WO2015083120A1

WO2015083120A1 - USE OF IL-1β BINDING ANTIBODIES

Info

Publication number: WO2015083120A1
Application number: PCT/IB2014/066601
Authority: WO
Inventors: William DOLE
Original assignee: Novartis Ag
Priority date: 2013-12-04
Filing date: 2014-12-04
Publication date: 2015-06-11

Abstract

The present invention relates to a method for treating or alleviating the symptoms of abdominal aortic aneurysm (AAA) in a subject, comprising administering about 25 mg to about 300 mg of an IL-1β binding antibody or functional fragment thereof, and wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of ≥30 mm and ≤60 mm before treatment..

Description

USE OF IL-Ιβ BINDING ANTIBODIES

TECHNICAL FIELD The present invention relates to a novel use and dosage regimens of an IL-Ιβ binding antibody or functional fragments thereof, for treating or alleviating the symptoms of abdominal aortic aneurysm.

BACKGROUND OF THE INVENTION

Abdominal aortic aneurysm (AAA) is a condition characterized by abnormal dilation of the abdominal aorta. Often the aorta exceeds the normal diameter by more than 50 percent. Approximately 90 percent of abdominal aortic aneurysms occur infrarenally (below the kidneys), but they can also occur pararenally (at the level of the kidneys) or suprarenally (above the kidneys). As the AAA grows, the risk of aortic rupture and death also grows. AAA affects -3.5 million individuals in the USA alone, resulting in -55,000 deaths annually in the USA and EU. The incidence of AAA is expected to increase with the world's aging population, and it remains vastly undertreated. AAA is prevalent in smokers and patients with hypertension, and its incidence increases with age. While atherosclerosis is commonly associated with AAA, it is not considered a causal risk factor.

Current clinical management of AAA relies on appropriately timed endovascular stent graft procedures or open surgery, usually triggered by a critical AAA size. Assessing aneurysm size and growth rate are the foundations for clinical decision making at this time, since both are associated with AAA rupture rate (Brady et al (2004), Circulation, 110(1), pp. 16-21, Klink et al (2011) Nature Reviews Cardiology, 8(6), pp. 338-347, and Sakalihasan et al, (2005) Lancet, 365(9470), pp. 1577-1589). Current guidelines recommend periodic imaging surveillance of aneurysms between 3.0-5.0 cm in diameter. Surveillance intervals vary by country, but typically decrease based on the size of the AAA since smaller AAAs grow more slowly than large AAAs. Intervals range from 12-36 months for small 3 cm AAAs, and 6-12 months for AAA diameters from 4.0-5.0 cm RESCAN Collaborators (2013) JAMA, 309(8), pp. 806-813). Aortic rupture is the most feared clinical sequela of an AAA, and the risk of rupture increases with AAA diameter Moll et al (2011) European journal of vascular and endovascular surgery: the official journal of the European Society for Vascular Surgery, 41 Suppl 1, pp. S 1-S58. A diameter of >5.5 cm is widely considered a threshold for intervention, as is an expansion rate of >1 cm/year (Klink et al. 2011). While surgical intervention for AAA remains the standard of care and new technologies such as endovascular stent grafts appear promising (Greenhalgh et al, (2008) The New England journal of medicine, 358(5), pp. 494- 501), these options are not without detriment. Surgical mortality is high (-5% open repair, up to 1.7% endovascular), late complications are frequent (25-40% for endovascular), and procedures are costly (EVAR trial participants (2005) Lancet, 365(9478), pp. 2179-2186, United Kingdom EVAR Trial Investigators, (2010) New England journal of medicine, 362(20), pp. 1863-1871, Jackson et al., (2012) JAMA 307(15), pp. 1621-1628). One recent retrospective review suggests that patients undergoing endovascular repair had a lower overall mortality at 5 years post procedure than those undergoing an open surgical repair (Jackson et al., 2012). Safe and effective medical therapy that could slow AAA growth may delay or prevent the need for surgical therapies, saving patients from associated morbidity and mortality. Other than standard therapies for comorbid conditions like hypertension, there are no current medical therapies approved for the treatment of AAA, and common cardiovascular therapies such as beta-blockers, statins, and ACE inhibitors have proven largely ineffective (Moll et al., 2011, Klink et al., 2011 and Sweeting et al, (2010) Journal of vascular surgery, 52(1), pp. 1-4).

The pathophysiology of AAA involves three main processes: inflammation, proteolysis, and apoptosis (Nordon et al (2011) Nature Reviews Cardiology, 8(2), pp.92-102). Substantial evidence suggests that the IL-Ιβ protein plays a role in each of these processes. Preclinical data document that IL-Ιβ amplifies inflammation via adhesion molecules and cytokines; it mediates proteolysis by stimulating matrix metalloproteases, inhibiting collagen synthesis, upregulating cathepsins, and inhibiting elastin; and, it can induce vascular smooth muscle cell apoptosis. Murine models of AAA show that genetic ablation of IL-Ιβ or the IL-1 receptor protects against AAA formation (Johnston et al, (2013) Arteriosclerosis, thrombosis, and vascular biology, 33(2), pp. 294-304). Human studies have shown that serum IL-Ιβ levels are elevated in AAA patients compared with normal control patients and those with coronary heart disease (Juvonen et al., (1997) Arteriosclerosis, thrombosis, and vascular biology, 17(11), pp. 2843-2847). In addition, cultured human AAA biopsy samples constitutively express more IL-Ιβ than normal samples (Pearce et al., (1992) Journal of vascular surgery, 16(5), pp. 784-789). Collectively, these data support a hypothesis that IL-Ιβ is important in AAA pathogenesis. Preclinical data are available from reports that IL-IR knockout (KO) or IL-Ιβ KO mice demonstrated significant protection against AAA formation in an elastase perfusion model of AAA (Thompson et al (2006) Annals of the New York Academy of Sciences, 1085, pp. 59-73). In addition, IL-Ιβ KO and IL-IR KO aortas had reduced macrophage and neutrophil staining with greater elastin preservation compared with wild type (WT) aortas (Johnston et al., 2013) consistent with reduced inflammation. The effects of IL- IR blockade on AAA were also assessed in WT mice treated with anakinra (Kineret), a commercially available recombinant IL-IR antagonist. When mice were pre-treated with anakinra, there was a dose-dependent decrease in maximal aortic dilatation observed in the elastase perfusion model of AAA. Importantly, WT mice treated with anakinra after AAA initiation with elastase also demonstrated significant protection against AAA progression (Johnston et al., 2013). No human data are available to date regarding IL-Ιβ blockade in AAA.

ACZ885 (canakinumab) is a high-affinity, fully human monoclonal antibody to interleukin- 1β, developed originally for the treatment of IL-^-driven inflammatory diseases. Canakinumab has been approved under the trade name ILARIS^® in the USA for patients > 4 years of age with Cryopyrin-Associated Periodic Syndromes (CAPS), [Familial Cold-Associated Syndrome (FCAS) and Muckle-Wells syndrome (MWS) phenotypes included], and in the EEA for CAPS patients > 4 years of age (FCAS, MWS and Neonatal Onset Multisystem Inflammatory Disease/chronic infantile neurologic cutaneous articular phenotypes). Clinical studies have already been conducted in healthy volunteers and in patients with mild asthma, rheumatoid arthritis, psoriasis, age-related macular degeneration and Type 2 diabetes. A study (CACZ885M2301) to examine the effect of ACZ885 on cardiovascular risk in high-risk coronary disease patients is ongoing.

ACZ885 (canakinumab), functional fragments thereof and structurally similar equivalents are described in WO 02/16436. SUMMARY OF THE INVENTION

Accordingly, in one aspect, the present invention is directed to a method of treating or alleviating the symptoms of abdominal aortic aneurysm (AAA) in a subject, comprising administering about 25 mg to about 300 mg of an IL-Ιβ binding antibody or functional fragment thereof and wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >30 mm and <60 mm before treatment.

Accordingly, in another aspect, the present invention is directed to an IL-Ιβ binding antibody or a functional fragment thereof for use as a medicament for treating or alleviating the symptoms of abdominal aortic aneurysm (AAA) in a subject, wherein about 25 mg to about 300 mg of an IL-Ιβ binding antibody or functional fragment thereof is administered and wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >30 mm and <60 mm before treatment.

Accordingly, in yet another aspect, the present invention is directed to the use of an IL-Ιβ binding antibody or a functional fragment thereof for the manufacture of a medicament for treating or alleviating the symptoms of abdominal aortic aneurysm (AAA) in a subject, wherein about 25 mg to about 300 mg of an IL-Ιβ binding antibody or functional fragment thereof is administered and wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >30 mm and <60 mm before treatment.

When administering an IL-Ιβ binding antibody and especially canakinumab to subject with AAA, inhibition of systemic IL-Ιβ decreases inflammation, reduces proteolysis, and diminishes smooth muscle cell apoptosis. These effects should, in turn, structurally stabilize the aneurysm and ultimately slow or halt its growth. Applying the method and/or the use according the invention in subjects with AAA will delay or obviate the need for risky and expensive procedures and surgeries. Further features and advantages of the invention will become apparent from the following description. DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method of treating or alleviating the symptoms of abdominal aortic aneurysm (AAA) in a subject, comprising administering about 25 mg to about 300 mg of an IL-Ιβ binding antibody or functional fragment thereof and wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >30 mm and <60 mm before treatment. In a preferred embodiment of any method of the invention, the IL-Ιβ binding antibody is canakinumab.

In one embodiment, the subject is >40 years of age or >45 years of age. In one embodiment, the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >30 mm and <55 mm before treatment or a maximum diameter of >33 mm and <52 mm before treatment or maximum diameter of >35 mm and <50 mm before treatment or a maximum diameter of >35 mm and <45 mm before treatment or a maximum diameter of >38 mm and <46 mm before treatment or a maximum diameter of >32 mm and <43 mm before treatment, or a maximum diameter of >30 mm and <40 mm before treatment. In another embodiment, the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >40 mm and <50 mm for men and >38 mm and <48 mm for women before treatment. The above mentioned maximum diameter is measured by means of ultrasound imaging or contrast enhanced CT angiography.

In different embodiments, the growth of the aneurysm has retarded or stopped after 3 months of treatment or after 6 months of treatment or after 9 months of treatment or after 12 months of treatment. According to a preferred embodiment, a 40 % decrease of the growth rate of the abdominal aortic aneurysm is observed in the subject, measured at 12 months after the start of treatment with canakinumab or another IL-Ιβ binding antibody or functional fragment thereof.

Said IL-Ιβ 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 preferred embodiment said IL-Ιβ binding antibody or functional fragment thereof may be administered monthly. In another preferred embodiment the IL-Ιβ binding antibody or functional fragment thereof may be administered every 3 monthls. About 25, 50, 75, 80, 100, 125, 150, 175, 200, 225, 250, 275, 300 mg or any combination thereof of the IL-Ιβ binding antibody or functional fragment thereof may be administered. In another embodiment, 25-75 mg is administered or 50-100 mg or 75-125 mg or 100-150 mg is administered monthly, every 2 months or every third month. In another embodiment, said method is comprising administering about 50 mg, about 75 mg, about 80 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg or about 300 mg of the IL-Ιβ binding antibody or functional fragment thereof. In another ambodiment said method comprising administering the patient an additional dose of about 25 mg to about 300 mg of the IL-Ιβ binding antibody or functional fragment thereof at week 2, week 4 or week 6 from the first administration. The additional dose may be about 25 mg, 50 mg, about 75 mg, about 100 mg, about 150 mg or about 300 mg of the IL-Ιβ binding antibody or functional fragment thereof.

In one embodiment said IL-Ιβ binding antibody or functional fragment thereof is an human IL-Ιβ binding antibody. In one embodiment, said IL-Ιβ binding antibody or functional fragment thereof is capable of inhibiting the binding of IL-Ιβ to its receptor and has a K_D for binding to IL-Ιβ of about 50 pM or less.

In other embodiments of any method of the invention said IL-Ιβ binding antibody is selected from the group consisting of:

a) an IL-Ιβ binding antibody directed to an antigenic epitope of human IL-Ιβ which includes the loop comprising the Glu64 residue of the mature IL-Ιβ, wherein said IL-Ιβ binding antibody is capable of inhibiting the binding of IL-Ιβ to its receptor, and further wherein said IL-Ιβ binding antibody has a K_D for binding to IL-Ιβ of about 50 pM or less; b) an IL-Ιβ binding antibody that competes with the binding of an IL-Ιβ binding antibody comprising a VH domain comprising SEQ ID NO: l and a VL domain comprising SEQ ID NO:2;

c) an IL-Ιβ binding antibody comprising the three CDRs of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5;

d) an anti-IL-Ιβ binding antibody comprising the three CDRs of SEQ ID NO: 6, SEQ

ID NO:7 , SEQ ID NO:8;

e) an anti-IL-Ιβ 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; f) an anti-IL-Ιβ binding antibody comprising a VH domain comprising SEQ ID NO: 1; g) an anti-IL-Ιβ binding antibody comprising a VL domain comprising SEQ ID NO: 2; h) an anti-IL-Ιβ binding antibody comprising a VH domain comprising SEQ ID NO: 1 and a VL domain comprising SEQ ID NO:2.

In one embodiment of any method of the invention, said IL-Ιβ 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.

In other embodiments of any method of the invention, the IL-Ιβ binding antibody comprises: 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:4, a third CDR having 0, 1 or 2 amino acid substitutions in comparison to the CDR set forth in SEQ ID NO: 5; and

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_D for IL-lbeta of 50 pM or les and wherein said antibody inhibits the binding of IL-Ιβ to its receptor. Substituted amino acids are ideally conservative substitutions, and once substituted a skilled artisan could use an assay such as those described in WO 02/16436.

In some embodiments of any of the method described above, the antibody or fragment binds to human IL- 1β with a dissociation constant of about 50 pM or less. In some embodiments, the antibody or fragment binds to human IL-I β with a dissociation constant of about 500 pM or less. In some embodiments, the IL-Ιβ binding antibody or functional fragment thereof binds to human IL-I β with a dissociation constant of about 250 pM or less. In some embodiments, the IL-Ιβ binding antibody or functional fragment thereof binds to human IL- 1β with a dissociation constant of about 100 pM or less. In some embodiments of any of the methods described above, the IL-Ιβ binding antibody or functional fragment thereof binds to human IL- 1β with a dissociation constant of about 5 pM or less. In some embodiments, the IL-Ιβ binding antibody or functional fragment thereof binds to human IL- 1β with a dissociation constant of about 1 pM or less. In some embodiments, the IL- 1β binding antibody or functional fragment thereof binds to human IL- 1β with dissociation constant of about 0.3 pM or less. In some embodiments of any and/or all of the methods described above, the IL-Ιβ binding antibody or functional fragment thereof is a neutralizing antibody.

The canakinumab heavy chain variable region (VH) is set forth as SEQ ID NO: l 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. 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. In some embodiments of any and/or all of the methods described above, the anti-IL-Ιβ 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.

In some embodiments, the disclosed methods comprise administering an anti-IL-Ιβ binding antibody having the three CDRs of SEQ ID NO: 1. In further embodiments, the three CDRs of SEQ ID NO: l are set forth as SEQ ID NOs: 3-5. In some embodiments, the disclosed methods comprise administering an anti-IL-Ιβ 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.

Preferably the IL-Ιβ binding antibody is canakinumab. Canakinumab is a fully human monoclonal anti-human IL-Ιβ antibody of the IgGl/k isotype, being developed for the treatment of IL-Ιβ driven inflammatory diseases. It is designed to bind to human IL-Ιβ and thus blocks the interaction of this cytokine with its receptors. The antagonism of the IL-Ιβ 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. Canakinumab is disclosed in WO02/16436 which is hereby incorporated by reference in its entirety. In other embodiments of any method of the invention, said IL-Ιβ binding antibody or functional fragment thereof is selected from the group consisting of gevokizumab, LY- 2189102 or AMG-108. Said IL-Ιβ binding antibody or functional fragment thereof is administered parentally, e.g., intravenously or subcutaneously. Preferably, canakinumab is administered subcutanously. Canakinumab can be administered in a reconstituted formulation comprising canakinumab at a concentration of 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. Canakinumab can also be administered in a liquid formulation comprising 10-200 mg/ml canakinumab, mannitol, histidine and polysorbate 80, wherein the pH of the formulation is 6.2-6.8. Canakinumab can also be administered in a liquid formulation comprising canakinumab at a concentration of 10-200 mg/ml, 270 mM mannitol, 20 mM histidine and 0.04% polysorbate 80, wherein the pH of the formulation is 6.5.

Said IL-Ιβ 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. In one embodiment, said patient is concomitantly receiving a statin such as lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin, mevastatin, pitavastatin, rosuvastatin; and /or aspirin; and/or beta-adrenergic blocking drugs such as esmolol, metoprolol, nadolol, penbutolol; and/or an angiotensin-converting enzyme (ACE) inhibitor such as ramipril, ramiprilat, captopril, lisinopril; and/or an angiotensin II receptor blocker such as losartan, valsartan, olmesartan, irbesartan, candesartan, telmisartan, eprosartan; and/or an inhibitor of platelet aggregation such clopidogrel, prasugrel or ticagrelor.

According to another aspect of the invention, an IL-Ιβ binding antibody or a functional fragment thereof for use as a medicament for treating or alleviating the symptoms of abdominal aortic aneurysm (AAA) in a subject, comprising administering about 25 mg to about 300 mg of an IL-Ιβ binding antibody or functional fragment thereof, and wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >30 mm and <60 mm before treatment. According yet another aspect of the invention, the use of an IL-Ιβ binding antibody or a functional fragment thereof is provided for the manufacture of a medicament for treating or alleviating the symptoms of abdominal aortic aneurysm (AAA) in a subject, comprising administering about 25 mg to about 300 mg of an IL-Ιβ binding antibody or functional fragment thereof and wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >30 mm and <60 mm before treatment.

In the following paragraphs below, 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 can all be combined 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-Ιβ binding antibody or a functional fragment containing the same variable domain as canakinumab will be regarded as especially preferred.

In one embodiment, the subject is >40 years of age or >45 years of age. In one embodiment, the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >30 mm and <55 mm before treatment or a maximum diameter of >33 mm and <52 mm before treatment or maximum diameter of >35 mm and <50 mm before treatment or a maximum diameter of >35 mm and <45 mm before treatment or a maximum diameter of >38 mm and <46 mm before treatment or a maximum diameter of >32 mm and <43 mm before treatment or a maximum diameter of >30 mm and <40 mm before treatment. In another embodiment, the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >40 mm and <50 mm for men and >38 mm and <48 mm for women before treatment. The said maximum diameter is measured by means of ultrasound imaging or contrast enhanced CT angiography.

In different embodiments, the growth of the aneurysm has retarded or stopped after 3 months of treatment or after 6 months of treatment or after 9 months of treatment or after 12 months of treatment. According to a preferred embodiment, a 40 % decrease of the growth rate of the abdominal aortic aneurysm is observed in the subject, measured at 12 months after the start of treatment with canakinumab or another IL-Ιβ binding antibody or functional fragment thereof. Said IL-Ιβ 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 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-Ιβ binding antibody or functional fragment thereof. IL-Ιβ 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-Ιβ binding antibody or functional fragment thereof is administered monthly.

In one embodiment the IL-Ιβ binding antibody is canakinumab and may be administered monthly. In another embodiment canakinumab may be administered every third month. About 25, 50, 75, 80, 100, 125, 150, 175, 200, 225, 250, 275, 300 mg of canakinumab or any combination thereof may be administered. In another embodiment 25-75 mg is administered or 50-100 mg or 75-125 mg or 100-150 mg is administered monthly, every 2 months or every third months. In another embodiment, about 50, about 75, about 100 mg, about 125 mg, about 150 mg, about 200 mg or about 300 mg of canakinumab is administered monthly, every 2 month or every third month. In one embodiment, the use comprises administering about 150 mg of canakinumab monthly or every 3 months.

In another ambodiment said use comprises administering the patient an additional dose of about 25 mg to about 300 mg of the IL-Ιβ binding antibody or functional fragment thereof or canakinumab at week 2, week 4 or week 6 from the first administration. The additional dose may be about 25 mg, 50 mg, about 75 mg, about 100 mg, about 150 mg or about 300 mg of the IL-Ιβ binding antibody or functional fragment thereof. In one embodiment of any use of the invention, said IL-Ιβ binding antibody or functional fragment thereof is an IL-Ιβ binding antibody. In one embodiment of any use of the invention, said IL-Ιβ binding antibody or functional fragment thereof is capable of inhibiting the binding of IL-Ιβ to its receptor and has a K_D for binding to IL-Ιβ of about 50 pM or less. In other embodiments of any use of the invention said IL-Ιβ binding antibody is selected from the group consisting of:

a) an IL-Ιβ binding antibody directed to an antigenic epitope of human IL-Ιβ which includes the loop comprising the Glu64 residue of the mature IL-Ιβ, wherein said IL-Ιβ binding antibody is capable of inhibiting the binding of IL-Ιβ to its receptor, and further wherein said IL-Ιβ binding antibody has a KD for binding to IL-Ιβ of about 50 pM or less; b) an IL-Ιβ binding antibody that competes with the binding of an IL-Ιβ binding antibody comprising a VH domain comprising SEQ ID NO: 1 and a VL domain comprising SEQ ID NO:2;

c) an anti-IL-Ιβ binding antibody comprising the three CDRs of SEQ ID NO: 3, SEQ ID NO:4, SEQ ID NO:5;

d) an anti-IL-Ιβ binding antibody comprising the three CDRs of SEQ ID NO: 6, SEQ ID NO:7 , SEQ ID NO:8;

e) an anti-IL-Ιβ 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; f) an anti-IL-Ιβ binding antibody comprising a VH domain comprising SEQ ID NO: 1; g) an anti-IL-Ιβ binding antibody comprising a VL domain comprising SEQ ID NO: 2; h) an anti-IL-Ιβ binding antibody comprising a VH domain comprising SEQ ID NO: 1 and a VL domain comprising SEQ ID NO:2.

In one embodiment of any use of the invention, said IL-Ιβ binding antibody or fragment thereof comprises the 3 CDRs of SEQ ID NO: l 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. In other embodiments of any use of the invention, said IL-Ιβ binding antibody or functional fragment thereof comprises:

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:4, a third CDR having 0, 1 or 2 amino acid substitutions in comparison to the CDR set forth in SEQ ID NO: 5; and

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_D for IL-lbeta of 50 pM or les and wherein said antibody inhibits the binding of IL-Ιβ to its receptor. Substituted amino acids are ideally conservative substitutions, and once substituted a skilled artisan could use an assay such as those described in WO02/16436.

In a preferred embodiment of any use of the invention, said IL-Ιβ binding antibody is canakinumab. However said IL-Ιβ binding antibody or functional fragment thereof can be selected from the group consisting of canakinumab, gevokizumab, LY-2189102 or AMG-108. In some embodiments of any of the use described above, said IL-Ιβ binding antibody or functional fragment thereof binds to human IL- 1β with a dissociation constant of about 50 pM or less. In some embodiments, the antibody or fragment binds to human IL-I β with a dissociation constant of about 500 pM or less. In some embodiments, the IL-Ιβ binding antibody or functional fragment thereof binds to human IL-I β with a dissociation constant of about 250 pM or less. In some embodiments, the IL-Ιβ binding antibody or functional fragment thereof binds to human IL- 1β with a dissociation constant of about 100 pM or less. In some embodiments of any of the uses described above, the IL-Ιβ binding antibody or functional fragment thereof binds to human IL- 1β with a dissociation constant of about 5 pM or less. In some embodiments, the IL-Ιβ binding antibody or functional fragment thereof binds to human IL- 1β with a dissociation constant of about 1 pM or less. In some embodiments, the IL- 1β binding antibody or functional fragment thereof binds to human IL- 1β with dissociation constant of about 0.3 pM or less. In some embodiments of any of the uses described above, the IL-Ιβ binding antibody or fragment thereof is a neutralizing antibody. The canakinumab heavy chain variable region (VH) is set forth as SEQ ID NO: l of the sequence listing. CDRl 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. The canakinumab light chain variable region (VL) is set forth as SEQ ID NO:2 of the sequence listing. CDRl 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. In some embodiments of any of the uses described above, the IL-Ιβ 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.

In some embodiments, the disclosed uses, said IL-Ιβ 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-Ιβ 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. In some embodiments, the disclosed uses comprise administering an anti-IL-Ιβ binding antibody having the three CDRs of SEQ ID NO: l and the three CDRs of SEQ ID NO:2. In further embodiments, the three CDRs of SEQ ID NO: l 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.

In some embodiments of any of the use described above, said IL-Ιβ binding antibody or functional fragment thereof is to be administered subcutaneously or intravenously.

When administered subcutaneously, canakinumab can be administered in a reconstituted formulation comprising: 50-150 mg/ml canakinumab, sucrose, histidine and polysorbate 80, wherein the pH of the formulation is 6.2-6.8, preferably 6.5. When administered subcutaneously, canakinumab can be administered in a liquid formulation comprising: 50-150 mg/ml, canakinumab, mannitol, histidine and polysorbate 80 (or polysorbate 20), wherein the pH of the formulation is 6.2-6.8, preferably 6.5 or 50-150 mg/ml, canakinumab, 270 mM mannitol, 20 mM histidine and 0.04% polysorbate 80 (or polysorbate 20), wherein the pH of the formulation is 6.2-6.8, preferably 6.5.

When administered subcutaneously, canakinumab or any of said IL-Ιβ binding antibody or functional fragment thereof can be administered to the patient in a liquid form or lyophilized form for reconstitution. Preferably such liquid formulation is contained in a prefilled syringe that can be stored for at least 2 years. In one embodiment said prefilled syringe can be contained in an autoinjector. Such autoinjector makes it possible for the patient to selfadminister the liquid formulation subcutanously in an easy manner. 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. In other aspects, said patient is concomitantly recieving beta-adrenergic blocking drugs such as esmolol, metoprolol, nadolol, penbutolol; and/or an angiotensin-converting enzyme (ACE) inhibitor such as ramipril, ramiprilat, captopril, lisinopril; and/or an angiotensin II receptor blocker such as losartan, valsartan, olmesartan, irbesartan, candesartan, telmisartan, eprosartan; and/or an inhibitor of platelet aggregation such clopidogrel, prasugrel, cangrelor, ticagrelor, ticlopidine, dipyridamole, picodamide eptifibatide, abciximab, eptifibatide, tirofiban or terutroban.

In another aspect the present invention provides a pharmaceutical composition comprising 25 mg to about 300 mg of an IL-Ιβ binding antibody or functional fragment thereof for use as a medicament for treating or alleviating the symptoms of AAA in a subject. Preferably, said IL- 1β binding antibody is canakinumab. In some aspects, said composition comprise about 25, 50, 75, 80, 100, 125, 150, 175, 200, 225, 250, 275, 300 mg of the IL-Ιβ binding antibody or functional fragment thereof. Said composition comprise about 50 mg, about 75 mg, about 80 mg, 150 mg, about 200 mg or about 300 mg of the IL-Ιβ binding antibody or functional fragment thereof. Preferably, said composition comprises about 100-150 mg of canakinumab or a functional fragment thereof.

When administered subcutaneously, canakinumab can be administered in a liquid formulation comprising: 50-150 mg/ml canakinumab, mannitol, histidine and polysorbate 80 (or polysorbate 20),wherein the pH of the formulation is 6.2-6.8, preferably 6.5 or 50-150 mg/ml of canakinumab, 270 mM mannitol, 20 mM histidine and 0.04% polysorbate 80 (or polysorbate 20), wherein the pH of the formulation is 6.2-6.8, preferably 6.5. When administered subcutaneously, canakinumab or any of said IL-Ιβ binding antibody or functional fragment thereof can be administered to the patient in a liquid form or lyophilized form for reconstitution. Preferably such liquid formulation is contained in a prefilled syringe that can be stored for at least 2 years. In one embodiment said prefilled syringe can be contained in an autoinjector. Such autoinjector makes it possible for the patient to selfadminister the liquid formulation subcutanously in an easy manner. General:

All patents, published patent applications, publications, references and other material referred to herein are incorporated by reference herein in their entirety.

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.

As used herein, the term "administering" in relation to a compound, e.g., an IL-Ιβ binding antibody or standard of care agent, is used to refer to delivery of that compound by any route of delivery.

As used herein, the term "about" in relation to a numerical value x means, for example, +/- 10%. 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 invention.

By "IL-ip binding antibody" is meant any antibody capable of binding to the IL-Ιβ 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-Ιβ 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-Ιβ binding antibodies used in the methods of the invention to IL-Ιβ may be shown in a competitive binding assay.

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 VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CHI, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL 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 VH and VL 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 (Clq) of the classical complement system.

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-Ιβ). 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 VL, VH, CL and CHI 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 VH and CHI domains; a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a dAb fragment (Ward et al, 1989), which consists of a VH 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, VL and VH, 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 VL and VH 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. 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.

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 invention 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. As used herein, the term "KD", as used herein, is intended to refer to the dissociation constant, which is obtained from the ratio of K_d to K_a (i.e. K,j/K_a) and is expressed as a molar concentration (M). K_D values for antibodies can be determined using methods well established in the art. A method for determining the K_D of an antibody is by using surface plasmon resonance, or using a biosensor system such as a Biacore® system.

As used herein, the term "patient" and "subject" includes any human or nonhuman animal and can be used interchangeably. 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.

As used herein, an antibody that "inhibits" one or more of these IL-Ιβ 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-Ιβ 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 invention may inhibit greater than 95%, 98% or 99% of IL-Ιβ functional activity.

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

A randomized, double-blind, placebo controlled multiple dose study of subcutaneous ACZ885 for the treatment of abdominal aortic aneurysm

This study will be performed in patients with known AAA of screening diameter 40-50mm

(men) and 38-48mm (women). This study will examine the ability of ACZ885 (canakinumab; anti-IL-Ιβ antibody) to slow or halt growth of AAAs as measured at screening, after 6 months and 12 months of treatment using abdominal ultrasound imaging. The proposed primary trial endpoint is reduction in AAA growth rate, assessed after 12 months of treatment.

Approximately 100 subjects will be enrolled in this clinical trial to ensure approximately 80 completed subjects.

This is a non-confirmatory, double-blind, randomized, placebo-controlled, two-arm parallel group study in subjects who have been diagnosed with AAA. Men and women with AAA size within the required inclusion criteria will be enrolled. AAA size is a predictive measure of AAA rupture risk. The diameter based inclusion criteria selected for this study balance factors important for trial execution: including subjects with AAAs that can safely benefit from medical intervention with the study drug, including a surveillance interval that meets or exceeds current guidelines, and ensuring that the AAAs in the study will demonstrate measurable growth rate within the duration of the trial. Within this population, subjects will additionally be selected based on smoking (included but not required) and diabetic status (excluded) in order to enrich the study for individuals with a more rapid AAA growth rate and who have higher potential for benefit from ACZ885 treatment. Active smoking has been associated with increased AAA growth rate, and diabetes has been associated with reduced growth rate.

Repeated serial safety measurements will be obtained to safeguard subjects in the study. These assessments include monitoring cardiovascular status using laboratory tests related to cardiovascular health, functional measures including blood pressure, and periodic imaging assessments of AAA size to ensure that unexpected changes in the aneurysm are detected in a timely manner and appropriate action taken. Blinded data on AAA maximum diameter as determined by the core imaging lab will be provided to the investigators after the 7-month and 13-month ultrasound assessments to assist in safety evaluation for enrolled subjects. The overall frequency for imaging assessment is every 3 months, which exceeds the standard surveillance frequencies currently accepted for AAA monitoring.

Eligible subjects will receive 12 monthly doses of 150mg of ACZ885 or placebo administered subcutaneously as randomized in a 1 : 1 ratio (approximately 50 subjects per arm). Following the first dose, subsequent doses will be administered each calendar month, relative to the date of the initial dose. The study will consist of an up to 30-day screening period, a 12-month treatment period, and an End of Study evaluation approximately 1 month after the last study drug administration. In addition, a 3-month follow-up period is included after the last study treatment for those subjects who test positive for immunogenicity to ACZ885.

During the screening period, ultrasonography of the abdominal aorta will be performed per imaging manual specifications to qualify subjects based on maximum abdominal aortic diameter as interpreted by the imaging core lab. Subjects will be assigned to one of the two treatment arms (monthly doses of 150 mg ACZ885 s.c. or monthly doses of placebo to match 150 mg ACZ885 s.c.) in a ratio of 1 : 1. At specific timepoints, additional assessments will be obtained to address pharmacokinetics, pharmacodynamics and safety. Subjects will then undergo End of Study (EOS) evaluations approximately 30 days after their last dose.

An ultrasound of the abdominal aorta will be obtained at Screening, and after 3, 6, 9 and 12 months of treatment (pre-dose, month 7 and month 13 (EOS) visit). Additionally, a CT scan of the abdominal aorta with IV contrast will be obtained at Screening, and after 6 and 12 months of treatment. In the USA, CT angiography (CTA) is the clinical gold standard to support interventional decision making for the AAA size range of subjects included in this trial and is readily available at all clinical sites that manage AAA. The EU clinical approach is to routinely utilize ultrasound imaging throughout all stages of disease. CTA availability is limited to only a few centers and this, coupled with other challenges, makes it difficult for multiple CTA assessments at EU sites.

This design will allow for the assessment of both potential acute and chronic effects of ACZ885 on AAA size and growth rate in these subjects, as well as allow for an expeditious assessment of any safety concerns.

Study design

L= CT Scan (US sites only) ^: Ultrasound

Dosing *30 days post last dose

"Additional sample may be collected 90 days post last dose

for immunogenicity positive subjects only

Inclusion criteria

1. Male and female subjects age >45 years of age

2. Infrarenal abdominal aortic aneurysm with maximum diameter:

• for men >40mm and <50mm • for women >38mm and <48mm

The maximum diameter must be determined from ultrasound images obtained according to imaging manual specifications and interpreted by the imaging core lab.

4. On a stable medical regimen for at least 2 weeks prior to dosing, per investigator assessment.

5. Have an evaluable ultrasound image at screening for the quantitative determination of the AAA size, per imaging core lab assessment.

6. At screening and pre-dose on Day 1, 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 three minutes. Sitting vital signs should be within the following ranges:

oral body temperature between 35.0-37.5°C

systolic blood pressure, 90-170 mm Hg

diastolic blood pressure, 50-100 mm Hg

pulse rate, 40 - 100 bpm

Treatment arms

Subjects will be assigned to one of the following two treatment arms in a ratio of 1 : 1.

Study treatments are defined as:

• monthly doses of 150 mg ACZ885 s.c.

• monthly doses of placebo to match 150 mg ACZ885 s.c.

Subjects will be maintained on their pre-existing stable medical regimen for treatment of preexisting medical conditions including hypertension. Subjects may already be on medications for hypertension and hyperlipidemia (e.g., ACE inhibitors and statins). These concomitant medications are allowed. Blood pressure optimization should be addressed by the subject's pre-existing medical team and verified by the Investigator. Subjects with SBP greater than 140 but less than 170 mm Hg or DBP greater than 90 but less than 100 mm Hg may be enrolled and treated in the study, but are required to be referred back to their primary care physician for further optimization of blood pressure management. This referral should be documented in the case source documents. Changes in medical regimen that are considered medically necessary will be allowed during the study, but should be monitored by the subject's medical team and the Investigator to ensure subject adherence and compliance with standard of care safety parameters. Common concomitant medications in this study population are anticipated to include aspirin, statins, beta-blockers, ACE inhibitors and/or ARBs, calcium channel blockers, and nitrates. Clopidogrel may be used in these subjects if they are aspirin-intolerant or have had a prior myocardial infarction, but is not a first-line medication for AAA subjects, nor is it recommended to add clopidogrel to aspirin in these subjects in the absence of other compelling clinical indications, e.g., post-myocardial infarction.

Abdominal Aortic Ultrasound

Five abdominal aortic ultrasounds will be obtained over the course of this study at Screening, 4, 7, 10, and 13 months. AAA is diagnosed when the diameter is 30 mm or more, and subjects are typically followed with ultrasound measurements with respect to changes in maximum diameter. In clinical practice risk assessment and the decision for surgical intervention is mainly driven by the diameter measurement. The AAA diameter as well as the growth rate serves as criterion for surgery. The growth rate is the determinant for when the critical diameter threshold will be reached and therefore represents a relevant primary efficacy endpoint. The ultrasound operator will perform the measurement of the maximum aortic diameter by assessment of the leading edge at the adventitia anterior wall to leading edge media/adventitia posterior wall. The image in cross section is selected that represents the maximum diameter of the aorta acquired during systole and at right angles to the direction of the aorta/AAA. A detailed imaging acquisition guideline and training will be provided to all clinical trial sites. A central laboratory will be dedicated for blinded quantitative image analysis.

Contrast-Enhanced CT Angiography

Three CTA's will be acquired over the course of the study at Screening, 7 and 13 months. A detailed imaging acquisition guideline will be provided to all clinical trial sites. In summary, a prospective CT protocol utilizing electrocardiography-gating will be applied in subjects with a heart rate less than 75 beats/min. Retrospective gating is applied in subjects with heart rate greater than 75 beats/min or a significant arrhythmia. Typically, 70-100 mis of iodinated contrast (e.g., Visipaque) are utilized for the CT aortogram. Breath-hold times range from 20 to 25 s with automatic triggering initiated when the contrast in the aorta crosses a certain threshold. Aortic images are the reconstructed using the best diastolic phase images to allow assessment of aortic root dimensions. Mediastinal and abdominal images are reconstructed at 2 to 2.2 mm thickness every 1 mm. An imaging CRO will provide detailed scanning parameters for each type of CT platform and collect and process all data for the quantitative assessment of aortic aneurysm dimensions. The baseline and end of study (13-month) CT angiogram visit must occur within +/- 5 days of the target date. A CT angiogram visit for the baseline or 13-month CT angiogram outside this window will be considered a protocol deviation. The 7-month CT angiogram visit should occur within +/- 14 days of the target date. A CT angiogram visit for the 7-month CT angiogram outside this window or not completed will not be considered a protocol deviation, and subjects will be allowed to continue in the study.

Anova analysis

A repeated measures analysis of variance (ANOVA) will be performed for AAA size measured by ultrasound at each visit (Screening, Month 7, Month 13). The model will include effects for treatment, visit, and treatment by visit interaction. An unstructured variance- covariance structure will be used to account for correlation among multiple measurements from the same subject and variance heterogeneity. Point estimates, the associated confidence intervals as well as the p-values for treatment differences in the AAA growth rate will be provided within the repeated measures ANOVA framework. The null hypothesis of no treatment difference in AAA growth rate will be tested at the two-sided 0.05 significance level. A treatment difference of at least 40% in favor of ACZ will be considered clinically significant.

Volumetric and biophysical profiling data from CT scan of AAA, as well as hs-CRP, IL-6, total IL-Ιβ and immunoglobulins, will be analyzed using the same method as described above. Log-transformation for variables such as hs-CRP may be employed prior to the analysis.

Example 2

An ongoing clinical study designed according to Example 1 was initiated in December 2013. Preliminary results from an interim analysis of the this study (ACZ885X2201) suggest a reduction in AAA growth rate after 3 and 6 months of treatment (150 mg monthly s.c. dosing) with ACZ885. Embodiments:

1. Method of treating or alleviating the symptoms of abdominal aortic aneurysm (AAA) in a subject, comprising administering about 25 mg to about 300 mg of an IL-Ιβ binding antibody or functional fragment thereof, and wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >30 mm and <60 mm before treatment.

2. The method according to embodiment 1, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >30 mm and <55 mm before treatment.

3. The method according to embodiment 1 or 2, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >33 mm and <52 mm before treatment.

4. The method according to any of the preceding embodiments, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >35 mm and <50 mm before treatment.

5. The method according to any of the preceding embodiments, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >35 mm and <45 mm before treatment.

6. The method according to any of the preceding embodiments, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >38 mm and <46 mm before treatment before treatment.

7. The method according to any of the preceding embodiments, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >32 mm and <43 mm before treatment.

8. The method according to any of the preceding embodiments, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >40 mm and <50 mm for men and >38mm and <48mm for women before treatment.

9. The method according to to any of the preceding embodiments, wherein the subject is >40 years of age.

10. The method according to to any of the preceding embodiments, wherein the subject is >45 years of age.

11. The method according to any of the preceeding embodiments, wherein said maximum diameter is measured by means of ultrasound imaging.

12. The method according to any of the preceeding embodiments, wherein the growth of the aneurysm has retarded or stopped after 3 months of treatment. 13. The method according to any of the preceeding embodiments, wherein the growth of the aneurysm has retarded or stopped after 6 months of treatment.

14. The method according to any of the preceeding embodiments, wherein the growth of the aneurysm has retarded or stopped after 9 months of treatment.

15. The method according to any of the preceeding embodiments, wherein the growth of the aneurysm has retarded or stopped after 12 months of treatment.

16. The method according to any of the preceeding embodiments, wherein said IL-Ιβ 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.

17. The method according to any of the preceeding embodiments, wherein said IL-Ιβ binding antibody or functional fragment thereof is administered monthly.

18. The method according to any of the preceeding embodiments, wherein 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-Ιβ binding antibody or functional fragment thereof.

19. The method according to any of the preceeding embodiments, wherein said method comprises administering about 50 mg of the IL-Ιβ binding antibody or functional fragment thereof .

20. The method according to any of the preceeding embodiments, wherein said method comprises administering about 80 mg of the IL-Ιβ binding antibody or functional fragment thereof .

21. The method according to any of the preceeding embodiments, wherein said method comprises administering about 100 mg of the IL-Ιβ binding antibody or functional fragment thereof .

22. The method according to any of the preceeding embodiments, wherein said method comprises: administering about 150 mg of the IL-Ιβ binding antibody or functional fragment thereof.

23. The method according to any of the preceeding embodiments, wherein said method comprises: administering about 200 mg of the IL-Ιβ binding antibody or functional fragment thereof.

24. The method according to any of the preceeding embodiments, wherein said method comprises: administering about 300 mg of the IL-Ιβ binding antibody or functional fragment thereof. 25. The method according to any of the preceeding embodiments, further comprising, administering the patient an additional dose of about 25 mg to about 300 mg of the IL-Ιβ binding antibody or functional fragment thereof at week 2, week 4 or week 6 from the first administration.

26. The method according to embodiment 22, further comprising, wherein the additional dose is about 25 mg, 50 mg, about 80 mg, about 100 mg or about 150 mg of the IL-Ιβ binding antibody or functional fragment thereof.

27. The method according to any of the preceeding embodiments, wherein said IL-Ιβ binding antibody or functional fragment thereof is an IL-Ιβ binding antibody.

28. The method according to any of the preceeding embodiments, wherein said IL-Ιβ binding antibody is selected from the group consisting of:

a) an IL-Ιβ binding antibody directed to an antigenic epitope of human IL-Ιβ which includes the loop comprising the Glu64 residue of the mature IL-Ιβ, wherein said IL-Ιβ binding antibody is capable of inhibiting the binding of IL-Ιβ to its receptor, and further wherein said IL-Ιβ binding antibody has a K_D for binding to IL-Ιβ of about 50 pM or less; b) an IL-Ιβ binding antibody that competes with the binding of an IL-Ιβ binding antibody comprising a VH domain comprising SEQ ID NO: 1 and a VL domain comprising SEQ ID NO:2;

29. The method according to any of the preceeding embodiments, wherein said IL-Ιβ binding antibody is canakinumab.

30. The method according to embodiment 27, wherein said IL-Ιβ binding antibody or functional fragment thereof is selected from the group consisting of gevokizumab, LY- 2189102 or AMG-108. 31. The method according to any of the preceeding embodiments, wherein said IL-Ιβ binding antibody or functional fragment thereof is administered subcutaneously.

32. The method according to embodiment 29 or 31, wherein canakinumab is administered in a liquid formulation comprising: 50-200 mg/ml canakinumab, mannitol, histidine and polysorbate 80, wherein the pH of the formulation is 6.2-6.8.

33. The method according to any of the preceding embodiments, wherein said patient is concomitantly receiving a statin and /or aspirin; and /or beta-adrenergic blocking drugs and/or an angiotensin-converting enzyme (ACE) inhibitor; and/or an angiotensin II receptor blocker; and/or an inhibitor of platelet aggregation such clopidogrel, prasugrel or ticagrelor.

34. An IL-Ιβ binding antibody or a functional fragment thereof for use as a medicament for treating or alleviating the symptoms of abdominal aortic aneurysm (AAA) in a subject, wherein about 25 mg to about 300 mg of an IL-Ιβ binding antibody or functional fragment thereof is administered, and wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >30 mm and <60 mm before treatment.

35. Use of an IL-Ιβ binding antibody or a functional fragment thereof for the manufacture of a medicament for treating or alleviating the symptoms of abdominal aortic aneurysm (AAA) in a subject, wherein about 25 mg to about 300 mg of an IL-Ιβ binding antibody or functional fragment thereof is administered, and wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >30 mm and <60 mm before treatment.

36. Use according to embodiment 34 or 35, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >30 mm and <55 mm before treatment.

37. Use according to embodiment 34 or 35, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >33 mm and <52 mm before treatment.

38. Use according to embodiment 34 or 35, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >35 mm and <50 mm before treatment.

39. Use according to embodiment 34 or 35, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >35 mm and <45 mm before treatment.

40. Use according to embodiment 34 or 35, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >38 mm and <46 mm before treatment before treatment.

41. Use according to embodiment 34 or 35, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >32 mm and <43 mm before treatment. 42. Use according to embodiment 34 or 35, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >40mm and <50mm for men and >38mm and <48mm for women before treatment.

43. Use according to to any of the embodiments 34-42, wherein the subject is >40 years of age.

44. The method according to to any of the embodiments 34-42, wherein the subject is >45 years of age.

45. Use according to any of the embodiments 34-44, wherein said maximum diameter is measured by means of ultrasound imaging.

46. Use according to any of the embodiments 34-45, wherein the growth of the aneurysm has retarded or stopped after 3 months of treatment.

47. Use according to any of the embodiments 34-45, wherein the growth of the aneurysm has retarded or stopped after 6 months of treatment.

48. Use according to any of the embodiments 34-45, wherein the growth of the aneurysm has retarded or stopped after 9 months of treatment.

49. Use according to any of the embodiments 34-45, wherein the growth of the aneurysm has retarded or stopped after 12 months of treatment.

50. Use according to any of the embodiments 34-49, wherein said IL-Ιβ 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.

51. Use according to any of the embodiments 34-49, wherein said IL-Ιβ binding antibody or functional fragment thereof is administered monthly.

52. Use according to any of the embodiments 34-49, wherein 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-Ιβ binding antibody or functional fragment thereof.

53. Use according to any of the embodiments 34-52, wherein said method comprises administering about 50 mg of the IL-Ιβ binding antibody or functional fragment thereof .

54. Use according to any of the embodiments 34-52, wherein said method comprises administering about 80 mg of the IL-Ιβ binding antibody or functional fragment thereof .

55. Use according to any of the embodiments 34-52, wherein said method comprises administering about 100 mg of the IL-Ιβ binding antibody or functional fragment thereof . 56. Use according to any of the embodiments 34-52, wherein said method comprises: administering about 150 mg of the IL-Ιβ binding antibody or functional fragment thereof.

57. Use according to any of the embodiments 34-52, wherein said method comprises: administering about 200 mg of the IL-Ιβ binding antibody or functional fragment thereof. 58. Use according to any of the embodiments 34-52, wherein said method comprises: administering about 300 mg of the IL-Ιβ binding antibody or functional fragment thereof. 59. Use according to any of the embodiments 34-58, further comprising, administering the patient an additional dose of about 25 mg to about 300 mg of the IL-Ιβ binding antibody or functional fragment thereof at week 2, week 4 or week 6 from the first administration.

60. Use according to embodiments 59, further comprising, wherein the additional dose is about 25 mg, about 50 mg, about 80 mg, about 100 mg or about 150 mg of the IL-Ιβ binding antibody or functional fragment thereof.

61. Use according to any of the embodiments 34-60, wherein said IL-Ιβ binding antibody or functional fragment thereof is an human IL-Ιβ binding antibody.

62. Use according to any of the embodiments 34-61, wherein said IL-Ιβ binding antibody is selected from the group consisting of:

a) an IL-Ιβ binding antibody directed ton antigenic epitope of human IL-Ιβ which includes the loop comprising the Glu64 residue of the mature IL-Ιβ, wherein said IL-Ιβ binding antibody is capable of inhibiting the binding of IL-Ιβ to its receptor, and further wherein said IL-Ιβ binding antibody has a K_D for binding to IL-Ιβ of about 50 pM or less; b) an IL-Ιβ binding antibody that competes with the binding of an IL-Ιβ binding antibody comprising a VH domain comprising SEQ ID NO: 1 and a VL domain comprising SEQ ID NO:2;

e) an anti-IL-Ιβ 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; f) an anti-IL-Ιβ binding antibody comprising a VH domain comprising SEQ ID NO: 1; g) an anti-IL-Ιβ binding antibody comprising a VL domain comprising SEQ ID NO: 2; h) an anti-IL-Ιβ binding antibody comprising a VH domain comprising SEQ ID NO: 1 and a VL domain comprising SEQ ID NO:2. 63. Use according to any of the embodiments 34-62, wherein said IL-Ιβ binding antibody is canakinumab.

64. Use according to embodiment 63, wherein said IL-Ιβ binding antibody or functional fragment thereof is selected from the group consisting of gevokizumab, LY-2189102 or AMG-108.

65. Use according to any of the embodiments 34-64, wherein said IL-Ιβ binding antibody or functional fragment thereof is administered subcutaneously.

66. Use according to embodiment 65, wherein canakinumab is administered as a liquid formulation comprising: 50-200 mg/ml canakinumab, mannitol, histidine and polysorbate 80, wherein the pH of the formulation is 6.2-6.8.

67. Use according to any of the embodiments 34-66, wherein said patient is concomitantly receiving a statin and /or aspirin; and /or beta-adrenergic blocking drugs and/or an angiotensin-converting enzyme (ACE) inhibitor; and/or an angiotensin II receptor blocker; and/or an inhibitor of platelet aggregation such clopidogrel, prasugrel or ticagrelor.

SEQUENCE LISTING

<110> Novartis AG

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<170> Patentln version 3.5

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Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Val Tyr

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Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala lie lie Trp Tyr Asp Gly Asp Asn Gin Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

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Ala Arg Asp Leu Arg Thr Gly Pro Phe Asp Tyr Trp Gly Gin Gly Thr

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Leu His Trp Tyr Gin Gin Lys Pro Asp Gin Ser Pro Lys Leu Leu He

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Lys Tyr Ala Ser Gin Ser Phe Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Asn Ser Leu Glu Ala 65 70 75 80

Glu Asp Ala Ala Ala Tyr Tyr Cys His Gin Ser Ser Ser Leu Pro Phe

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Claims

2. The method according to claim 1, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >30 mm and <55 mm before treatment.

3. The method according to claim 1 or 2, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >33 mm and <52 mm before treatment.

4. The method according to any of the preceding claims, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >35 mm and <50 mm before treatment.

5. The method according to any of the preceding claims, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >35 mm and <45 mm before treatment.

6. The method according to any of the preceding claims, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >38 mm and <46 mm before treatment before treatment.

7. The method according to any of the preceding claims, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >32 mm and <43 mm before treatment.

8. The method according to any of the preceding claims, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >40 mm and <50 mm for men and >38 mm and <48 mm for women before treatment.

9. The method according to to any of the preceding claims, wherein the subject is >40 years of age.

10. The method according to to any of the preceding claims, wherein the subject is >45 years of age.

11. The method according to any of the preceeding claims, wherein said maximum diameter is measured by means of ultrasound imaging.

12. The method according to any of the preceeding claims, wherein the growth of the aneurysm has retarded or stopped after 3 months of treatment.

13. The method according to any of the preceeding claims, wherein the growth of the aneurysm has retarded or stopped after 6 months of treatment.

14. The method according to any of the preceeding claims, wherein the growth of the aneurysm has retarded or stopped after 9 months of treatment.

15. The method according to any of the preceeding claims, wherein the growth of the aneurysm has retarded or stopped after 12 months of treatment.

16. The method according to any of the preceeding claims, wherein said IL-Ιβ 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.

17. The method according to any of the preceeding claims, wherein said IL-Ιβ binding antibody or functional fragment thereof is administered monthly.

18. The method according to any of the preceeding claims, wherein 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-Ιβ binding antibody or functional fragment thereof.

19. The method according to any of the preceeding claims, wherein said method comprises administering about 50 mg of the IL-Ιβ binding antibody or functional fragment thereof.

20. The method according to any of the preceeding claims, wherein said method comprises administering about 80 mg of the IL-Ιβ binding antibody or functional fragment thereof.

21. The method according to any of the preceeding claims, wherein said method comprises administering about 100 mg of the IL-Ιβ binding antibody or functional fragment thereof.

22. The method according to any of the preceeding claims, wherein said method comprises: administering about 150 mg of the IL-Ιβ binding antibody or functional fragment thereof.

23. The method according to any of the preceeding claims, wherein said method comprises: administering about 200 mg of the IL-Ιβ binding antibody or functional fragment thereof.

24. The method according to any of the preceeding claims, wherein said method comprises: administering about 300 mg of the IL-Ιβ binding antibody or functional fragment thereof.

25. The method according to any of the preceeding claims, further comprising, administering the patient an additional dose of about 25 mg to about 300 mg of the IL-Ιβ binding antibody or functional fragment thereof at week 2, week 4, or week 6 from the first administration.

26. The method according to claim 25, wherein the additional dose is about 25 mg, 50 mg, about 75 mg, about 80 mg, about 100 mg, or about 150 mg of the IL-Ιβ binding antibody or functional fragment thereof.

27. The method according to any of the preceeding claims, wherein said IL-Ιβ binding antibody or functional fragment thereof is administered subcutaneously.

28. The method according to any of the preceeding claims, wherein said IL-Ιβ binding antibody or functional fragment thereof is selected from the group consisting of canakinumab, gevokizumab, LY-2189102 or AMG-108.

29. The method according to claim 28, wherein said IL-Ιβ binding antibody or functional fragment thereof is canakinumab.

30. The method according to claim 29, wherein canakinumab is administered in a liquid formulation comprising: 50-200 mg/ml canakinumab, mannitol, histidine and polysorbate 80, wherein the pH of the formulation is 6.2-6.8.

31. The method according to any of the preceding claims, wherein said patient is concomitantly receiving a statin and/or aspirin; and/or beta-adrenergic blocking drugs and/or an angiotensin-converting enzyme (ACE) inhibitor; and/or an angiotensin II receptor blocker; and/or an inhibitor of platelet aggregation such clopidogrel, prasugrel or ticagrelor.

32. An IL-Ιβ binding antibody or a functional fragment thereof for use as a medicament for treating or alleviating the symptoms of abdominal aortic aneurysm (AAA) in a subject, wherein about 25 mg to about 300 mg of an IL-Ιβ binding antibody or functional fragment thereof is administered, and wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >30 mm and <60 mm before treatment.

33. Use of an IL-Ιβ binding antibody or a functional fragment thereof for the manufacture of a medicament for treating or alleviating the symptoms of abdominal aortic aneurysm (AAA) in a subject, wherein about 25 mg to about 300 mg of an IL-Ιβ binding antibody or functional fragment thereof is administered, and wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >30 mm and <60 mm before treatment.

34. Use according to claim 32 or 33, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >30 mm and <55 mm before treatment.

35. Use according to claim 32 or 33, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >33 mm and <52 mm before treatment.

36. Use according to claim 32 or 33, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >35 mm and <50 mm before treatment.

37. Use according to claim 32 or 33, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >35 mm and <45 mm before treatment.

38. Use according to claim 32 or 33, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >38 mm and <46 mm before treatment before treatment.

39. Use according to claim 32 or 33, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >32 mm and <43 mm before treatment.

40. Use according to claim 32 or 33, wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >40 mm and <50 mm for men and >38 mm and <48 mm for women before treatment.

41. Use according to to any of the claims 32-40, wherein the subject is >40 years of age.

42. The method according to to any of the claims 32-40, wherein the subject is >45 years of age.

43. Use according to any of the claims 32-42, wherein said maximum diameter is measured by means of ultrasound imaging.

44. Use according to any of the claims 32-43, wherein the growth of the aneurysm has retarded or stopped after 3 months of treatment.

45. Use according to any of the claims 32-43, wherein the growth of the aneurysm has retarded or stopped after 6 months of treatment.

46. Use according to any of the claims 32-43, wherein the growth of the aneurysm has retarded or stopped after 9 months of treatment.

47. Use according to any of the claims 32-43, wherein the growth of the aneurysm has retarded or stopped after 12 months of treatment.

48. Use according to any of the claims 32-47, wherein said IL-Ιβ 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.

49. Use according to any of the claims 32-48, wherein said IL-Ιβ binding antibody or functional fragment thereof is administered monthly.

50. Use according to any of the claims 32-49, wherein 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-Ιβ binding antibody or functional fragment thereof.

51. Use according to any of the claims 32-49, wherein said method comprises administering about 50 mg of the IL-Ιβ binding antibody or functional fragment thereof.

52. Use according to any of the claims 32-49, wherein said method comprises administering about 80 mg of the IL-Ιβ binding antibody or functional fragment thereof.

53. Use according to any of the claims 32-49, wherein said method comprises administering about 100 mg of the IL-Ιβ binding antibody or functional fragment thereof.

54. Use according to any of the claims 32-49, wherein said method comprises administering about 150 mg of the IL-Ιβ binding antibody or functional fragment thereof.

55. Use according to any of the claims 32-49, wherein said method comprises administering about 200 mg of the IL-Ιβ binding antibody or functional fragment thereof.

56. Use according to any of the claims 32-49, wherein said method comprises: administering about 300 mg of the IL-Ιβ binding antibody or functional fragment thereof.

57. Use according to any of the claims 32-56, further comprising, administering the patient an additional dose of about 25 mg to about 300 mg of the IL-Ιβ binding antibody or functional fragment thereof at week 2, week 4 or week 6 from the first administration.

58. Use according to claims 57, further comprising, wherein the additional dose is about 25 mg, about 50 mg, about 75 mg, about 80 mg, about 100 mg or about 150 mg of the IL-Ιβ binding antibody or functional fragment thereof.

59. Use according to any of the claims 32-58, wherein said IL-Ιβ binding antibody or functional fragment thereof is selected from the group consisting of canakinumab, gevokizumab, LY-2189102 or AMG-108.

60. Use according to any of the claims 32-59, wherein said IL-Ιβ binding antibody is canakinumab.

61. Use according to any of the claims 32-60, wherein said IL-Ιβ binding antibody or functional fragment thereof is administered subcutaneously.

62. Use according to claim 60 or 61, wherein canakinumab is administered as a liquid formulation comprising: 50-200 mg/ml canakinumab, mannitol, histidine and polysorbate 80, wherein the pH of the formulation is 6.2-6.8.

63. A pharmaceutical composition comprising canakinumab for use as a medicament for treating or alleviating the symptoms of abdominal aortic aneurysm (AAA) in a subject and wherein the subject has infrarenal abdominal aortic aneurysm with maximum diameter of >30 mm and <60 mm before treatment.

64. Composition according to claim 63, wherein said composition is a liquid formulation comprising 50-200 mg/ml canakinumab, mannitol, histidine and polysorbate 80, wherein the pH of the formulation is 6.2-6.8.

65. Composition according to claim 63 or 64, wherein said composition comprise about 80 mg canakinumab/ml.

66. Composition according to claim 63 or 64, wherein said composition comprise about 100 mg canakinumab/ml.

67. Composition according to claim 63 or 64, wherein said composition comprise about 150 mg canakinumab/ml.