during and after treatment. The protocol had
pre-specified criteria to reduce or permanently withdraw study
drug according to SBP values. The proportion of patients who had
a confirmed SBP decrease and therefore a study drug dose was
higher in the serelaxin group (dose reduction: serelaxin 13% vs pla-
cebo 7%; drug discontinuation: serelaxin 19% vs placebo 12%;
dose reduction and discontinuation: serelaxin 3% vs placebo 2%).
However, the majority of SBP decrease adverse event were of low
intensity and required treatment, mainly with IV fluids, only in
19 (12%) patients in the serelaxin group compared with nine
(8%) in the placebo. Interestingly, the incidence of renal and
hepatic adverse events was higher in the placebo group, again
underscoring the organ protective properties of serelaxin.
Previous studies have raised some issues regarding the possible
effects of serelaxin on hemoglobin and red blood cell count. In
the RELAX-AHF study, minor decreases in hemoglobin were
observed in the serelaxin group versus placebo with a mean dif-
ference from baseline between serelaxin and placebo in the range
of 0.3 mg/dl (through Day 3) and 0.1 (Day 4, Day 5).
However, slight decreases in hemoglobin and red blood cell
count were occasionally reported in both treatment groups with
comparable frequencies and overall, these hematology changes
are not clinically relevant [6]. Another reported adverse event in
serelaxin studies is the possibility to develop anti-serelaxin anti-
body (Ab). Among the patients enrolled in the serelaxin study
program 559 have been tested for anti-serelaxin-Ab develop-
ment and only one patient was positive. Nevertheless, in a dif-
ferent clinical setting, sero-conversion was noted in 108 (43%)
out of 251 patients, who were exposed to serelaxin in seven sys-
temic sclerosis studies. In patients tested (n =42), Abs were
non-neutralizing using an in vitro bioassay. The likelihood of
developing anti-serelaxin Abs was positively related to the dura-
tion of serelaxin exposure and dosing, while no gender differ-
ence was observed. Abs formation was not associated with
changes in blood pressure, hemoglobin, osmolality, serum creat-
inine, predicted creatinine clearance and uric acid. However, all
of these patients received continuous daily subcutaneous infu-
sion of serelaxin for at least 2 weeks to approximately up to
48 weeks. This regimen is considered to be more immunogenic
than the IV route of administration used in the heart failure
population. In addition, the underlying autoimmune disease
might have stimulated Ab formation [39]. To assess the propor-
tion of CHF patients who develop anti-serelaxin Abs at any
time following repeated infusions of serelaxin for up to 48 h, a
Phase IIb multi-center double-blind, placebo-controlled study is
currently ongoing (ClinicalTrials.gov identifier [40]).
AHF: the current landscape
Despite several efforts, the treatment of AHF has not changed in
the last few decades and none of the new drugs has shown favor-
able effects on outcomes in large clinical trials. The mainstay
treatment of AHF is represented by IV loop diuretics that reduce
congestion and relieve dyspnea in the clinical setting [41,42].How-
ever, the use of diuretics has been associated with an unfavorable
prognosis and may be limited by the development of worsening
renal function and diuretic-resistance [4345]. Nitrates use is sup-
ported by few data coming from clinical trials, and a recent meta-
analysis has shown no benefit in patients hospitalized for
AHF [46]. In addition, the use of inotropes has been associated
with increased mortality risk even with novel drugs [47].Thus,in
the last two decades, researchers have focused on new drugs able
to improve the poor outcomes of patients admitted for AHF. To
date, no new drug or device has, however, shown favorable results
in large Phase III clinical trials [4851]. In this setting, treatment
with serelaxin may favor decongestion improving long-term out-
comes. In fact, persistent congestion at the time of hospital dis-
charge, neurohormonal and inflammatory activation are the
major causes of organ damage and eventually lead to high event
rates in patients with AHF [3,4,52,53]. Inflammation and oxidative
stress have been recently recognized as important prognostic
markers in these patients [5456]. The reactive oxygen species
(ROS) act on the endothelium to increase permeability, enhance
synthesis of inflammatory cytokines, causing endothelial dysfunc-
tion and apoptosis favoring end-organ damage. Recent studies
have observed that decreased endothelial function is an early risk
factor in patients with HF [5760]. The clinical efficacy of serelaxin
may also be associated with its pleiotropic properties, namely the
effect on oxidative stress and inflammation. Studies have
described a protective effect of serelaxin against vascular damage,
including reduced formation of ROS, downregulation of adhe-
sion molecules in the endothelial cells, decreased inflammatory
mediators production [61]. Another major contributor to organ
damage is congestion that enhances organ injury to the heart, the
kidney and the liver, leading to a progressive function loss, which
in turn increases the risk of recurrent hospitalizations and mortal-
ity. Indeed several clinical trials demonstrated that the organ dam-
age to cardiac myocytes (as a rise in troponin levels) [62],renal[63]
and hepatic [64] function is associated with worse prognosis in
patients hospitalized for AHF. In the RELAX-AHF trial, an
increase in serum troponin-T, serum cystatin-C and serum transa-
minases had an independent prognostic value for 180-day mortal-
ity [7]. Treatment with serelaxin was associated with lower levels of
all these biomarkers, and this can explain why a drug administered
only in the first 48 h of hospitalization have a strong beneficial
effect on 6 months mortality.
Drug Profile Castrini, Carubelli, Lazzarini, Bonadei, Lombardi & Metra
554 Expert Rev. Clin. Pharmacol. 8(5), (2015)
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The reduction of mortality associated with serelaxin adminis-
tration in the RELAX-AHF trials has important implications
because it suggests that protection from organ damage may be
a mechanism of improved survival in AHF patients. However,
the RELAX-AHF trial was underpowered to confirm mortality
results and thus a second study, the RELAX-AHF-2, a larger
clinical trial with mortality as primary end point, is currently
recruiting patients.
Conclusion
Serelaxin is a novel vasodilator that has unique associated pleio-
tropic properties. Several clinical trials in patients with AHF
demonstrated that serelaxin improves symptoms and hemody-
namics with an excellent safety profile. In addition, serelaxin
showed a beneficial effect preventing the AHF-related damage
to cardiac, renal and hepatic function and this may explain the
reduction of 6 months mortality observed in serelaxin-treated
patients. Although promising, these findings on prognosis need
to be confirmed in the RELAX-AHF-2 trial, which is currently
ongoing.
Expert commentary
Despite several efforts, the treatment of AHF has not changed
in the last few decades and none of the new drugs has shown
favorable effects on outcomes in large clinical trials. Serelaxin is
a novel vasodilator that has unique associated pleiotropic prop-
erties. The reduction of mortality associated with serelaxin
administration in the RELAX-AHF trials has important
implications because it suggests that protection from organ
damage may be a mechanism of improved survival in AHF
patients. However, the RELAX-AHF trial was underpowered to
confirm mortality results and thus a second study, the RELAX-
AHF-2, a larger clinical trial with mortality as primary end
point, is currently recruiting patients.
Five-year view
Thus, in the last two decades, researchers have focused on new
drugs able to improve the poor outcomes of patients admitted
for AHF. To date, no new drug or device has, however, shown
favorable results in large Phase III clinical trials. Serelaxin is a
novel vasodilator that has unique associated pleiotropic proper-
ties. Several clinical trials in patients with AHF demonstrated
that serelaxin improves symptoms and hemodynamics with an
excellent safety profile. Serelaxin showed a beneficial effect pre-
venting the AHF-related damage to cardiac, renal and hepatic
function and this may explain the reduction of 6 months mor-
tality observed in serelaxin-treated patients. Although promis-
ing, these findings on prognosis need to be confirmed in the
RELAX-AHF-2 trial, which is currently ongoing.
Financial & competing interests disclosure
M Metra has received consulting honoraria from Novartis and Bayer. The
authors have no other relevant affiliations or financial involvement with
any organization or entity with a financial interest in or financial conflict
with the subject matter or materials discussed in the manuscript apart
from those disclosed.
Key issues
.Relaxin is a naturally occurring human peptide initially identified as a reproductive hormone. Recently, the new molecule serelaxin, a
recombinant form of the naturally occurring hormone relaxin, released during pregnancy, has been studied in patients hospitalized for
acute heart failure (AHF).
.Relaxin is synthesized in the corpus luteum of the ovary and women are exposed to monthly elevation of relaxin during the luteal phase.
In men, relaxin is synthesized and is present in the prostate and very low levels may be present in the circulation although little is known
about the physiology of relaxin in male subjects [9]. Serelaxin (RLX030, Novartis) is the recombinant form of human relaxin-2.
.Serelaxin is cleared in the body via catabolism by proteases/peptidases, which are not affected by cytochrome P450 enzyme. Serelaxin
has two G-protein coupled receptors, relaxin family peptide 1 (RXFP-1) and RXFP2. Activation of nitric oxide synthase appears to be cen-
tral in the vascular modulation effects of serelaxin. The serelaxin-induced sustained vasodilator pathway utilizes the endogenous ET sys-
tem, which regulates vascular tone via a balance between vasodilation and vasoconstriction.
.In the dose-finding, Pre-RELAX-AHF trial serelaxin provided the most notable beneficial effects in five of seven primary treatment targets,
with some nominal improvement in dyspnea relief, cardiovascular death or readmission at 60 days, and cardiovascular death at 180 days,
as well as non-significant improvement in length of hospital stay and days alive out of hospital at 60 days.
.In the clinical trials designed to evaluate systemic and renal hemodynamic response, serelaxin reduced pulmonary capillary wedge
pressure and improved renal plasma flow respectively.
.In the RELAX-AHF study, in patients hospitalized for AHF serelaxin significantly reduced dyspnea over the first 24 hours and showed a
significant reduction of 180-day all-cause and cardiovascular mortality.
.Several clinical trials in patients with AHF demonstrated that serelaxin improves symptoms and hemodynamics with an excellent safety
profile.
Serelaxin a novel treatment for acute heart failure Drug Profile
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Article
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Heart failure remains one of the main problems in contemporary cardiology, taken high frequency of hospitalizations due to acute decompensation, and worse prognosis for this category of patients. One of the drugs influencing prognosis is serelaxin (recombinant human relaxin-2). Experience of serelaxin usage as 48-hour infusion for patients with ADHF showed rapid positive influence of the drug on clinical signs and symptoms, target organ damage markers (BNP, creatinine), hemodynamics parameters (MPAP).
... Serelaxin is a relaxin receptor agonist and recombinant form of the naturally occurring vasoactive human relaxin-2 peptide hormone. 1 Relaxin plays a central role in haemodynamic and renal adaptations to pregnancy. 2,3 Serelaxin mediates its effects through binding to its cognate receptor, relaxin/insulin-like family peptide receptor 1 (RXFP1). Serelaxin is pleiotropic with vasodilatory, anti-fibrotic, and end-organ protective effects. ...
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Full-text available
Aims: The effects of serelaxin, a recombinant form of human relaxin-2 peptide, on vascular function in the coronary microvascular and systemic macrovascular circulation remain largely unknown. This mechanistic, clinical study assessed the effects of serelaxin on myocardial perfusion, aortic stiffness, and safety in patients with stable coronary artery disease (CAD). Methods and results: In this multicentre, double-blind, parallel-group, placebo-controlled study, 58 patients were randomized 1:1 to 48 h intravenous infusion of serelaxin (30 µg/kg/day) or matching placebo. The primary endpoints were change from baseline to 47 h post-initiation of the infusion in global myocardial perfusion reserve (MPR) assessed using adenosine stress perfusion cardiac magnetic resonance imaging, and applanation tonometry-derived augmentation index (AIx). Secondary endpoints were: change from baseline in AIx and pulse wave velocity, assessed at 47 h, Day 30, and Day 180; aortic distensibility at 47 h; pharmacokinetics and safety. Exploratory endpoints were the effect on cardiorenal biomarkers [N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), endothelin-1, and cystatin C]. Of 58 patients, 51 were included in the primary analysis (serelaxin, n = 25; placebo, n = 26). After 2 and 6 h of serelaxin infusion, mean placebo-corrected blood pressure reductions of -9.6 mmHg (P = 0.01) and -13.5 mmHg (P = 0.0003) for systolic blood pressure and -5.2 mmHg (P = 0.02) and -8.4 mmHg (P = 0.001) for diastolic blood pressure occurred. There were no between-group differences from baseline to 47 h in global MPR (-0.24 vs. -0.13, P = 0.44) or AIx (3.49% vs. 0.04%, P = 0.21) with serelaxin compared with placebo. Endothelin-1 and cystatin C levels decreased from baseline in the serelaxin group, and there were no clinically relevant changes observed with serelaxin for NT-proBNP or hsTnT. Similar numbers of serious adverse events were observed in both groups (serelaxin, n = 5; placebo, n = 7) to 180-day follow-up. Conclusion: In patients with stable CAD, 48 h intravenous serelaxin reduced blood pressure but did not alter myocardial perfusion.
... Serelaxin is also known to participate in various cellular processes with antioxidative, anti-inflammatory, and antifibrotic actions. 41) A recent large-scale clinical trial found that the intravenous injection of serelaxin for 48 hours at the initial stage of AHF caused rapid hemodynamic improvement, which ameliorated symptoms associated with pulmonary congestion and improved some clinical outcomes including 180-day mortality. [42][43][44][45] However, the clinical use of serelaxin is not yet approved in the United States or Europe, warranting the need for data on long-term patient prognosis and stability. ...
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... Serelaxin is a recombinant human relaxin-2 vasoactive peptide that causes systemic and renal vasodilation. The clinical benefits may including improving systemic, cardiac, and renal hemodynamics, and protecting cells and organs from damage via neurohormonal, anti-remodeling, anti-fibrotic, antiischemic, anti-inflammatory, and pro-angiogenic effects [24][25][26]. ...
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Heart failure patients need multiple medications to treats a different symptom or contributing factor. Individuals diagnosed with heart failure typically take 5 or more different medications daily. Treatment may help live longer and reduce your chance of dying suddenly. This review describes the main drugs used to treat heart failure with reduced ejection fraction.
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Use of recombinant relaxin in the treatment of systemic sclerosis (or sclero-derma) has been explored and determined as ineffective. However, continued research has revealed that relaxin is not limited to its role as a hormone. Relaxin has also been shown to decrease collagen formation and secretion, increase collagenase production, influence renal vasodilation, increase vascular endothelial growth factor expression and angiogenesis, promote dilation of blood vessels, and inhibit release of histamine. Further studies to discover other potential uses of relaxin are well-justified.