U.S. patent application number 15/984993 was filed with the patent office on 2018-09-13 for use of il-1 beta binding antibodies for treating peripheral arterial disease.
The applicant listed for this patent is Novartis AG. Invention is credited to Craig Basson, Mark C. Fishman, Shi Yin Foo, Tom Thuren.
Application Number | 20180258166 15/984993 |
Document ID | / |
Family ID | 49679654 |
Filed Date | 2018-09-13 |
United States Patent
Application |
20180258166 |
Kind Code |
A1 |
Basson; Craig ; et
al. |
September 13, 2018 |
USE OF IL-1 BETA BINDING ANTIBODIES FOR TREATING PERIPHERAL
ARTERIAL DISEASE
Abstract
The present invention relates to a method for treating or
alleviating the symptoms of peripheral arterial disease (PAD) in a
subject, comprising administering about 25 mg to about 300 mg of an
IL-1.beta. binding antibody or functional fragment thereof.
Inventors: |
Basson; Craig; (Cambridge,
MA) ; Thuren; Tom; (East Hanover, NJ) ; Foo;
Shi Yin; (Cambridge, MA) ; Fishman; Mark C.;
(Cambridge, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Novartis AG |
Basel |
|
CH |
|
|
Family ID: |
49679654 |
Appl. No.: |
15/984993 |
Filed: |
May 21, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14442536 |
May 13, 2015 |
10000565 |
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PCT/US2013/070042 |
Nov 14, 2013 |
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15984993 |
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61727334 |
Nov 16, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07K 2317/565 20130101;
C07K 2317/21 20130101; C07K 16/245 20130101; A61K 2039/505
20130101; C07K 2317/56 20130101; A61P 43/00 20180101; A61K 2039/545
20130101; C07K 2317/76 20130101; A61P 9/08 20180101; A61P 29/00
20180101; A61P 9/00 20180101; C07K 2317/92 20130101 |
International
Class: |
C07K 16/24 20060101
C07K016/24 |
Claims
1. A method for treating or alleviating the symptoms of peripheral
arterial disease (PAD) in a patient, comprising administering a
therapeutically effective amount of an antibody or antigen binding
fragment thereof that binds to IL-1.beta. to a patient in need
thereof, wherein said antibody or antigen binding fragment thereof
comprises: i) an immunoglobulin V.sub.H domain comprising the amino
acid sequence set forth as SEQ ID NO:1 and an immunoglobulin
V.sub.L domain comprising the amino acid sequence set forth as SEQ
ID NO:2; ii) an immunoglobulin V.sub.H domain comprising, in
sequence, a complementarity determining region (CDR) 1 comprising
the amino acid sequence set forth as SEQ ID NO:3, a CDR2 comprising
the amino acid sequence set forth as SEQ ID NO:4, and a CDR3
comprising the amino acid sequence set forth as SEQ ID NO:5, and an
immunoglobulin V.sub.L domain comprising, in sequence, a CDR1
comprising the amino acid sequence set forth as SEQ ID NO:6, a CDR2
comprising the amino acid sequence set forth as SEQ ID NO:7 and a
CDR3 comprising the amino acid sequence set forth as SEQ ID
NO:8.
2. The method according to claim 1, wherein the antibody or antigen
binding fragment is capable of inhibiting the binding of IL-1.beta.
to its receptor and has a K.sub.D for binding to IL-1.beta. of
about 50 pM or less.
3. The method according to claim 1, wherein the antibody or antigen
binding fragment thereof is a Fab, Fab', F(ab').sub.2, Fv, or a
single chain Fv.
4. The method according to claim 1, wherein the antibody or antigen
binding fragment thereof is a human or humanized monoclonal
antibody.
5. The method according to claim 1, wherein the antibody or antigen
binding fragment is canakinumab.
6. The method according to claim 1, wherein the antibody or antigen
binding fragment thereof is administered to the patient at a dose
of about 50 mg or about 80 mg or about 150 mg or about 300 mg.
7. The method according to claim 1, wherein the antibody or antigen
binding fragment thereof is administered to the patient
intravenously.
8. The method according to claim 1, wherein the antibody or antigen
binding fragment thereof is administered to the patient
subcutaneously.
9. The method according to claim 1, wherein the antibody or antigen
binding fragment is administered every 2 weeks, twice a month,
monthly, every 6 weeks, every 2 months, every 3 months, every 4
months, every 5 months, or every 6 months from the first
administration.
10. The method according to claim 1, wherein the antibody or
antigen binding fragment thereof is comprised in a lyophilized
pharmaceutical formulation.
11. The method according to claim 1, wherein the antibody or
antigen binding fragment thereof is comprised in a liquid
pharmaceutical formulation.
12. The method according to claim 1, wherein the formulation is
disposed within a pre-filled syringe, vial, or autoinjector.
13. The method according to claim 1, wherein the antibody or
antigen binding fragment thereof is comprised in a dosage unit form
suitable for intravenous administration.
14. The method according to claim 1, wherein said patient is
concomitantly receiving a beta-adrenergic blocking drug, a statin,
an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin
II receptor blocker.
15. The method according to claim 1, wherein the subject is
exhibiting an ankle-brachial index between 0.5 and 0.85 in at least
one leg before treatment.
16. The method according to claim 1, wherein the subject has
improved vascular structure and function after 3 months of
treatment.
17. The method according to claim 1, wherein reduced plaque burden
in the peripheral artery walls of said subject is observed after at
least 3 months of treatment.
18. The method according to claim 1, wherein a reduced plaque
burden compared to before treatment in said subject is determined
in the superficial femoral artery after at least 3 months of
treatment.
19. The method according to claim 1, wherein a reduced plaque
burden compared to before treatment in said subject is determined
in the superficial femoral artery after at least 12 months of
treatment.
20. The method according to claim 5, wherein canakinumab is
administered in a liquid formulation comprising 10-200 mg/ml
canakinumab, mannitol, histidine and polysorbate 80, wherein the pH
of the formulation is 6.1-6.9.
Description
TECHNICAL FIELD
[0001] The present disclosure relates to a novel use and dosage
regimens of an IL-1.beta. binding antibody or functional fragments
thereof for treating or alleviating the symptoms of peripheral
arterial disease.
BACKGROUND OF THE DISCLOSURE
[0002] Periferal arterial disease PAD, also known as peripheral
vascular disease (PVD) or peripheral arterial occlusive disease
(PAOD) refers to the obstruction of large arteries not within the
coronary, aortic arch vasculature, or brain. PAD can result from
atherosclerosis, inflammatory processes leading to stenosis, an
embolism, or thrombus formation. It causes either acute or chronic
ischemia (lack of blood supply). PAD is a form of atherosclerotic
disease that affects the peripheral arteries. It commonly manifests
in the blood vessels of the legs as claudication, an intermittent
pain that occurs with exercise and/or at rest. PAD is prevalent in
smokers and diabetics; its incidence increases with age. PAD
affects .about.10 million individuals in the US alone. Management
of PAD overlaps with coronary disease risk modification, but
approved medical therapies for PAD affect platelet viscosity to
improve blood flow to peripheral muscles and do not modify disease.
PAD shares pathologic features with coronary atherosclerosis, such
a chronic vascular inflammation. Interleukins (ILs) are key
mediators in the chronic vascular inflammatory response. IL-1.beta.
activates endothelial cells, leading to the upregulation of
adhesion molecules that promote inflammatory cell adhesion to the
vessel wall. IL-1.beta. also increases extracellular matrix and
collagen deposition, thereby contributing to plaque burden and
arterial wall thickening. Antagonism of IL-1.beta. is an attractive
target to ameliorating vessel wall inflammation associated with
atherosclerosis.
[0003] Inhibition of IL-1 activity is being currently explored for
a number of cardiovascular indications via different mechanisms.
Anakinra (Kineret) is a human interleukin-1 receptor antagonist
that requires daily subcutaneous dosing of approximately 100 mg for
efficacy. The MRC-ILA-HEART study is a clinical trial investigating
the effects of anakinra upon markers of inflammation in patients
with non-ST elevation myocardial infarction (NSTEMI) (Crossman, et
al., 2008).
[0004] ACZ885 (canakinumab) is a high-affinity, fully human
monoclonal antibody to interleukin-1.beta., developed originally
for the treatment of IL-1.beta.-driven inflammatory diseases.
Canakinumab has been approved under the trade name ILARIS.RTM. in
the US for patients .gtoreq.4 year of age with Cryopyrin-Associated
Periodic Syndromes (CAPS), [Familial Cold-Associated Syndrome
(FCAS) and Muckle-Wells syndrome (MWS) phenotypes included,
Canakinumab has also received regulatory approvals for treatment of
SJIA and gout.
SUMMARY OF THE DISCLOSURE
[0005] Accordingly, in a one aspect, the present disclosure is
directed to a method for treating or alleviating the symptoms of
peripheral arterial disease (PAD) in a subject, comprising
administering about 25 mg to about 300 mg of an IL-1.beta. binding
antibody or functional fragment thereof. The therapy of the
invention will decrease the amount of plaque in peripheral
arteries, and/or may also improve endothelial function to promote
more blood flow, and thereby improve the ability of patients to
ambulate without pain.
[0006] Accordingly, in a another aspect, the present disclosure is
directed to an IL-1.beta. binding antibody or a functional fragment
thereof for use as a medicament for treating or alleviating the
symptoms of peripheral arterial disease (PAD) in a subject,
comprising administering about 25 mg to about 300 mg of an
IL-1.beta. binding antibody or functional fragment thereof.
[0007] Accordingly, in yet another aspect, the present disclosure
is directed to the use of an IL-1.beta. binding antibody or a
functional fragment thereof for the manufacture of a medicament for
treating or alleviating the symptoms of peripheral arterial disease
(PAD) in a subject, comprising administering about 25 mg to about
300 mg of an IL-1.beta. binding antibody or functional fragment
thereof.
[0008] Further features and advantages of the disclosure will
become apparent from the following detailed description of the
invention.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0009] Periferal arterial disease PAD, also known as peripheral
vascular disease (PVD) or peripheral arterial occlusive disease
(PAOD) refers to the obstruction of large arteries not within the
coronary, aortic arch vasculature, or brain. PAD can result from
atherosclerosis, inflammatory processes leading to stenosis, an
embolism, or thrombus formation. It causes either acute or chronic
ischemia (lack of blood supply). Often PAD is a term used to refer
to atherosclerotic blockages found in the lower extremity.
[0010] The present invention provides a method for treating or
alleviating the symptoms of peripheral arterial disease (PAD) in a
subject, comprising administering about 25 mg to about 300 mg of an
IL-1.beta. binding antibody or functional fragment thereof. In one
embodiment of any method of the invention, the subject has moderate
PAD. Moderate PAD is associated with an ankle-brachial index (ABI)
below 0.8. ABI or ABPI (ankle brachial pressure index) is
determined by comparing the blood pressure measured in the ankles
to the blood pressure measured in the arms. Patients with severe
ichemic disease and severe PAD has an ABI below 0.5 or below 0.4
and these patients can also benefit from treatment with the methods
and uses according to the present invention. In one embodiment the
subject is exhibiting an ankle-brachial index between 0.5 and 0.85
in at least one leg before treatment. In another embodiment, the
subject is exhibiting an ankle-brachial index less than 0.5 in at
least one leg or the subject is exhibiting an ankle-brachial index
less than 0.9 in at least one leg.
[0011] Moderate PAD is associated with the subject having
symptomatic intermittent claudication, i.e., the patients
exhibiting severe pain when walking relatively short distances
e.g., less than 150 m or less than 400 m.
[0012] In one embodiment of any method of the invention, the
subject has improved vascular structure and function after 3 months
of treatment or after 12 months of treatment. In one embodiment,
reduced plaque burden in the peripheral artery walls of said
subject is observed after at least 3 months of treatment or at
least 12 months of treatment. The reduced plaque burden compared to
before treatment in said subject can be determined in the
superficial femoral artery after at least 3 months of treatment or
after at least 12 months of treatment. The improvements of vascular
structure and function can be determined by magnetic resonance
imaging (MRI).
[0013] The subject's ability to walk for 6 min will improve after
treatment with the methods and uses according to the present
invention.
[0014] IL-1.beta. binding antibody or functional fragment thereof
is administered every 2 weeks, twice a month, monthly, every 6
weeks, every 2 months, every 3 months, every 4 months, every 5
months, or every 6 months from the first administration. In one
embodiment, said IL-1.beta. binding antibody or functional fragment
thereof is administered monthly.
[0015] In one embodiment, said method comprises administering about
25, 50, 75, 80, 100, 125, 150, 175, 200, 225, 250, 275, 300 mg or
any combination thereof of the IL-1.beta. binding antibody or
functional fragment thereof. Said method comprises administering
about 50 mg, about 80 mg or about 200 mg or about 300 mg of the
IL-1.beta. binding antibody or functional fragment thereof. In one
embodiment, said method comprises administering about 150 mg of the
IL-1.beta. binding antibody or functional fragment thereof.
[0016] In another embodiment said method comprising administering
the patient an additional dose of about 25 mg to about 300 mg of
the IL-.beta. binding antibody or functional fragment thereof at
week 2, week 4 or week 6 from the first administration.
[0017] In one embodiment of any method of the invention, said
IL-1.beta. binding antibody or functional fragment thereof is an
IL-1.beta. binding antibody. In one embodiment of any method of the
invention, said IL-1.beta. binding antibody or functional fragment
thereof is capable of inhibiting the binding of IL-1.beta. to its
receptor and has a K.sub.D for binding to IL-1.beta. of about 50 pM
or less.
[0018] In other embodiments of any method of the invention said
IL-1.beta. binding antibody is selected from the group consisting
of: [0019] a) an IL-1.beta. binding antibody directed to an
antigenic epitope of human IL-1.beta. which includes the loop
comprising the Glu64 residue of the mature IL-1.beta., wherein said
IL-1.beta. binding antibody is capable of inhibiting the binding of
IL-1.beta. to its receptor, and further wherein said IL-1.beta.
binding antibody has a K.sub.D for binding to IL-1.beta. of about
50 pM or less; [0020] b) an IL-1.beta. binding antibody that
competes with the binding of an IL-1.beta. binding antibody
comprising a VH domain comprising SEQ ID NO:1 and a VL domain
comprising SEQ ID NO:2; [0021] c) an IL-1.beta. binding antibody
comprising the three CDRs of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5;
[0022] d) an anti-IL-1.beta. binding antibody comprising the three
CDRs of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8; [0023] e) an
anti-IL-1.beta. binding antibody comprising the three CDRs of SEQ
ID NO:3, SEQ ID NO:4, SEQ ID NO:5 and the three CDRs of SEQ ID
NO:6, SEQ ID NO:7, SEQ ID NO:8; [0024] f) an anti-IL-1.beta.
binding antibody comprising a VH domain comprising SEQ ID NO:1;
[0025] g) an anti-IL-1.beta. binding antibody comprising a VL
domain comprising SEQ ID NO:2; [0026] h) an anti-IL-1.beta. binding
antibody comprising a VH domain comprising SEQ ID NO: 1 and a VL
domain comprising SEQ ID NO:2.
[0027] In one embodiment of any method of the invention, said
IL-1.beta. binding antibody or fragment thereof comprises the 3
CDRs of SEQ ID NO:1 are set forth in SEQ ID NO:3, 4, and 5 and
wherein the 3 CDRs of SEQ ID NO:2 are set forth in SEQ ID NO:6, 7,
and 8.
[0028] In other embodiments of any method of the invention, the
IL-1.beta. binding antibody comprises:
[0029] a) a VH having a first CDR having 0, 1 or 2 amino acid
substitutions in comparison to the CDR set forth in SEQ ID NO:3, a
second CDR having 0, 1 or 2 amino acid substitutions in comparison
to the CDR set forth in SEQ ID NO:3, a third CDR having 0, 1 or 2
amino acid substitutions in comparison to the CDR set forth in SEQ
ID NO:5; and
[0030] b) a VL having a first CDR having 0, 1 or 2 amino acid
substitutions in comparison to the CDR set forth in SEQ ID NO:6, a
second CDR having 0, 1 or 2 amino acid substitutions in comparison
to the CDR set forth in SEQ ID NO:7, and a third CDR having 0, 1 or
2 amino acid substitutions in comparison to the CDR set forth in
SEQ ID NO:8, wherein said antibody has a K.sub.D for IL-1beta of 50
pM or less and wherein said antibody inhibits the binding of
IL-1.beta. to its receptor.
[0031] Substituted amino acids are ideally conservative
substitutions, and once substituted a skilled artisan could use an
assay such as those described in WO02/16436.
[0032] In some embodiments of any of the method described above,
the antibody or fragment binds to human IL-1.beta. with a
dissociation constant of about 50 pM or less. In some embodiments,
the antibody or fragment binds to human IL-1.beta. with a
dissociation constant of about 500 pM or less. In some embodiments,
the IL-1.beta. binding antibody or functional fragment thereof
binds to human IL-I .beta. with a dissociation constant of about
250 pM or less. In some embodiments, the IL-1.beta. binding
antibody or functional fragment thereof binds to human IL-1.beta.
with a dissociation constant of about 100 pM or less. In some
embodiments of any of the methods described above, the IL-1.beta.
binding antibody or functional fragment thereof binds to human
IL-1.beta. with a dissociation constant of about 5 pM or less. In
some embodiments, the IL-1.beta. binding antibody or functional
fragment thereof binds to human IL-1.beta. with a dissociation
constant of about 1 pM or less. In some embodiments, the IL-1.beta.
binding antibody or functional fragment thereof binds to human
IL-1.beta. with dissociation constant of about 0.3 pM or less.
[0033] In some embodiments of any and/or all of the methods
described above, the IL-1.beta. binding antibody or functional
fragment thereof is a neutralizing antibody.
[0034] One example of an IL-1.beta. binding antibody is canakinumab
which has a heavy chain variable region (VH) is set forth as SEQ ID
NO: 1 of the sequence listing. CDR1 of the VH of canakinumab is set
forth as SEQ ID NO:3 of the sequence listing. CDR2 of the VH of
canakinumab is set forth as SEQ ID NO:4 of the sequence listing.
CDR3 of the VH of canakinumab is set forth as SEQ ID NO:5 of the
sequence listing.
[0035] The canakinumab light chain variable region (VL) is set
forth as SEQ ID NO:2 of the sequence listing. CDR1 of the VL of
canakinumab is set forth as SEQ ID NO:6 of the sequence listing.
CDR2 of the VL of canakinumab is set forth as SEQ ID NO:7 of the
sequence listing. CDR3 of the VL of canakinumab is set forth as SEQ
ID NO:8 of the sequence listing.
[0036] In some embodiments of any and/or all of the methods
described above, the anti-IL-1.beta. binding antibody or binding
fragment thereof competes with the binding of an antibody having
the light chain variable region of SEQ ID NO:1 and the heavy chain
variable region of SEQ ID NO:2.
[0037] In some embodiments, the disclosed methods comprise
administering an anti-IL-1.beta. binding antibody having the three
CDRs of SEQ ID NO: 1. In further embodiments, the three CDRs of SEQ
ID NO:1 are set forth as SEQ ID NOs:3-5. In some embodiments, the
disclosed methods comprise administering an anti-IL-1.beta. binding
antibody having the three CDRs of SEQ ID NO:2. In further
embodiments, the three CDRs of SEQ ID NO:2 are set forth as SEQ ID
NOs:6-8.
[0038] Preferably the IL-1.beta. binding antibody is canakinumab.
Canakinumab is a fully human monoclonal anti-human IL-1.beta.
antibody of the IgG1/k isotype, being developed for the treatment
of IL-1.beta. driven inflammatory diseases. It is designed to bind
to human IL-1.beta. and thus blocks the interaction of this
cytokine with its receptors. The antagonism of the IL-1.beta.
mediated inflammation using canakinumab in lowering high
sensitivity C-reactive protein (hsCRP) and other inflammatory
marker levels has shown an acute phase response in patients with
Cryopyrin-Associated Periodic Syndrome (CAPS) and rheumatoid
arthritis. This evidence has been replicated in patients with type
2 diabetes mellitus (T2DM) using canakimnumab and with other
IL-1.beta. antibody therapies in development.
[0039] Canakinumab is disclosed in WO02/16436 which is hereby
incorporated by reference in its entirety.
[0040] In other embodiments of any method of the invention, said
IL-1.beta. binding antibody or functional fragment thereof is
selected from the group consisting of gevokizumab, LY-2189102 or
AMG-108.
[0041] Said IL-1.beta. binding antibody or functional fragment
thereof is administered parentally, e.g., intravenously or
subcutaneously. Preferably, canakinumab is administered
subcutaneously. Canakinumab can be administered in a reconstituted
formulation comprising canakinumab at a concentration of 10-200
mg/ml, 270 mM sucrose, 30 mM histidine and 0.06% polysorbate 80,
wherein the pH of the formulation is 6.5. Canakinumab can also be
administered in a liquid formulation comprising canakinumab at a
concentration of 10-200 mg/ml, mannitol, histidine and polysorbate
80, wherein the pH of the formulation is 5.5-7.0. Canakinumab can
also be administered in a liquid formulation comprising canakinumab
at concentration: 10-200 mg/ml, 270 mM mannitol, 20 mM histidine
and 0.04% polysorbate 80, wherein the pH of the formulation is
6.5.
[0042] Said IL-1.beta. binding antibody e.g. canakinumab or
functional fragment can be administered to the patient in a liquid
form or lyophilized form for reconstitution contained in a
prefilled syringe. In one embodiment, the prefilled syringe is
contained in an autoinjector.
[0043] In other embodiments of any method of the invention, said
patient is concomitantly receiving a statin such as lovastatin,
pravastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin,
mevastatin, pitavastatin, rosuvastatin Preferably said patient is
concomitantly receiving simvastatin, atorvastatin, rosuvastatin or
aspirin. In one aspect, said patient is concomitantly receiving
cilostazol or pentoxifylline. In other aspects, said patient is
concomitantly receiving beta-adrenergic blocking drugs such as
esmolol, metoprolol, nadolol, penbutolol; or an
angiotensin-converting enzyme (ACE) inhibitor such as ramipril,
ramiprilat, captopril, lisinopril; or an angiotensin II receptor
blocker such as losartan, valsartan, olmesartan, irbesartan,
candesartan, telmisartan, eprosartan; or an inhibitor of platelet
aggregation such clopidogrel, elinogrel, prasugrel, cangrelor,
ticagrelor, ticlopidine, dipyridamole, picodamide eptifibatide,
abciximab, eptifibatide, tirofiban or teitroban; or a nitrate such
as glyceryl trinitrate (GTN)/nitroglycerin, isosorbide dinitrate,
isosorbide mononitrate.
[0044] According to another aspect of the invention, an IL-1.beta.
binding antibody or a functional fragment thereof for use as a
medicament for treating or alleviating the symptoms of peripheral
arterial disease (PAD) in a subject, comprising administering about
25 mg to about 300 mg of an IL-1.beta. binding antibody or
functional fragment thereof.
[0045] According yet another aspect of the invention, the use of an
IL-1.beta. binding antibody or a functional fragment thereof is
provided for the manufacture of a medicament for treating or
alleviating the symptoms of peripheral arterial disease (PAD) in a
subject, comprising administering about 25 mg to about 300 mg of an
IL-1.beta. binding antibody or functional fragment thereof.
[0046] In the following, various aspects of the two uses stated in
the two paragraphs above are described and all these aspects could
be combined together. The skilled person realizes that the teaching
in the following six pages are all combinable with each other and
particular aspect combining features from various parts of these
pages will be considered to be adequately disclosed to the skilled
person. In addition, all embodiment combining all the various
aspects below with selecting canakinumab as IL-1.beta. binding
antibody or a functional fragment containing the same variable
domain as canakinumab will be regarded as especially preferred.
[0047] In one aspect the subject has moderate PAD. Moderate PAD is
associated with an ankle-brachial index (ABI) below 0.8. Patients
with severe ichemic disease and severe PAD has an ABI below 0.5 or
below 0.4 and these patients can also benefit from treatment with
the methods and uses according to the present invention. In one
embodiment the subject is exhibiting an ankle-brachial index
between 0.5 and 0.85 in at least one leg before treatment. In
another embodiment, the subject is exhibiting an ankle-brachial
index less than 0.5 in at least one leg or the subject is
exhibiting an ankle-brachial index less than 0.9 in at least one
leg.
[0048] Moderate PAD is associated with the subject having
symptomatic intermittent claudication, i.e., the patients
exhibiting severe pain when walking relatively short distances like
some 100 m e.g., lee than 150 m or less than 400 m.
[0049] In one embodiment of any use of the invention, the subject
has improved vascular structure and function after 3 months of
treatment or after 12 months of treatment. In one embodiment,
reduced plaque burden in the peripheral artery walls of said
subject is observed after at least 3 months of treatment or at
least 12 months of treatment. The reduced plaque burden compared to
before treatment in said subject can be determined in the
superficial femoral artery after at least 3 months of treatment or
after at least 12 months of treatment. The improvements of vascular
structure and function can be determined by magnetic resonance
imaging (MRI).
[0050] The subject's ability to walk for 6 min will improve after
treatment with the methods and uses according to the present
invention.
[0051] IL-1.beta. binding antibody or functional fragment thereof
is administered every 2 weeks, twice a month, monthly, every 6
weeks, every 2 months, every 3 months, every 4 months, every 5
months, or every 6 months from the first administration. In one
embodiment, said IL-1.beta. binding antibody or functional fragment
thereof is administered monthly.
[0052] In other embodiments of the uses described above, said
patient is to be administered about 25, 30, 35, 40, 45, 50, 55, 60,
65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135,
140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200,
205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265,
270, 275, 280, 285, 290, 295, 300 mg or any combination thereof of
said IL-1.beta. binding antibody or functional fragment
thereof.
[0053] In one embodiment, the use comprises administering about 25,
50, 75, 80, 100, 125, 150, 175, 200, 225, 250, 275, 300 mg or any
combination thereof of the IL-1.beta. binding antibody or
functional fragment thereof. The use comprises administering about
50 mg, about 80 mg or about 200 mg or about 300 mg of the
IL-1.beta. binding antibody or functional fragment thereof. In one
embodiment, the use comprises administering about 150 mg of the
IL-1.beta. binding antibody or functional fragment thereof.
[0054] In another embodiment the use comprising administering the
patient an additional dose of about 25 mg to about 300 mg of the
IL-1.beta. binding antibody or functional fragment thereof at week
2, week 4 or week 6 from the first administration.
[0055] In one embodiment of any use of the invention, said
IL-1.beta. binding antibody or functional fragment thereof is an
IL-1.beta. binding antibody. In one embodiment of any use of the
invention, said IL-1.beta. binding antibody or functional fragment
thereof is capable of inhibiting the binding of IL-1.beta. to its
receptor and has a K.sub.D for binding to IL-1.beta. of about 50 pM
or less.
[0056] In other embodiments of any use of the invention said
IL-1.beta. binding antibody is selected from the group consisting
of: [0057] a) an IL-1.beta. binding antibody directed ton antigenic
epitope of human IL-1.beta. which includes the loop comprising the
Glu64 residue of the mature IL-1.beta., wherein said IL-1.beta.
binding antibody is capable of inhibiting the binding of IL-1.beta.
to its receptor, and further wherein said IL-1.beta. binding
antibody has a K.sub.D for binding to IL-1.beta. of about 50 pM or
less; [0058] b) an IL-1.beta. binding antibody that competes with
the binding of an IL-1.beta. binding antibody comprising a VH
domain comprising SEQ ID NO:1 and a VL domain comprising SEQ ID
NO:2; [0059] c) an anti-IL-1.beta. binding antibody comprising the
three CDRs of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5; [0060] d) an
anti-IL-1.beta. binding antibody comprising the three CDRs of SEQ
ID NO:6, SEQ ID NO:7, SEQ ID NO:8; [0061] e) an anti-IL-1.beta.
binding antibody comprising the three CDRs of SEQ ID NO:3, SEQ ID
NO:4, SEQ ID NO:5 and the three CDRs of SEQ ID NO:6, SEQ ID NO:7,
SEQ ID NO:8; [0062] f) an anti-IL-1.beta. binding antibody
comprising a VH domain comprising SEQ ID NO: 1; [0063] g) an
anti-IL-1.beta. binding antibody comprising a VL domain comprising
SEQ ID NO:2; [0064] h) an anti-IL-1.beta. binding antibody
comprising a VH domain comprising SEQ ID NO:1 and a VL domain
comprising SEQ ID NO:2.
[0065] In one embodiment of any use of the invention, said
IL-1.beta. binding antibody or fragment thereof comprises the 3
CDRs of SEQ ID NO:1 are set forth in SEQ ID NO:3, 4, and 5 and
comprises the 3 CDRs of SEQ ID NO:2 are set forth in SEQ ID NO:6,
7, and 8.
[0066] In other embodiments of my use of the invention, said
IL-1.beta. binding antibody or functional fragment thereof
comprises:
[0067] a) a VH having a first CDR having 0, 1 or 2 amino acid
substitutions in comparison to the CDR set forth in SEQ ID NO:3, a
second CDR having 0, 1 or 2 amino acid substitutions in comparison
to the CDR set forth in SEQ ID NO:3, a third CDR having 0, 1 or 2
amino acid substitutions in comparison to the CDR set forth in SEQ
ID NO:5; and
[0068] b) a VL having a first CDR having 0, 1 or 2 amino acid
substitutions in comparison to the CDR set forth in SEQ ID NO:6, a
second CDR having 0, 1 or 2 amino acid substitutions in comparison
to the CDR set forth in SEQ ID NO:7, and a third CDR having 0, 1 or
2 amino acid substitutions in comparison to the CDR set forth in
SEQ ID NO:8, wherein said antibody has a K.sub.D for IL-1beta of 50
pM or lea and wherein said antibody inhibits the binding of
IL-1.beta. to its receptor.
[0069] Substituted amino acids are ideally conservative
substitutions, and once substituted a skilled artisan could use an
assay such as those described in WO02/16436.
[0070] In one embodiment of any use of the invention, said
IL-1.beta. binding antibody is canakinumab. In other embodiments of
any use of the invention, said IL-1.beta. binding antibody or
functional fragment thereof is selected from the group consisting
of gevokizumab, LY-2189102 or AMG-108.
[0071] In some embodiments of any of the use described above, said
IL-1.beta. binding antibody or functional fragment thereof binds to
human IL-1.beta. with a dissociation constant of about 50 pM or
less. In some embodiments, the antibody or fragment binds to human
IL-I .beta. with a dissociation constant of about 500 pM or less.
In some embodiments, the IL-1.beta. binding antibody or functional
fragment thereof binds to human IL-I .beta. with a dissociation
constant of about 250 pM or less. In some embodiments, the
IL-1.beta. binding antibody or functional fragment thereof binds to
human IL-1.beta. with a dissociation constant of about 100 pM or
less. In some embodiments of any of the uses described above, the
IL-1.beta. binding antibody or functional fragment thereof binds to
human IL-1.beta. with a dissociation constant of about 5 pM or
less. In some embodiments, the IL-1.beta. binding antibody or
functional fragment thereof binds to human IL-1.beta. with a
dissociation constant of about 1 pM or less. In some embodiments,
the IL-1.beta. binding antibody or functional fragment thereof
binds to human IL-1.beta. with dissociation constant of about 0.3
pM or less.
[0072] In some embodiments of any of the uses described above, the
IL-1.beta. binding antibody or fragment thereof is a neutralizing
antibody.
[0073] In one aspect the IL-1.beta. binding antibody, the
canakinumab heavy chain variable region (VH) is set forth as SEQ ID
NO:1 of the sequence listing. CDR1 of the VH of canakinumab is set
forth as SEQ ID NO:3 of the sequence listing. CDR2 of the VH of
canakinumab is set forth as SEQ ID NO:4 of the sequence listing.
CDR3 of the VH of canakinumab is set forth as SEQ ID NO:5 of the
sequence listing.
[0074] The canakinumab light chain variable region (VL) is set
forth as SEQ ID NO:2 of the sequence listing. CDR1 of the VL of
canakinumab is set forth as SEQ ID NO:6 of the sequence listing.
CDR2 of the VL of canakinumab is set forth as SEQ ID NO:7 of the
sequence listing. CDR3 of the VL of canakinumab is set forth as SEQ
ID NO:8 of the sequence listing.
[0075] In some embodiments of any of the uses described above, the
IL-1.beta. binding antibody or fragment thereof competes with the
binding of an antibody having the light chain variable region of
SEQ ID NO:1 and the heavy chain variable region of SEQ ID NO:2.
[0076] In some embodiments, the disclosed uses, said IL-1.beta.
binding antibody having the three CDRs of SEQ ID NO:1. In further
embodiments, the three CDRs of SEQ ID NO:1 are set forth as SEQ ID
NOs:3-5. In some embodiments, the disclosed uses comprise
administering an anti-IL-1.beta. binding antibody having the three
CDRs of SEQ ID NO:2. In further embodiments, the three CDRs of SEQ
ID NO:2 are set forth as SEQ ID NOs:6-8.
[0077] In some embodiments, the disclosed uses comprise
administering an anti-IL-1.beta. binding antibody having the three
CDRs of SEQ ID NO:1 and the three CDRs of SEQ ID NO:2. In further
embodiments, the three CDRs of SEQ ID NO:1 are set forth as SEQ ID
NOs:3-5 and the three CDRs of SEQ ID NO:2 are set forth as SEQ ID
NOs:6-8.
[0078] In some embodiments of any of the use described above, said
IL-1.beta. binding antibody or functional fragment thereof is to be
administered subcutaneously or intravenously.
[0079] When administered subcutaneously, canakinumab can be
administered in a reconstituted formulation from a lyophilisate
comprising canakinumab at a concentration of 10-150 mg/ml, 270 mM
sucrose, 30 mM histidine and 0.06% polysorbate 80, wherein the pH
of the formulation is 6.3-6.7, preferably 6.5.
[0080] When administered subcutaneously, canakinumab can be
administered in a liquid formulation comprising canakinumab at a
concentration of 10-200 mg/ml, mannitol, histidine and polysorbate
80 (or polysorbate 20), wherein the pH of the formulation is
5.5-7.0, or more preferred 6.3-6.7, and preferably 6.5. In one
aspect the formulation comprises 10-150 mg/ml, 270 mM mannitol, 20
mM histidine and 0.04% polysorbate 80 (or polysorbate 20), wherein
the pH of the formulation is 6.3-6.7, preferably 6.5.
[0081] When administered subcutaneously, canakinumab or any of said
IL-1.beta. binding antibody or functional fragment thereof can be
administered to the patient in a liquid form or lyophilized form
for reconstitution contained in a prefilled syringe. In one
embodiment said prefilled syringe can be contained in an
autoinjector. Such autoinjector makes it possible for the patient
to self administer the liquid formulation subcutaneously in an easy
manner.
[0082] In other embodiments of any use according to the invention,
said patient is concomitantly receiving a statin such as
lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin,
cerivastatin, mevastatin, pitavastatin, rosuvastatin Preferably
said patient is concomitantly receiving simvastatin, atorvastatin,
rosuvastatin or aspirin. In one aspect, said patient is
concomitantly receiving cilostazol or pentoxifylline. In other
aspects, said patient is concomitantly receiving beta-adrenergic
blocking drugs such as esmolol, metoprolol, nadolol, penbutolol; or
an angiotensin-converting enzyme (ACE) inhibitor such as ramipril,
ramiprilat, captopril, lisinopril; or an angiotensin II receptor
blocker such as losartan, valsartan, olmesartan, irbesartan,
candesartan, telmisartan, eprosartan; or an inhibitor of platelet
aggregation such clopidogrel, elinogrel, prasugrel, cangrelor,
ticagrelor, ticlopidine, dipyridamole, picodamide eptifibatide,
abciximab, eptifibatide, tirofiban or terutroban; or a nitrate such
as glyceryl trinitrate (GTN)/nitroglycerin, isosorbide dinitrate,
isosorbide mononitrate.
[0083] In another aspect the present invention provides a
pharmaceutical composition comprising 25 mg/ml to about 300 mg/ml
of an IL-1.beta. binding antibody or functional fragment thereof
for use as a medicament for treating or alleviating the symptoms of
peripheral arterial disease (PAD) in a subject. In some aspects,
said composition comprise about 25, 50, 75, 80, 100, 125, 150, 175,
200, 225, 250, 275, 300 mg/ml of the IL-1.beta. binding antibody or
functional fragment thereof.
[0084] Said composition comprise about 50 mg/ml, about 80 mg/ml,
about 200 mg/ml or about 300 mg/ml of the IL-1.beta. binding
antibody or functional fragment thereof. Preferably, said
composition comprises about 50 or 150 mg/ml of the IL-1.beta.
binding antibody or functional fragment thereof. Preferably, said
IL-1.beta. binding antibody is canakinumab. In one aspect said
composition is a reconstituted formulation comprising 10-200 mg/ml
canakinumab, 270 mM sucrose, 30 mM histidine and 0.06% polysorbate
80, wherein the pH of the formulation is 6.5. In another aspect
said composition is a liquid formulation comprising 10-200 mg/ml
canakinumab, mannitol, histidine and polysorbate 80, wherein the pH
of the formulation is between 6.1-6.9, or 63-6.7. In another aspect
said composition is a liquid formulation comprising 10-200 mg/ml
canakinumab, 270 mM mannitol, 20 mM histidine and 0.04% polysorbate
80, wherein the pH of the formulation is 6.5.
General:
[0085] All patents, published patent applications, publications,
references and other material referred to herein are incorporated
by reference herein in their entirety.
[0086] As used herein, the term "comprising" encompasses
"including" as well as "consisting," e.g. a composition
"comprising" X may consist exclusively of X or may include
something additional, e.g., X+Y.
[0087] As used herein, the term "administering" in relation to a
compound, e.g., an IL-1.beta. binding antibody or standard of care
agent, is used to refer to delivery of that compound by any route
of delivery.
[0088] As used herein, the term "assaying" is used to refer to the
act of detecting, identifying, screening or determining, which act
may be performed by any conventional means. For example, a sample
may be assayed for the presence of a particular marker by using an
ELISA assay, a Northern blot, imaging, etc. to detect whether that
marker is present in the sample.
[0089] As used herein, The term "about" in relation to a numerical
value x means, for example, +/-10%.
[0090] As used herein, The word "substantially" does not exclude
"completely," e.g., a composition which is "substantially free"
from Y may be completely free from Y. Where necessary, the word
"substantially" may be omitted from the definition of the
disclosure.
[0091] As used herein, "C-reactive protein" and "CRP" refers to
serum C-reactive protein, which is used as an indicator of the
acute phase response to inflammation. The level of CRP in plasma
may be given in any concentration, e.g., mg/dl, mg/L, nmol/L.
Levels of CRP may be measured by a variety of well known methods,
e.g., radial immunodiffusion, electroimmunoassay,
immunoturbidimetry, ELISA, turbidimetric methods, fluorescence
polarization immunoassay, and laser nephelometry. Testing for CRP
may employ a standard CRP test or a high sensitivity CRP (hsCRP)
test (i.e., a high sensitivity test that is capable of measuring
low levels of CRP in a sample using laser nephelometry). Kits for
detecting levels of CRP may be purchased from various companies,
e.g., Calbiotech, Inc, Cayman Chemical, Roche Diagnostics
Corporation, Abazyme, DADE Behring, Abnova Corporation, Aniara
Corporation, Bio-Quant Inc., Siemens Healthcare Diagnostics,
etc.
[0092] As used herein, the term "hsCRP" refers to the level of CRP
in the blood as measured by high sensitivity CRP testing.
[0093] Each local laboratory will employ a cutoff value for
abnormal (high) CRP based on that laboratory's rule for calculating
normal maximum CRP. A physician generally orders a CRP test from a
local laboratory, and the local laboratory reports normal or
abnormal (low or high) CRP using the rule that particular
laboratory employs to calculate normal CRP.
[0094] By "IL-1.beta. binding antibody" is meant any antibody
capable of binding to the IL-1.beta. antigen either alone or
associated with other molecules. The binding reaction may be shown
by standard methods (qualitative assays) including, for example, a
bioassay for determining the inhibition of IL-1.beta. binding to
its receptor or any kind of binding assays, with reference to a
negative control test in which an antibody of unrelated specificity
but of the same isotype, e.g. an anti-CD25 antibody, is used.
Advantageously, the binding of the IL-1.beta. binding antibodies
used in the methods of the invention to IL-1.beta. may be shown in
a competitive binding assay.
[0095] As used herein the term "antibody" as referred to herein
includes whole antibodies and any antigen binding fragment or
single chains thereof (i.e., "functional fragment"). A naturally
occurring "antibody" is a glycoprotein comprising at least two
heavy (H) chains and two light (L) chains inter-connected by
disulfide bonds. Each heavy chain is comprised of a heavy chain
variable region (abbreviated herein as V.sub.H) and a heavy chain
constant region. The heavy chain constant region is comprised of
three domains, CH1, CH2 and CH3. Each light chain is comprised of a
light chain variable region (abbreviated herein as V.sub.L) and a
light chain constant region. The light chain constant region is
comprised of one domain, CL. The V.sub.H and V.sub.L regions can be
further subdivided into regions of hypervariability, termed
complementarity determining regions (CDR), interspersed with
regions that are more conserved, termed framework regions (FR).
Each V.sub.H and V.sub.L is composed of three CDRs and four FRs
arranged from amino-terminus to carboxy-terminus in the following
order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions
of the heavy and light chains contain a binding domain that
interacts with an antigen. The constant regions of the antibodies
may mediate the binding of the immunoglobulin to host tissues or
factors, including various cells of the immune system (e.g.,
effector cells) and the first component (C1q) of the classical
complement system.
[0096] As used herein, the term "functional fragment" of an
antibody as used herein, refers to portions or fragments of an
antibody that retain the ability to specifically bind to an antigen
(e.g., IL-1.beta.). It has been shown that the antigen-binding
function of an antibody can be performed by fragments of a
full-length antibody. Examples of binding fragments encompassed
within the term "functional fragment" of an antibody include a Fab
fragment, a monovalent fragment consisting of the V.sub.L, V.sub.H,
CL and CH1 domains; a F(ab)2 fragment, a bivalent fragment
comprising two Fab fragments linked by a disulfide bridge at the
hinge region; a Fd fragment consisting of the V.sub.H and CH1
domains; a Fv fragment consisting of the V.sub.L and V.sub.H
domains of a single arm of an antibody; a dAb fragment (Ward et
al., 1989), which consists of a V.sub.H domain; and an isolated
complementarity determining region (CDR). Exemplary antigen binding
sites include the CDRs of canakinumab as set forth in SEQ ID NOs:
3-5 and SEQ ID NOs: 6-8. Although the two domains of the Fv
fragment, V.sub.L and V.sub.H, are coded for by separate genes,
they can be joined, using recombinant methods, by a synthetic
linker that enables them to be made as a single protein chain in
which the V.sub.L and V.sub.H regions pair to form monovalent
molecules (known as single chain Fv (scFv); see, e.g., Bird et al.,
1988; and Huston et al., 1988). Such single chain antibodies are
also intended to be encompassed within the term "functional
fragments" of an antibody. These antibody fragments are obtained
using conventional techniques known to those of skill in the art,
and the fragments are screened for utility in the same manner as
are intact antibodies.
[0097] As used herein, the terms "monoclonal antibody" or
"monoclonal antibody composition" as used herein refer to a
preparation of antibody molecules of single molecular composition.
A monoclonal antibody composition displays a single binding
specificity and affinity for a particular epitope.
[0098] As used herein, the term "human antibody", as used herein,
is intended to include antibodies having variable regions in which
both the framework and CDR regions are derived from sequences of
human origin. Furthermore, if the antibody contains a constant
region, the constant region also is derived from such human
sequences, e.g., human germline sequences, or mutated versions of
human germline sequences or antibody containing consensus framework
sequences derived from human framework sequences analysis as
described in Knappik, et al. A "human antibody" need not be
produced by a human, human tissue or human cell. The human
antibodies of the disclosure may include amino acid residues not
encoded by human sequences (e.g., mutations introduced by random or
site-specific mutagenesis in vitro or by somatic mutation in vivo).
However, the term "human antibody", as used herein, is not intended
to include antibodies in which CDR sequences derived from the
germline of another mammalian species, such as a mouse, have been
grafted onto human framework sequences.
[0099] As used herein, the term "K.sub.D", as used herein, is
intended to refer to the dissociation constant, which is obtained
from the ratio of K.sub.d to K.sub.a (i.e. K.sub.d/K.sub.a) and is
expressed as a molar concentration (M). K.sub.D values for
antibodies can be determined using methods well established in the
art. A method for determining the K.sub.D of an antibody is by
using surface plasmon resonance, or using a biosensor system such
as a Biacore.RTM. system.
[0100] As used herein, the term "patient" includes any human or
nonhuman animal. The term "nonhuman animal" includes all
vertebrates, e.g., mammals and non-mammals, such as nonhuman
primates, sheep, dogs, cats, horses, cows, chickens, amphibians,
reptiles, etc.
[0101] As used herein, an antibody that "inhibits" one or more of
these IL-1.beta. functional properties (e.g., biochemical,
immunochemical, cellular, physiological or other biological
activities, or the like) as determined according to methodologies
known to the art and described herein, will be understood to relate
to a statistically significant decrease in the particular activity
relative to that seen in the absence of the antibody (or when a
control antibody of irrelevant specificity is present). An antibody
that inhibits IL-1.beta. activity affects a statistically
significant decrease, e.g., by at least 10% of the measured
parameter, by at least 50%, 80% or 90%, and in certain embodiments
an antibody of the disclosure may inhibit greater than 95%, 98% or
99% of IL-17 functional activity.
[0102] As used herein the term "polypeptide", if not otherwise
specified herein, includes any peptide or protein comprising amino
acids joined to each other by peptide bonds, having an amino acid
sequence starting at the N-terminal extremity and ending at the
C-terminal extremity.
Example 1
[0103] A Muticenter, Randomized, Double-Blind, Placebo-Controlled
Study of the Safety, Tolerability and Effects on Arterial Structure
and Function of ACZ885 in Patients with Intermittent
Claudication
[0104] Because ACZ885 (canakinumab) does not cross-react with
rodent, canine or pig IL-1.beta., preclinical efficacy data with
this antibody in other species have not been obtained. However,
supportive data is available from reports of reduced
atherosclerosis in IL-1 knockout or IL-1 type I receptor knockout
mice (Kirii, et al., 2003). IL-1 receptor antagonist deficient mice
are more prone to neointima development after endothelia injury and
more prone to atherogenesis (Isoda at al, m 2003; Isoda and Obsuzu,
2006). Independent of atherosclerosis, the effects of IL-1.beta.
blockade on infarct size after coronary ligation or
ischemia-reperfusion has been assessed in IL-1R1 knockout mice, and
in mice treated with anakinra or IL-1.beta. antibodies. In these
studies, the blockade of IL-1 signaling is either protective or
neutral (Abbate at al 2008; Salloum et al 2009). A single report
(Hwang et al 2001) showed that co-administration of an
anti-IL-1.beta. antibody in an infarction model in C57BL/6 mice
worsened mortality and increased rupture of the ventricular wall,
but was complicated by a higher-than-normal 24-hour perioperative
mortality rate in the control groups. Mice have limited collateral
coronary circulations and the extent of these collateral vessels
are strain-dependent. Thus these in vivo studies may have limited
ability to reflect the complex multifactorial interactions that
modulate IL-1.beta. responses in humans.
[0105] In this study, subjects will be selected to be at least 3
months from previous events requiring healing processes, e.g.
myocardial infarction, coronary artery bypass grafting, stroke, or
carotid endarterectomy, to allow for adequate wound healing.
The Objectives of this Study are: [0106] To assess the effect of
ACZ885 on peripheral artery total plaque burden using MRI
techniques at baseline, 3 months and 12 months. [0107] To assess
the effect of ACZ885 on serum amyloid A protein, high-sensitivity
C-reactive protein and Interleukin-6 levels [0108] To assess the
effect of ACZ885 on functional capacity parameters, as measured by
a 6 minute walk test, including pain-free walk distance and maximum
walk distance. [0109] To explore the effects of ACZ885 on
functional capacity, as measured by outpatient activity levels
(average number of steps taken daily and average time upright
daily) documented by the activPAL device)
[0110] The ActivPAL.TM. monitor (PAL Technologies Ltd., Glasgow,
UK) will be used. This device's accuracy is well documented, it
provides more detailed information than some other monitors, and
this has been used in other cancer studies (Maddocks et al 2011).
The device is a small and lightweight (20.times.30.times.5 mm, 20
g) uniaxial accelerometer that is applied to the anterior thigh
using adhesive PALStickies.TM. and a layer of Tegaderm.TM.
dressing. The ActivPAL.TM. records periods spent sitting, standing
and walking, sit-to-stand transitions, step count and rate of
stepping (cadence) over a maximum period of 10 days with a fully
charged new battery.
[0111] Accompanying software allows each of these outcomes to be
displayed by hour, day or week. During the study the device will be
worn for 6 consecutive days. These devices may be removed at night
or kept on but should be removed during bathing, showering, or
swimming. The monitor also provides an estimate of energy
expenditure in metabolic equivalent hours (METh), based on the time
spent sitting, standing, walking and cadence; however, this outcome
has not been validated. [0112] To explore the effects of ACZ885 on
serum D-dimer levels and in an ex vivo cholesterol efflux in vitro
assay [0113] To explore the effects of ACZ885 on the incidence of
adjudicated major cardiovascular events and on peripheral arterial
events
[0114] This is a non-confirmatory, double-blind, randomized,
placebo-controlled, parallel group study in patients with
intermittent claudication. The study will consist of a 28 day
screening period, a 28 day run-in period with initiation of a
standardized exercise regimen, a 12 month treatment period and a 1
month follow-up period. MRI of the peripheral vessels will be
obtained at the end of the run-in period (considered `baseline`)
and after 3 and 12 months of treatment. Additional assessments will
include functional tests (6 minute walk test) and other objective
measures of functional capacity (ActivPAL recorded outpatient
activity) after 1, 2, 3, 6, 9 and 12 months of treatment. This
design will allow for the assessment of both potential acute and
chronic effects of ACZ885 on peripheral artery disease in these
patients, as well as allow for an expeditious assessment of any
safety concerns. Patients who meet the eligibility criteria at
screening will be admitted to baseline evaluations. All baseline
safety evaluation results must be available prior to dosing.
Patients will attend the study site the day before dosing in each
period for baseline evaluations. Following a single dose of ACZ885,
pharmacokinetic, pharmacodynamic, and safety assessments will be
done. Patients will then undergo Study Completion evaluations
approximately 30 days after their last dose. Safety assessments
will include physical examinations, ECGs, vital signs, standard
clinical laboratory evaluations (hematology, blood chemistry,
urinalysis) adverse event and serious adverse event monitoring.
[0115] Subjects who meet the inclusion/exclusion criteria at
screening will be admitted to baseline evaluations. All baseline
safety evaluation results must be available prior to dosing.
[0116] Subjects will attend the study site the day before dosing in
each period for baseline evaluations. Following a single dose of
ACZ885, pharmacokinetic, pharmacodynamic, and safety assessments
will be made during monthly visits over 12 months. Subjects will
then undergo Study Completion evaluations approx 30 days after
their last dose.
[0117] Safety assessments will include physical examinations, ECGs,
vital signs, standard clinical laboratory evaluations (hematology,
blood chemistry, urinalysis) adverse event and serious adverse
event monitoring.
[0118] This study is a randomized, placebo-controlled, double-blind
study. The design of this study addresses the primary objective of
evaluating the change in vascular structure and functional capacity
in patients with peripheral artery disease and intermittent
claudication as a result of treatment with ACZ885. Patients with an
ankle-brachial index of between 0.50 and 0.85 (inclusive) will be
enrolled as ABI is a predictive measure of impaired vascular blood
flow to the lower extremities. Within this population, patients
will additionally selected, who have a 6 minute walk distance of
.ltoreq.400 m (based published data in subjects with measurable
plaque volume via MRI having walk distances below 400 m (McDermott
2011)). Some measures of peripheral artery disease severity (e.g.
walk distances) can be influenced by psychosocial cues such as
verbal encouragement or perception of pain, or the knowledge of
drug administration. Therefore this study is double-blinded to
mitigate these effects. Enrollment in studies is also known to
positively impact patients' motivation to exercise, which in turn
improves walk distance. Therefore to minimize variability from
being enrolled in the study, all patients will be enrolled in a
standardized home exercise program beginning in the one month
run-in period, and lasting through the duration of treatment.
[0119] As there are no currently approved or effective therapies
known to mediate disease progression in PAD, placebo will be used
to aim in demonstrating an effect of ACZ885 on PAD. Patients will
be maintained on their stable regimen, including aspirin and
statin, as recommended for PAD risk modification.
[0120] Approximately 180 subjects will be enrolled to participate
in the study and randomized, with a goal of at least 120 patients
expected to complete the study.
[0121] Subjects eligible for inclusion in this study have to
fulfill all of the following criteria: [0122] 1. Male and female
subjects age 18 to 74 years of age (inclusive) at screening, with
clinical evidence of moderate peripheral artery disease. This must
be demonstrated by an ankle-brachial index of 0.54-0.8 (inclusive)
in at least one leg. [0123] 2. Moderate symptomatic intermittent
claudication, as defined by pain and/or fatigue in any of the leg
muscles with ambulation of less than 400 meters. Atypical symptoms
may also be considered at the discretion of the investigator,
including but not limited to parasthesias, pallor and coolness of
the lower peripheral limbs with ambulation. [0124] 3. On stable
aspirin and statin therapy for at least 6 weeks prior to screening,
or have documentation of intolerance. If patients are not on an
aspirin or statin, they must have a documented contraindication,
e.g. GI distress with aspirin, or statin intolerance or myopathy.
[0125] 4. Acquisition of evaluable MRI images at baseline to assess
the vessel wall morphometry of the superficial femoral artery to
determine plaque burden and regions of stenosis. [0126] 5. At
Screening, and Baseline, vital signs (systolic and diastolic blood
pressure and pulse rate) will be assessed in the sitting position
after the subject has rested for at least five (5) minutes. An
appropriately sized BP cuff should be used for the given subject's
body habitus. Vital signs should be within: [0127] oral body
temperature between 35.0-37.5.degree. C. [0128] systolic blood
pressure, 90-170 mm Hg [0129] diastolic blood pressure, 50-100 mm
Hg [0130] pulse rate, 40-100 bpm
[0131] The investigational drug, ACZ885 and matching placebo will
be prepared by Novartis as lyophilized powder in glass vials and
supplied to the clinical sites as open label bulk medication.
Please see pharmacy manual for details of preparation. The drug
will be delivered at a dose of 150 mg subcutaneously monthly for a
treatment period of 12 months.
[0132] Subjects will be assigned to one of the following 2
treatments in a ratio of 1:1
[0133] Study treatments are defined as: [0134] Monthly doses of 150
mg ACZ885 [0135] Monthly doses of placebo to 150 mg ACZ85
REFERENCES
[0135] [0136] Abbate A, Salloum F N, Veci E. et al (2008) Anakinra,
a recombinant human interleukin-1 receptor antagonist, inhibits
apoptosis in experimental acute myocardial infarction. Circulation
117:2670-2683 [0137] Crossman D C, Morton A C, Gunn J P et al
(2008) Investigation of the effect of Interleukin-1 receptor
antagonist (IL-1ra) on markers of inflammation in non-ST elevation
acute coronary syndromes. (The MRC-ILA-HEART study). Trials; 9:8-21
[0138] Hwang M W, Matsumori A, Furukawa Y, et al (2001)
Neutralization of interleukin-1 beta in the acute phase of
myocardial infarction promotes the progression of left ventricular
remodeling. J Am Coll Cardiol; 38:1546-53 [0139] Isoda K and Ohauzu
F (2006) The effect of interleukin-1 receptor antagonist on
arteries and cholesterol metabolism. J Atheroscler Thromb; 13:21-30
[0140] Isoda K, Shiigai M, Ishigami H et al (2003) Deficiency of
interleukin-1 receptor antagonist promotes neointimal formation
after injury. Circulation 108:516-8 [0141] Kirii H, Niwa T, Yamada
Y, et al (2003) Lack of interleukin-1 beta decreases the severity
of atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc
Biol 23:656-60 [0142] Salloum F N, Chau V, Varma A et al (2009)
Anakinra in experimental acute myocardial infarction--does dosage
or duration of treatment matter? Cardiovasc Drugs Ther 23:129-135
Sequence CWU 1
1
81118PRThomo sapiens 1Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val
Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Val Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln
Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ile Ile Trp Tyr
Asp Gly Asp Asn Gln Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu
Gln Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Arg Asp Leu Arg Thr Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110 Leu Val Thr Val Ser Ser 115 2107PRThomo sapiens 2Glu
Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val Thr Pro Lys 1 5 10
15 Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Ser Ser
20 25 30 Leu His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Leu
Leu Ile 35 40 45 Lys Tyr Ala Ser Gln Ser Phe Ser Gly Val Pro Ser
Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
Ile Asn Ser Leu Glu Ala 65 70 75 80 Glu Asp Ala Ala Ala Tyr Tyr Cys
His Gln Ser Ser Ser Leu Pro Phe 85 90 95 Thr Phe Gly Pro Gly Thr
Lys Val Asp Ile Lys 100 105 35PRTHOMO SAPIENS 3Val Tyr Gly Met Asn
1 5 417PRTHOMO SAPIENS 4Ile Ile Trp Tyr Asp Gly Asp Asn Gln Tyr Tyr
Ala Asp Ser Val Lys 1 5 10 15 Gly 56PRTHOMO SAPIENS 5Asp Leu Arg
Thr Gly Pro 1 5 611PRTHOMO SAPIENS 6Arg Ala Ser Gln Ser Ile Gly Ser
Ser Leu His 1 5 10 76PRTHOMO SAPIENS 7Ala Ser Gln Ser Phe Ser 1 5
87PRTHOMO SAPIENS 8His Gln Ser Ser Ser Leu Pro 1 5
* * * * *