U.S. patent application number 15/412447 was filed with the patent office on 2017-06-01 for method of treating dyspnea associated with acute heart failure.
The applicant listed for this patent is Gad Cotter, Dennis Stewart, Sam L Teichman, Elaine Unemori, Martha Jo Whitehouse. Invention is credited to Gad Cotter, Dennis Stewart, Sam L Teichman, Elaine Unemori, Martha Jo Whitehouse.
Application Number | 20170151311 15/412447 |
Document ID | / |
Family ID | 40834101 |
Filed Date | 2017-06-01 |
United States Patent
Application |
20170151311 |
Kind Code |
A1 |
Unemori; Elaine ; et
al. |
June 1, 2017 |
Method of treating dyspnea associated with acute heart failure
Abstract
The disclosure pertains to methods of reducing decompensation
through acute intervention including in subjects afflicted with
acute decompensated heart failure. Particularly, the disclosure
provides methods for treating acute cardiac decompensation by
administering a pharmaceutically effective amount of relaxin.
Inventors: |
Unemori; Elaine; (Oakland,
CA) ; Teichman; Sam L; (Alamo, CA) ; Cotter;
Gad; (Chapel Hill, NC) ; Stewart; Dennis; (Los
Gatos, CA) ; Whitehouse; Martha Jo; (San Francisco,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Unemori; Elaine
Teichman; Sam L
Cotter; Gad
Stewart; Dennis
Whitehouse; Martha Jo |
Oakland
Alamo
Chapel Hill
Los Gatos
San Francisco |
CA
CA
NC
CA
CA |
US
US
US
US
US |
|
|
Family ID: |
40834101 |
Appl. No.: |
15/412447 |
Filed: |
January 23, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14723701 |
May 28, 2015 |
9579363 |
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15412447 |
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13734301 |
Jan 4, 2013 |
9066916 |
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14723701 |
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13242012 |
Sep 23, 2011 |
8372809 |
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13734301 |
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12467214 |
May 15, 2009 |
8053411 |
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13242012 |
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61127889 |
May 16, 2008 |
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61190545 |
Aug 28, 2008 |
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61201240 |
Dec 8, 2008 |
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61164333 |
Mar 27, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 9/00 20180101; A61P
9/04 20180101; A61P 11/00 20180101; A61P 9/08 20180101; A61P 9/10
20180101; A61P 13/12 20180101; A61P 9/12 20180101; C07K 14/64
20130101; A61K 38/2221 20130101; A61P 43/00 20180101; A61P 7/10
20180101; A61K 38/2221 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 38/22 20060101
A61K038/22 |
Claims
1. A method of reducing death from cardiovascular causes in a
hypertensive or normotensive human subject with acute heart failure
comprising administering a therapeutically effective amount of a
pharmaceutically active H2 relaxin to the subject.
2. The method of claim 1 wherein fewer deaths from cardiovascular
causes occur by day 180 in subjects administered relaxin than in
subjects administered placebo.
3. The method of claim 2 wherein fewer deaths from cardiovascular
causes occur by day 60 in subjects administered relaxin than in
subjects administered placebo.
4. The method of claim 3 wherein fewer deaths from cardiovascular
causes occur by day 30 in subjects administered relaxin than in
subjects administered placebo.
5. A method of reducing renal impairment in a hypertensive or
normotensive human subject with acute heart failure comprising
administering a therapeutically effective amount of a
pharmaceutically active H2 relaxin to the subject.
6. The method of claim 5 wherein the incidence of renal impairment
is reduced to less than or equal to about 5%.
7. The method of claim 5 wherein the renal impairment comprises
renal failure.
8. The method of claim 5 wherein the renal impairment comprises a
rise in serum creatinine.
9. The method of claim 8 wherein the serum creatinine level on day
five is lower in subjects who were administered relaxin than in
subjects who were administered a placebo.
10. The method of claim 8 wherein serum creatinine increases of
more than about 0.5 mg/dl occur in fewer subjects who were
administered relaxin than in subjects who were administered a
placebo.
Description
RELATED APPLICATIONS
[0001] Field
[0002] The present disclosure relates to methods for treating
decompensation in human subjects afflicted with symptoms of acute
decompensated heart failure. The methods described herein employ
administration of relaxin.
[0003] Background
[0004] Acute heart failure (AHF) or acute decompensated heart
failure (ADHF) encompasses a heterogeneous group of disorders that
typically includes dyspnea (shortness of breath), edema (fluid
retention) and fatigue. For example, a patient who presents with
shortness of breath from an exacerbation of congestive heart
failure would fall within the group of AHF patients. However, the
diagnosis of AHF can be difficult and the optimal treatment remains
poorly defined despite the high prevalence of this condition and
its association with major morbidity and mortality. The
difficulties surrounding treatment begin with the lack of a clear
definition of the disease. The term "acute decompensated heart
failure" broadly represents new or worsening symptoms or signs of
dyspnea, fatigue or edema that lead to hospital admission or
unscheduled medical care. These symptoms are consistent with an
underlying worsening of left ventricular function. "Acute heart
failure" is sometimes defined as the onset of symptoms or signs of
heart failure in a patient with no prior history of heart failure
and previously normal function. This is an uncommon cause of AHF,
particularly in patients without concomitant acute coronary
syndromes. More frequently, AHF occurs in patients with previously
established myocardial dysfunction (systolic or diastolic) such as
in congestive heart failure (CHF) patients who present with an
exacerbation of symptoms or signs after a period of relative
stability (Allen and O'Connor, CMAJ 176(6):797-805, 2007).
Consequently, AHF can result without prior history of CHF, be based
on a pathophysiological origin in prior CHF patients (functional),
or be the result of anatomic causes in prior CHF patients
(structural). Thus, AHF can be a functional and/or a structural
disease.
[0005] The identification of the acute triggers for the
decompensation, as well as noninvasive characterization of cardiac
filling pressures and cardiac output is central to management.
Diuretics, vasodilators, continuous positive airway pressure and
inotropes can be used to alleviate symptoms. However, there are no
agents currently available for the treatment of AHF that have been
shown (in large prospective randomized clinical trials) to provide
significant improvements in intermediate-term clinical
outcomes.
[0006] AHF is the single most costly hospital admission diagnosis
according to the Center for Medicare and Medicaid Administration.
AHF accounts for more than one million hospitalizations per year
and re-hospitalizations within six months are as high as fifty
percent. The annual mortality rate approaches fifty percent (for
those patients with New York Heart Association class III or IV
symptoms). Generally, non-aggressive medical care during the
initial hospitalization, sub-optimal treatment before re-admission,
and patient noncompliance contribute strongly to the high
readmission rate. Fifty percent of patients with classic AHF
symptoms before admission receive no alteration in their treatment
at the initial consultation with their health care provider
(McBride et al., Pharmacotherapy 23(8):997-1020, 2003).
[0007] While AHF was traditionally viewed as a disorder associated
with sodium and water retention and left ventricular (LV)
dysfunction, it is now also understood to be associated with
neurohormonal activation (Schrier et al., The New England Journal
of Medicine 341(8):577-585, 1999). As indicated above, the clinical
syndrome of AHF is characterized by the development of dyspnea
associated with the rapid accumulation of fluid within the lung's
interstitial and alveolar spaces, resulting from acutely elevated
cardiac filling pressures (cardiogenic pulmonary edema). More
specifically, AHF can also present as elevated left ventricular
filling pressures and dyspnea without pulmonary edema. It is most
commonly due to left ventricular systolic or diastolic dysfunction,
with or without additional cardiac pathology, such as coronary
artery disease or valve abnormalities. In addition, a variety of
conditions or events can cause cardiogenic pulmonary edema due to
an elevated pulmonary capillary wedge pressure in the absence of
heart disease, including severe hypertension, particularly
renovascular hypertension, and severe renal disease.
[0008] Hospital admissions for AHF have increased during the past
few decades and are projected to continue to increase in the
future. AHF is usually diagnosed and managed based on tradition
rather than evidence. In order to reduce the costs associated with
this disorder and optimize patient outcomes, new approaches and
better treatment options are essential. Diuretic therapy has been
the main treatment for symptom relief for pulmonary congestion and
fluid retention. Continuous infusions of loop diuretic therapy
rather than bolus dosing may enhance efficacy and reduce the extent
of diuretic resistance. Catecholamine- and phosphodiesterase-based
inotropic therapies are efficacious, but the increased risk of
arrhythmogenesis and the potential for negative effects on survival
limit their use. NATROCOR (nesiritide marketed by Scios) used in
vasodilator therapy, is a pharmacological preload and afterload
reducer, but based on clinical trial evidence should be reserved
for those with resistance to intravenous nitrate therapy (McBride
et al., supra). Vasopressin receptor antagonists and adenosine
receptor antagonists offer some improved renal preservation during
aggressive diuresis (Tang et al., Current Cardiology Reviews
1(1):1-5, 2005).
[0009] Volume and perfusion status provide useful clues to a
patient's cardiac performance and help shape the treatment plan for
patients with AHF. Caregivers must frequently reassess the
patient's hemodynamic status to determine volume and perfusion
status. Volume status is determined by assessing if the patient is
wet, dry, or has a balanced fluid level (hypervolemia, hypovolemia,
or euvolemia, respectively), and perfusion is assessed by
determining if the patient is cold, cool/lukewarm, or warm (has
perfusion that is very low, slightly low, or normal, respectively).
Evidence of congestion includes the signs of neck vein distension,
elevated pressure in the right internal jugular vein, positive
abdominal jugular neck vein reflex, edema, ascites, and crackles
(rarely), as well as the symptoms of dyspnea, orthopnea, and
paroxysmal nocturnal dyspnea. In addition, various tests can be
performed at the time of admission including chest radiographs,
arterial blood gas levels, liver function tests, hematologic tests,
electrocardiograms, and basic metabolic profile. The findings on
physical examination and the results of assays of serum levels of
natriuretic peptides can be used to guide treatment in patients
with acute decompensated heart failure. Brain natriuretic peptide
or B-type natriuretic peptide (BNP) is secreted mainly from the
ventricular myocardium in response to elevations in end-diastolic
pressure and ventricular volume expansion. The measurement of BNP
can aid in diagnosis of CHF as AHF, and BNP levels can also be used
to assess clinical status and the effectiveness of therapies during
an admission for acute decompensation (Albert et al., Critical Care
Nurse 24(6):14-29, 2004).
[0010] While significant advances have been made in the realm of
chronic heart failure management, clinicians continue to grapple
with optimal strategies to treat acutely decompensated patients
including patients afflicted with AHF. There is now an increasing
awareness of the complex interplay that occurs between the heart
and kidneys among patients with heart failure. As such, many of the
traditional therapeutics used to treat this patient population can
significantly alter renal function and are, thus, no longer
considered optimal treatment options. A more comprehensive approach
is desired and the present disclosure addresses this need.
BRIEF SUMMARY OF PREFERRED EMBODIMENTS
[0011] The present disclosure provides methods for treating
conditions associated with acute decompensated heart failure (AHF)
by administering relaxin. The number of hospital admissions due to
AHF related symptoms are on the steady rise and the cost associated
with caring for this population of patients is staggering. Thus, a
new therapeutic approach is needed and the disclosure addresses
this need. One advantage of this disclosure is that the
administration of relaxin results in a balanced vasodilation that
prevents subjects diagnosed with conditions associated with AHF
from further deteriorating. As such, the subjects can be maintained
at a steady-state level where hospitalization is not required and
the number or duration of hospital visits is significantly reduced.
Another advantage of the present disclosure is that relaxin, when
administered to patients, shows effectiveness with little to no
adverse drug reactions (ADRs). Herein, relaxin is shown to have a
beneficial effect on reducing acute decompensation without causing
ADRs. Thus, the present disclosure provides a treatment that leads
to balanced vasodilation in a specific patient population that
suffers from acute decompensation and is specifically suited to
benefit from relaxin treatment.
[0012] One aspect of the disclosure provides a method of reducing
acute cardiac decompensation events including selecting a human
subject with acute cardiac decompensation, wherein the subject has
a vasculature and the vasculature has relaxin receptors. The method
further includes administering to the subject a pharmaceutical
formulation including pharmaceutically active relaxin in an amount
effective to reduce acute cardiac decompensation in the subject by
binding to the relaxin receptors in the vasculature of the subject,
resulting in balanced vasodilation. The cardiac decompensation can
be due to any one or more causes, including but not limited to,
neurohormonal imbalance, fluid overload, cardiac arrhythmia, and
cardiac ischemia. In one embodiment, the human subject suffers from
acute vascular failure.
[0013] Relaxin employed in the pharmaceutical formulations of the
disclosure can be, for example, synthetic or recombinant relaxin,
or a pharmaceutically effective relaxin agonist. In one embodiment
of the disclosure, relaxin is H1 human relaxin. In another
embodiment, relaxin is H2 human relaxin. In yet another embodiment,
relaxin is H3 human relaxin. In a further embodiment, relaxin is
synthetic or recombinant human relaxin, or a pharmaceutically
effective relaxin agonist. Thus, the subject can be treated with a
pharmaceutical formulation of synthetic or recombinant human
relaxin or relaxin agonist. In one embodiment of the disclosure,
the subject is treated with synthetic human relaxin. In another
embodiment, the subject is treated with recombinant human relaxin.
In yet another embodiment, the subject is treated with a
pharmaceutically effective relaxin agonist. Relaxin can be
administered to the subject through a number of different routes,
including but not limited to, intravenously, subcutaneously,
intramuscularly, sublingually and via inhalation. More
specifically, the pharmaceutical formulation of relaxin or relaxin
agonist can be administered to the subject in an amount in a range
of about 10 to 1000 .mu.g/kg of subject body weight per day. As
such, relaxin is administered to the subject so as to maintain a
serum concentration of relaxin of from about 1 to 500 ng/ml.
[0014] Human subjects that would benefit from the methods of the
disclosure usually present with acute cardiac decompensation
events, including but not limited to, dyspnea, hypertension,
arrhythmia, reduced renal blood flow, and renal insufficiency,
wherein these events are often associated with readmission to the
hospital. In one embodiment of the disclosure, these acute cardiac
decompensation events are pathophysiological in nature. Most
commonly, such events are associated with acute decompensated heart
failure (AHF). In one embodiment, the human subject suffers from
acute vascular failure. In another embodiment, the acute cardiac
decompensation is intermittent. In an alternative embodiment, the
acute cardiac decompensation is chronic.
[0015] Another aspect of the disclosure provides a method of
treating acute cardiac decompensation associated with acute
decompensated heart failure (AHF). The method includes selecting a
human subject with acute cardiac decompensation, wherein the
subject has a vasculature and the vasculature has relaxin
receptors, and further, administering to the subject a
pharmaceutical formulation including pharmaceutically active
relaxin or pharmaceutically effective relaxin agonist. Relaxin is
administered in an amount effective to reduce the acute cardiac
decompensation in the subject by binding to the relaxin receptors
in the vasculature of the subject, resulting in balanced
vasodilation. The cardiac decompensation can be due to any one or
more causes, including but not limited to, neurohormonal imbalance,
fluid overload, cardiac arrhythmia, and cardiac ischemia. In one
embodiment, the human subject suffers from acute vascular
failure.
[0016] The disclosure further encompasses a method of treating
acute cardiac decompensation associated with acute decompensated
heart failure (AHF), including administering a formulation which
includes pharmaceutically active synthetic human relaxin or
pharmaceutically effective relaxin agonist to a human subject in an
amount in a range of about 10 to 1000 .mu.g/kg of subject body
weight per day, and continuing the administration over a period of
time sufficient to achieve an amelioration in acute cardiac
decompensation events, including but not limited to, dyspnea,
hypertension, arrhythmia, reduced renal blood flow, and renal
insufficiency. In one preferred embodiment, pharmaceutically
effective relaxin or an agonist thereof is administered at about 30
.mu.g/kg/day which results in serum concentrations of 10 ng/ml. In
another preferred embodiment, pharmaceutically effective relaxin or
an agonist thereof is administered at about 10 to about 250
.mu.g/kg/day. The amelioration may manifest itself as a reduced
number of acute cardiac decompensation events and/or less severe
acute cardiac decompensation events in the subject. In one
embodiment, the human subject suffers from acute vascular
failure.
[0017] Still, another aspect of the disclosure provides a method of
treating acute decompensated heart failure (AHF) in a human subject
who also suffers from renal insufficiency. This method includes
selecting a human subject with symptoms of acute cardiac
decompensation and renal insufficiency, wherein the subject has a
systemic and renal vasculature comprising relaxin receptors. The
method further includes administering to the subject a
pharmaceutical formulation comprising pharmaceutically active
relaxin or pharmaceutically effective relaxin agonist, wherein
relaxin performs a dual action by binding to the relaxin receptors
in the systemic and renal vasculature of the subject, resulting in
balanced vasodilation. In one embodiment, the human subject suffers
from acute vascular failure. The cardiac decompensation can be due
to any one or more causes, including but not limited to,
neurohormonal imbalance, fluid overload, cardiac arrhythmia, and
cardiac ischemia. The subject may suffer from symptoms such as
dyspnea, hypertension, arrhythmia, reduced renal blood flow, and
the like, wherein the symptoms are commonly further associated with
readmission to the hospital. Notably, the subject may be further
experiencing elevated levels of brain natriuretic peptide (BNP). In
addition, a reversal of the acute cardiac decompensation may occur
in combination with a decrease in circulating levels of BNP.
[0018] Another aspect of the present disclosure provides a method
of modulating endothelin in a human subject, including selecting a
human subject with a neurohormonal imbalance, wherein the subject
has a vasculature and the vasculature has relaxin receptors. The
method further includes administering to the subject a
pharmaceutical formulation which includes pharmaceutically active
relaxin or pharmaceutically effective relaxin agonist in an amount
effective to reduce the neurohormonal imbalance in the subject by
binding to the relaxin receptors in the vasculature of the subject,
resulting in balanced vasodilation. In one embodiment, the human
subject suffers from acute vascular failure.
[0019] The disclosure further contemplates a method of reducing
mortality risk in a human patient with symptoms of acute cardiac
decompensation. This method includes selecting a human subject with
acute cardiac decompensation, wherein the subject has a vasculature
and the vasculature has relaxin receptors, and administering to the
subject a pharmaceutical formulation including pharmaceutically
active relaxin or pharmaceutically effective relaxin agonist. The
relaxin is administered in an amount effective to reduce the acute
cardiac decompensation in the subject by binding to the relaxin
receptors in the vasculature of the subject, thereby resulting in
reduced levels of brain natriuretic peptide (BNP). The reduced
levels of BNP can be physically measured in order to predict risk
of mortality in the patient. Generally, the reduced levels of BNP
are due to reduced cardiac stress following a reduction in vascular
resistance. The reduction in vascular resistance is in turn due to
the balanced vasodilation which is the result of relaxin binding to
relaxin receptors that are found on smooth muscle cells of the
renal vasculature. In one embodiment, the human subject suffers
from acute vascular failure.
[0020] Generally, the reversal of the acute cardiac decompensation
in the subjects occurs through activation of specific relaxin
receptors such as the LGR7 and LGR8 receptors. In particular, LGR7
and LGR8 receptors are activated through the binding of relaxin or
a relaxin agonist, wherein the binding triggers the production of
nitric oxide (NO) which results in a balanced vasodilation. These
relaxin specific receptors are located on smooth muscle tissue of
the vasculature which includes systemic and renal vasculature.
[0021] Yet another aspect of the disclosure provides a method of
reducing acute cardiac decompensation events, including selecting a
human subject with acute cardiac decompensation, wherein the
subject has a vasculature and the vasculature has relaxin
receptors. The method further includes administering to the subject
a pharmaceutical formulation including pharmaceutically active
relaxin or pharmaceutically effective relaxin agonist in an amount
effective to reduce acute cardiac decompensation in the subject by
binding to the relaxin receptors in the vasculature of the subject,
resulting in balanced vasodilation, wherein the relaxin is
administered to the subject so as to maintain a serum concentration
of relaxin of equal or greater than about 3 ng/ml. The method
further includes administering to the subject a pharmaceutical
formulation including pharmaceutically active relaxin or
pharmaceutically effective relaxin agonist in an amount effective
to reduce acute cardiac decompensation in the subject by binding to
the relaxin receptors in the vasculature of the subject, resulting
in balanced vasodilation, wherein the relaxin is administered to
the subject so as to maintain a serum concentration of relaxin of
equal or greater than about 10 ng/ml. In one embodiment, the human
subject suffers from acute vascular failure.
[0022] Still, another aspect of the disclosure provides relaxin for
use in the treatment of acute cardiac decompensation. The acute
cardiac decompensation is commonly associated with acute
decompensated heart failure (AHF). The method includes selecting a
human subject with acute cardiac decompensation, wherein the
subject has a vasculature and the vasculature has relaxin
receptors, and further, administering to the subject a
pharmaceutical formulation including pharmaceutically active
relaxin or pharmaceutically effective relaxin agonist. In one
embodiment, the human subject suffers from acute vascular failure.
Relaxin or a relaxin agonist is administered in an amount effective
to reduce the acute cardiac decompensation in the subject by
binding to the relaxin receptors in the vasculature of the subject,
resulting in balanced vasodilation. The cardiac decompensation can
be due to any one or more causes, including but not limited to,
neurohormonal imbalance, fluid overload, cardiac arrhythmia, and
cardiac ischemia. The disclosure also contemplates relaxin for use
in reducing acute cardiac decompensation events.
[0023] The disclosure further encompasses relaxin for use in
treating acute decompensated heart failure (AHF) in a human subject
who also suffers from renal insufficiency; relaxin for use in
modulating endothelin in a human subject; and relaxin for use in
reducing mortality risk in a human patient with symptoms of acute
cardiac decompensation as discussed herein.
[0024] Another aspect of the disclosure provides a method of
reducing acute cardiac decompensation events. The method includes
selecting a human subject with acute cardiac decompensation,
wherein the subject has a vasculature and the vasculature has
relaxin receptors; and administering to the subject a
pharmaceutical formulation including pharmaceutically active
relaxin in an amount effective to reduce acute cardiac
decompensation in the subject by binding to the relaxin receptors
in the vasculature of the subject. In this method, treatment with
relaxin results in a reduction of acute cardiac decompensation
events lasting for at least about 1 to 14 days from onset of
relaxin treatment. The acute cardiac decompensation events include,
but are not limited to dyspnea, extra body weight due to retention
of fluids, length of hospital stay, likelihood of hospital
re-admission, need for loop diuretics, need for intravenous
nitroglycerin, and an incidence of worsening heart failure. In one
embodiment, the patients are treated with relaxin for 48 hours. In
another embodiment, the patients are treated with relaxin for 24
hours. In yet another embodiment, the patients are treated with
relaxin for 12 hours. In still another embodiment, the patients are
treated with relaxin for 6 hours. The effects of relaxin can be
measured at any time point, for example, at 1 day, 2 days, 3 days,
4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days,
12 days, 13 days, 14 days or later.
[0025] In one preferred embodiment, relaxin is administered at
about 30 mcg/kg/day. In one preferred embodiment, relaxin is
administered at about 30 mcg/kg/day. In another preferred
embodiment, relaxin is administered at about 35 mcg/kg/day. In
another preferred embodiment, relaxin is administered at about 40
mcg/kg/day. In another preferred embodiment, relaxin is
administered at about 45 mcg/kg/day. In another preferred
embodiment, relaxin is administered at about 50 mcg/kg/day. In
another preferred embodiment, relaxin is administered at about 55
mcg/kg/day. In another preferred embodiment, relaxin is
administered at about 60 mcg/kg/day. In another preferred
embodiment, relaxin is administered at about 65 mcg/kg/day. In
another preferred embodiment, relaxin is administered at about 70
mcg/kg/day. In another preferred embodiment, relaxin is
administered at about 75 mcg/kg/day. In another preferred
embodiment, relaxin is administered at about 80 mcg/kg/day. In
another preferred embodiment, relaxin is administered at about 85
mcg/kg/day. In another preferred embodiment, relaxin is
administered at about 100 mcg/kg/day. Relaxin may also be
administered at a dosage of 90 to 200 mcg/kg/day. Pharmaceutically
effective relaxin includes recombinant or synthetic H1 human
relaxin, H2 human relaxin or H3 human relaxin or an agonist or a
variant thereof. In one preferred embodiment, relaxin is
administered to the subject so as to maintain a serum concentration
of about 10 ng/ml. The pharmaceutical formulation of relaxin can be
administered intravenously, subcutaneously, intramuscularly,
sublingually or via inhalation. In one preferred embodiment, the
pharmaceutical formulation of relaxin is administered
intravenously. The relaxin receptors are activated through the
binding of relaxin and include, but are not limited to, LRG7, LGR8,
GPCR135, and GPCR142. The binding of relaxin to the relaxin
receptors triggers the production of nitric oxide (NO) which
results in balanced vasodilation. The relaxin receptors are
located, for example, on the smooth muscle tissue of the
vasculature.
[0026] The present disclosure also provides a method for treating a
cardiovascular condition comprising: administering to a human
subject a pharmaceutically active H2 relaxin in an amount effective
to treat the cardiovascular condition, wherein the cardiovascular
condition is diagnosed based on the presence of two or more of the
group consisting of dyspnea at rest or with minimal exertion,
pulmonary congestion on chest X-ray, and elevated natriuretic
peptide levels [brain natriuretic peptide (BNP).gtoreq.350 pg/mL or
NT-pro-BNP.gtoreq.1400 pg/mL]. In some embodiments, the
cardiovascular condition is acute heart failure and the two or more
comprise dyspnea at rest or with minimal exertion, and pulmonary
congestion on chest X-ray. In some embodiments, the cardiovascular
condition is acute heart failure and the two or more comprise
dyspnea at rest or with minimal exertion, and elevated natriuretic
peptide levels [brain natriuretic peptide (BNP).gtoreq.350 pg/mL or
NT-pro-BNP.gtoreq.1400 pg/mL]. In some embodiments, the
cardiovascular condition is acute heart failure and the two or more
comprise pulmonary congestion on chest X-ray and elevated
natriuretic peptide levels [brain natriuretic peptide
(BNP).gtoreq.350 pg/mL or NT-pro-BNP.gtoreq.1400 pg/mL]. In some
preferred embodiments, the subject is a male or a nonpregnant
female. In some preferred embodiments, the subject has a systolic
blood pressure of at least about 125 mmHg.
[0027] In addition, the present disclosure provides a method for
treating dyspnea associated with acute heart failure, comprising:
administering to a human subject a pharmaceutically active H2
relaxin in an amount effective to reduce dyspnea in the subject,
wherein the subject has dyspnea associated with acute heart failure
and is in a hypertensive or normotensive state at the onset of the
administering. In some embodiments, the methods further comprise
selecting the human subject having dyspnea associated with acute
heart failure and in a hypertensive or normotensive state, prior to
the administering step. In some embodiments, the H2 relaxin is
administered for at least 24 or 48 hours, while in others the H2
relaxin is administered over 48 hours. In some embodiments, the H2
relaxin is administered at an intravenous infusion rate in the
range of about 10 .mu.g/kg/day to about 250 .mu.g/kg/day, in a
range of about 30 .mu.g/kg/day to about 100 .mu.g/kg/day, or at
about 30 .mu.g/kg/day. In some embodiments, the reduction in
dyspnea is statistically significant at 6 hours after the onset of
treatment compared to treatment without H2 relaxin, at 12 hours
after the onset of treatment compared to treatment without H2
relaxin, or at 6, 12 and 24 hours after the onset of treatment
compared to placebo. In some embodiments, the reduction in dyspnea
lasts for at least about twice the duration of treatment, at least
about 4 times the duration of treatment, or at least about 7 times
the duration of treatment. In some embodiments, the methods further
comprise reducing the body weight of the subject by at least about
0.5 kg over a 14-day period compared to treatment without H2
relaxin, or at least about 1 kg over a 14-day period compared to
treatment without H2 relaxin. In some embodiments, the subject is
renally impaired. In a subset of these embodiments, the subject has
a creatinine clearance in the range of about 35 to about 75 mL/min.
In some embodiments, the methods further comprise reducing the
60-day risk of death or rehospitalization of the subject compared
to treatment of acute decompensated heart failure without H2
relaxin. In a subset of these embodiments, the 60-day risk of death
or rehospitalization is reduced by at least 50%. In some preferred
embodiments, the subject has dyspnea requiring hospitalization. In
some embodiments, the methods further comprise reducing the
hospitalization length of stay by at least one day compared to
treatment of acute decompensated heart failure without H2 relaxin.
In some methods, the H2 relaxin is administered at an intravenous
infusion rate in the range of about 30 .mu.g/kg/day and the
hospitalization length of stay is reduced by at least two days
compared to treatment of acute decompensated heart failure without
H2 relaxin. In some embodiments, the methods further comprise
reducing the 60-day risk of rehospitalization due to heart failure
or renal insufficiency of the subject compared to treatment of
acute decompensated heart failure without H2 relaxin. In some
preferred embodiments, the 60-day risk of rehospitalization due to
heart failure or renal insufficiency is reduced by at least about
50%. In some methods, the H2 relaxin is administered at an
intravenous infusion rate in the range of about 30 .mu.g/kg/day and
the 60-day risk of rehospitalization due to heart failure or renal
insufficiency is reduced by at least about 70%. In some
embodiments, the methods comprise reducing the 180-day risk of
cardiovascular death of the subject compared to treatment of acute
decompensated heart failure without H2 relaxin. In some preferred
embodiments, the 180-day risk of cardiovascular death is reduced by
at least about 50%. In some embodiments, the H2 relaxin is
administered at an intravenous infusion rate less than about 250
.mu.g/kg/day and the 180-day risk of cardiovascular death is
reduced by at least about 70%. In some embodiments, the methods
further comprise reducing the 180-day risk of all-cause mortality
of the subject compared to treatment of acute decompensated heart
failure without H2 relaxin. In some preferred embodiments, the
180-day risk of all-cause mortality is reduced by at least about
25%. In some embodiments, the H2 relaxin is administered at an
intravenous infusion rate less than about 250 .mu.g/kg/day and the
180-day risk of all-cause mortality is reduced by at least about
50%. In some preferred embodiments, the subject is a male or a
nonpregnant female. In some preferred embodiments, the subject has
a systolic blood pressure of at least about 125 mmHg.
[0028] The disclosure further provides a method for treating
dyspnea associated with acute decompensated heart failure,
comprising: administering to a human subject a pharmaceutically
active H2 relaxin in an amount effective to reduce dyspnea in the
subject, wherein the subject has dyspnea associated with acute
decompensated heart failure and at least one indicia of cardiac
ischemia. In some embodiments, the method further comprises
selecting the human subject having dyspnea associated with acute
decompensated heart failure and at least one indicia of cardiac
ischemia, prior to the administering step. In some embodiments, the
at least one indicia of cardiac ischemia is selected from the group
consisting of a positive troponin test, an abnormal
electrocardiogram, the presence of chest pain, the presence of an
arrhythmia, a positive creatine kinase-MB test, and an abnormal
echocardiogram. In some embodiments of the method, the subject also
has a left ventricular ejection fraction in the range of 20-40%. In
another embodiment, the subject has a left ventricular ejection
fraction of at least 40%. In some embodiments of the method, the
subject is normotensive or hypertensive. In another embodiment, the
subject has a systolic blood pressure of at least about 125 mm Hg.
In some embodiments of the method, the subject is renally impaired.
In another embodiment, the subject has a creatinine clearance in
the range of about 35 to about 75 mL/min. In some embodiments of
the method for treating a cardiovascular condition, the H2 relaxin
is administered for at least 24 or 48 hours. In another embodiment,
the H2 relaxin is administered over 48 hours. In yet another
embodiment, the H2 relaxin is administered at an infusion rate in
the range of about 10 .mu.g/kg/day to about 960 .mu.g/kg/day. In
yet another embodiment of the method, the H2 relaxin is
administered at an intravenous infusion rate in the range of about
10 .mu.g/kg/day to about 250 .mu.g/kg/day. In yet another
embodiment, the H2 relaxin is administered at an intravenous
infusion rate in the range of about 30 .mu.g/kg/day to about 100
.mu.g/kg/day. In yet another embodiment, the H2 relaxin is
administered at an intravenous infusion rate in the range of about
30 .mu.g/kg/day. In some embodiments of the method, the subject has
dyspnea requiring hospitalization. In some preferred embodiments,
the subject is a male or a nonpregnant female.
[0029] The disclosure further provides a method for treating acute
decompensated heart failure, comprising: a) identifying a subject
with acute decompensated heart failure; b) assessing the orthopnea
status in the subject; c) selecting an initial dosage of a
pharmaceutically active H2 relaxin based upon the orthopnea status
in the patient; and d) administering the dosage to the subject. In
some embodiments of the method, the selected initial dosage is
higher in the presence of orthopnea than in the absence of
orthopnea. In some embodiments, the selected initial dosage is at
least about 30 .mu.g/kg/day but below about 100 .mu.g/kg/day in the
presence of orthopnea. In some preferred embodiments, the subject
is a male or a nonpregnant female. In some preferred embodiments,
the subject has a systolic blood pressure of at least about 125
mmHg.
[0030] The disclosure further provides a method for treating
dyspnea associated with acute decompensated heart failure,
comprising: administering to a human subject a pharmaceutically
active H2 relaxin in an amount effective to reduce dyspnea in the
subject, wherein the subject has acute decompensated heart failure
and a left ventricular ejection from of at least 20%. In some
embodiments, the method further comprises selecting the human
subject having acute decompensated heart failure and a left
ventricular ejection from of at least 20%, prior to the
administering step. In some embodiments, the subject has a left
ventricular ejection fraction of at least about 20%. In some
embodiments of the method, the subject has a left ventricular
ejection fraction of at least about 40%. In one embodiment, the
subject is normotensive, while in other embodiments the subject is
hypertensive. In some embodiments, the subject has a systolic blood
pressure of at least about 125 mm Hg. In another embodiment, the
subject is renally impaired. In another embodiment, the subject has
a creatinine clearance in the range of about 35 to about 75 mL/min.
In another embodiment of the method, the H2 relaxin is administered
for at least 24 or 48 hours. In yet another embodiment, the H2
relaxin is administered over 48 hours. In yet another embodiment,
the H2 relaxin is administered at an infusion rate in the range of
about 10 .mu.g/kg/day to about 960 .mu.g/kg/day. In yet another
embodiment, H2 relaxin is administered at an intravenous infusion
rate in the range of about 10 .mu.g/kg/day to about 250
.mu.g/kg/day. In yet another embodiment, H2 relaxin is administered
at an intravenous infusion rate in the range of about 30
.mu.g/kg/day to about 100 .mu.g/kg/day. In yet another embodiment,
H2 relaxin is administered at an intravenous infusion rate in the
range of about 30 .mu.g/kg/day. In some embodiments, the methods
further comprise reducing the 60-day risk of death or
rehospitalization of the subject compared to treatment of acute
decompensated heart failure without H2 relaxin. In some
embodiments, the 60-day risk of death or rehospitalization is
reduced by at least 50%. In some embodiments of the method, the
subject has dyspnea requiring hospitalization. In some embodiments,
the methods further comprise reducing the hospitalization length of
stay by at least one day compared to treatment of acute
decompensated heart failure without H2 relaxin. In some
embodiments, the H2 relaxin is administered at an intravenous
infusion rate in the range of about 30 .mu.g/kg/day and the
hospitalization length of stay is reduced by at least two days
compared to treatment of acute decompensated heart failure without
H2 relaxin. In some embodiments, the methods further comprise
reducing the 60-day risk of rehospitalization due to heart failure
or renal insufficiency of the subject compared to treatment of
acute decompensated heart failure without H2 relaxin. In another
embodiment, the 60-day risk of rehospitalization due to heart
failure or renal insufficiency is reduced by at least about 50%. In
another embodiment, the H2 relaxin is administered at an
intravenous infusion rate in the range of about 30 .mu.g/kg/day and
the 60-day risk of rehospitalization due to heart failure or renal
insufficiency is reduced by at least about 70%. In some
embodiments, the methods further comprise reducing the 180-day risk
of cardiovascular death of the subject compared to treatment of
acute decompensated heart failure without H2 relaxin. In some
embodiments, the 180-day risk of cardiovascular death is reduced by
at least about 50%. In some embodiments of the method, the H2
relaxin is administered at an intravenous infusion rate less than
about 250 .mu.g/kg/day and the 180-day risk of cardiovascular death
is reduced by at least about 70%. In some embodiments, the methods
further comprise reducing the 180-day risk of all-cause mortality
of the subject compared to treatment of acute decompensated heart
failure without H2 relaxin. In another embodiment, the 180-day risk
of all-cause mortality is reduced by at least about 25%. In another
embodiment, the H2 relaxin is administered at an intravenous
infusion rate less than about 250 .mu.g/kg/day and the 180-day risk
of all-cause mortality is reduced by at least about 50%. In some
preferred embodiments, the subject is a male or a nonpregnant
female.
[0031] The disclosure further provides a method for treating acute
decompensated heart failure, comprising: a) selecting a subject
with acute decompensated heart failure and a systolic blood
pressure of at least 125 mm Hg; and b) administering to the subject
a pharmaceutically active H2 relaxin in an amount effective to
reduce in-hospital worsening heart failure in the subject. In some
embodiments of the method, the subject is renally impaired. In some
preferred embodiments, the in-hospital worsening heart failure
comprises one or more of worsening dyspnea, need for additional
intravenous therapy to treat the heart failure, need for mechanical
support of breathing, and need for mechanical support of blood
pressure. In another embodiment, the subject has a creatinine
clearance in the range of about 35 to about 75 mL/min. In some
embodiments, the H2 relaxin is administered for at least 24 or 48
hours. In some embodiments, the H2 relaxin is administered over 48
hours. In another embodiment, the H2 relaxin is administered at an
infusion rate in the range of about 10 .mu.g/kg/day to about 960
.mu.g/kg/day. In another embodiment, the H2 relaxin is administered
at an intravenous infusion rate in the range of about 10
.mu.g/kg/day to about 250 .mu.g/kg/day. In yet another embodiment,
the H2 relaxin is administered at an intravenous infusion rate in
the range of about 30 .mu.g/kg/day to about 100 .mu.g/kg/day. In
yet another embodiment, the H2 relaxin is administered at an
intravenous infusion rate in the range of about 30 .mu.g/kg/day. In
some embodiments, the method further comprises reducing the 60-day
risk of death or rehospitalization of the subject compared to
treatment of acute decompensated heart failure without H2 relaxin.
In some embodiments, the 60-day risk of death or rehospitalization
is reduced by at least 50%. In some embodiments, the subject has
pulmonary congestion as defined by the presence of interstitial
edema on chest radiograph. In some embodiments, the method further
comprises reducing the hospitalization length of stay by at least
one day compared to treatment of acute decompensated heart failure
without H2 relaxin. In some embodiments, the H2 relaxin is
administered at an intravenous infusion rate in the range of about
30 .mu.g/kg/day and the hospitalization length of stay is reduced
by at least two days compared to treatment of acute decompensated
heart failure without H2 relaxin. In some embodiments, the method
further comprises reducing the 60-day risk of rehospitalization due
to heart failure or renal insufficiency of the subject compared to
treatment of acute decompensated heart failure without H2 relaxin.
In some embodiments, the 60-day risk of rehospitalization due to
heart failure or renal insufficiency is reduced by at least about
50%. In some embodiments, the H2 relaxin is administered at an
intravenous infusion rate in the range of about 30 .mu.g/kg/day and
the 60-day risk of rehospitalization due to heart failure or renal
insufficiency is reduced by at least about 70%. In some
embodiments, the method further comprises reducing the 180-day risk
of cardiovascular death of the subject compared to treatment of
acute decompensated heart failure without H2 relaxin. In another
embodiment, the 180-day risk of cardiovascular death is reduced by
at least about 50%. In another embodiment, the H2 relaxin is
administered at an intravenous infusion rate less than about 250
.mu.g/kg/day and the 180-day risk of cardiovascular death is
reduced by at least about 70%. In some embodiments, the method
further comprises reducing the 180-day risk of all-cause mortality
of the subject compared to treatment of acute decompensated heart
failure without H2 relaxin. In another embodiment of the method,
the 180-day risk of all-cause mortality is reduced by at least
about 25%. In another embodiment, the H2 relaxin is administered at
an intravenous infusion rate less than about 250 .mu.g/kg/day and
the 180-day risk of all-cause mortality is reduced by at least
about 50%. In some preferred embodiments, the subject is a male or
a nonpregnant female.
[0032] The disclosure further provides a method for treating, acute
decompensated heart failure comprising: a) selecting a subject with
acute decompensated heart failure and a left ventricular ejection
fraction of at least about 20%; and b) administering to the subject
a pharmaceutically active H2 relaxin in an amount effective to
reduce at least one acute heart failure sign or symptom in the
subject. In some embodiments, the at least one acute heart failure
sign or symptom comprises one or more of the group consisting of
dyspnea at rest, orthopnea, dyspnea on exertion, edema, rales,
pulmonary congestion, jugular venous pulse or distension, edema
associated weight gain, high pulmonary capillary wedge pressure,
high left ventricular end-diastolic pressure, high systemic
vascular resistance, low cardiac output, low left ventricular
ejection fraction, need for intravenous diuretic therapy, need for
additional intravenous vasodilator therapy, and incidence of
worsening in-hospital heart failure. In another embodiment, the
subject has a left ventricular ejection fraction of at least 40%.
In another embodiment, the subject is normotensive or hypertensive.
In yet another embodiment, the subject has a systolic blood
pressure of at least about 125 mm Hg. In some embodiments, the
subject is renally impaired. In another embodiment, the subject has
a creatinine clearance in the range of about 35 to about 75 mL/min.
In some embodiments of the method, the H2 relaxin is administered
for at least 24 or 48 hours. In another embodiment, the H2 relaxin
is administered over 48 hours. In another embodiment, the H2
relaxin is administered at an infusion rate in the range of about
10 .mu.g/kg/day to about 960 .mu.g/kg/day. In yet another
embodiment, the H2 relaxin is administered at an intravenous
infusion rate in the range of about 10 .mu.g/kg/day to about 250
.mu.g/kg/day. In yet another embodiment, the H2 relaxin is
administered at an intravenous infusion rate in the range of about
30 .mu.g/kg/day to about 100 .mu.g/kg/day. In yet another
embodiment, the H2 relaxin is administered at an intravenous
infusion rate in the range of about 30 .mu.g/kg/day. In some
embodiments, the method further comprises reducing the 60-day risk
of death or rehospitalization of the subject compared to treatment
of acute decompensated heart failure without H2 relaxin. In some
embodiments, the 60-day risk of death or rehospitalization is
reduced by at least 50%. In some embodiments, the subject has
dyspnea requiring hospitalization. In some embodiments, the method
further comprises reducing the hospitalization length of stay by at
least one day compared to treatment of acute decompensated heart
failure without H2 relaxin. In another embodiment, the H2 relaxin
is administered at an intravenous infusion rate in the range of
about 30 .mu.g/kg/day and the hospitalization length of stay is
reduced by at least two days compared to treatment of acute
decompensated heart failure without H2 relaxin. In some
embodiments, the method further comprises reducing the 60-day risk
of rehospitalization due to heart failure or renal insufficiency of
the subject compared to treatment of acute decompensated heart
failure without H2 relaxin. In another embodiment, the 60-day risk
of rehospitalization due to heart failure or renal insufficiency is
reduced by at least about 50%. In another embodiment, the H2
relaxin is administered at an intravenous infusion rate in the
range of about 30 .mu.g/kg/day and the 60-day risk of
rehospitalization due to heart failure or renal insufficiency is
reduced by at least about 70%. In some embodiments, the method
further comprises reducing the 180-day risk of cardiovascular death
of the subject compared to treatment of acute decompensated heart
failure without H2 relaxin. In some embodiments, the 180-day risk
of cardiovascular death is reduced by at least about 50%. In
another embodiment, the H2 relaxin is administered at an
intravenous infusion rate less than about 250 .mu.g/kg/day and the
180-day risk of cardiovascular death is reduced by at least about
70%. In some embodiments, the method further comprises reducing the
180-day risk of all-cause mortality of the subject compared to
treatment of acute decompensated heart failure without H2 relaxin.
In another embodiment, the 180-day risk of all-cause mortality is
reduced by at least about 25%. In another embodiment, the H2
relaxin is administered at an intravenous infusion rate less than
about 250 .mu.g/kg/day and the 180-day risk of all-cause mortality
is reduced by at least about 50%. In some preferred embodiments,
the subject is a male or a nonpregnant female.
[0033] The disclosure further provides a method for treating acute
decompensated heart failure, comprising administering to a subject
with acute decompensated heart failure a pharmaceutically active H2
relaxin in an amount effective to reduce diuretic use during a
hospital stay compared to treatment of acute decompensated heart
failure without using H2 relaxin. In some embodiments, the H2
relaxin is administered at an infusion rate in the range of about
10 .mu.g/kg/day to about 100 .mu.g/kg/day. In some embodiments, the
loop diuretic use during the hospital stay is reduced compared to
treatment of acute decompensated heart failure without H2 relaxin.
In another embodiment, the loop diuretic use is reduced by at least
10% over a 14-day period compared to treatment without H2 relaxin.
In yet another embodiment, the loop diuretic use is reduced by at
least 20% over a 14-day period compared to treatment without H2
relaxin. In yet another embodiment, the loop diuretic use is
reduced by at least 30% over a 14-day period compared to treatment
without H2 relaxin. In some embodiments, the subject has a left
ventricular ejection fraction of at least 40%. In some embodiments,
the subject is normotensive or hypertensive. In another embodiment,
the subject has a systolic blood pressure of at least about 125 mm
Hg. In another embodiment, the subject is renally impaired. In yet
another embodiment, the subject has a creatinine clearance in the
range of about 35 to about 75 mL/min. In some embodiments, the H2
relaxin is administered for at least 24 or 48 hours. In another
embodiment, the H2 relaxin is administered over 48 hours. In yet
another embodiment, the H2 relaxin is administered at an infusion
rate in the range of about 10 .mu.g/kg/day to about 960
.mu.g/kg/day. In yet another embodiment, the H2 relaxin is
administered at an intravenous infusion rate in the range of about
10 .mu.g/kg/day to about 250 .mu.g/kg/day. In yet another
embodiment, the H2 relaxin is administered at an intravenous
infusion rate in the range of about 30 .mu.g/kg/day to about 100
.mu.g/kg/day. In yet another embodiment, the H2 relaxin is
administered at an intravenous infusion rate in the range of about
30 .mu.g/kg/day. In some embodiments, the method further comprises
reducing the 60-day risk of death or rehospitalization of the
subject compared to treatment of acute decompensated heart failure
without H2 relaxin. In some embodiments, the 60-day risk of death
or rehospitalization is reduced by at least 50%. In some
embodiments, the subject has dyspnea requiring hospitalization. In
some embodiments, the method further comprises reducing the
hospitalization length of stay by at least one day compared to
treatment of acute decompensated heart failure without H2 relaxin.
In some embodiments, the H2 relaxin is administered at an
intravenous infusion rate in the range of about 30 .mu.g/kg/day and
the hospitalization length of stay is reduced by at least two days
compared to treatment of acute decompensated heart failure without
H2 relaxin. In some embodiments, the method further comprises
reducing the 60-day risk of rehospitalization due to heart failure
or renal insufficiency of the subject compared to treatment of
acute decompensated heart failure without H2 relaxin. In some
embodiments, the 60-day risk of rehospitalization due to heart
failure or renal insufficiency is reduced by at least about 50%. In
another embodiment, the H2 relaxin is administered at an
intravenous infusion rate in the range of about 30 .mu.g/kg/day and
the 60-day risk of rehospitalization due to heart failure or renal
insufficiency is reduced by at least about 70%. In some
embodiments, the method further comprises reducing the 180-day risk
of cardiovascular death of the subject compared to treatment of
acute decompensated heart failure without H2 relaxin. In some
embodiments, the 180-day risk of cardiovascular death is reduced by
at least about 50%. In another embodiment, the H2 relaxin is
administered at an intravenous infusion rate less than about 250
.mu.g/kg/day and the 180-day risk of cardiovascular death is
reduced by at least about 70%. In some embodiments, the method
further comprises reducing the 180-day risk of all-cause mortality
of the subject compared to treatment of acute decompensated heart
failure without H2 relaxin. In some embodiments, the 180-day risk
of all-cause mortality is reduced by at least about 25%. In another
embodiment, the H2 relaxin is administered at an intravenous
infusion rate less than about 250 .mu.g/kg/day and the 180-day risk
of all-cause mortality is reduced by at least about 50%. In some
preferred embodiments, the subject is a male or a nonpregnant
female. In some preferred embodiments, the subject has a systolic
blood pressure of at least about 125 mmHg. Moreover the disclosure
provides a method for treating acute decompensated heart failure,
comprising administering to a human subject with acute
decompensated heart failure a pharmaceutically active H2 relaxin in
an amount effective to reduce the 60-day risk of death or
rehospitalization of the subject compared to treatment of acute
decompensated heart failure without H2 relaxin. In some
embodiments, the subject has at least one acute heart failure sign
or symptom selected from the group consisting of dyspnea at rest,
orthopnea, dyspnea on exertion, edema, rales, pulmonary congestion,
jugular venous pulse or distension, edema associated weight gain,
high pulmonary capillary wedge pressure, high left ventricular
end-diastolic pressure, high systemic vascular resistance, low
cardiac output, low left ventricular ejection fraction, need for
intravenous diuretic therapy, need for additional intravenous
vasodilator therapy, and incidence of worsening in-hospital heart
failure. In another embodiment, the subject has a left ventricular
ejection fraction of at least 20% or at least 40%. In another
embodiment, the subject is normotensive or hypertensive. In yet
another embodiment, the subject has a systolic blood pressure of at
least about 125 mm Hg. In some embodiments, the subject is renally
impaired. In another embodiment, the subject has a creatinine
clearance in the range of about 35 to about 75 mL/min. In some
embodiments of the method, the H2 relaxin is administered for at
least 24 hours. In another embodiment, the H2 relaxin is
administered over 48 hours. In another embodiment, the H2 relaxin
is administered at an infusion rate in the range of about 10
.mu.g/kg/day to about 960 .mu.g/kg/day. In yet another embodiment,
the H2 relaxin is administered at an intravenous infusion rate in
the range of about 10 .mu.g/kg/day to about 250 .mu.g/kg/day. In
yet another embodiment, the H2 relaxin is administered at an
intravenous infusion rate in the range of about 30 .mu.g/kg/day to
about 100 .mu.g/kg/day. In yet another embodiment, the H2 relaxin
is administered at an intravenous infusion rate in the range of
about 30 .mu.g/kg/day. In some embodiments, the 60-day risk of
death or rehospitalization is reduced by at least 50%. In some
embodiments, the subject has dyspnea requiring hospitalization. In
some embodiments, the method further comprises reducing the
hospitalization length of stay by at least one day compared to
treatment of acute decompensated heart failure without H2 relaxin.
In another embodiment, the H2 relaxin is administered at an
intravenous infusion rate in the range of about 30 .mu.g/kg/day and
the hospitalization length of stay is reduced by at least two days
compared to treatment of acute decompensated heart failure without
H2 relaxin. In some embodiments, the method further comprises
reducing the 60-day risk of rehospitalization due to heart failure
or renal insufficiency of the subject compared to treatment of
acute decompensated heart failure without H2 relaxin. In another
embodiment, the 60-day risk of rehospitalization due to heart
failure or renal insufficiency is reduced by at least about 50%. In
another embodiment, the H2 relaxin is administered at an
intravenous infusion rate in the range of about 30 .mu.g/kg/day and
the 60-day risk of rehospitalization due to heart failure or renal
insufficiency is reduced by at least about 70%. In some
embodiments, the method further comprises reducing the 180-day risk
of cardiovascular death of the subject compared to treatment of
acute decompensated heart failure without H2 relaxin. In some
embodiments, the 180-day risk of cardiovascular death is reduced by
at least about 50%. In another embodiment, the H2 relaxin is
administered at an intravenous infusion rate less than about 250
.mu.g/kg/day and the 180-day risk of cardiovascular death is
reduced by at least about 70%. In some embodiments, the method
further comprises reducing the 180-day risk of all-cause mortality
of the subject compared to treatment of acute decompensated heart
failure without H2 relaxin. In another embodiment, the 180-day risk
of all-cause mortality is reduced by at least about 25%. In another
embodiment, the H2 relaxin is administered at an intravenous
infusion rate less than about 250 .mu.g/kg/day and the 180-day risk
of all-cause mortality is reduced by at least about 50%. In some
preferred embodiments, the subject is a male or a nonpregnant
female.
BRIEF DESCRIPTION OF THE DRAWINGS
[0034] The present disclosure is best understood when read in
conjunction with the accompanying figures, which serve to
illustrate the preferred embodiments. It is understood, however,
that the disclosure is not limited to the specific embodiments
disclosed in the figures.
[0035] FIG. 1A depicts the peptide hormone H2 relaxin which is
similar in size and shape to insulin. FIG. 1B provides the amino
acid sequence of the B chain (SEQ ID NO:1) and the A chain (SEQ ID
NO:2 with X representing glutamic acid [E] or glutamine [Q]) of
human relaxin 2 (H2).
[0036] FIG. 2 is an illustration of a possible mechanism of action
for relaxin. Relaxin receptors LGR7 and LGR8 bind relaxin which
activates matrix metalloproteinases MMP-2 and MMP-9 to convert
endothelin-1 to truncated endothelin-1 (1-32) which in turn binds
to the endothelin B receptor (ET.sub.B receptor). This triggers
nitric oxide synthase (NOS) to produce nitric oxide (NO) which
increases vasodilation.
[0037] FIG. 3 is an illustration of the lumen of a blood vessel.
Arrows show the smooth muscle cells (SM) and the endothelium (E).
Relaxin receptors are located on the smooth muscle cells of the
blood vessels (systemic and renal vasculature).
[0038] FIG. 4 depicts stable decreases in systolic blood pressure
(SBP) in hypertensive and normotensive subjects in the clinical
trial of relaxin in patients with systemic sclerosis. Decreases in
blood pressure in patients that were hypertensive at study entry
was greater than the decreases in blood pressure in patients that
were normotensive at study entry. Blood pressure decreases were
stable during the six months of continuous dosing. None of the
patients developed hypotension during dosing.
[0039] FIG. 5 depicts stable improvement in renal function,
measured as predicted creatinine clearance (CrCl), during six
months of continuous dosing with relaxin but not with placebo in
patients with systemic sclerosis.
[0040] FIG. 6 depicts a Likert graph of percent moderate or marked
improvement in dyspnea in AHF patients treated with various dosages
of relaxin (i.e., 10, 30, 100 and 250 .mu.g/kg/day). as an average
of all time points.
[0041] FIG. 7 depicts a Likert graph of percent moderate or marked
improvement in dyspnea when patients suffering from AHF with a
systolic blood pressure (SBP) greater than the median were treated
with various dosages of relaxin (i.e., 10, 30, 100 and 250
.mu.g/kg/day). A beneficial effect was first seen at 6 hours of
treatment and relaxin administered at 30 .mu.g/kg/day showed a
sustained effect with about 90% improvement lasting over a period
of 14 days. In comparison, placebo treated patients continued to
decline after the placebo effect wore off.
[0042] FIG. 8 depicts a Likert graph of percent moderate or marked
improvement in dyspnea when patients suffering from AHF with a
creatinine clearance (CrCl) of less than the median were treated
with various dosages of relaxin (i.e., 10, 30, 100 and 250
.mu.g/kg/day) over a period of 48 hours. A beneficial effect was
first seen at 6 hours of treatment and relaxin showed a sustained
effect across various dosages lasting over a period of 14 days. In
comparison, placebo treated patients continued to decline after the
placebo effect wore off.
[0043] FIG. 9 shows a VAS graph of dyspnea improvement when AHF
patients with NT-pro-BNP levels greater than 2000 were treated with
various dosages of relaxin (i.e., 10, 30, 100 and 250 .mu.g/kg/day)
over a period of 48 hours. A marked improvement was seen in
patients treated with relaxin dosages of 30 .mu.g/kg/day and higher
compared to patients treated with placebo.
[0044] FIG. 10 shows a VAS graph of dyspnea improvement when AHF
patients with systolic blood pressure (SBP) levels greater than the
median were treated with various dosages of relaxin (i.e., 10, 30,
100 and 250 .mu.g/kg/day) over a period of 48 hours. A particularly
marked improvement was seen in patients treated with relaxin at 30
.mu.g/kg/day compared to patients treated with placebo.
[0045] FIG. 11 shows a VAS graph of dyspnea improvement when AHF
patients with creatinine clearance (CrCl) less than the median were
treated with various dosages of relaxin (i.e., 10, 30, 100 and 250
.mu.g/kg/day) over a period of 48 hours. A marked improvement was
seen in patients treated with various relaxin dosages. At 30
.mu.g/kg/day of relaxin patients experienced a sustained beneficial
effect compared to patients treated with placebo.
[0046] FIG. 12 depicts a graph showing that relaxin treatment
caused rapid relief of dyspnea in AHF patients within 6, 12 and 24
hours of administration. In particular administration of 30
.mu.g/kg/day of rhRlx resulted in a statistically significant
improvement in dyspnea.
[0047] FIG. 13 depicts a graph showing that relaxin treatment
caused sustained relief of dyspnea in AHF patients that lasted up
to 14 days (i.e., the maximum period measured).
[0048] FIG. 14 depicts a graph showing that the placebo-treated
patient group experienced a worsening of acute heart failure
compared to the relaxin-treated groups.
[0049] FIG. 15 shows that more AHF patients in the placebo group
received IV nitroglycerin by study day 5, than AHF patients in the
relaxin-treated groups. Nitroglycerin administration is a hospital
measure in the clinical study described herein.
[0050] FIGS. 16A and 16B respectively show that AHF patients in
several of the relaxin treated groups had a greater reduction in
body weight reflecting diuresis, while receiving less diuretic
(e.g., hospital measures and endpoints). This outcome indicates
that relaxin treatment resulted in renal vasodilation.
[0051] FIGS. 17A and 17B respectively show that relaxin treatment
was associated with a reduction in the length of hospital stay and
an increase in longevity out of the hospital.
[0052] FIG. 18 depicts a graph shows the percent cardiovascular
death (CV) or re-hospitalization on day 60 in AHF patients treated
with relaxin as compared to AHF patients treated with placebo. A
lower proportion of patients treated with relaxin had died as a
result of worsened cardiovascular disease. Likewise a lower
proportion of patients treated with relaxin required
re-hospitalization.
[0053] FIGS. 19A and 19B respectively show the percent
cardiovascular (CV) death and all cause mortality in
relaxin-treated AHF patients as compared to placebo-treated AHF
patients within a 180 day time frame post treatment. As illustrated
in the graphs, relaxin-treated patients fared dramatically better
with a significant reduction in both the number of cardiovascular
related deaths and in death by all causes as compared to patients
receiving placebo.
[0054] FIG. 20 shows the mean change in pulse from baseline in
relaxin and placebo treated AHF patients through day 14. The
differences between the groups are not significant, with all groups
seeing a small reduction in pulse after hospital admission,
indicating that relaxin treatment was not chronotropic.
[0055] FIG. 21 shows the mean change in systolic blood pressure
(mmHg) from baseline in relaxin and placebo treated AHF patients
during infusion. The average decrease in blood pressure over all
time points did not differ between any of the treatment groups and
the placebo groups.
[0056] FIGS. 22A and 22B show that relaxin treatment reduces blood
pressure in AHF patients in the study having a baseline systolic
blood pressure (SBP) above the median of the group, but not in AHF
patients having a baseline SBP below the median of the group. This
indicates that relaxin treatment preferentially vasodilates
vasoconstricted arteries, and does not cause deleterious
hypotension when administered to normotensive patients.
[0057] FIG. 23 shows that relaxin mediated improvement in dyspnea
is correlated with a normal or elevated baseline systolic blood
pressure (SBP).
DETAILED DESCRIPTION
General Overview
[0058] The present disclosure relates to methods of reducing
decompensation in populations of subjects that are specifically
prone to symptoms and events of acute decompensated heart failure
(AHF) such as dyspnea and fluid retention. Since AHF is the most
common reason why patients over 65 years of age are admitted to the
hospital, it is associated with staggering costs to the health care
system. The prognosis for patients that are admitted with AHF or
symptoms thereof has so far been dismal as it is associated with
high readmission and mortality rates within six months of
admission. As disclosed herein, when patients who have previously
been diagnosed with AHF and/or acute vascular failure or exhibit
symptoms that are typical of AHF and/or acute vascular failure are
treated with relaxin, their condition improves markedly and
stabilizes over a short period of time. More specifically, when
relaxin is administered to subjects who suffer from acute
decompensation associated with AHF, significant cardiovascular and
renal improvements are seen in these subjects. For example, when
patients were administered relaxin for as little as 48 hours the
improvements lasted over a period of 14 days. The improvements
included significant reductions in acute cardiac decompensation
events including a noticeable reduction in dyspnea (shortness of
breath), a reduction in excessive body weight due to fluid
retention (e.g., patients lost on the average about 1 kg of body
weight), shorter hospital stays (e.g., by as much as 2.5 days), a
decreased likelihood of hospital re-admissions, a lower need for
loop diuretics, a lower need for intravenous nitroglycerin and a
decreased incidence of worsening heart failure. These changes
significantly improved patient well-being and have strong future
implications on pharmacoeconomics including reductions in cost of
care.
[0059] Without wanting to be bound by theory, relaxin is
contemplated to act through specific receptors that are found on
smooth muscle cells that make up the vasculature (FIG. 3). As such,
relaxin is a specific, moderate, systemic and renal vasodilator
that improves heart and renal function via specific and balanced
vasodilation. Since AHF is a cardio-renal disease, relaxin benefits
patients afflicted with AHF and/or acute vascular failure and/or
symptoms thereof.
DEFINITIONS
[0060] The term "relaxin" refers to a peptide hormone which is well
known in the art (see FIG. 1). The term "relaxin", as used herein,
encompasses human relaxin, including intact full length human
relaxin or a portion of the relaxin molecule that retains
biological activity. The term "relaxin" encompasses human H1
preprorelaxin, prorelaxin, and relaxin; H2 preprorelaxin,
prorelaxin, and relaxin; and H3 preprorelaxin, prorelaxin, and
relaxin. The term "relaxin" further includes biologically active
(also referred to herein as "pharmaceutically active") relaxin from
recombinant, synthetic or native sources as well as relaxin
variants, such as amino acid sequence variants. As such, the term
contemplates synthetic human relaxin and recombinant human relaxin,
including synthetic H1, H2 and H3 human relaxin and recombinant H1,
H2 and H3 human relaxin. The term further encompasses active agents
with relaxin-like activity, such as relaxin agonists and/or relaxin
analogs and portions thereof that retain biological activity,
including all agents that competitively displace bound relaxin from
a relaxin receptor (e.g., LGR7 receptor, LGR8 receptor, GPCR135,
GPCR142, etc.). Thus, a pharmaceutically effective relaxin agonist
is any agent with relaxin-like activity that is capable of binding
to a relaxin receptor to elicit a relaxin-like response. In
addition, the nucleic acid sequence of human relaxin as used herein
must not be 100% identical to nucleic acid sequence of human
relaxin (e.g., H1, H2 and/or H3) but may be at least about 40%,
50%, 60%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%,
76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%,
89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical
to the nucleic acid sequence of human relaxin. Relaxin, as used
herein, can be made by any method known to those skilled in the
art. Examples of such methods are illustrated, for example, in U.S.
Pat. No. 5,759,807 as well as in Bullesbach et al. (1991) The
Journal of Biological Chemistry 266(17):10754-10761. Examples of
relaxin molecules and analogs are illustrated, for example, in U.S.
Pat. No. 5,166,191. Naturally occurring biologically active relaxin
may be derived from human, murine (i.e., rat or mouse), porcine, or
other mammalian sources. Also encompassed is relaxin modified to
increase in vivo half life, e.g., PEGylated relaxin (i.e., relaxin
conjugated to a polyethylene glycol), modifications of amino acids
in relaxin that are subject to cleavage by degrading enzymes, and
the like. The term also encompasses relaxin comprising A and B
chains having N- and/or C-terminal truncations. In general, in H2
relaxin, the A chain can be varied from A(1-24) to A(10-24) and B
chain from B(1-33) to B(10-22); and in H1 relaxin, the A chain can
be varied from A(1-24) to A(10-24) and B chain from B(1-32) to
B(10-22). Also included within the scope of the term "relaxin" are
other insertions, substitutions, or deletions of one or more amino
acid residues, glycosylation variants, unglycosylated relaxin,
organic and inorganic salts, covalently modified derivatives of
relaxin, preprorelaxin, and prorelaxin. Also encompassed in the
term is a relaxin analog having an amino acid sequence which
differs from a wild-type (e.g., naturally-occurring) sequence,
including, but not limited to, relaxin analogs disclosed in U.S.
Pat. No. 5,811,395. Possible modifications to relaxin amino acid
residues include the acetylation, formylation or similar protection
of free amino groups, including the N-terminal, amidation of
C-terminal groups, or the formation of esters of hydroxyl or
carboxylic groups, e.g., modification of the tryptophan (Trp)
residue at B2 by addition of a formyl group. The formyl group is a
typical example of a readily-removable protecting group. Other
possible modifications include replacement of one or more of the
natural amino-acids in the B and/or A chains with a different amino
acid (including the D-form of a natural amino-acid), including, but
not limited to, replacement of the Met moiety at B24 with
norleucine (Nle), valine (Val), alanine (Ala), glycine (Gly),
serine (Ser), or homoserine (HomoSer). Other possible modifications
include the deletion of a natural amino acid from the chain or the
addition of one or more extra amino acids to the chain. Additional
modifications include amino acid substitutions at the B/C and C/A
junctions of prorelaxin, which modifications facilitate cleavage of
the C chain from prorelaxin; and variant relaxin comprising a
non-naturally occurring C peptide, e.g., as described in U.S. Pat.
No. 5,759,807. Also encompassed by the term "relaxin" are fusion
polypeptides comprising relaxin and a heterologous polypeptide. A
heterologous polypeptide (e.g., a non-relaxin polypeptide) fusion
partner may be C-terminal or N-terminal to the relaxin portion of
the fusion protein. Heterologous polypeptides include
immunologically detectable polypeptides (e.g., "epitope tags");
polypeptides capable of generating a detectable signal (e.g., green
fluorescent protein, enzymes such as alkaline phosphatase, and
others known in the art); therapeutic polypeptides, including, but
not limited to, cytokines, chemokines, and growth factors. All such
variations or alterations in the structure of the relaxin molecule
resulting in variants are included within the scope of this
disclosure so long as the functional (biological) activity of the
relaxin is maintained. Preferably, any modification of relaxin
amino acid sequence or structure is one that does not increase its
immunogenicity in the individual being treated with the relaxin
variant. Those variants of relaxin having the described functional
activity can be readily identified using in vitro and in vivo
assays known in the art.
[0061] The term "heart failure" generally means that the heart is
not working as efficiently as it should. Heart failure occurs when
the heart muscle cannot keep up with the needs the body has for
blood flow. It is a syndrome, i.e., a collection of findings which
may arise from a number of causes. Heart failure can be caused by
weakening of the heart muscle (i.e., cardiomyopathy), leaving it
unable to pump enough blood. Heart failure is also termed
congestive heart failure (CHF) because fluids typically build up in
the body, which is then said to be congested. In addition to heart
failure caused from a weakened heart, there are also other
varieties of heart failure. These are CHF due to the body having
needs which are too high for even a normal heart to keep up with,
for example, in some cases of thyroid disease in which too much
thyroid hormone is produced, in patients with anemia, or several
other conditions; and CHF due to neurohormonal imbalances that
eventually leads to acute episodes of dyspnea or other acute events
such as hypertension, high blood pressure, arrhythmia, reduced
renal blood flow, renal insufficiency and in severe cases
mortality, shifting the patient from compensated CHF to acute
decompensated heart failure (AHF) and/or acute vascular
failure.
[0062] The terms "acute cardiac decompensation" and "acute
decompensation" are used interchangeably herein, and mean for the
purpose of the specification and claims, an inability of the heart
muscle to compensate for systemic and renal vasoconstriction due to
neurohormonal imbalances in the body. Acute cardiac decompensation
is characterized by altered cardiac function and fluid regulation,
leading to the onset of hemodynamic instability and physiologic
changes (particularly congestion and edema), and heart failure
symptoms (most commonly dyspnea). This form of functional
decompensation could be misdiagnosed as being caused by a valvular
or myocardial defect (i.e., a structural defect) although it is not
usually associated with hypotension. However, "acute cardiac
decompensation" as used herein, is a functional decompensation that
is often associated with any one or more of certain decompensation
events, including but not limited to, dyspnea, hypertension, high
blood pressure, arrhythmia, reduced renal blood flow, renal
insufficiency and mortality. Patients presenting with "acute
cardiac decompensation", as used herein, typically have, but may
not have previously been diagnosed with chronic heart failure
(CHF). Such patients may have a history of heart disease or the
complete absence thereof.
[0063] "Administering" refers to giving or applying to a subject a
pharmaceutical remedy or formulation via a specific route,
including but not limited to, intravenously, subcutaneously,
intramuscularly, sublingually and via inhalation.
[0064] The term "vasculature" refers to the network of blood
vessels in an organ or body part, including arteries and
capillaries.
[0065] The term "balanced vasodilation" means, for purpose of the
specification and claims, a dual vasodilation that occurs in the
systemic (mostly arterial) and renal vasculature as a result of the
binding of relaxin or a relaxin agonist to specific relaxin
receptors.
[0066] The terms "neurohormonal imbalance" and "neurohumoral
imbalance" are used interchangeably herein, and refer to a hormonal
disturbance in the body that can lead to heart failure. For
example, excessive signaling through Gs-coupled adrenergic or
Gq-coupled angiotensin pathways can cause neurohormonal imbalances.
In both cases, excessive neurohormonal signaling can cause, as well
as accelerate, functional decompensation (see Schrier et al.,
supra). In addition, excessive neurohormonal signaling can cause,
as well as accelerate, acute vascular failure.
[0067] The term "fluid overload", as used herein, refers to a
condition that occurs when the blood contains too much water. Fluid
overload (hypervolemia) is commonly seen with heart failure that
can cause fluid overload by activation of the
renin-angiotensin-aldosterone system. This fluid, primarily salt
and water, builds up in various locations in the body and leads to
an increase in weight, swelling in the legs and arms (peripheral
edema), and/or in the abdomen (ascites). Eventually, the fluid
enters the air spaces in the lungs, reduces the amount of oxygen
that can enter the blood, and causes shortness of breath (dyspnea).
Fluid can also collect in the lungs when lying down at night and
can make night time breathing and sleeping difficult (paroxysmal
nocturnal dyspnea). Fluid overload is one of the most prominent
features of AHF and/or acute vascular failure.
[0068] The term "cardiac arrhythmia" means a condition where the
muscle contraction of the heart becomes irregular. An unusually
fast rhythm (more than 100 beats per minute) is called tachycardia.
An unusually slow rhythm (fewer than 60 beats per minute) is called
bradycardia.
[0069] "Cardiac ischemia" occurs when blood flow to the heart
muscle (myocardium) is obstructed by a partial or complete blockage
of a coronary artery. A sudden, severe blockage may lead to a heart
attack (myocardial infarction). Cardiac ischemia may also cause a
serious abnormal heart rhythm (arrhythmia), which can cause
fainting and in severe cases death.
[0070] The term "pathophysiological" refers to a disturbance of any
normal mechanical, physical, or biochemical function, either caused
by a disease, or resulting from a disease or abnormal syndrome or
condition that may not qualify to be called a disease.
"Pathophysiology" is the study of the biological and physical
manifestations of disease as they correlate with the underlying
abnormalities and physiological disturbances.
[0071] The term "nitric oxide" and "NO" are used interchangeably
herein and refer to an important signaling molecule involved in
many physiological and pathological processes within the mammalian
body, including in humans. NO can act as a vasodilator that relaxes
the smooth muscle in blood vessels, which causes them to dilate.
Dilation of arterial blood vessels (mainly arterioles) leads to a
decrease in blood pressure. Relaxin is believed to elicit at least
some vasodilation through NO. As such, relaxin binds to specific
relaxin receptors such as LGR7 and LGR8 receptors on smooth muscle
cells of the vasculature which in turn activates the endothelin
cascade to activate nitric oxide synthase (NOS) to produce NO (FIG.
2).
[0072] The terms "AHF," "acute heart failure" and "acute
decompensated heart failure" as used herein is defined by the
presence of all of the following at screening: dyspnea at rest or
with minimal exertion, pulmonary congestion on chest X-ray and
elevated natriuretic peptide levels [brain natriuretic peptide
(BNP).gtoreq.350 pg/mL or NT-pro-BNP.gtoreq.1400 pg/mL].
[0073] The term "dyspnea" refers to difficult or labored breathing.
It is a sign of a variety of disorders and is primarily an
indication of inadequate ventilation or of insufficient amounts of
oxygen in the circulating blood. The term "orthopnea" refers to
difficult or labored breathing when lying flat, which is relieved
when in an upright position (sitting or standing as opposed to
reclining).
[0074] Clinical studies and practice guidelines typically define
hypertension as a systolic blood pressure (SBP) greater than about
140 mm Hg, and normal blood pressure as a SBP below about 140 mm
Hg, 130 mm Hg or 120 mm Hg, depending upon the particular study or
guideline. In the context of acute heart failure or other cardiac
disease, hypotension may be characterized as a SBP below about 110
mm Hg, 100 mm Hg, or 90 mm Hg. In some preferred embodiments, the
phrase a "normotensive or hypertensive state" refers to a SBP of
greater than 125 mmHg at the time of study screening or relaxin
administration.
[0075] As used herein, the phrase "impaired renal function" is
defined as an estimated glomerular filtration rate (eGFR) of
between 30 to 75 mL/min/1.73 m2, calculated using the simplified
Modification of Diet in Renal Disease (sMDRD) equation.
[0076] The term "placebo" refers to a physiologically inert
treatment that is often compared in clinical research trials to a
physiologically active treatment. These trials are usually carried
out as double blind studies and neither the prescribing doctor nor
the patients know if they are taking the active drug or the
substance without any apparent pharmaceutical effect (placebo). It
has been observed that a patient receiving a physiologically inert
treatment can demonstrate improvement for his or her condition if
he or she believes they are receiving the physiologically active
treatment (placebo effect). Therefore, the inclusion of a placebo
in a trial assures that the statistically significant beneficial
effect is related to the physiologically active treatment and not
simply a result of a placebo effect.
[0077] The definition of "rehospitalization" is a hospital
readmission during a certain time period after initial treatment.
The time period is generally dependent on the kind of treatment and
the condition of the patient.
[0078] As used herein the term "cardiovascular death" refers to
death that is primarily due to a cardiovascular cause, such as
death due to stroke, acute myocardial infarction, refractory
congestive heart failure and any sudden.
[0079] A "loop diuretic" means a drug used in patients with
congestive heart failure or renal insufficiency to reduce symptoms
of hypertension and edema. A loop diuretic belongs to a class of
diuretic agents that reduces readsorption of sodium and chloride by
the kidney leading to an increased secretion of urine.
[0080] The term "about" when used in the context of a stated value,
encompasses a range of up to 10% above or below the stated value
(e.g., 90-110% of the stated value). For instance, an intravenous
(IV) infusion rate of about 30 mcg/kg/day, encompasses IV infusion
rates of 27 mcg/kg/day to 33 mcg/kg/day.
[0081] "Therapeutically effective" refers to the amount of
pharmaceutically active relaxin that will result in a measurable
desired medical or clinical benefit to a patient, as compared to
the patient's baseline status or to the status of an untreated or
placebo-treated (e.g., not treated with relaxin) subject.
Relaxin
[0082] Relaxin is a polypeptide hormone that is similar in size and
shape to insulin (FIG. 1). More specifically, relaxin is an
endocrine and autocrine/paracrine hormone belonging to the insulin
gene superfamily. The active form of the encoded protein consists
of an A chain and a B chain, held together by disulphide bonds, two
inter-chains and one intra-chain. Thus, the structure closely
resembles insulin in the disposition of disulphide bonds. In
humans, there are three known non-allelic relaxin genes, relaxin-1
(RLN-1 or H1), relaxin-2 (RLN-2 or H2) and relaxin-3 (RLN-3 or H3).
H1 and H2 share high sequence homology. There are two alternatively
spliced transcript variants encoding different isoforms described
for this gene. H1 and H2 are differentially expressed in
reproductive organs (U.S. Pat. No. 5,023,321 and Garibay-Tupas et
al., Molecular and Cellular Endocrinology 219:115-125, 2004), while
H3 is found primarily in the brain. The evolution of the relaxin
peptide family in its receptors is generally well known in the art
(Wilkinson et al., BMC Evolutionary Biology 5(14):1-17, 2005; and
Wilkinson and Bathgate, Chapter 1, Relaxin and Related Peptides,
Landes Bioscience and Springer Science+Business Media, 2007).
[0083] Relaxin activates specific relaxin receptors, i.e., LGR7
(RXFP1) and LGR8 (RXFP2) as well as GPCR135 and GPCR142. LGR7 and
LGR8 are leucine-rich repeat-containing, G protein-coupled
receptors (LGRs) which represent a unique subgroup of G
protein-coupled receptors. They contain a heptahelical
transmembrane domain and a large glycosylated ectodomain, distantly
related to the receptors for the glycoproteohormones, such as the
LH-receptor or FSH-receptor. These relaxin receptors are found in
the heart, smooth muscle, connective tissue, and central and
autonomous nervous system. Potent relaxins such as H1, H2, porcine
and whale relaxin possess a certain sequence in common, i.e., the
Arg-Glu-Leu-Val-Arg-X-X-Ile sequence (SEQ ID NO:3) or binding
cassette. These relaxins activate the LGR7 and LGR8 receptors.
Relaxins that deviate from this sequence homology such as rat,
shark, dog and horse relaxins show a reduction in bioactivity
through the LGR7 and LGR8 receptors (see Bathgate et al. (2005)
Ann. N.Y. Acad. Sci. 1041:61-76; Receptors for Relaxin Family
Peptides). However, similar to H2 relaxin, H3 relaxin activates the
LGR7 receptor (see Satoko et al. (2003) The Journal of Biological
Chemistry 278(10):7855-7862). In addition, H3 has been shown to
activate the GPCR135 receptor (see Van der Westhuizen (2005) Ann.
N.Y. Acad. Sci. 1041:332-337) and GPCR142 receptor. GPCR135 and
GPCR142 are two structurally related G-protein-coupled receptors.
Mouse and rat GPCR135 exhibit high homology (i.e., greater than
85%) to the human GPCR135 and have very similar pharmacological
properties to that of the human GPCR135. Human and mouse as well as
rat relaxin-3 binds to and activates mouse, rat, and human GPCR135
at high affinity. In contrast, the mouse GPCR142 is less well
conserved (i.e., 74% homology) with human GPCR142. GPCR142 genes
from monkey, cow, and pig were cloned and shown to be highly
homologous (i.e., greater than 84%) to human GPCR142.
Pharmacological characterization of GPCR142 from different species
has shown that relaxin-3 binds to GPCR142 from different species at
high affinity (see Chen et al. (2005) The Journal of Pharmacology
and Experimental Therapeutics 312(1): 83-95).
[0084] Relaxin is found in both, women and men (see Tregear et al.;
Relaxin 2000, Proceedings of the Third International Conference on
Relaxin & Related Peptides (22-27 Oct. 2000, Broome,
Australia). In women, relaxin is produced by the corpus luteum of
the ovary, the breast and, during pregnancy, also by the placenta,
chorion, and decidua. In men, relaxin is produced in the testes.
Relaxin levels rise after ovulation as a result of its production
by the corpus luteum and its peak is reached during the first
trimester, not toward the end of pregnancy. In the absence of
pregnancy its level declines. In humans, relaxin is plays a role in
pregnancy, in enhancing sperm motility, regulating blood pressure,
controlling heart rate and releasing oxytocin and vasopressin. In
animals, relaxin widens the pubic bone, facilitates labor, softens
the cervix (cervical ripening), and relaxes the uterine
musculature. In animals, relaxin also affects collagen metabolism,
inhibiting collagen synthesis and enhancing its breakdown by
increasing matrix metalloproteinases. It also enhances angiogenesis
and is a renal vasodilator.
[0085] Relaxin has the general properties of a growth factor and is
capable of altering the nature of connective tissue and influencing
smooth muscle contraction. H1 and H2 are believed to be primarily
expressed in reproductive tissue while H3 is known to be primarily
expressed in brain (supra). As disclosed herein, H2 plays a major
role in cardiovascular and cardiorenal function and can thus be
used to treat associated diseases. H1 and H3 due to their homology
with H2 are contemplated to be suitable for treating cardiovascular
disease. In addition, pharmaceutically effective relaxin agonists
with relaxin-like activity would be capable of activating relaxin
receptors and to elicit a relaxin-like response.
Acute Heart Failure (AHF) Patients
[0086] AHF is the most common cause for hospital admission in
patients older than 65 years and for congestive heart
failure-related morbidity (Cotter et al., American Heart Journal
155(1):9-18, 2008). In spite of the progress made in
mortality-reducing drug therapies for chronic (systolic) heart
failure, including angiotensin-converting enzyme inhibitors,
angiotensin II receptor blockers, .beta.-blockers, and aldosterone
antagonists, no comparable progress has been made in the art for
AHF, where both therapy and mortality have not changed
significantly over the past 30 years (Allen et al., CMAJ
176:797-805, 2007). The classic AHF drugs such as loop diuretics,
nitroglycerin/nitroprusside, dobutamine, or milrinone have not been
able to improve AHF outcome (Allen et al., supra). The same is true
for therapeutic strategies including endothelin-1 receptor blockade
with TEZOSENTAN, vasopressin V2 receptor antagonism using
TOLVAPTAN, the natriuretic peptide NESIRITIDE, and LEVOSIMENDAN
which combines calcium-sensitizing and vasodilatory properties.
Chronic renal dysfunction is frequently a part of the complex
morbidity of AHF, particularly in older AHF patients. Deterioration
of renal function can induce or worsen AHF (i.e., cardiorenal
syndrome) and is related to significant morbidity in the AHF
population. According to the ADHERE registry (Heywood, Heart Fail.
Rev. 9:195-201, 2004), impairment of renal function correlates with
a worse prognosis for AHF. Hence, treatment with relaxin provides a
novel AHF therapy with favorable renal effects, which significantly
improves the prognosis for patients that are part of the AHF
population. In accordance, pharmaceutically active relaxin can be
used to treat these AHF patients, or subjects afflicted with acute
cardiac decompensation events or symptoms, or subjects afflicted
with acute cardiac decompensation that is associated with AHF.
[0087] Patients with AHF can be classified into three groups based
on their systolic blood pressure at the time of presentation (See,
e.g., Gheorghiade et al., JAMA, 296: 2217-2226, 2006; and Shin et
al., Am J Cardiol, 99[suppl]:4A-23A. 2007). The three groups
include: 1) the hypotensive group (low blood pressure); 2) the
normotensive group (normal blood pressure) and 3) the hypertensive
group (high blood pressure).
[0088] Hypotensive AHF patients having a very low left ventricle
ejection fraction (LVEF) are described as having "low cardiac
output" or "cardiogenic shock." Such hypotensive AHF patients have
hearts that fail to adequately pump blood, meaning that the
percentage of the blood in the ventricle that is pumped out with
each contraction is reduced.
[0089] Normotensive AHF patients have higher blood pressure and
typically a greater LVEF than hypotensive AHF patients and are
sometimes described as having "cardiac failure." The cause of AHF
in these patients is a combination of both depressed cardiac
function and vasoconstriction.
[0090] Hypertensive AHF patients have higher blood pressure and
typically a greater LVEF than normotensive AHF patients and are
generally described as having "vascular failure." Even though these
patients have some degree of abnormal cardiac function, the
predominant cause of their AHF is vasoconstriction.
[0091] Current data indicates that vascular failure and cardiac
failure may be the most common types of AHF, as opposed to low
cardiac output (ADHERE Scientific Advisory Committee, Acute
Decompensated Heart Failure National Registry (ADHERE) Core Module
Q1 2006 Final Cumulative National Benchmark Report, Scios, Inc. pp.
1-19, 2006). Many patients presenting with acute heart failure
signs and symptoms, including pulmonary congestion on x-ray,
difficulty breathing (dyspnea) and normal (normotensive) or high
(hypertensive) blood pressure have preserved left ventricular
function (generally >40% EF). These acute heart failure patients
exhibit problems with excessive vasoconstriction and with filling
the ventricle with blood, rather than the ability of the ventricle
to pump blood. These patients are clearly distinguishable from
hypotensive AHF patients.
[0092] Traditional treatment of low cardiac output or cardiogenic
shock (hypotensive AHF) involve pharmacologic agents that cause the
heart to contract harder (inotropic) and/or faster (chronotropic)
to maintain the perfusion of vital organs (See, e.g., Nieminen et
al., Eur Heart 26:384-416, 2005; and Shin et al., Am J Cardiol,
99[suppl]:4A-23A. 2007). However, normotensive (vascular failure)
and hypertensive (cardiac failure) HF patients are extremely
sensitive to changes in heart rate since an increase in heart rate
reduces the filling time between vascular contractions, and hence
lowers the volume of blood filling the ventricle (Satpathy et al.,
American Family Physician, 73:841-846, 2006). For this reason,
treatments for acute heart failure that increase heart rate would
be detrimental to hypertensive acute heart failure patients, if not
contraindicated (Satpathy et al., supra)
[0093] Generally, pharmaceutically effective relaxin or a
pharmaceutically effective relaxin agonist should be administered
at a constant rate to provide safe relief and achieve a steady
state in the patient. For example, it is preferred to administer
relaxin intravenously to maintain a serum concentration of relaxin
of from about 1 to 500 ng/ml. More specifically, the administration
of relaxin is continued as to maintain a serum concentration of
relaxin of from about 0.5 to about 500 ng/ml, more preferably from
about 0.5 to about 300 ng/ml, and most preferably from about 3 to
about 75 ng/ml. The subject would be treated with relaxin at about
10 to 1000 .mu.g/kg of subject body weight per day rather than via
a loading dose such as a bolus. More preferably, the subject would
be treated with relaxin at about 10 to about 250 .mu.g/kg of
subject body weight per day. In another preferred embodiment,
pharmaceutically effective relaxin or an agonist thereof is
administered at about 30 .mu.g/kg/day. Other forms of administering
relaxin are also contemplated by the disclosure including, but not
limited to, subcutaneously, intramuscularly, sublingually and via
inhalation. Notably, acute situations are normally treated with a
loading dose (bolus) because the patient is "acute" and needs
instant relief. However, this can lead to situation where the
patient is overcompensated, thus, leading to worsening of heart
failure symptoms or even death. As described herein, administering
relaxin at a constant rate in acute situations is a safe and
effective form of administration.
Relaxin Treatment Results in Balanced Vasodilation
[0094] Without wanting to be bound by theory, the beneficial effect
of relaxin is believed to be a direct result of relaxin acting as a
receptor-specific vasodilator in the renal and systemic vasculature
by binding to specific relaxin receptors that are found on the
smooth muscle tissue of the vasculature. This in turn results in
balanced vasodilation as both systemic and renal arteries are
vasodilated in a moderate but effective way without causing
hypotension in the treated patient. This property of relaxin as a
receptor-specific and balancing vasodilator is particularly
advantageous in context in which it is desirable to obtain
increased vasodilation in specific areas of the body where
vasoconstriction causes a serious ill effect such as in the
arteries that supply blood to the heart and the kidneys. Notably,
the balanced vasodilation occurs without causing any deleterious
side effect during the process of treatment. A common problem with
treatment with non-specific vasodilators is that these drugs often
lead to serious side effects in the treated patients, mainly
because general agonists act too potently and non-specifically. In
comparison, the moderate effect of relaxin slowly increases
vasodilation in areas of the body where it is needed the most. It
is important to note that relaxin treatment does not cause
hypotension as is the case with many drugs that overcompensate for
vasoconstriction. In particular, non-specific vasodilators can
cause large and small arteries and veins throughout the body to
dilate excessively, causing hypotension. Thus, when the patient
receives a pharmaceutical composition with pharmaceutically active
relaxin or pharmaceutically effective relaxin agonist which targets
systemic and renal blood vessels via localized specific relaxin
receptors (e.g., LRG7, LGR8, GPCR135, GPCR142 receptors) the result
is balanced vasodilation without hypotension.
[0095] Consequently, relaxin can be used to reduce cardiac
decompensation events by selecting human subjects including AHF
patients and/or individuals with AHF symptoms and/or individuals
suffering from acute vascular failure who present with acute
cardiac decompensation, and administering to those subjects a
pharmaceutical formulation with pharmaceutically active relaxin.
Relaxin reduces the acute cardiac decompensation events by binding
to the relaxin receptors (e.g., LRG7, LGR8, GPCR135, GPCR142
receptors) resulting in balanced vasodilation, i.e., a dual
vasodilation in both the systemic and renal vasculature. Based on
those same principles, relaxin can be used to treat cardiac
decompensation in human subjects including AHF patients and/or
individuals associated with symptoms of AHF and/or individuals
suffering from acute vascular failure. Particularly, such subjects
receive pharmaceutically active human relaxin (e.g., synthetic,
recombinant) or pharmaceutically effective relaxin agonist in an
amount in a range of about 10 to 1000 .mu.g/kg of subject body
weight per day. In one embodiment, the dosages of relaxin are 10,
30, 100 and 250 .mu.g/kg/day. In another embodiment, these dosages
result in serum concentrations of relaxin of about 3, 10, 30 and 75
ng/ml, respectively. In one preferred embodiment, pharmaceutically
effective relaxin or an agonist thereof is administered at about 30
.mu.g/kg/day. In another preferred embodiment, pharmaceutically
effective relaxin or an agonist thereof is administered at about 10
to about 250 .mu.g/kg/day. In another embodiment, the
administration of relaxin is continued as to maintain a serum
concentration of relaxin of from about 0.5 to about 500 ng/ml, more
preferably from about 0.5 to about 300 ng/ml, and most preferably
from about 3 to about 75 ng/ml. Most preferably, the administration
of relaxin is continued as to maintain a serum concentration of
relaxin of about 10 ng/ml or greater. Relaxin has also been shown
to be fully effective at a serum concentration of 3-6 ng/ml. Thus,
the methods of the present disclosure include administrations that
result in these serum concentrations of relaxin. These relaxin
concentrations can ameliorate or reduce decompensation events such
as dyspnea, hypertension, arrhythmia, reduced renal blood flow, and
renal insufficiency. Furthermore, these relaxin concentrations can
ameliorate or reduce neurohormonal imbalance, fluid overload,
cardiac arrhythmia, cardiac ischemia, risk of mortality, cardiac
stress, vascular resistance, and the like.
[0096] The duration of relaxin treatment is preferably kept at a
range of about 4 hours to about 96 hours depending on the patient,
and one or more optional repeat treatments as needed. For example,
with respect to frequency of administration, relaxin administration
can be a continuous infusion lasting from about 8 hr to 72 hours of
treatment. Relaxin can be given continuously via intravenous or
subcutaneous administration. For intravenous administration,
relaxin can be delivered by syringe pump or through an IV bag. The
IV bag can be a standard saline, half normal saline, 5% dextrose in
water, lactated Ringer's or similar solution in a 100, 250, 500 or
1000 ml IV bag. For subcutaneous infusion, relaxin can be
administered by a subcutaneous infusion set connected to a wearable
infusion pump. Depending on the subject, the relaxin administration
is maintained for as specific period of time or for as long as
needed to achieve stability in the subject.
[0097] Some subjects are treated indefinitely while others are
treated for specific periods of time. It is also possible to treat
a subject on and off with relaxin as needed. Thus, administration
can be continued over a period of time sufficient to achieve an
amelioration or reduction in acute cardiac decompensation events,
including but not limited to, dyspnea, hypertension, arrhythmia,
reduced renal blood flow and renal insufficiency. Relaxin may be
administered in higher doses if necessary to prevent death due to
AHF and/or acute vascular failure associated complications such as
sudden cardiac arrest.
Relaxin Treatment does not Cause Renal Toxicity and is
Diuretic-Sparing
[0098] Renal dysfunction is a common and progressive complication
of acute and chronic heart failure. The clinical course typically
fluctuates with the patient's clinical status and treatment.
Despite the growing recognition of the frequent presentation of
combined cardiac and renal dysfunction, also termed the
"cardiorenal syndrome," its underlying pathophysiology is not well
understood. No consensus as to its appropriate management has been
achieved in the art. Because patients with heart failure are
surviving longer and die less frequently from cardiac arrhythmia,
cardiorenal syndrome is more and more prevalent and proper
management is needed (Gary Francis (2006) Cleveland Clinic Journal
of Medicine 73(2):1-13). The disclosure solves this need. It
provides a method of treating acute decompensated heart failure
(AHF) and/or acute vascular failure in a human subject who also
suffers from renal insufficiency. This method includes selecting a
human subject with symptoms of acute cardiac decompensation and
renal insufficiency, wherein the subject has a systemic and renal
vasculature comprising relaxin receptors. Relaxin is administered
to the subject and performs a dual action by binding to the relaxin
receptors in the systemic and renal vasculature, resulting in
balanced vasodilation. As noted above, such subjects receive
pharmaceutically active human relaxin (e.g., synthetic,
recombinant) or pharmaceutically effective relaxin agonist in an
amount in a range of about 10 to 1000 .mu.g/kg of subject body
weight per day. In one embodiment, the dosages of relaxin are 10,
30, 100 and 250 .mu.g/kg/day. In another embodiment, these dosages
result in serum concentrations of relaxin of about 3, 10, 30 and 75
ng/ml, respectively. In one preferred embodiment, pharmaceutically
effective relaxin or an agonist thereof is administered at about 30
.mu.g/kg/day. In another preferred embodiment, pharmaceutically
effective relaxin or an agonist thereof is administered at about 10
to about 250 .mu.g/kg/day. The administration of relaxin is
continued as to maintain a serum concentration of relaxin of from
about 0.5 to about 500 ng/ml, more preferably from about 0.5 to
about 300 ng/ml, and most preferably from about 3 to about 75
ng/ml. Most preferably, the administration of relaxin is continued
as to maintain a serum concentration of relaxin of 10 ng/ml or
greater. Depending on the subject, the relaxin administration is
maintained for as specific period of time or for as long as needed
to achieve stability in the subject. For example, the duration of
relaxin treatment is preferably kept at a range of about 4 hours to
about 96 hours, more preferably from about 8 hr to 72 hours,
depending on the patient, and one or more optional repeat
treatments as needed.
[0099] Subjects who suffer from renal insufficiency associated with
AHF often also experience elevated levels of brain natriuretic
peptide (BNP). BNP is synthesized in the cardiac ventricles in
response to heart failure and left ventricular dysfunction. It is
used as a diagnostic marker of heart failure. Its effects include
systemic vasodilation and unbalanced vasodilation in the kidney,
i.e., efferent arteriolar constriction and afferent arteriole
vasodilation. As described herein, brain natriuretic peptide (BNP)
levels are reduced when relaxin is administered to AHF patients
and/or patients with acute vascular failure. This makes BNP a
convenient AHF marker since it is reduced as the severity of AHF is
reduced. Monitoring BNP levels in patients that are treated with
relaxin is, thus, a convenient way to assess the risk of mortality
associated with AHF and/or acute vascular failure. Thus, the
disclosure provides a method for reducing mortality risk in a human
subject with symptoms of acute cardiac decompensation. The relaxin
is administered in an amount effective to reduce the acute cardiac
decompensation in the subject by binding to the relaxin receptors
in the vasculature of the subject, thereby resulting in reduced
levels of BNP. The reduced levels of BNP can be physically measured
in order to predict risk of mortality in the AHF and/or acute
vascular failure patient. Generally, the reduced levels of BNP are
due to reduced cardiac stress following a reduction in vascular
resistance. The reduction in vascular resistance is in turn due to
the balanced vasodilation which is the result of relaxin binding to
relaxin receptors that are found on smooth muscle cells of the
vasculature.
[0100] Relaxin causes low to no renal toxicity when it is given to
AHF and/or acute vascular failure patients in comparison to most
available drugs. Even with higher serum concentrations of about 75
ng/ml relaxin is far less toxic than currently available
medications (e.g., loop diuretics such as furosemide, angiotensin
converting enzyme inhibitors such as captopril, angiotensin
receptor blockers such as candesartan, and the like). One important
feature of this disclosure is that relaxin preserves the renal
function while causing little to no renal toxicity during
treatment. Although existing drugs may preserve some renal function
they also increase renal toxicity in patients. This renal toxicity
then further deteriorates the heart condition. In comparison,
relaxin will achieve a steady-state maintenance of most patients
due to the absence of renal toxicity. This allows the unstable AHF
and/or acute vascular failure population to revert back to a more
stable CHF population or to achieve a stable condition where the
likelihood of exacerbating heart failure is significantly
reduced.
Relaxin Compositions and Formulations
[0101] Relaxin, relaxin agonists and/or relaxin analogs are
formulated as pharmaceuticals to be used in the methods of the
disclosure. Any composition or compound that can stimulate a
biological response associated with the binding of biologically or
pharmaceutically active relaxin (e.g., synthetic relaxin,
recombinant relaxin) or a relaxin agonist (e.g., relaxin analog or
relaxin-like modulator) to relaxin receptors can be used as a
pharmaceutical in the disclosure. General details on techniques for
formulation and administration are well described in the scientific
literature (see Remington's Pharmaceutical Sciences, Maack
Publishing Co, Easton Pa.). Pharmaceutical formulations containing
pharmaceutically active relaxin can be prepared according to any
method known in the art for the manufacture of pharmaceuticals. The
formulations containing pharmaceutically active relaxin or relaxin
agonists used in the methods of the disclosure can be formulated
for administration in any conventionally acceptable way including,
but not limited to, intravenously, subcutaneously, intramuscularly,
sublingually, topically, orally and via inhalation. Illustrative
examples are set forth below. In one preferred embodiment, relaxin
is administered intravenously.
[0102] When the drugs are delivered by intravenous injection, the
formulations containing pharmaceutically active relaxin or a
pharmaceutically effective relaxin agonist can be in the form of a
sterile injectable preparation, such as a sterile injectable
aqueous or oleaginous suspension. This suspension can be formulated
according to the known art using those suitable dispersing or
wetting agents and suspending agents which have been mentioned
above. The sterile injectable preparation can also be a sterile
injectable solution or suspension in a nontoxic
parenterally-acceptable diluent or solvent. Among the acceptable
vehicles and solvents that can be employed are water and Ringer's
solution, an isotonic sodium chloride. In addition, sterile fixed
oils can conventionally be employed as a solvent or suspending
medium. For this purpose any bland fixed oil can be employed
including synthetic mono- or diglycerides. In addition, fatty acids
such as oleic acid can likewise be used in the preparation of
injectables.
[0103] Pharmaceutical formulations for oral administration can be
formulated using pharmaceutically acceptable carriers well known in
the art in dosages suitable for oral administration. Such carriers
enable the pharmaceutical formulations to be formulated in unit
dosage forms as tablets, pills, powder, capsules, liquids,
lozenges, gels, syrups, slurries, suspensions, etc., suitable for
ingestion by the patient. Pharmaceutical preparations for oral use
can be obtained through combination of relaxin compounds with a
solid excipient, optionally grinding a resulting mixture, and
processing the mixture of granules, after adding suitable
additional compounds, if desired, to obtain tablets or pills.
Suitable solid excipients are carbohydrate or protein fillers which
include, but are not limited to, sugars, including lactose,
sucrose, mannitol, or sorbitol; starch from corn, wheat, rice,
potato, or other plants; cellulose such as methyl cellulose,
hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose;
and gums including arabic and tragacanth; as well as proteins such
as gelatin and collagen. If desired, disintegrating or solubilizing
agents may be added, such as the cross-linked polyvinyl
pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium
alginate. Pharmaceutical preparations of the disclosure that can
also be used orally are, for example, push-fit capsules made of
gelatin, as well as soft, sealed capsules made of gelatin and a
coating such as glycerol or sorbitol. Push-fit capsules can contain
relaxin mixed with a filler or binders such as lactose or starches,
lubricants such as talc or magnesium stearate, and, optionally,
stabilizers. In soft capsules, the relaxin compounds may be
dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycol with or without
stabilizers.
[0104] Aqueous suspensions of the disclosure contain relaxin in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients include a suspending agent, such as
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylnethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing
or wetting agents such as a naturally occurring phosphatide (e.g.,
lecithin), a condensation product of an alkylene oxide with a fatty
acid (e.g., polyoxyethylene stearate), a condensation product of
ethylene oxide with a long chain aliphatic alcohol (e.g.,
heptadecaethylene oxycetanol), a condensation product of ethylene
oxide with a partial ester derived from a fatty acid and a hexitol
(e.g., polyoxyethylene sorbitol mono-oleate), or a condensation
product of ethylene oxide with a partial ester derived from fatty
acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan
monooleate). The aqueous suspension can also contain one or more
preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or
more coloring agents, one or more flavoring agents and one or more
sweetening agents, such as sucrose, aspartame or saccharin.
Formulations can be adjusted for osmolarity.
[0105] Oil suspensions can be formulated by suspending relaxin in a
vegetable oil, such as arachis oil, olive oil, sesame oil or
coconut oil, or in a mineral oil such as liquid paraffin. The oil
suspensions can contain a thickening agent, such as beeswax, hard
paraffin or cetyl alcohol. Sweetening agents can be added to
provide a palatable oral preparation. These formulations can be
preserved by the addition of an antioxidant such as ascorbic
acid.
[0106] Dispersible powders and granules of the disclosure suitable
for preparation of an aqueous suspension by the addition of water
can be formulated from relaxin in admixture with a dispersing,
suspending and/or wetting agent, and one or more preservatives.
Suitable dispersing or wetting agents and suspending agents are
exemplified by those disclosed above. Additional excipients, for
example sweetening, flavoring and coloring agents, can also be
present.
[0107] The pharmaceutical formulations of the disclosure can also
be in the form of oil-in-water emulsions. The oily phase can be a
vegetable oil, such as olive oil or arachis oil, a mineral oil,
such as liquid paraffin, or a mixture of these. Suitable
emulsifying agents include naturally-occurring gums, such as gum
acacia and gum tragacanth, naturally occurring phosphatides, such
as soybean lecithin, esters or partial esters derived from fatty
acids and hexitol anhydrides, such as sorbitan mono-oleate, and
condensation products of these partial esters with ethylene oxide,
such as polyoxyethylene sorbitan mono-oleate. The emulsion can also
contain sweetening and flavoring agents. Syrups and elixirs can be
formulated with sweetening agents, such as glycerol, sorbitol or
sucrose. Such formulations can also contain a demulcent, a
preservative, a flavoring or a coloring agent.
Administration and Dosing Regimen of Relaxin Formulations
[0108] The formulations containing pharmaceutically active relaxin
or pharmaceutically effective relaxin agonist used in the methods
of the disclosure can be administered in any conventionally
acceptable way including, but not limited to, intravenously,
subcutaneously, intramuscularly, sublingually, topically, orally
and via inhalation. Administration will vary with the
pharmacokinetics and other properties of the drugs and the
patients' condition of health. General guidelines are presented
below.
[0109] The methods of the disclosure reduce acute cardiac
decompensation events in subjects who suffer from acute cardiac
decompensation associated with AHF and/or acute vascular failure,
and/or related conditions. In addition, the methods of the
disclosure treat acute cardiac decompensation in subjects who
suffer from acute cardiac decompensation associated with AHF,
including AHF patients and/or patients with acute vascular failure.
The amount of relaxin alone or in combination with another agent or
drug (e.g., diuretic) that is adequate to accomplish this is
considered the therapeutically effective dose. The dosage schedule
and amounts effective for this use, i.e., the "dosing regimen,"
will depend upon a variety of factors, including the stage of the
disease or condition, the severity of the disease or condition, the
severity of the adverse side effects, the general state of the
patient's health, the patient's physical status, age and the like.
In calculating the dosage regimen for a patient, the mode of
administration is also taken into consideration. The dosage regimen
must also take into consideration the pharmacokinetics, i.e., the
rate of absorption, bioavailability, metabolism, clearance, and the
like. Based on those principles, relaxin can be used to treat
cardiac decompensation in human subjects including AHF patients
and/or individuals associated with symptoms of AHF and/or
individuals who suffer from acute vascular failure.
[0110] The disclosure provides relaxin and a diuretic for
simultaneous, separate or sequential administration. The disclosure
also provides relaxin and a diuretic for combined use in therapy.
The disclosure also provides the combination of relaxin and a
diuretic for use in therapy. The disclosure also provides the use
of relaxin and a diuretic in the manufacture of a medicament for
treating acute cardiac decompensation events. The disclosure also
provides the use of relaxin in the manufacture of a medicament for
treating acute cardiac decompensation events, wherein the
medicament is prepared for administration with a diuretic. The
disclosure also provides the use of a diuretic in the manufacture
of a medicament for treating acute cardiac decompensation events,
wherein the medicament is prepared for administration with relaxin.
The disclosure also provides relaxin and a diuretic for use in a
method of treating acute cardiac decompensation events.
[0111] The disclosure further provides relaxin for use in a method
of treating acute cardiac decompensation events, wherein relaxin is
prepared for administration with a diuretic. The disclosure also
provides a diuretic for use in a method of treating acute cardiac
decompensation events, wherein relaxin is prepared for
administration with relaxin. The disclosure also provides relaxin
for use in a method of treating acute cardiac decompensation
events, wherein relaxin is administered with a diuretic. The
disclosure also provides a diuretic for use in a method of treating
acute cardiac decompensation events, wherein relaxin is
administered with relaxin.
[0112] Further contemplates is the use of relaxin in the
manufacture of a medicament for treating acute cardiac
decompensation events, wherein the patient has previously (e.g., a
few hours before, one or more days before, etc.) been treated with
a diuretic. In one embodiment, the diuretic is still active in vivo
in the patient. The disclosure also provides the use of a diuretic
in the manufacture of a medicament for treating acute cardiac
decompensation events, wherein the patient has previously been
treated with relaxin.
[0113] The state of the art allows the clinician to determine the
dosage regimen of relaxin for each individual patient. As an
illustrative example, the guidelines provided below for relaxin can
be used as guidance to determine the dosage regimen, i.e., dose
schedule and dosage levels, of formulations containing
pharmaceutically active relaxin administered when practicing the
methods of the disclosure. As a general guideline, it is expected
that the daily dose of pharmaceutically active H1, H2 and/or H3
human relaxin (e.g., synthetic, recombinant, analog, agonist, etc.)
is typically in an amount in a range of about 10 to 1000 .mu.g/kg
of subject body weight per day. In one embodiment, the dosages of
relaxin are 10, 30, 100 and 250 .mu.g/kg/day. In another
embodiment, these dosages result in serum concentrations of relaxin
of about 3, 10, 30 and 75 ng/mL, respectively. In one preferred
embodiment, pharmaceutically effective relaxin or an agonist
thereof is administered at about 30 .mu.g/kg/day. In another
preferred embodiment, pharmaceutically effective relaxin or an
agonist thereof is administered at about 10 to about 250
.mu.g/kg/day. In another embodiment, the administration of relaxin
is continued as to maintain a serum concentration of relaxin of
from about 0.5 to about 500 ng/ml, more preferably from about 0.5
to about 300 ng/ml, and most preferably from about 3 to about 75
ng/ml. Most preferably, the administration of relaxin is continued
as to maintain a serum concentration of relaxin of 10 ng/ml or
greater. Relaxin has also been shown to be fully effective at a
serum concentration of 3-6 ng/ml (see FIG. 6, vide infra). Thus,
the methods of the present disclosure include administrations that
result in these serum concentrations of relaxin. These relaxin
concentrations can ameliorate or reduce decompensation events such
as dyspnea, hypertension, high blood pressure, arrhythmia, reduced
renal blood flow, renal insufficiency and mortality. Furthermore,
these relaxin concentrations can ameliorate or reduce neurohormonal
imbalance, fluid overload, cardiac arrhythmia, cardiac ischemia,
risk of mortality, cardiac stress, vascular resistance, and the
like. Depending on the subject, the relaxin administration is
maintained for as specific period of time or for as long as needed
to achieve stability in the subject. For example, the duration of
relaxin treatment is preferably kept at a range of about 4 hours to
about 96 hours, more preferably 8 hours to about 72 hours,
depending on the patient, and one or more optional repeat
treatments as needed.
[0114] Single or multiple administrations of relaxin formulations
may be administered depending on the dosage and frequency as
required and tolerated by the patient who suffers from acute
cardiac decompensation, AHF and/or conditions related to AHF and/or
individuals suffering from acute vascular failure. The formulations
should provide a sufficient quantity of relaxin to effectively
ameliorate the condition. A typical pharmaceutical formulation for
intravenous administration of relaxin would depend on the specific
therapy. For example, relaxin may be administered to a patient
through monotherapy (i.e., with no other concomitant medications)
or in combination therapy with another medication such as a
diuretic or other drug. In one embodiment, relaxin is administered
to a patient daily as monotherapy. In another embodiment, relaxin
is administered to a patient daily as combination therapy with
another drug. Notably, the dosages and frequencies of relaxin
administered to a patient may vary depending on age, degree of
illness, drug tolerance, and concomitant medications and
conditions.
[0115] In some embodiments, relaxin is provided as a 1 mg/mL
solution (3.5 mL in 5 mL glass vials). Placebo, which is identical
to the diluent for relaxin, is provided in identical vials. Relaxin
or placebo is administered intravenously to the patient in small
volumes using a syringe pump in combination with normal saline in a
piggyback configuration. Compatible tubing and a 3-way stopcock,
which have been tested and qualified for use with relaxin are used
to administer the relaxin formulation. Doses are administered on a
weight basis and adjusted for each patient by adjusting the rate of
relaxin drug delivered by the infusion pump. In some embodiments,
each subject is dosed for up to 48 hours with study drug.
Adjunct Therapies for Treating Normotensive and Hypertensive AHF
Patients
[0116] There are a wide variety of approved antihypertensive drugs
including vasodilators, adrenergic blockers, centrally acting
alpha-agonists, angiotensin-converting enzyme (ACE) inhibitors,
angiotensin II receptor blockers (ARBs), calcium channel blockers
and multiple types of diuretics (e.g., loop, potassium-sparing,
thiazide and thiazide-like). In some embodiments, the present
disclosure provides methods of treating dyspnea associated with
acute heart failure in normotensive and hypertensive patients
comprising administration of relaxin in combination with an adjunct
therapy such as an antihypertensive drug. In some methods, the
antihypertensive drug is selected from but not limited to the
following ACE inhibitors, beta-blockers and diuretics.
[0117] Angiotensin Converting Enzyme (ACE) inhibitors have been
used for the treatment of hypertension for many years. ACE
inhibitors block the formation of angiotensin II, a hormone with
adverse effects on the heart and circulation in CHF patients. Side
effects of these drugs include a dry cough, low blood pressure,
worsening kidney function and electrolyte imbalances, and
sometimes, allergic reactions. Examples of ACE inhibitors include
captopril (CAPOTEN), enalapril (VASOTEC), lisinopril (ZESTRIL,
PRINIVIL), benazepril (LOTENSIN), and ramipril (ALTACE). For those
patients who are unable to tolerate ACE inhibitors, an alternative
group of drugs, called the angiotensin receptor blockers (ARBs),
can be used. These drugs act on the same hormonal pathway as ACE
inhibitors, but instead block the action of angiotensin II at its
receptor site directly. Side effects of these drugs are similar to
those associated with ACE inhibitors, although the dry cough is
less common. Examples of this class of medications include losartan
(COZAAR), candesartan (ATACAND), telmisartan (MICARDIS), valsartan
(DIOVAN), and irbesartan (AVAPRO).
[0118] Beta-blockers are drugs that block the action of certain
stimulating hormones, such as epinephrine (adrenaline),
norepinephrine, and other similar hormones, which act on the beta
receptors of various body tissues. The natural effect of these
hormones on the beta receptors of the heart is a more forceful
contraction of the heart muscle. Beta-blockers are agents that
block the action of these stimulating hormones on the beta
receptors. The stimulating effect of these hormones, while
initially useful in maintaining heart function, appears to have
detrimental effects on the heart muscle over time. Generally, if
CHF patients receive beta-blockers they are given at a very low
dose at first which is then gradually increased. Side effects
include fluid retention, low blood pressure, low pulse, and general
fatigue and lightheadedness. Beta-blockers should also not be used
in people with diseases of the airways (e.g., asthma, emphysema) or
very low resting heart rates. Carvedilol (COREG) has been the most
thoroughly studied drug in the setting of congestive heart failure
and remains the only beta-blocker with FDA approval for the
treatment of congestive heart failure. However, research comparing
carvedilol directly with other beta-blockers in the treatment of
congestive heart failure is ongoing. Long acting metopropol (TOPROL
XL) is also effective in patients with congestive heart failure.
Digoxin (LANOXIN) is naturally produced by the Foxglove flowering
plant and has been used for treatment of CHF patients for a decade.
Digoxin stimulates the heart muscle to contract more forcefully.
Side effects include nausea, vomiting, heart rhythm disturbances,
kidney dysfunction, and electrolyte abnormalities. In patients with
significant kidney impairment the dose of digoxin needs to be
carefully adjusted and monitored.
[0119] Diuretics are often used in the treatment of CHF patients to
prevent or alleviate the symptoms of fluid retention. These drugs
help keep fluid from building up in the lungs and other tissues by
promoting the flow of fluid through the kidneys. Although they are
effective in relieving symptoms such as shortness of breath and leg
swelling, they have not been demonstrated to positively impact long
term survival. When hospitalization is required, diuretics are
often administered intravenously because the ability to absorb oral
diuretics may be impaired. Side effects of diuretics include
dehydration, electrolyte abnormalities, particularly low potassium
levels, hearing disturbances, and low blood pressure. It is
important to prevent low potassium levels by providing supplements
to patients, when appropriate. Any electrolyte imbalances may make
patients susceptible to serious heart rhythm disturbances. Examples
of various classes of diuretics include furosemide (LASIX),
hydrochlorothiazide, bumetanide (BUMEX), torsemide (DEMADEX), and
metolazone (ZAROXOLYN). Spironolactone (ALDACTONE) has been used
for many years as a relatively weak diuretic in the treatment of
various diseases. This drug blocks the action of the hormone
aldosterone. Aldosterone has theoretical detrimental effects on the
heart and circulation in congestive heart failure. Its release is
stimulated in part by angiotensin II (supra). Side effects of this
drug include elevated potassium levels and, in males, breast tissue
growth (gynecomastia). Another aldosterone inhibitor is eplerenone
(INSPRA).
Relaxin Agonists
[0120] In some embodiments, the present disclosure provides methods
of treating dyspnea associated with acute heart failure in
normotensive or hypertensive patients comprising administration of
a relaxin agonist. In some methods, the relaxin agonist activates
one or more relaxin-related G-protein coupled receptors (GPCR)
selected from but not limited to RXFP1, RXFP2, RXFP3, RXFP4, FSHR
(LGR1), LHCGR (LGR2), TSHR (LGR3), LGR4, LGR5, LGR6 LGR7 (RXFP1)
and LGR8 (RXFP2). In some embodiments, the relaxin agonist
comprises the amino acid sequence of Formula I of WO 2009/007848 of
Compugen (herein incorporated by reference for the teaching of
relaxin agonist sequences).
[0121] Formula I peptides are preferably from 7 to 100 amino acids
in length and comprise the amino acid sequence:
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X2-
1-X22-X23-X24-X25-X26-X27-X28-X29-X30-X31-X32-X33; wherein X1 is
absent or G or a small naturally or non-naturally occurring amino
acid; X2 is absent or Q or a polar naturally or non-naturally
occurring amino acid; X3 is absent or K or a basic naturally or
non-naturally occurring amino acid; X4 is absent or G or a small
naturally or non-naturally occurring amino acid; X5 is absent or Q
or S a polar naturally or non-naturally occurring amino acid; X6 is
absent or V or A or P or M or a hydrophobic naturally or
non-naturally occurring amino acid; X7 is absent or G or a small
naturally or non-naturally occurring amino acid; X8 is absent or P
or L or A naturally or non-naturally occurring amino acid; X9 is
absent or P or Q naturally or non-naturally occurring amino acid;
X10 is absent or G or a small naturally or non-naturally occurring
amino acid; X11 is absent or A or H or E or D or a hydrophobic or a
small or an acidic naturally or non-naturally occurring amino acid;
X12 is absent or A or P or Q or S or R or H or a hydrophobic or a
small naturally or non-naturally occurring amino acid; X13 is
absent or C or V or a hydrophobic naturally or non-naturally
occurring amino acid; X14 is absent or R or K or Q or P or a basic
or a polar naturally or non-naturally occurring amino acid; X15 is
absent or R or Q or S or a basic or a polar naturally or
non-naturally occurring amino acid; X16 is absent or A or L or H or
Q or a hydrophobic or a small naturally or non-naturally occurring
amino acid; X17 is absent or Y or a hydrophobic or an aromatic
naturally or non-naturally occurring amino acid; X18 is absent or A
or a hydrophobic or small naturally or non-naturally occurring
amino acid; X19 is absent or A or a hydrophobic small naturally or
non-naturally occurring amino acid; X20 is absent or F or a
hydrophobic or an aromatic naturally or non-naturally occurring
amino acid; X21 is absent or S or T or a polar naturally or
non-naturally occurring amino acid; X22 is absent or V or a
hydrophobic naturally or non-naturally occurring amino acid; X23 is
absent or G or hydrophobic or small non-naturally occurring amino
acid or replaced by an amide; X24 is absent or R or a basic
naturally or non-naturally occurring amino acid; X25 is absent or R
or a basic naturally or non-naturally occurring amino acid; X26 is
A or a hydrophobic or small naturally or non-naturally occurring
amino acid; X27 is Y or a hydrophobic or an aromatic naturally or
non-naturally occurring amino acid; X28 is A or a hydrophobic or
small naturally or non-naturally occurring amino acid; X29 is A or
a hydrophobic or small naturally or non-naturally occurring amino
acid; X30 is F or a hydrophobic naturally or non-naturally
occurring amino acid; X31 is S or T or a polar naturally or
non-naturally occurring amino acid; X32 is V or a hydrophobic
naturally or non-naturally occurring amino acid; X33 is absent or G
or hydrophobic or small naturally or non-naturally occurring amino
acid or replaced by an amide; or a pharmaceutically acceptable salt
thereof (SEQ ID NO:4). In some preferred embodiments, the relaxin
agonist comprises the sequence of peptide P59C13V (free acid)
GQKGQVGPPGAA VRRA Y AAFSV (SEQ ID NO:5). In another preferred
embodiment, the relaxin agonist comprises the sequence of peptide
P74C13V (free acid) GQKGQVGPPGAA VRRA Y AAFS VGRRA Y AAFS V (SEQ DD
NO: 6). Further derivatives of the human complement C1Q tumor
necrosis factor-related protein 8 (CTRP8 or C1QT8) such as peptide
P59-G (free acid Gly) GQKGQVGPPGAACRRA Y AAFSVG (SEQ ID NO:7) are
also contemplated to be suitable for use in the methods of the
present disclosure. The amino acid sequence of C1QT8 is set forth
as SEQ ID NO:8
TABLE-US-00001 MAAPALLLLALLLPVGAWPGLPRRPCVHCCRPAWPPGPYARVSDRDLWRG
DLWRGLPRVRPTIDIEILKGEKGEAGVRGRAGRSGKEGPPGARGLQGRRG
QKGQVGPPGAACRRAYAAFSVGRRAYAAFSVGRREGLHSSDHFQAVPFDT
ELVNLDGAFDLAAGRFLCTVPGVYFLSLNVHTWNYKETYLHIMLNRRPAA
VLYAQPSERSVMQAQSLMLLLAAGDAVWVRMF QRDRDNAIYGEHGDLYI TFSGHLVKP
AAEL
[0122] The present disclosure also encompasses encompasses
homologues of these polypeptides, such homologues can be at least
50%, at least 55%, at least 60%, at least 65%, at least 70%, at
least 75%, at least 80%, at least 85%, at least 85%, at least 90%,
at least 95% or more say 100% identical to the amino acid sequence
of an exemplary relaxin agonist (e.g., SEQ ID NO:5 or SEQ ID NO:6),
as can be determined using BlastP software of the National Center
of Biotechnology Information (NCBI) using default parameters,
optionally and preferably including the following: filtering on
(this option filters repetitive or low-complexity sequences from
the query using the Seg (protein) program), scoring matrix is
BLOSUM62 for proteins, word size is 3, E value is 10, gap costs are
1 1, 1 (initialization and (initialization and extension).
Optionally and preferably, nucleic acid sequence identity/homology
is determined with BlastN software of the National Center of
Biotechnology Information (NCBI) using default parameters, which
preferably include using the DUST filter program, and also
preferably include having an E value of 10, filtering low
complexity sequences and a word size of 1 1. Finally the present
disclosure also encompasses fragments of the above described
polypeptides and polypeptides having mutations, such as deletions,
insertions or substitutions of one or more amino acids, either
naturally occurring or artificially induced, either randomly or in
a targeted fashion.
Medical Uses
[0123] The disclosure provides medical uses of relaxin as defined
above. Thus, for example, the disclosure provides a relaxin for use
in treating dyspnea in a human subject. In another embodiment the
disclosure provides a relaxin for use in treating acute
decompensated heart failure in a human subject, wherein the subject
has acute decompensated heart failure and a systolic blood pressure
of at least 125 mm Hg, and wherein the method comprises
administering the H2 relaxin to the subject in an amount effective
to reduce their in hospital worsening heart failure. In another
embodiment the disclosure provides a relaxin for use in treating
acute decompensated heart failure in a human subject, wherein the
subject has acute decompensated heart failure and a left
ventricular ejection fraction of at least about 20%, and wherein
the method comprises administering the H2 relaxin to the subject in
an amount effective to reduce at least one acute heart failure sign
or symptom in the subject. The disclosure also provides a relaxin
for use in treating acute decompensated heart failure in a human
subject, wherein the subject has acute decompensated heart failure,
and wherein the method comprises administering the H2 relaxin to
the subject in an amount effective to reduce diuretic use during a
hospital stay.
[0124] The disclosure also provides the use of a relaxin in the
manufacture of a medicament for treating dyspnea in a human
subject. The disclosure also provides the use of a relaxin in the
manufacture of a medicament for treating acute decompensated heart
failure in a human subject, wherein the subject has acute
decompensated heart failure and a systolic blood pressure of at
least 125 mm Hg. The disclosure also provides the use of a relaxin
in the manufacture of a medicament for treating acute decompensated
heart failure in a human subject, wherein the subject has acute
decompensated heart failure and a left ventricular ejection
fraction of at least about 20%.
[0125] Other features of the relaxin and the treatments associated
with these uses are disclosed above.
[0126] The disclosure also provides the use of a relaxin and an
antihypertensive drug in the manufacture of a medicament for
treating the conditions discussed above. The antihypertensive drug
may be selected as described above e.g. from the group consisting
of vasodilators, adrenergic blockers, centrally acting
alpha-agonists, angiotensin-converting enzyme inhibitors,
angiotensin II receptor blockers, calcium channel blockers and
diuretics.
[0127] The disclosure also provides a relaxin and an
antihypertensive drug, as a combined preparation for simultaneous
separate or sequential use in treating the conditions discussed
above. Similarly, the disclosure provides a relaxin and an
antihypertensive drug, for combined use in treating the conditions
discussed above.
[0128] The disclosure also provides a relaxin for use, in
combination with an antihypertensive drug, in treating the
conditions discussed above. Similarly, the disclosure provides an
antihypertensive drug for use, in combination with a relaxin, in
treating the conditions discussed above.
[0129] The disclosure also provides a relaxin for use in a method
for treating the conditions discussed above, wherein the relaxin is
administered, or is prepared for administration, with an
antihypertensive drug. Similarly, the disclosure provides an
antihypertensive drug for use in a method for treating the
conditions discussed above, wherein the antihypertensive drug is
administered, or is prepared for administration, with a relaxin.
The relaxin and/or antihypertensive drug may also be used in this
way in the manufacture of a medicament.
[0130] The disclosure also provides a relaxin for use in a method
for treating the conditions discussed above, wherein the subject
previously received an antihypertensive drug in the preceding 48
hours. Similarly, the disclosure provides an antihypertensive drug
for use in a method for treating the conditions discussed above,
wherein the subject previously received a relaxin drug in the
preceding 48 hours. The relaxin and/or antihypertensive drug may
also be used in this way in the manufacture of a medicament. For
these embodiments, the subjects may have received the other drug
less than 48 hours previously e.g. in the preceding 24 hours, the
preceding 12 hours, or the preceding 6 hours. Typically, the
previously-administered drug will still be present in the subject's
body and will be detectable. The remaining presence of this
previously-administered drug distinguishes these subjects from the
general human population.
EXPERIMENTAL
[0131] The following specific examples are intended to illustrate
the disclosure and should not be construed as limiting the scope of
the claims.
[0132] Abbreviations: AHF (acute heart failure or decompensated
congestive heart failure); AUC (area under the curve); BNP (brain
natriuretic peptide); (BP) blood pressure; BUN (blood urea
nitrogen); CHF (congestive heart failure); CI (cardiac index); CO
(cardiac output); CrC1 (creatine clearance); DBP (diastolic blood
pressure); dL (deciliters); eGFR (estimated glomerular filtration
rate); hr (hour); HR (heart rate); ICU (intensive care unit); IV
(intravenous); IVCD (intraventricular conduction delay); kg
(kilogram); L (liter); LAHB (left anterior hemiblock); LBBB (left
bundle branch block); LVEDP (left ventricular end diastolic
pressure); LVEF (left ventricular ejection fraction); mcg or .mu.g
(microgram); mEq (milliequivalents); MI (myocardial infarction);
mIU (milli-international units); mL (milliliter); NYHA (New York
Heart Association); PAH (para-aminohippurate); PAP (pulmonary
arterial pressure); PCWP (pulmonary capillary wedge pressure); PD
(pharmacodynamic); RAP (right atrial pressure); RBBB (right bundle
branch block); RBF (renal blood flow); rhRlx or rhRLX (recombinant
human relaxin); Rlx or RLX (relaxin); RR (respiratory rate); SBP
(systolic blood pressure); SI (stroke index); sMDRD (simplified
Modification of Diet in Renal Disease); SQ (subcutaneous SQ); SVR
(systemic vascular resistance); T (temperature); VAS (visual analog
scale); VF (ventricular fibrillation); VT (ventricular
tachycardia); and WHF (worsening heart failure).
Example 1
Study of Recombinant Human Relaxin in Patients with Systemic
Sclerosis
[0133] Overview.
[0134] Clinical trials with relaxin have also been conducted on
systemic sclerosis patients. 257 human subjects who suffer from
systemic sclerosis, a serious fibrotic disease, have been treated
with relaxin by continuous and subcutaneous (SQ) infusion for six
months. The results, which include extensive and long term safety
information, have shown that these patients did not experience any
serious hypotensive events as a result of relaxin (FIG. 4),
confirming the later CHF findings. The systemic sclerosis trials
showed that relaxin administration was associated with stable
decreases in blood pressure, with no serious episodes of
hypotension, and a statistically significant increase in predicted
creatinine clearance (see FIG. 5). These findings support the
hypothesis that relaxin administration was associated with balanced
systemic and renal vasodilation.
[0135] In addition, 570 human subjects have been treated with
relaxin in 19 completed trials. These subjects included patients
with fibromyalgia, women undergoing egg donation, pregnant women at
term, healthy female and male volunteers, healthy adults undergoing
orthodontic therapy, and systemic sclerosis patients.
[0136] Findings and Conclusion.
[0137] As described herein, relaxin can be administered safely in
subjects with a variety of underlying conditions. In a number of
these trials, data suggested that relaxin causes balanced systemic
and renal vasodilation.
Example 2
Study of Recombinant Human Relaxin in Patients with Acute Heart
Failure
[0138] Overview.
[0139] A multi-center, randomized, double-blind, placebo-controlled
clinical trial was conducted to determine the safety and efficacy
of recombinant human relaxin (rhRLX) in patients with decompensated
congestive heart failure (CHF). The terms decompensated CHF and
acute heart failure (AHF) are used interchangeably herein. Patients
hospitalized for AHF (defined as including all of dyspnea at rest
or with minimal exertion, pulmonary congestion as evidenced by
interstitial edema on chest radiograph, and an elevated BNP or
NTproBNP), and having an estimated glomerular filtration rate of
30-75 ml/min/1.73 m.sup.2 and a SBP>125 mmHg at the time of
screening were eligible for randomization within 16 hours from
presentation to standard AHF care plus a 48-hour IV infusion of
placebo or relaxin (RLX; 10, 30, 100 or 250 mcg/kg/d) and were
followed up to day 180. A total of 234 patients were enrolled in
the study.
[0140] Inclusion Criteria.
[0141] Men and women aged 18 years or older who were hospitalized
for AHF, with preserved or elevated blood pressure and with
impaired renal function were eligible for inclusion in the study.
AHF was defined by the presence of all of the following at
screening: dyspnea at rest or with minimal exertion, pulmonary
congestion on chest X-ray and elevated natriuretic peptide levels
[brain natriuretic peptide (BNP).gtoreq.350 pg/mL or
NT-pro-BNP.gtoreq.1400 pg/mL]. Systolic blood pressure (SBP) had to
be >125 mmHg at the time of screening. Impaired renal function
was defined as an estimated glomerular filtration rate (eGFR) of
between 30 to 75 mL/min/1.73 m.sup.2, calculated using the
simplified Modification of Diet in Renal Disease (sMDRD) equation
(Levey et al., Ann Intern Med, 130:461-470, 1999). Randomization
was to occur within 16 hours of initial presentation. Patients had
to qualify after receipt of at least 40 mg of intravenous (IV)
furosemide (or equivalent dose of alternative loop diuretic).
[0142] Exclusion Criteria.
[0143] Fever (temperature greater than 38.degree. C.); acute
contrast-induced nephropathy or recent administration of contrast;
ongoing or planned IV treatment with positive inotropic agents,
vasopressors, vasodilators (with the exception of IV nitrates
infused at a dose .ltoreq.0.1 mg/kg/h if SBP>150 mmHg), or
mechanical support (intra-aortic balloon pump, endotracheal
intubation, mechanical ventilation or any ventricular assist
device); severe pulmonary disease; significant stenotic cardiac
valvular disease; previous organ transplantation or admission for
cardiac transplantation; clinical diagnosis of acute coronary
syndrome within 45 days prior to screening; major surgery within 30
days of screening; hematocrit less than 25%; major neurologic event
within 45 days prior to screening; troponin level at screening
greater than 3 times the upper limit of normal; AHF caused by
significant arrhythmias; non-cardiac pulmonary edema; or known
significant liver disease.
[0144] Study Drug.
[0145] Recombinant human relaxin (rhRlx) was produced using a
proprietary process as a single chain precursor, termed
Mini-C-prorelaxin, in a recombinant E. coli strain. Inclusion
bodies containing the precursor were released from the cells by
homogenization and recovered by centrifugation. Mini-C-prorelaxin
was extracted from the inclusion bodies, refolded with a redox
buffer (in order to build the disulfide bridges), and partially
purified by silica adsorption and ion exchange chromatography. The
leader sequence and the peptide connecting the B-chain to the
A-chain were then removed enzymatically. The resulting relaxin was
then purified by three successive chromatography steps (ion
exchange and reversed phase). Formulation of the product was
achieved by ultra- and diafiltration. The rhRlx was formulated as a
sterile acetate buffered parenteral solution.
[0146] Study Procedures.
[0147] The study was approved by the relevant ethics committees,
institutional review boards and regulatory authorities, and
conducted under the International Conference on Harmonization Good
Clinical Practice guidelines. All patients provided informed
written consent prior to participation. Consenting patients who met
all study inclusion and none of the study exclusion criteria were
randomized to receive in double blind manner, either IV placebo or
relaxin at 10, 30, 100 or 250 mcg/kg/d for 48 hours in addition to
standard therapy for AHF at the discretion of the investigator. The
placebo used for the study was the same solution as the diluent
used to prepare the 100 .mu.g/kg/day dose. The randomization ratio
was 3:2:2:2:2, respectively. Relaxin (Corthera, San Mateo, Calif.)
was manufactured using recombinant techniques and was identical to
the naturally-occurring peptide hormone. By protocol, the study
drug infusion was to be terminated if the patient's SBP was reduced
to <100 mmHg or by >40 mmHg compared to baseline in two
successive measurements, 15 minutes apart. Investigators were not
prohibited from utilizing any standard medication thought necessary
to treat patients enrolled in the study, including additional
vasodilators. Following a 4-hour washout period during which time
IV vasodilators, IV pure inotropes and meals were withheld,
hemodynamic, renal, and clinical responses to 48 hours of study
drug infusion were assessed.
[0148] Patient-reported dyspnea was assessed using both a standard
7-point Likert Scale and a standard 100-mm Visual Analog Scale
(VAS). Assessments were performed at baseline (VAS only), 6 h, 12
h, 24 h, 48 h after initiation of drug therapy and at Days 3, 4, 5
and 14. Questionnaires were administered in the local language, and
investigators received training in the standardized administration
of these evaluations. Daily, serial physician-reported assessments
of heart failure signs and symptoms were conducted including
jugular venous distension, rales, edema, orthopnea, and dyspnea on
exertion. In-hospital worsening heart failure was defined as a
physician-determined assessment based on worsening symptoms or
signs of heart failure and the need for the addition or institution
of IV medications or mechanical support to treat AHF. Vital status
and rehospitalization information was collected by telephone at Day
30, Day 60 and (vital status only at) Day 180. When the last
enrolled patient reached Day 60, telephone contact was made with
all patients who were between Day 60 and Day 180 of follow-up to
complete the study.
[0149] Study Endpoints.
[0150] As an exploratory, dose-finding study, Pre-RELAX-AHF did not
have a single pre-specified primary endpoint. Instead, the overall
effect of IV relaxin on seven primary treatment efficacy targets
was evaluated. 1.) Relief of dyspnea, assessed with two
complementary instruments: (a) Change in dyspnea by Likert scale,
and (b) Change from baseline by Visual Analog Scale. 2.)
In-hospital worsening heart failure (WHF) to Day 5. 3.) Renal
impairment, assessed by multiple measures, including: (a) Renal
impairment as defined by a .gtoreq.25% increase in serum creatinine
from baseline to day 5, and (b) Persistent renal impairment as
defined by creatinine increase of 0.3 mg/dL or above at both day 5
and 14 from randomization. 4.) Length of initial hospital stay. 5.)
Days alive and out-of-hospital to Day 60. 6.) Death due to
cardiovascular causes or rehospitalization for heart failure or
renal failure to Day 60. 7.) Mortality due to cardiovascular causes
to Day 180. In addition, serial assessments of safety were
performed including vital signs, physical examinations, adverse
events and clinical laboratory evaluations.
[0151] Statistical Methods.
[0152] Data are presented as means with standard deviations unless
otherwise specified. Missing data were generally imputed by a
last-observation-carried-forward approach. The worst observed
dyspnea Likert or VAS score was carried forward from the time of
death or worsening heart failure. The area under the curve
representing the change in VAS score from baseline through Day 5
was computed by trapezoidal rule. For patients who died during the
initial hospitalization, length of stay was imputed as the maximum
observed plus 1 day (33 days). Each relaxin group was compared to
placebo, without adjustment for multiple comparisons, using
logistic regression for the binary outcomes, and the Wilcoxon rank
sum test for continuous measures (with the van Elteren extension
for the analysis of the length of stay and days alive out of
hospital at Day 60), unless otherwise noted. To control for
regional variations in this relatively small study, region as a
covariate or stratifying variable was prospectively pre-specified
in the analyses of treatment effect. Rehospitalization and
mortality rates through Day 180 were estimated using Kaplan-Meier
(product-limit) methods, and groups compared using the Wald test of
the treatment effect from Cox regression models, where
time-to-event was censored at last patient contact for patients
without the event of interest.
[0153] The sample size in this phase 2 study was selected
empirically and the study was not prospectively powered for
statistical significance of any specific outcome measure. A
p<0.05 was considered statistically significant, while
0.05.ltoreq.p.ltoreq.0.20 was considered a trend suggestive of drug
effect. The main goals of the study were to identify a dose of
relaxin that was associated with multiple trends in the above
mentioned primary treatment targets and is not associated with
safety concerns, to determine which endpoints demonstrated
treatment sensitivity and to document the effect size for further
statistical power calculations. The chairperson of an unblinded,
independent Data Safety and Monitoring Board reviewed safety data
monthly during the conduct of the study.
[0154] Study Population.
[0155] The study enrolled 234 patients at 54 sites in 8 countries
(USA, Belgium, Italy, Poland, Israel, Hungary, Romania and Russia)
from December, 2007 to August, 2008 with the final study contact in
October, 2008. The safety analysis population consists of 230
patients who received any amount of study drug. The efficacy
analysis population consists of 229 patients who received study
drug, excluding one patient who violated multiple major eligibility
criteria. Patients were 70.3.+-.10.5 years old and 56% male, with a
screening blood pressure of 147.+-.19 mmHg and extensive
co-morbidities (Table 3-1). There were no clinically meaningful or
statistically significant differences in characteristics among the
five treatment groups. Patients were randomized at a mean of
8.4.+-.5.4 hours from presentation [median 6.6 hours (Q1-Q3:
4.0-13.4)] and were treated with study drug within 1.0.+-.1.8 hours
from randomization. Patients in the placebo group received a mean
duration of infusion of 44 hours, while those in the relaxin 10,
30, 100 and 250 mcg/kg/d groups received an average of 39, 41, 41
and 42 hours of study drug, respectively. Patients received
standard therapy in addition to study drug with 18.0% of the
placebo group receiving intravenous nitroglycerin during the first
24 hours, compared to 10.0%, 9.5%, 13.5 and 4.1% in the relaxin 10,
30, 100 and 250 mcg/kg/d groups, respectively.
[0156] Dyspnea Responses.
[0157] Results are presented via the Visual Analog Score (VAS) and
the Likert Score. The VAS score measures a characteristic or
attitude that ranges across a continuum of values. For example, the
amount of discomfort an AHF patient feels ranges across a continuum
from none to an extreme amount of discomfort and/or pain including
dyspnea, hypertension, high blood pressure, arrhythmia and reduced
renal blood flow. From the patient's perspective this spectrum
appears continuous, which the VAS captures. Operationally a VAS is
usually a horizontal line, 100 mm in length, anchored by word
descriptors at each end (e.g., no discomfort on one end and severe
discomfort on the other end). The patients marked on the line the
point that they felt represented their perception of their current
state. The VAS score is determined by measuring in millimeters from
the left hand end of the line to the point that the patient marks
(Wewers et al., Research in Nursing and Health 13:227-236,
1990).
[0158] The Likert Score is a unidimensional scaling method known in
the art, wherein the set of scale items are rated on a numerical
(herein 7-point) Disagree-Agree response scale. Each patient was
asked to rate each item on the response scale. The final score for
the respondents on the scale is the sum of their ratings for all of
the items.
[0159] Relaxin-treated patients had rapid, meaningful and sustained
dyspnea improvement compared to those in the placebo group. The
combined relaxin-treated group had a larger improvement in dyspnea
severity compared to placebo as early as 6 hours after initiation
of therapy, persisting throughout all time points assessed. The
best response to treatment was observed in the patients receiving
relaxin at the dose of 30 mcg/kg/d. Moderately or markedly better
dyspnea on the Likert Scale at all of the 6 h, 12 h and 24 h
assessments occurred in 23.0% of patients in the placebo group
compared to 40.5% in the relaxin 30 mcg/kg/d group (p=0.044; Table
3-2). The VAS similarly demonstrated a sustained, positive trend of
drug effect on relief of dyspnea. The area under the curve (AUC)
for change from baseline to Day 5 in the dyspnea VAS was
1679.+-.2556 mm*hr in the placebo group compared to 2567.+-.2898
mm*hour in the relaxin 30 mcg/kg/d group (p=0.11; Table 3-2), and
these observed changes correspond to averages of 14, 21, 22, 21 and
18 mm improvement over the 5 days for the placebo and relaxin 10,
30, 100 and 250 mcg/kg/d groups, respectively. Similar results are
evident for the VAS AUC through Day 14 (Table 3-2) where placebo
mean was 4622.+-.9003 mm*hr compared to 8214.+-.8712 mm*hour in the
relaxin 30 mcg/kg/d group (p=0.053). These changes correspond to
averages of 14, 10, 25, 25 and 21 mm over the 14 days, for the
respective groups.
[0160] Short-Term Outcomes.
[0161] There were consistent trends (p<0.20) in favor of relaxin
therapy compared to placebo in multiple in-hospital assessments. In
particular, the relaxin dose of 30 mcg/kg/d appeared most effective
with supportive trends in the groups receiving 10 and 100 mcg/kg/d.
Physician-assessed resolution of jugular venous distension, rales,
and edema were all improved in the relaxin 30 mcg/kg/d group
compared to placebo at Day 5 (Table 3-3) and at Day 14, associated
with trends toward greater decrease in body weight and decreased
diuretic use in the relaxin-treated patients. The cumulative
incidence of worsening heart failure by day 5 was lower in the
relaxin groups compared to placebo (Table 3-2), and the mean length
of stay for the index hospitalization tended to be 0.9-1.8 days
shorter in the relaxin groups than for placebo (Table 3-2; p=0.18
for relaxin 30 mcg/kg/d vs. placebo group).
[0162] Post-Discharge Outcomes.
[0163] Patients were followed for an average of 122.+-.53 days. A
total of 15 patients died by Day 60, and 20 patients by Day 180, 12
for cardiovascular causes. Forty-three patients were rehospitalized
by Day 60; 15 due to heart failure and none due to renal failure.
Relaxin-treated patients demonstrated trends toward improvement in
longer-term clinical outcomes (Table 3-2). At Day 60, the mean
number of days alive and out-of-hospital was 44.2.+-.14.2 in the
placebo group, while it was approximately 4 days greater in the
relaxin-treated patients (p=0.16 for 30 mcg/kg/d vs. placebo
group). The Kaplan-Meier estimate of the combined incidence of
death due to cardiovascular causes or rehospitalization due to
heart failure or renal failure at day 60 was 17.2% in the group
receiving placebo, but much less in the relaxin-treated patients
with an estimated 87% hazard reduction in the relaxin 30 mcg/kg/d
group (p=0.053 vs. placebo). Similar findings were evident when
all-cause mortality was included (Table 3-2). The Kaplan-Meier
estimate of Day 180 cardiovascular mortality was 14.3% in the
placebo group, but was considerably less in the relaxin-treated
groups (p=0.046 for relaxin 30 mcg/kg/d compared to placebo by
Fisher's exact test of the incidence densities). The corresponding
Kaplan-Meier estimates for all-cause mortality demonstrated similar
trends.
[0164] Safety Endpoints.
[0165] Adverse events and serious adverse events were evenly
distributed across study groups and represented the natural history
of patients hospitalized with AHF (Table 3-4). There were no
individual or pattern of adverse events suggesting a deleterious
study drug effect.
[0166] Relaxin has known vasodilating activity and consequently,
changes in blood pressure were carefully monitored. During the
48-hour infusion period, the placebo group had a 12-20 mmHg
decrease from baseline in systolic blood pressure (SBP) and the
relaxin-treated patients had similar reductions (FIG. 21). The
average decrease in blood pressure over all time points did not
differ between any of the treatment groups and the placebo group by
repeated measures ANOVA (p-values for the average change in SBP
comparing 10, 30, 100, and 250 mcg/kg/day with placebo were 0.41,
0.16, 0.13, and 0.32, respectively), although there was a trend in
the 30 and 100 mcg/kg/d groups with a mean decrease of 3-4 mmHg
compared to placebo. There were 36 adverse events of hypotension
and/or decreases in SBP which met protocol-specified study drug
stopping rules, two of which were serious adverse events (both in
the relaxin 250 mcg/kg/d group). Protocol-specified study drug
discontinuation due to blood pressure reduction occurred in 10.9%
of patients across all groups, and was more frequent in
relaxin-treated groups (20.0%, 9.5%, 7.9% and 16.3% with relaxin
10, 30, 100 and 250 mcg/kg/d, respectively) compared to placebo
(3.3%) with no apparent dose-response. Most blood pressure
reductions occurred during the first 6-12 hours of therapy. In no
cases did the trough SBP fall below 80 mmHg. After discontinuation
of study drug, SBP stabilized or rose in most of these patients
with no therapy (1 of 2 placebo patients with SBP reductions; 18 of
23 relaxin-treated patients). In the placebo group, 1 patient
(1.6%) received intravenous fluids for hypotension, while 5
patients from the four relaxin-treated groups (3.0%) received
intravenous fluids and one asymptomatic patient also received
dobutamine in the relaxin 250 mcg/kg/d group. None of the patients
in the 10 or 30 mcg/kg/d groups required treatment of blood
pressure reduction.
[0167] There were no differences in the incidence of renal failure
reported as a serious adverse event among the study groups (Table
3-4). At Day 14, mean changes in creatinine from baseline were
0.08.+-.0.46, 0.07.+-.0.24, 0.13.+-.0.49, 0.08.+-.0.39 and
0.10.+-.0.39 mg/dL (p-value for each group vs. placebo
.gtoreq.0.97). The proportion of patients at Day 14 with an
increase of 0.3 mg/dL or more was 16.7%, 19.4%, 26.3%, 24.2% and
37.2% (p=0.03 for 250 mcg/kg/d vs. placebo). Persistent renal
impairment (0.3 mg/dL or greater increase in creatinine at both Day
5 and 14) also trended to being greater in patients receiving
relaxin 250 mcg/kg/d (p=0.19 vs. placebo).
[0168] As with many vasodilators, there was a transient and
clinically insignificant decrease in hematocrit in all active
treatment groups that occurred during study drug administration
(change from baseline in mean hematocrit at 48 hours: +0.42% in
placebo group and 0.57%, 1.45%, 0.25%, 0.64% in relaxin 10, 30, 100
and 250 mcg/kg/d groups, respectively; p=0.019 vs. placebo for
relaxin 30 mcg/kg/d group), resolving by Day 5. There were no other
clinical laboratory changes of note during the study.
TABLE-US-00002 TABLE 3-1 Baseline Patient Characteristics Relaxin
(mcg/kg/d) Group Placebo 10 30 100 250 Number of Subjects in 61 40
42 37 49 Efficacy Analysis Men, % 65.6 52.5 42.9 51.4 61.2 Age, yr
68.4 (9.9) 72.2 (11.0) 71.6 (9.2) 69.2 (11.6) 70.7 (11.0) Weight,
kg 80.7 (15.6) 80.2 (16.9) 79.9 (13.0) 84.5 (25.0) 80.2 (16.7)
Ischemic heart disease, % 67.2 62.5 78.6 64.9 73.5 Hypertension
history, % 82.0 87.5 90.5 81.1 87.8 Diabetes history, % 49.2 32.5
52.4 32.4 40.8 Mitral regurgitation, % 23.0 30.0 31.0 32.4 36.7
Atrial fibrillation/flutter, % 42.6 60.0 42.9 56.8 38.8 Ejection
fraction <40%, % 44.2 48.4 53.6 68.0 55.6 Hospitalized for AHF
in 29.5 32.5 38.1 43.2 30.6 prior year, % NYHA class, % I 3.3 0.0
0.0 0.0 4.1 II 26.2 35.0 14.3 21.6 10.2 III 37.7 42.5 40.5 35.1
44.9 IV 19.7 12.5 33.3 37.8 28.6 NT-pro-BNP >2000 pg/mL, % 75.4
70.0 83.3 70.3 71.4 Troponin .gtoreq.0.1 ng/mL 23.3 18.4 10.3 13.9
16.7 and <3 x ULN, % SBP at screening, mmHg 147.5 (20.3) 145.4
(16.0) 150.3 (19.5) 146.5 (18.7) 145.5 (20.5) eGFR 53.9 (16.8) 56.5
(15.8) 50.6 (14.1) 53.4 (22.0) 53.4 (15.2) Serum creatinine, mg/dL
1.4 (0.5) 1.2 (0.5) 1.3 (0.4) 1.3 (0.4) 1.3 (0.5) BUN, mg/dL 28.3
(12.4) 25.2 (11.7) 28.2 (10.7) 25.7 (10.7) 26.7 (10.8) Sodium,
meq/L 140.7 (3.4) 139.9 (3.2) 140.4 (4.0) 140.8 (4.1) 139.9 (4.9)
Time from presentation to 9.0 (5.7) 7.5 (4.8) 7.6 (4.8) 9.0 (5.5)
8.4 (5.7) randomization, hr [median] [6.4] [6.0] [6.1] [7.5] [6.6]
Time from randomization to 1.0 (1.1) 0.9 (1.2) 0.6 (0.5) 0.7 (0.4)
1.6 (3.6) drug administration, hr Medications 1 month prior to
presentation, % ACE inhibitor or ARB 75.4 55.0 73.8 75.7 69.4
Beta-blocker 60.7 67.5 69.0 59.5 63.3 Aldosterone inhibitor 27.9
27.5 28.6 29.7 38.8 Results expressed as mean (SD), unless
otherwise noted. NYHA (New York Heart Association) class when last
in stable condition; eGFR by sMDRD, ml/min/1.73 m.sup.2; ULN, upper
limit of normal.
TABLE-US-00003 TABLE 3-2 Effect Of Relaxin On Primary Treatment
Targets Relaxin (mcg/kg/d) Placebo 10 30 100 250 Number of Subjects
in 61 40 42 37 49 Efficacy Analysis Short-term Outcomes: %
moderately/markedly 23.0% 27.5% 40.5% 13.5% 22.4% better dyspnea at
6, 12 p = 0.54 p = 0.044 p = 0.28 p = 0.86 and 24 hrs (Likert)
Dyspnea AUC Change 1679 .+-. 2556 2500 .+-. 2908 2567 .+-. 2898
2486 .+-. 2865 2155 .+-. 2338 from baseline to Day 5 p = 0.15 p =
0.11 p = 0.16 p = 0.31 (VAS; mm*hr) Dyspnea AUC Change 4621 .+-.
9003 6366 .+-. 10078 8214 .+-. 8712 8227 .+-. 9707 6856 .+-. 7923
from baseline to Day 14 p = 0.37 p = 0.053 p = 0.064 p = 0.16 (VAS;
mm*hr) Worsening HF through 21.3% 20.0% 11.9% 13.5% 10.2% Day 5
(%)* p = 0.75 p = 0.29 p = 0.40 p = 0.15 Length of Hospital Stay
12.0 .+-. 7.3 10.9 .+-. 8.5 10.2 .+-. 6.1 11.1 .+-. 6.6 10.6 .+-.
6.6 (days) p = 0.36 p = 0.18 p = 0.75 p = 0.20 Day 60 Outcomes Days
alive out of hospital 44.2 .+-. 14.2 47.0 .+-. 13.0 47.9 .+-. 10.1
.sup. 48 .+-. 10.1 47.6 .+-. 12.0 p = 0.40 p = 0.16 p = 0.40 p =
0.048 Cardiovascular death or 17.2% 10.1% 2.6% 8.4% 6.2%
Rehospitalization (KM %; [0.55 (0.17- [0.13 (0.02- [0.46 (0.13-
[0.32 (0.09- [HR (95% CI)]) .dagger. 1.77)] 1.03)] 1.66)] 1.17)] p
= 0.32 p = 0.053 p = 0.23 p = 0.085 All-cause death or 18.6% 12.5%
7.6% 10.9% 8.3% Rehospitalization (KM %; [0.63 (0.22- [0.36 (0.10-
[0.56 (0.18- [0.41 (0.13- [HR (95% CI)]) .dagger. 1.81)] 1.29)]
1.76)] 1.28)] p = 0.39 p = 0.12 p = 0.32 p = 0.12 Day 180 Outcomes
Cardiovascular death 14.3% 2.5% 0.0% 2.9% 6.2% (KM %; [HR (95%
[0.19 (0.00- [0.00 (0.00- [0.23 (0.01- [0.56 (0.09- CI)])**,
.dagger. 1.49)] 0.98)] 1.79)] 2.47)] p = 0.15 p = 0.046 p = 0.17 p
= 0.53 All-cause death (KM %; 15.8% 5.0% 8.7% 5.5% 10.7% [HR (95%
CI)]) .dagger. [0.34 (0.07- [0.54 (0.14- [0.41 (0.09- [0.08 (0.26-
1.62] 2.03] 1.91] 2.47] p = 0.18 p = 0.36 p = 0.25 p = 0.70 Results
expressed as mean .+-. SD; *For Wilcoxon rank sum test of time to
worsening HF through Day 5; subjects without worsening HF were
assigned a value of 6 days; **by Fisher's exact test comparing
incidence densities; .dagger. Analyses performed on safety
population which included one additional patient (n = 38) in the
100 mcg/kg/d group. Rehospitalization included hospitalization for
heart failure or renal failure; KM, Kaplan-Meier estimates of event
rate at specified time period; HR, hazard ratio.
TABLE-US-00004 TABLE 3-3 Improvement in Signs of Heart Failure
Relaxin (mcg/kg/d) Placebo 10 30 100 250 Number of Subjects in 61
40 42 37 49 Efficacy population % of subjects at Day 5 with: No
edema 47.5 55.0 64.3 .dagger. 51.4 * 61.2 .dagger. No rales 67.2
65.0 76.2 70.3 71.4 JVP <6 cm 67.2 72.5 78.6 73.0 76.6 + Median
total IV diuretic dose 170 100 100 90 + 140 from randomization to
Day 5 (80-300) (40-200) (60-360) (40-200) (60-340) [mg; median
(Q1-Q3)] Median change in body -2.0 -2.0 -3.0 -2.5 -2.0 weight from
baseline to Day (-4.2-0.0) (-4.5-0.0) (-5.0-0.0) (-4.7-0.8)
(-4.0-0.0) 14 [kg; median (Q1; Q3)] .dagger. p < 0.001; * 0.001
.ltoreq. p .ltoreq. 0.05; +, 0.05 .ltoreq. p .ltoreq. 0.20 for
Wilcoxon rank sum test of change in score from baseline (for
signs), van Elteren extension of the Wilcoxon test (for diuretic
dose), or ANOVA (for body weight). JVP, jugular venous
pressure.
TABLE-US-00005 TABLE 3-4 Selected Adverse Events Relaxin (mcg/kg/d)
Group Placebo 10 30 100 250 Number of Subjects in Safety 61 40 42
38 49 Groups Serious adverse events (SAEs) to Day 30 Patients with
any SAEs to Day 10 (16.4%) 7 (17.5%) 7 (16.7%) 3 (7.9%) 8 (16.3%)
30, n (%) Total number of SAEs 13 8 12 3 11 Cardiac failure, n (%)
5 (8.2%) 2 (5.0%) 1 (2.4%) 0 2 (6.1%) Ventricular fibrillation, n
(%) 0 1 (2.5%) 0 0 0 Noncardiac chest pain, n (%) 0 2 (5.0%) 0 0 1
(2.0%) Hypotension, n (%) 0 0 0 0 2 (4.1%) Acute respiratory
failure, n (%) 0 0 0 1 (2.6%) 0 Pneumonia, n (%) 1 (1.6%) 0 3
(7.1%) 0 0 Bronchitis, n (%) 0 0 1 (2.4%) 0 1 (2.0%) Urinary tract
infection, n (%) 0 0 1 (2.4%) 0 1 (2.0%) Cerebrovascular accident,
n (%) 1 (1.6%) 0 2 (4.8%) 0 0 Renal failure, n (%) 1 (1.6%) 0 1
(2.4%) 0 0 Urinary retention, n (%) 0 0 0 2 (5.3%) 0 Adverse events
to Day 30 Patients with any adverse 45 (73.8%) 32 (80.0%) 25
(59.5%) 24 (63.2%) 25 (51.0%) events to Day 30, n (%) Patients with
any AE from Day 6 (9.8%) 4 (10.0%) 5 (11.9%) 2 (5.3%) 3 (6.1%) 15
to Day 30, n (%) Renal impairment Patients with .gtoreq.25%
increase in 8 (13.3%) 4 (10.0%) 9 (22.0%) .sup. 11 (29.7%) * 12
(25.5%) creatinine at Day 5 Patients with .gtoreq.0.3 mg/dL 11
(19.3%) 3 (7.9%) 7 (18.9%) 9 (26.5%) 10 (22.7%) increase in
creatinine at Day 5 Patients with .gtoreq.0.3 mg/dL 4 (6.8%) 3
(7.5%) 3 (7.3%) 4 (10.8%) .sup. 7 (15.2%) + increase in creatinine
at Day 5 and Day 14 * P < 0.05; +, p < 0.20.
[0169] Findings.
[0170] As shown in FIGS. 6-11 of the interim analysis and FIGS. 12
and 13 of the final analysis, relaxin treatment resulted in
measurable improvements in dyspnea. Although all patients received
benefit from relaxin treatment, patients with NT-pro-BNP of greater
than 2000, patients with systolic blood pressure greater than the
median, and patients with creatinine clearance of less than the
median, received the greatest benefit (FIGS. 7-11). Surprisingly, a
low dosage of 30 .mu.g/kg/day of relaxin provided the most rapid
and marked relief of dyspnea as measured using a 7-point Likert
score (FIG. 12). Across all relaxin-treated groups, the trends in
VAS measurements (FIG. 13) of dyspnea also unexpectedly indicated
that the beneficial effect of relaxin treatment was persistent
(e.g., through day 14). Both instruments (VAS and Likert) are
accepted measures of dyspnea in heart failure patients, although
the categorical scale (Likert) appears more sensitive to early
changes, while the ordinal scale (VAS) appears more sensitive to
late changes.
[0171] The beneficial effect of relaxin included a reduction of
acute cardiac decompensation events including not only dyspnea, but
extra body weight due to retention of fluids, length of hospital
stay, likelihood of hospital re-admission, need for loop diuretics,
need for intravenous (IV) nitroglycerin, and an incidence of
worsening heart failure (FIGS. 14-19). Specifically a decrease in
the incidence of worsening of heart failure compared to placebo was
found to be clinically relevant, while shorter hospital stays and a
reduced incidence of re-hospitalization promises a positive impact
in pharma-economics. In addition, there were no apparent adverse
effects on renal function, and there were no safety or tolerability
issues. Noteworthy in their absences were untoward heart rate
elevations and symptomatic hypotension in relaxin-treated patients
(see, FIGS. 20 and 21), which one of skill in the art may have
expected of a chronotropic agent or an indiscriminate
vasodilator.
CONCLUSION
[0172] This is the first prospective study to examine the effects
of IV relaxin in patients with acute heart failure (AHF),
presenting with systolic blood pressure greater than 125 mmHg and
mild to moderate renal impairment. Treatment with relaxin was
associated with significant improvement in dyspnea that was
substantial in magnitude, rapid in onset (within 6 hours), and
sustained to 14 days. Treatment with relaxin was associated with
trends toward improvement in other important clinical endpoints,
including signs of heart failure, in-hospital worsening of heart
failure, length of stay, cardiovascular death or rehospitalization
at 60 days, and 180-day cardiovascular mortality. These effects
were most marked in the 30 mcg/kg/d relaxin group, although similar
but smaller trends were seen with 10 and 100 mcg/kg/d doses of
relaxin. There were no concerning safety signals for relaxin in AHF
patients identified in this study.
[0173] Various modifications and variations of the present
disclosure will be apparent to those skilled in the art without
departing from the scope and spirit of the disclosure. Although the
disclosure has been described in connection with specific preferred
embodiments, it should be understood that the claims should not be
unduly limited to such specific embodiments. Indeed, various
modifications of the described modes for carrying out the
disclosure, which are understood by those skilled in the art are
intended to be within the scope of the claims.
Sequence CWU 1
1
8129PRTHomo sapiens 1Asp Ser Trp Met Glu Glu Val Ile Lys Leu Cys
Gly Arg Glu Leu Val1 5 10 15 Arg Ala Gln Ile Ala Ile Cys Gly Met
Ser Thr Trp Ser 20 25 224PRTHomo sapiensVARIANT(1)...(24)Xaa = Glu
or Gln 2Xaa Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys
Thr1 5 10 15 Lys Arg Ser Leu Ala Arg Phe Cys 20 38PRTArtificial
SequenceRelaxin consensus sequence 3Arg Glu Leu Val Arg Xaa Xaa
Ile1 5 433PRTArtificial SequenceSynthesized Construct 4Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 5 10 15 Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 20 25
30 Xaa522PRTHomo sapiens 5Gly Gln Lys Gly Gln Val Gly Pro Pro Gly
Ala Ala Val Arg Arg Ala1 5 10 15 Tyr Ala Ala Phe Ser Val 20
632PRTHomo sapiens 6Gly Gln Lys Gly Gln Val Gly Pro Pro Gly Ala Ala
Val Arg Arg Ala1 5 10 15 Tyr Ala Ala Phe Ser Val Gly Arg Arg Ala
Tyr Ala Ala Phe Ser Val 20 25 30 723PRTHomo sapiens 7Gly Gln Lys
Gly Gln Val Gly Pro Pro Gly Ala Ala Cys Arg Arg Ala1 5 10 15 Tyr
Ala Ala Phe Ser Val Gly 20 8262PRTHomo sapiens 8Met Ala Ala Pro Ala
Leu Leu Leu Leu Ala Leu Leu Leu Pro Val Gly1 5 10 15 Ala Trp Pro
Gly Leu Pro Arg Arg Pro Cys Val His Cys Cys Arg Pro 20 25 30 Ala
Trp Pro Pro Gly Pro Tyr Ala Arg Val Ser Asp Arg Asp Leu Trp 35 40
45 Arg Gly Asp Leu Trp Arg Gly Leu Pro Arg Val Arg Pro Thr Ile Asp
50 55 60 Ile Glu Ile Leu Lys Gly Glu Lys Gly Glu Ala Gly Val Arg
Gly Arg65 70 75 80 Ala Gly Arg Ser Gly Lys Glu Gly Pro Pro Gly Ala
Arg Gly Leu Gln 85 90 95 Gly Arg Arg Gly Gln Lys Gly Gln Val Gly
Pro Pro Gly Ala Ala Cys 100 105 110 Arg Arg Ala Tyr Ala Ala Phe Ser
Val Gly Arg Arg Ala Tyr Ala Ala 115 120 125 Phe Ser Val Gly Arg Arg
Glu Gly Leu His Ser Ser Asp His Phe Gln 130 135 140 Ala Val Pro Phe
Asp Thr Glu Leu Val Asn Leu Asp Gly Ala Phe Asp145 150 155 160 Leu
Ala Ala Gly Arg Phe Leu Cys Thr Val Pro Gly Val Tyr Phe Leu 165 170
175 Ser Leu Asn Val His Thr Trp Asn Tyr Lys Glu Thr Tyr Leu His Ile
180 185 190 Met Leu Asn Arg Arg Pro Ala Ala Val Leu Tyr Ala Gln Pro
Ser Glu 195 200 205 Arg Ser Val Met Gln Ala Gln Ser Leu Met Leu Leu
Leu Ala Ala Gly 210 215 220 Asp Ala Val Trp Val Arg Met Phe Gln Arg
Asp Arg Asp Asn Ala Ile225 230 235 240 Tyr Gly Glu His Gly Asp Leu
Tyr Ile Thr Phe Ser Gly His Leu Val 245 250 255 Lys Pro Ala Ala Glu
Leu 260
* * * * *