Note: Descriptions are shown in the official language in which they were submitted.
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COMBINATION THERAPY WITH SULODEXIDE AND A BLOOD PRESSURE
REDUCING AGENT IN THE TREATMENT OF DIABETIC NEPHROPATHY
The present application claims benefit under 35 U.S.C. 119(e) of U.S.
Provisional
Application No. 60/679,096 filed May 5, 2005 and U.S. Provisional Application
No.
60/736,973 filed November 14, 2005, the disclosure of each of which is
incorporated by
reference herein in its entirety.
This patent disclosure contains material that is subject to copyright
protection. The
copyright owner has no objection to the facsimile reproduction by anyone of
the patent
document or the patent disclosure as it appears in the U.S. Patent and
Trademark Office
patent file or records, but otherwise reserves any and all copyright rights.
1. FIELD OF THE INVENTION
The present invention is directed to a method of treating patients suffering
from
nephropathy of diabetic origin by administration of sulodexide in combination
with an
inhibitor of an angiotensin converting enzyme (ACE) and/or with an angiotensin
II receptor
blocker (ARB).
2. BACKGROUND OF THE INVENTION
Diabetes is now the most common cause of end-stage renal disease (ESRD) in the
U.S. and in many other developed nations. Diabetic nephropathy now represents
44% of all
new cases of ESRD in the U.S. Despite advances in clinical care, including
improvements
in glycemic and blood pressure control, the number of new cases of diabetes
mellitus related
ESRD continues to rise. In particular, the incidence of type 2 diabetes
mellitus (DM2)-
related cases of ESRD is rapidly increasing. From 1993 to 1997, 71% of all
diabetes-related
ESRD was attributable to DM2.
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The current standard of care for the prevention and treatment of diabetic
renal
disease is treating patients who test positive for microalbuminuria with a
blood pressure
reducing agent such as an angiotensin converting enzyme (ACE) inhibitor or an
angiotensin
II (A2) receptor blocker (ARB). ACE inihibitors and ARBs are known to reduce
blood
pressure, but exhibit differential clinical effects. The final active
messenger of the rennin-
angiotensin pathway is angiotensin II which binds to AT1 receptors to cause
vasoconstriction and fluid retention, both of which lead to an increase in
blood pressure.
ACE inhibitors are known to reduce blood pressure and act as vasodilators in
hypertension
and congestive heart failure by inhibiting in the renin-angiotensin pathway
angiotensin II
which binds to the AT1 receptors to cause vasoconstriction and fluid
retention. ARB also
reduces blood pressure by blocking the AT1 receptors. Several ACE inhibitors
(e.g.,
captopril, enalapril, fosinopril, lisinopril, and ramipril) are currently
available on the market.
Several ARB's are also currently available of the market (e.g., losartan,
valsartan, irbesartan
and candesartan).
Therapies involving ACE inhibitors and ARBs have been shown to reduce levels
of
albuminuria in select patient populations. This improvement in proteinuria has
been
accompanied by a concomitant improvement in or delay of progression to a
number of
additional renal function parameters, as well as a minimal delay in certain
clinical events
including ESRD. However, reductions in albuminuria are not always clinically
meaningful
or consistently produced. Some patients achieve the majority of their
therapeutic effect of
ACE inhibitors or ARBs within the first six months of therapy, yet many of
these patients
continue to exhibit persistent microalbuminuria, and some of these patients do
not have the
desired therapeutic response. Therefore, these patients are at an increased
risk of
progressing to ESRD due to the lack of adequate benefit from their current
standard of
therapy.
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Sulodexide which belongs to a class of drugs known as glycosaminoglycans
(GAGs)
has been approved for "vascular indications" and has been marketed in multiple
countries
for such indications. US Patent No. 5,496,807 reports on the evaluation of
sulodexide in the
treatment of diabetic nephropathy, and when administered intramuscularly or
orally in doses
of approximately 50 to 100 mg/day, produces reductions in albumin excretion
rate (AER) of
35 to 62% in macroalbuminuric patients and 20 to 50% in microalbuminuric
patients.
Sulodexide has also been evaluated at a dose of at least 200 mg/day (US Patent
Publication
No. 2002/0065233) and normoalbuminuria was achieved in 42% of patients.
Not intending to be limited to a particular mechanism of action, the mechanism
by
which sulodexide decreases albumin excretion in patients with diabetic
nephropathy is
believed to include the following: (1) the restoration of the physiologic
glomerular
membrane anionic charge barrier via enhanced synthesis and sulfation of
heparan sulfate in
renal vascular membranes, and direct replenishment of renal heparan sulfate,
(2) the
inhibition of TGF beta-1 mediated mesangial matrix overproduction, (3) the
inhibition of
endothelin mediated tubulo-interstitial fibrosis, and (4) the inhibition of
mesangial cell
hyperplasia. (See Harenberg J., Med. Res. Rev. vol. 18, 1-20 (1998), Gambaro
G. and Van
Der Woude, J. Am. Soc. Nephrol. 11:359-368 (2000)). Kanwar Y. S. et al., Sem.
Nephrol.,
5, 307, (1985) and Groggel G. C. et al., Kidney Int., 33, 517, (1988) have
produced
evidence of the probable role of glycosaminoglycans in helping the integrity
and the
functioning of renal cells. Moreover, Canfield J. P. et al., Lab. Invest., 39,
505, (1978),
previously showed a decrease of glycosaminoglycans in the glomerular basement
membrane in many conditions of nephropathy, while Baggio B. et al., Nephron.,
43, 187,
(1986) showed an increased urinary elimination of glycosaminoglycans in
diabetic, non-
albuminuric, patients. This increased excretion of glycosaminoglycans in
diabetic
nephropathies was shown also by Partasarathy N. et al., Diabetes, 31, 738,
(1982). In
addition, Diamond J. R. et al., Renal Physiol., 9, 366, (1986) and Parkerson
M. B. et al., J.
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Clin. Invest., 81, 69, (1988), showed in animals the potential protective
effect of heparin
and its derivatives in models of experimental nephropathy not related to
diabetic
nephropathy, like chronic nephrosis from aminoglycosides and renal pathologies
resulting
from the subtotal renal ablation in the rat. Sulodexide therapy was
administered to patients
receiving ongoing ACE inhibitor therapy. Results demonstrate that reductions
in AER were
equivalent in patients treated concomitantly with ACE inhibitors and those not
treated with
ACE inhibitors.
Therefore, there is a need in the art to optimize the oral administration of
sulodexide
with the concurrent administration of a blood pressure reducing agent such as
an ACE
inhibitor or an ARB to achieve a maximum reduction in urinary albumin.
Citation or identification of any reference in Section 2 or in any other
section of this
application shall not be construed as an admission that such reference is
available as prior
art to the present invention.
3. SUMMARY OF THE INVENTION
The present invention is directed to a pharmaceutical composition comprising
(a)
sulodexide in an amount sufficient to significantly decrease the amount of
urinary albumin;
(b) a blood pressure reducing agent; and (c) a pharmaceutically acceptable
carrier. In one
embodiment, the blood pressure reducing agent is an angiotensin converting
enzyme (ACE)
inhibitor. In another embodiment, the blood pressure reducing agent is an
angiotensin II
(A2) receptor blocker (ARB). In specific embodiments, the amount of the blood
pressure
reducing agent in the composition is the maximal approved dosage for that
particular agent.
In yet another embodiment, the present invention is directed to a method for
treating
a patient suffering from type I or type II diabetic nephropathy comprising
administering a
pharmaceutical composition comprising sulodexide to a patient concurrently
with a blood
pressure reducing agent. In certain embodiments, concurrently administering
includes
administering the ACE inhibitor and/or ARB simultaneously with sulodexide, or
within 30
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minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours or
within 24
hours of each other. In a specific embodiment, the blood pressure reducing
agent is an ACE
inhibitor and/or an ARB. In yet another embodiment, the dosage of the blood
pressure
reducing agent administered to the patient is the maximum approved dose of
such agent. In
certain embodiments, the sulodexide and the blood pressure reducing agent can
be
administered together in a single dose or can be administered separately.
In yet other embodiments, patients were already being treated with a blood
pressure
reducing agent prior to the start of sulodexide administration.
In an embodiment of the invention, the patient is a mammal, preferably a
human. In
other embodiments, sulodexide is administered in an amount of 10-1000 mg/day,
preferably
50-500 mg/day, more preferably 100-400 mg/day. In a specific embodiment, the
patient is
administered 200 mg/day. In another specific embodiment, the patient is
administered 400
mg/day. In other preferred embodiments, the sulodexide is administered orally.
4. DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to pharmaceutical compositions and methods
for
the treatment of a patient suffering from diabetic nephropathy with persistent
microalbuminuria in type 1 and type 2 diabetes which encompasses co-
administering an
effective amount of sulodexide, preferably in orally administrable form, which
effective
amount is sufficient to significantly decrease the amount of albumin excreted
in the urine of
the patient, and a blood pressure reducing agent. In one embodiment, such
blood pressure
reducing agent is an angiotensin converting enzyme (ACE) inhibitor. In another
embodiment, such blood pressure reducing agent is an angiotensin II (A2)
receptor blockers
(ARB). In yet another embodiment, the blood pressure reducing agent is a
combination of
one or more ACE inhibitors and/or one or more ARBs. In another embodiment, the
amount
of the blood pressure reducing agent is a maximum approved dose for such
agent.
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The amount of sulodexide can be administered one or more times per day, and
said
amount being sufficient to reduce albumin excretion but insufficient to cause
adverse side
effects. The present invention encompasses unit dosage forms of sulodexide in
a range
from about 100 mg to about 1000 mg, and includes any value encompassed within
the
range. In a specific embodiment, a 200 mg dose of sulodexide is administered.
In another
embodiment, a 400 mg dose of sulodexide is administered. The method of
administration,
according to the present invention, may be oral, mucosal, parenteral,
intramuscular or
transdermal, and is preferably oral.
ACE inhibitors are well known in the art. Exemplary ACE inhibitors and their
approved maximum dose include, but are not limited to, Lotensin (benazepril)
40 mg/day,
Capoten (captopril) 450 mg/day, Vasotec (enalapril) 40 mg/day, Monoprilg
(fosinopril)
40 mg/day, Univasc (moexipril) 30 mg/day, Aceon (perindopril) 16 mg/day,
Accupril
(quinapril) 80 mg/day, Altace (ramipril) 20 mg/day, Mavik (trandolapril) 8
mg/day, and
Zestril or Prinivil (lisinopril) 80 mg/day. ARBs are also well known in the
art.
Exemplary ARBs and their approved maximum dose incldue, but are not limited
to,
Atacand (candesartan) 32 mg/day, Teveten (eprosartan) 800 mg/day, Avapro
(irbesartan) 300 mg/day, Cozaar (losartan) 100 mg/day, Diovan (valsartan)
320 mg/day,
Micardis (telmisartan) 80 mg/day, and Benicar (olmesartan) 40 mg/day.
In evaluating the efficacy of the dosage of sulodexide, the following
parameters can
be measured: (A) observed urinary albumin creatinine ratio (ACR) level, (B)
percentage of
patients achieving therapeutic "success," a binary composite endpoint defined
as conversion
to normoalbuminuria (ACR < 20 mg/g) and a 25% reduction in ACR level relative
to
baseline or a 50% reduction in ACR level relative to baseline, (C) percentage
of patients
achieving normoalbuminuria, (D) percent change from baseline on various
additional
endpoints, including plasma fibrinogen, serum creatinine, reciprocal of the
serum creatinine,
and serum albumin. The safety assessments included adverse events monitoring,
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concomitant medication use, physical examinations, sequential blood
chemistries,
hematology, coagulation profiles, urinalysis, and serum creatinine.
The invention having been described, the following examples are offered by way
of
illustration and not limitation.
5. EXAMPLE 1
The therapeutic efficacy and safety of sulodexide administered in the
treatment of
persistent microalbuminuria in type I or type II diabetic nephropathic
patients who are
concurrently receiving maximal dosage of a blood pressure reducing agent,
e.g., an inhibitor
of an angiotensin converting enzyme (ACE) and/or an angiotensin II (A2)
receptor blocker
as background therapy has been evaluated in the following study.
The patients were microalbuminuric diabetes mellitus (DM)-1 and DM-2 patients
who were currently receiving a maximum approved dose of either an ACE
inhibitor or A2
receptor blocker (stable for 2 months). All patients gave informed consent and
the study
was conducted in compliance with U.S. Food and Drug Administration
regulations.
Exemplary ACE inhibitors and their approved maximum dose that were being taken
by the patients in this study include Lotensin (benazepril) 40 mg/day,
Capoten
(captopril) 450 mg/day, Vasotec (enalapril) 40 mg/day, Monopril (fosinopril)
40
mg/day, Univasc (moexipril) 30 mg/day, Aceon (perindopril) 16 mg/day,
Accupril
(quinapril) 80 mg/day, Altace (ramipril) 20 mg/day, Mavik (trandolapril) 8
mg/day, and
Zestril or Prinivil (lisinopril) 80 mg/day. Exemplary A2 receptor blockers
and their
approved maximum dose that were being taken by the patients in this study
include
Atacand (candesartan) 32 mg/day, Teveten (eprosartan) 800 mg/day, Avapro
(irbesartan) 300 mg/day, Cozaar (losartan) 100 mg/day, Diovan (valsartan)
320 mg/day,
Micardis (telmisartan) 80 mg/day, and Benicar (olmesartan) 40 mg/day.
The patients were placed into one of three groups; Group I was administered
200 mg
of sulodexide orally for 6 months, Group II was administered 400 mg of
sulodexide orally
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for 6 months, and Group III was not administered any dosage of sulodexide but
instead was
administered a placebo. Patients on a maximum approved dose of a blood
pressure
reducing agent are treated with sulodexide or placebo for six (6) months and
are post-treated
for an additional two (2) months.
The following efficacy endpoints were analyzed after 2, 4, and 6 months of
therapy
and at the 2-month post-treatment follow-up: (A) observed urinary albumin
creatinine ratio
(ACR) level, (B) percentage of patients achieving "therapeutic success", which
is a binary
composite end point defined as conversion from microalbuminuria to
normalbunimuria
(with a least a 25% reduction in microalbumnuria) as measured by
albumin/creatinine ratio
(ACR), or at least a 50% reduction in ACR level relative to baseline, (C)
percentage of
patients achieving normoalbuminuria, (D) percent change from baseline on
various
additional endpoints, including plasma fibrinogen, serum creatinine,
reciprocal of the serum
creatinine, and serum albumin.
The safety assessments in this study included adverse events monitoring,
concomitant medication use, physical examinations, sequential blood
chemistries,
hematology, coagulation profiles, urinalysis, and serum creatinine.
Patients were randomized 1:1:1, placebo, 200 mg sulodexide and 400 mg
sulodexide, respectively. Table 1 summarizes therapeutic success for Group I
and Group II
patients combined as compared to Group III patients. Table 2 summarizes
therapeutic
success for Group I patients as compared to Group III patients.
Table 1
Sulodexide Placebo
(200 mg and 400 mg) (No. of patients = 38)
(No. of patients = 82)
Therapeutic Success 24% 13%
> 50% reduction 21% 11%
Normalization 13% 8%
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Table 2
Sulodexide Placebo
(200 mg) (No. of Patients = 38)
No. of Patients = 38)
Therapeutic Success 29% 13%
> 50% reduction 24% 11%
Normalization 16% 8%
The results of the study showed that administration of sulodexide as compared
to
placebo improved patients with persistent microalbuminuria. Further, the
safety
assessments showed that administration of sulodexide at either dosage amounts
was not
believed to be related to any serious adverse events.
6. EXAMPLE 2
In this study, two doses of sulodexide ("KRX-101") (200 mg and 400 mg) were
compared to placebo in patients with diabetic microalbuminuria on maximal
therapy with
an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor
blocker (ARB).
Patients were treated with sulodexide or placebo for six months and followed
for an
additional two months post-treatment. Patients were randomized 1:1:1, placebo,
200 mg
and 400 mg of sulodexide, respectively.
In this study, the primary endpoint for the study was the percentage of
patients
achieving "Therapeutic Success" at six months. A patient is considered a
"Therapeutic
Success" if they achieve one of the following outcomes following 6 months on
study:
(1) 50% reduction in albumin to creatinine ratio or "ACR" -- ACR is a standard
measurement used to assess the level of kidney disease in these patients. ACR
measures the
level of albumin protein in urine, also referred to as "albuminuria," or
(2) Nonnalization of ACR with at least a 25% reduction in ACR-in this study
the
normal laboratory range for albuminuria was defined as less than 20 mg of
albumin to 1 g of
creatinine.
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Data Analysis:
A total of 149 patients were randomized into the study. All patients evaluable
for
Therapeutic Success at 6 months (i.e., all patients with a baseline ACR and a
6-month ACR)
were included in the Intent to Treat analysis, for a total of 136 patients in
the Intent to Treat
population. All patients in the Intent to Treat population that at baseline
were within the
target eligibility range of microalbuminuria as defined in the protocol (ACR
20 mg/G to 200
mg/G) were included in the Per Protocol analysis, for a total population of
117 patients in
the Per Protocol population.
All of the primary and secondary analyses shown were pre-specified. For the
primary endpoint analysis, statistical nominal p values have been provided for
informational
purposes only since this study, as a pilot study, had less than a 20% power to
show
statistically significant results for these endpoints.
The data is being presented in two ways. First, the 200 mg arm is compared to
placebo. Next, the data is presented as Active (200 mg and 400 mg) vs.
Placebo; this was
the primary endpoint defined by the protocol. Information on the effects of
the 400 mg arm
alone can be found in the footnotes to the tables. The dose response
relationship of
sulodexide previously demonstrated up to 200 mg was not observed from 200 mg
to 400 mg
in this study.
Table 3 - Primary Endpoint Analysis (Therapeutic Success at 6 months) (200 mg
vs.
Placebo)
Number of p value
Patients Fisher's Exact Test
(Placebo/200mg) Placebo 200mg (2-sided)
Per Protocol 36/36 11.0 % 33.0 % P=.045
Intent to Treat 42/44 14.0% 32.0% P=.074
Table 4- Primary Endpoint Analysis (Therapeutic Success at 6 months) (200 mg
and 400
mgl vs. Placebo)
Number of Active, p value
Patients (200 mg and Fisher's Exact Test
(Placebo/Active) Placebo 400 mg) (2-sided)
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Per Protocol 36/81 11.0 % 25 % P-.136
Intent to Treat 42/94 14.0 % 26 % P=.180
For the 400ing group alone, the Therapeutic Success was 20% on inteltt to
treat basis and 18% on a per
protocol basis.
Table 5 - Secondary Endpoint Analysis at 6 months (Intent to Treat)
Active
(200 mg and 400
Placebo 200 mg mgl)
n=42 n=44 n=94
>50 % reduction in ACR 12.0 % 27.0 % 22.0 %
Normalization of ACR 9.0 % 23.0 % 17.0 %
1 For the 400rng group alone, tlte 50 fo reduction attd normalization were 18%
and 10%, respectively.
Table 6- Average Changes of ACR Over Time (Intent to Treat)r
200 mg vs. Placebo vs. 200 mg vs.
Placebo Baseline Baseline
Two months -17.00 % -4.00 % -21.00 %
Four months -25.78 % 7.50% -18.28%
Six months -28.03 % 12.57% -15.46%
Eight months
(2 months off therapy) -28.98% 18.50% -10.48%
l The average claanges front baselitte over tinte for tlte 400tng dose group
were 3.4%, 3.24%, 5.59% and
12.59 0, respectively.
There were no serious adverse events (SAEs) that were deemed by the
investigators
to be related, probably related or possibly related to the study drug.
A statistically significant benefit was achieved in the 200 mg group over
placebo in
patients with microalbuminuria, and a very strong trend nearing statistical
significance was
demonstrated in the intent to treat population.
Many modifications and variations of this invention can be made without
departing
from its spirit and scope, as will be apparent to those skilled in the art.
The specific
embodiments described herein are offered by way of example only, and the
invention is to
be limited only by the terms of the appended claims, along with the full scope
of equivalents
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to which such claims are entitled. Such modifications are intended to fall
within the scope
of the appended claims.
All references, patent and non-patent, cited herein are incorporated herein by
reference in their entireties and for all purposes, to the same extent as if
each individual
publication or patent or patent application was specifically and individually
indicated to be
incorporated by reference in its entirety for all purposes.
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