Interleukin-1 beta binding antibody

Abstract

An IL-1β binding antibody or functional fragment thereof for use in reducing the risk of having an event of acute pancreatitis in a patient who has had a prior event of acute pancreatitis.

Description

[0001] INTERLEUKIN-1 BETA BINDING ANTIBODY

[0002] The present disclosure relates to IL-1 p binding antibody for use in preventing or reducing risk of having a recurrent pancreatitis event after a patient has already suffered a pancreatitis event, particularly to canakinumab for use in preventing or reducing risk of having a recurrent pancreatitis event after a patient has already suffered a pancreatitis event.

[0003] Pancreatitis is inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types of pancreatitis, acute pancreatitis and chronic pancreatitis. Signs and symptoms of pancreatitis include pain in the upper abdomen, nausea and vomiting. The pain often goes into the back and is usually severe. In acute pancreatitis a fever may occur and symptoms typically resolve in a few days. In chronic pancreatitis weight loss, fatty stool, and diarrhoea may occur. Complications may include infection, bleeding, diabetes mellitus, or problems with other organs. The most common causes of acute pancreatitis are gallstones and heavy alcohol use. A patient who has recovered after a first bout of acute pancreatitis will typically be referred for medical investigation as to its cause. If the patient was a heavy alcohol user he will be encouraged to desist. If alcohol over use is eliminated as a cause, the dominant pathology in recurrent pancreatitis is related to a gallstone having been interfering with the delivery of pancreatic digestive enzymes into the gastrointestinal tract, for which the anatomy of the pancreas is adapted. In order better to describe this pathology some anatomy and physiology of the pancreas will be described.

[0004] The pancreatic enzymes are among others amylase (breaking down carbohydrate), protease (breaking down protein) lipase (breaking down fats) and trypsin. Because these digestive enzymes are so powerful they are normally inactive while they are in the pancreas. To reach the gastrointestinal tract these digestive enzymes travel through the pancreatic ducts and are eventually released into the duodenum. In about 90% of people most of the pancreatic enzymes pass through the Wirsung duct just upstream of the Greater papilla (which is the opening surrounded by the sphincter of Oddi connecting the Wirsung duct with the duodenum of the gastrointestinal tract). Once the pancreatic enzymes are completely out of the pancreas and into the duodenum the enzymes become active. Bile from the gall bladder travels through the pancreas in the bile duct which joins with the Wirsung duct near where the Wirsung duct connects with the duodenum, so that bile and pancreatic enzymes travel in a common duct downstream of where the bile duct joins the Wirsung duct and just upstream of the opening of Greater papilla where the common bile / pancreatic duct joins the duodenum. The pathology of pancreatitis involves the pancreatic enzymes becoming active before they exit the pancreas thereby causing trauma to the pancreas and nearby tissues. The pathology of gallstone involved pancreatitis involves gallstones contained within the bile blocking the common bile / pancreatic duct upstream of the opening of Greater papilla thereby causing ductal hypertension which causes the pancreatic enzymes to become active before they leave the pancreas, causing trauma to the pancreas.

[0005] When a patient with a first bout of acute pancreatiis presents to a physician, the physician will treat the symptoms of that acute pancreatitis first. Then that physician will over time eliminate alcohol over use and gallstones as a cause. Each of these causes will be considered eliminated once that patient has given up alcohol, has his / her gall bladder surgically removed, and yet he or she nevertheless continues periodically to suffer recurring bouts of acute pancreatitis. This situation pertains in about 10% of cases, and the underlying cause is difficult to diagnose. Administration of effective amounts of the IL- 1 P binding antibody to those 10% of patients is useful in preventing or reducing the risk of the patient experiencing a further bout of acute pancreatitis after the patient has already recovered from a first bout of acute pancreatitis.

[0006] Interleukins are key mediators in the inflammatory response in inflammatory disease and have been demonstrated in animal models and in humans to be potent modulators of pro- inflammatory processes. Thus, antagonism of the IL-1 p mediated inflammation is a primary and attractive target for ameliorating pancreatic inflammation associated with nonalcohol associated, non-gallstone associated recurring acute pancreatitis.

[0007] WO201 0 / 138939 generally relates to a method of treating cardiovascular disorders with an IL-13 antibody.

[0008] Canakinumab is a known commercially available IL-13 binding antibody. It has a web page in Wikipedia. Its web page in Wikipedia discloses that canakinumab is a whole monoclonal antibody targeting IL-13 and sourced from humans. There is a ribbon diagram of canakinumab (blue) shown bound to IL-13 (yellow). It is further disclosed in Wikipedia that canakinumab is sold under the brand name Haris and that it is a medication for the treatment of systemic juvenile idiopathic arthritis, active Still's disease and gout flares among other conditions. It is disclosed as having no cross reactivity with other members of the interleukin - 1 family including interleukin -1 alpha. Other names for canakinumab are ACZ885 and ACZ - 885. There is a photograph of the packaging of a dosage form of Haris available through the Wikipedia site (click on 'canakinumab' beside the paragraph dealing with License data on the web page). The packaging of this dosage form states (on its side) 'llaris (canakinumab) injection 150mg / ml - For Subcutaneous Use - Rx'. The packaging of this dosage form states (on its front) inter alia 'Please see package insert for dosage and administration....Vial contains canakinumab 150mg... inactive ingredients...L histidine 2.1 mg, L - histidine hydrochloride monohydrate 1.3mg, Mannitol 49.2mg, Polysorbate 80 0.4mg, sterile water for injection ad 1 mL. For more information visit www.llaris.com.'. There is an extensive entry for canakinumab on the National Library of Medicine (DailyMed) website. Information is given under the following headings: Indications and Usage (specifically mentioning periodic fever syndromes, Still's disease, systemic juvenile idiopathic arthritis and gout flares; Dosage and administration - it being stated for example 'the recommended dosage of Haris for adult patients with gout flare is 150mg administered subcutaneously. In patients who require re - treatment there should be an interval of at least 12 weeks before a new dose of llaris may be administered; Dosage Forms and Strengths: Contraindications: Warnings and Precautions: Adverse Reactions - including a big section on clinical trials experience; Drug interactions: Use in specific populations: Overdosage: Clinical pharmacology - including information on mechanism of action where it is stated 'Canakinumab is a human monoclonal anti-human IL-13 antibody of the lgG1 / K isotype. Canakinumab binds to human IL-13 and neutralizes its activity by blocking its interaction with IL-1 receptors, but it does not bind IL-1 a or IL-1 receptor antagonist (IL- 1 ra)' - and further including information on pharmacodynamics, and pharmacokinetics; Non Clinical Toxicology ; Clinical Studies: How supplied / storage and handling: Patient counselling information: and Medication guide.

[0009] A search of the EU clinical trials register displays 84 results for canakinumab. One of these is entitled 'A 2-year open-label second extension study to evaluate the safety, tolerability and efficacy of canakinumab (ACZ885) an anti-interleukin-1 (3 monoclonal antibody in patients with active rheumatoid arthritis'. It has EudraCT number 2008 - 005320 - 81 , its global completion date was 15 June 2009 and its results were published on 16 September 2016. It is a phase 2 clinical study. The primary objective of the extension studies was to assess long-term safety and tolerability of canakinumab (ACZ885) in patients with active rheumatoid arthritis. The secondary objectives of the extension studies were to evaluate the efficacy of canakinumab according to American College of Rheumatology(ACR) criteria; ACR20, ACR50 and ACR70 criteria, DAS28, and ACR components including hsCRP (a marker of inflammation) and the immunogenicity and pharmacokinetic profile of canakinumab were assessed. The study involved 15 subjects.

[0010] Canakinumab is also disclosed in WO02 / 16436. The various granted patents derived from this PCT patent publication are believed to be master patents protecting canakinumab.

[0011] Details of WO02 / 16436 are Applicant: Novartis AG. International filing date: 30 August 2001. Title: ANTIBODIES TO HUMAN IL-1 beta. This PCT publication was amended in the European regional phase - including during Opposition proceedings - and was maintained as amended following these Opposition proceedings. See the EP 1 ,313,769 B2 publication, published on 09.11.2011. This patent publication had a granted GB equivalent which was EP(UK) 1313769. EP(UK) 1313769 became term expired in the UK and not in force in the UK on 19 August 2021. EP(UK) 1313769 is however subject to an SPC which is SPC / GB10 / 002. The product protected by this SPC is a medicinal product containing canakinumab. Pursuant to Art 4 of the SPC regulation, that is Regulation EC # 469 / 2009, protection therefore extends only to a medicinal product containing canakinumab. This SPC has also now expired. Its normal expiry date was 26 October 2024. However on 09 March 2020 a paediatric extension was granted - extending the term of the SPC - with a maximum period expiring on 26 April 2025. Thus in around 4 months canakinumab is going to belong wholly to the public under the patent bargain.

[0012] Canakinumab is further disclosed for example in PCT patent publication WO 2018 / 015897 A1 published 25 / 01 / 2018 entitled 'Use of the IL-1 beta binding antibody canakinumab for treating or all ieviating symptoms of pulmonary sarcoidosis. This corresponds to EP3487584 which was deemed withdrawn with the notice of its withdrawal published on 07.12.2022.

[0013] SUMMARY OF THE DISCLOSURE

[0014] Inflammation contributes to the process of pancreatitis and patients with elevated inflammatory biomarkers such as hsCRP have increased risk of pancreatitis. The present disclosure concerns the administration of IL-1 £ binding antibodies contributing to preventing or reducing the risk of experiencing a recurrent pancreatitis event after a patient has already suffered a pancreatitis event.

[0015] Accordingly, the present disclosure is directed to an IL-1 £ binding antibody or functional fragment thereof for use in reducing the risk of having an event of acute pancreatitis in a patient that has already had a prior event of acute pancreatitis. In a preferred embodiment the said IL-1 p binding antibody or functional fragment thereof is canakinumab.

[0016] Further features and advantages of the disclosure will become apparent from the following detailed description of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 : Balancing the IL-13 system and its contributions to human disease. IL- 1 p=interleukin-l beta; IL-1 R=interleukin-1 receptor; IL-1Ra=interleukin-1 receptor antagonist; CAPS=cryopyrin-associated periodic syndrome; MWS=Muckle-Wells Syndrome; NOMID=neonatal-onset multi-system inflammatory disease.

[0018] FIG. 2: hsCRP lowering by canakinumab in gout patients supports quarterly dosing regimen (study H2251): the figure shows hsCRP lowering by a single canakinumab dose is durable for 3 months (85 days).

[0019] ACZ=ACZ885=canakinumab

[0020] Colch=colchicine

[0021] FIG. 3: Quarterly dosing regimen is supported by study CACZ885A2213 data on patients with T2DM. X axis indicates time in days (d)

[0022] FIG. 4: Phase II study data on hsCRP response supports selection of 15 and 50 mg monthly doses of canakinumab

[0023] Biological activity of canakinumab can be monitored using hsCRP as a surrogate Canakinumab dose selection based on primary analysis data from study 12202 (5 to 150 mg vs. placebo monthly, 16 weeks, N=524):

[0024] Safety (general safety and lipid effects) hsCRP lowering dose response characteristics 15 mg monthly dose of canakinumab was selected as a sub-maximal dose (30% hsCRP lowering and 95% upper CI<0)

[0025] 50 mg monthly dose of canakinumab as maximally efficacious dose (40% hsCRP lowering)

[0026] DETAILED DESCRIPTION OF THE DISCLOSURE

[0027] The present invention provides, inter alia, an IL-1 p binding antibody or functional fragment thereof for preventing or reducing risk of having a recurrent event of acute pancreatitis in a patient that has suffered a first acute event of pancreatitis.

[0028] General discussion

[0029] As disclosed herein the claimed IL-13 binding antibody (preferably canakinumab) its method of preparation and its use as a licensed medicine for treatment of human disease is known. The technical contribution of the subject invention is therefore directed to its new use in reducing the risk of having an event of acute pancreatitis in a patient that has already had a prior event of acute pancreatitis. As such this new use is featured in all the claims of the subject application as a functional technical feature to the effect that the claimed IL-1 p binding antibody or in a more specfic embodiment canakinumab has to work. Consequently the specification ought to disclose the suitability of the claimed IL-13 binding antibody / canakinumab for this therapeutic application. However, the patent system recognises the intrinsic difficulties that this requirement to disclose would place in the way of the patenting of pharmaceuticals if interpreted as requiring evidence of tests in humans or animals, since carrying out these tests before filing a patent application would likely render any subsequent patent invalid. Yet, this did not mean that a simple verbal statement in a patent specification that compound X may be used to treat disease Y is enough to ensure sufficiency of disclosure in relation to a claim to a pharmaceutical. It is required that the patent provides some information to the avail that it is plausible that the compound X may be used to treat disease Y. As a result a focus of the disclosure herein will be to establish that it is indeed plausible that the claimed IL-13 binding antibody (preferably canakinumab) does work in reducing the risk of having an event of acute pancreatitis in a patient that has already had a prior event of acute pancreatitis.

[0030] In is submitted that the skilled addressee to whom this specification is addressed knowing how inflammation works from a molecular biology perspective would immediately appreciate this plausibility just by inspecting Fig 1 herein. Pancreatitis involves inflammation of the pancreas. Fig 1 shows that suppression of IL-1 p is anti inflammatory. An IL-1 p binding antibody suppresses IL-1 p and so it is plausible both that an an IL-1 p binding antibody may be used to treat acute pancreatitis and that an IL-1 p antibody may be used for preventing or reducing the risk of having an event of acute pancreatitis in a patient that has already had a prior event of acute pancreatitis.

[0031] Assuming it is self evident to the skilled reader that it is plausible that an IL-1 p binding antibody may be used to treat acute pancreatitis for the following reasons it also follows that an IL-1 p antibody may be used for preventing or reducing the risk of having an event of acute pancreatitis in a patient that has already had a prior event of acute pancreatitis.

[0032] In this technical issue the biological mechanisms surrounding inflammation pertain. The skilled reader of this specification would know the following about the process of inflammation. Inflammation is a process which can start at the level of an individual cell. The inflammation process can then cascade through a process of inflammation cellular signalling to more widespread inflammation. Inflammasomes are centrally involved in this signalling process and inflammasomes are found inside the cell. Inflammasomes are cytoplasmic multi-protein complexes comprising a sensor or a receptor portion. Inflammasomes can be activated by a variety of stimuli - both internal to the cell - and external to the cell - including inflammatory signalling as a result of IL-1 p. Activated inflammasomes activate various caspases. In their turn caspases result in activation of among other things IL-i p.

[0033] A feed forward signalling cascade of IL-1 p can therefore lead to widespread inflammation including the pancreatitis disease state. This process can be explained on a cellular basis. The starting point is a non specific extracellular or intracellular inflammatory event. Then given a 2 cell system comprising the following components - an initial inflamed cell - with an assembled inflammasome - with the inflammasone resulting in the activation of several caspases - including caspase- 1 ; and caspase - 8 - the inflammatory signal is then cascaded to other cells - through secreted IL-1 p activated by caspase -1 and this would trigger a similar assembly of the inflammasome as discussed above - leading to a feed forward cascade of inflammatory signalling all mediated by IL-1 p - as well as sustaining the inflammatory signal in the original cell - and this explains why reducing the availability of activated IL-1 p with an antibody - makes it plausible to the skilled addressee that an IL-1 p antibody may be used specifically to prevent / reduce the risk of an event of acute pancreatitis.

[0034] Now going back to what was stated above about it being assumed that if it is self evident to the skilled reader that it is plausible that an IL-1 p binding antibody may be used to treat acute pancreatitis it also follows that an IL-1 p antibody may be used for preventing or reducing the risk of having an event of acute pancreatitis in a patient that has already had a prior event of acute pancreatitis the following pertains.

[0035] In this context we understand treat biologically speaking to mean mitigate cellular damage and reduce the severity of inflammation - the signalling events responsible for this in our 2 cell simplified model of the system occur due to the activation of other caspases by the inflammasome - parallel to caspase - 1 activation - from which the skilled addressee would appreciate that if it is admittedly plausible for IL-1 p suppression with a suitable antibody - to treat pancreatitis - it must be accepted as plausible that sustained suppression of IL-1 p by an IL-1 p antibody would reduce the risk or prevent an event of acute pancreatitis.

[0036] Figure 1

[0037] We now refer to Fig 1 herein. We note from the section above entitled 'Brief description of the Drawings' that in Fig 1 IL-1 p=interleukin-l beta; IL-1 R=interleukin-1 receptor; and IL- 1 Ra=interleukin-1 receptor antagonist.

[0038] In light of the above general discussion it can be understood that Fig 1 shows the following. The importance of the interplay between IL-1 p, its receptors and its antagonists in inflammatory disease - of which pancreatitis is one. Also how IL-1 p can be activated as a result of inflammasome assembly - and that we see a disease state when IL-1 p outcompetes the IL - 1 receptor antagonist for the IL - 1 receptor. As the skilled addressee would understand this is known to be the case for many inflammatory diseases e.g. those shown in Fig 1 . It can also be understood that the skilled addressee would appreciate that the title of Fig 1 (see above) of 'Balancing the IL - 1 beta system and its contributions to human disease' encapsulates the importance of IL-1 p in the progression towards a disease state and emphasises why an IL-1 p antibody may be used to reduce the risk of having an event of acute pancreatitis. It is worth mentioning that the therapeutic / commercial value of the IL-1 p antibody drug as claimed herein would be in preventing recurrent attacks of acute pancreatitis - which in themselves pose significant threat but are also known to cause progression towards chronic pancreatitis as a result of pancreatic scarring.

[0039] Figure 2

[0040] Figure 2 shows hsCRP lowering by canakinumab in gout patients supports quarterly dosing regimen and hsCRP lowering by a single canakinumab dose is durable for 3 months (85 days) and references study H2251. A search of the EU clinical trials register shows that the full title of this study is 'A 24-week, dose-ranging, multi-center, double-blind, double-dummy, active-controlled study to evaluate canakinumab (ACZ885) for prophylaxis of signs and symptoms of acute flares in chronic gout patients initiating allopurinol therapy'. Its EudraCT Number is 2008-005876-28. Its Sponsor Protocol Number is CACZ885H2251. A full report is available on clinicaltrials.gov.

[0041] Figure 3

[0042] Figure 3 is entitled Median hsCRP change over time after single canakinumab injection in Type-2 diabetes mellitus (T2DM) patients. It references study CACZ885A2213 and shows a quarterly dosing regimen is supported by study CACZ885A2213 data on patients with T2DM. X axis indicates time in days (d). Figure 4

[0043] Figure 4 is entitled 'Canakinumab hsCRP dose response curve' and references study CACZ88512202. It shows canakinumab dosage in mg on the x axis and on the y axis it shows placebo corrected hsCRP change from baseline to month 4 on a logarithmic scale. It is described above and for ease of reference its description is repeated here. Phase II study data on hsCRP response supports selection of 15 and 50 mg monthly doses of canakinumab

[0044] Biological activity of canakinumab can be monitored using hsCRP as a surrogate Canakinumab dose selection based on primary analysis data from study 12202 (5 to 150 mg vs. placebo monthly, 16 weeks, N=524): Safety (general safety and lipid effects) hsCRP lowering dose response characteristics 15 mg monthly dose of canakinumab was selected as a sub-maximal dose (30% hsCRP lowering and 95% upper CI<0) 50 mg monthly dose of canakinumab as maximally efficacious dose (40% hsCRP lowering).

[0045] As is by now well known canakinumab is a fully human monoclonal anti-human IL-13 antibody of the IgG 1 / k isotype, being developed for the treatment of IL-1 p driven inflammatory diseases. It is designed to bind to human IL-13 and thus blocks the interaction of this cytokine with its receptors. The antagonism of the IL-13 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 canakinumab and with other IL-13 antibody therapies in development.

[0046] Preferably the invention comprises a dosage of about 25 mg to about 300 mg of said IL- 1 binding antibody or functional fragment thereof for said use. More preferably the invention comprises the dosages of canakinumab disclosed above and already well known for commercially available canakinumab (Haris) preferably 150mg every 12 weeks. More preferably a patient receiving said dosage of said antibody or functional fragment thereof has a CRP level of about 1 mg / L before receiving said dosage of said antibody or functional fragment thereof.

[0047] Type-2 diabetes mellitus (T2DM) is a disease that is characterized by a high inflammatory state. Pre-clinical data suggests IL-1 p is of key importance in the progressive functional impairment and destruction of p-cells in type 2 diabetes. Pancreatic p cells secrete IL-1 p in response to elevated glucose exposure promoting further impairment of cellular viability via an autocrine action. IL-1 p antagonism inhibits p cell death, promotes p cell proliferation, potentiates p cell glucose-induced insulin secretion and improves insulin sensitivity. Blocking IL-1 p activity with an IL-1 receptor antagonist as well as a neutralizing IL-1 p with antibody in clinical trials reduced HbAlc (glycated haemoglobin). By measuring HbAlc clinicians are able to get an overall picture of what our average blood sugar levels have been over a period of weeks / months. Neutralization of IL-1 p activity in the pancreatic islets is thus emerging as an attractive target for the treatment and prevention of type 2 diabetes. For T2DM prevention canakinumab's primary direct action is expected to prevent the IL-1 p mediated destruction of pancreatic p-cells and thus prevent or delay progression of disease, which to date is a completely unmet need. The inflammatory biomarker hsCRP is an independent risk factor for a number of autoinflammatory syndromes including future cardiovascular events.

[0048] Canakinumab and other IL-1 beta inhibiting agents, in particular other IL-1 p binding antibodies, will reduce the risk of future occurrence of acute pancreatic events in patients with past acute pancreatic events.

[0049] As mentioned, the present invention provides, inter alia, an IL-1 p binding antibody or functional fragment thereof for preventing or reducing risk of having a recurrent event of pancreatitis in a patient that has suffered a first acute event of pancreatitis. Preferably the invention comprises a dosage of about 25 mg to about 300 mg of said IL-1 p binding antibody or functional fragment thereof for said use. More preferably a patient receiving said dosage of said antibody or functional fragment thereof has a CRP level of ^about 1 mg / L before receiving said dosage of said antibody or functional fragment thereof.

[0050] Preferably, said CRP level is Mahout 2 mg / L. More preferred CRP levels are ^about 1 , about 1.1 , ^about 1.2, ^about 1.3, ^about 1.4. ^about 1.5, ^about 1.6, ^about 1.7, about 1.8, ^about 1.9, Mahout 2.0, ^about 2.1 , ^about 2.2, ^about 2.3, Mahout 2.4, about 2.5, ^about 2.6, ^about 2.7, ^about 2.8. ^about 2.9, ^about 3.0 mg / L.

[0051] In some preferred embodiments said CRP level is 1-3 mg / L, or 1.5-2.5 mg / L, or 1.7-2.3 mg / L or 1 .8-2.2 mg / L or 1 .9-2.1 mg / L.

[0052] In more preferred embodiments, said level of CRP level is hsCRP level.

[0053] In one preferred embodiment of the invention, said IL-1 p binding antibody or functional fragment thereof is administered 2-5 weeks from an initial acute pancreatitis event or a subsequent recurrent acute pancreatitis event (herein sometimes referred to as a or the 'qualifying PC event').

[0054] In other preferred embodiments of the invention, said IL-1 p binding antibody or functional fragment thereof is administered 3 weeks or 21 days, 4 weeks or 1 month or 28 days, 5 weeks or 35 days, or 6 weeks or 42 days from the qualifying PC event.

[0055] In one preferred embodiment of the invention, said IL-1 p binding antibody or functional fragment thereof is administered every 2 weeks, monthly, every 6 weeks, bimonthly (every 2 months), quarterly (every 3 months), every 5 months, or every 6 months from the first administration.

[0056] In any embodiment of the invention, said any embodiment further comprises administering the patient an additional dose of about 25 mg to about 300 mg of the IL-1 p binding antibody or functional fragment thereof at week 2, week 4 or week 6 from the first administration.

[0057] In one preferred embodiment, the invention provides an IL-1 p binding antibody or functional fragment thereof for preventing or reducing the risk of having a recurrent pancreatitis event in a patient that has suffered a qualifying PC event, comprising administering about 50 mg of an IL-1 p binding antibody or functional fragment thereof 2-5 weeks from the qualifying PC event, wherein said patient has a CRP level of ^about 1 mg / L before administration of said antibody or functional fragment thereof, and further comprising administering the patient an additional dose of about 50 mg of the IL-1 p binding antibody or functional fragment thereof at week 2, week 4 or week 6 from the first administration and followed by a quarterly administration from the first administration.

[0058] In one preferred embodiment, the invention provides an IL-1 binding antibody or functional fragment thereof for preventing or reducing risk of having a recurrent pancreatitis event in a patient that has suffered a qualifying PC event, comprising administering about 150 mg of an IL-1 p binding antibody or functional fragment thereof 2-5 weeks from the qualifying PC event, wherein said patient has a CRP level of ^about 1 mg / L before administration of said antibody or functional fragment thereof, and further comprising administering the patient an additional dose of about 150 mg of the IL-1 p binding antibody or functional fragment thereof at week 2, week 4 or week 6 from the first administration and followed by a quarterly administration from the first administration.

[0059] In one preferred embodiment, the invention provides an IL-1 p binding antibody or functional fragment thereof for preventing or reducing risk of having a recurrent pancreatitis event in a patient that has suffered of a qualifying PC event, comprising administering about 300 mg of an IL-1 p binding antibody or functional fragment thereof 2-5 weeks from the qualifying PC event, wherein said patient has a CRP level of ^about 1 mg / L before administration of said antibody or functional fragment thereof and followed by a quarterly administration from the first administration.

[0060] Any embodiment of the invention, or any preferred embodiment of the invention comprises administering about 25, 75, 100, 125, 175, 200, 225, 250, 275, 300 mg or any combination thereof of the IL-1 p binding antibody or functional fragment thereof. In other embodiments of the administration regimens described above, a dose of 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,

[0061] 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245,

[0062] 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300 mg or any combination thereof of said IL-1 p binding antibody or functional fragment thereof can be administered.

[0063] In any embodiment of the invention, or any preferred embodiment of the invention, said IL- 1 P binding antibody or functional fragment thereof is an IL-1 p binding antibody. In any embodiment of the invention, or any preferred embodiment of the invention, said IL-1 p binding antibody or functional fragment thereof is capable of inhibiting the binding of IL-1 p to its receptor and has a KD for binding to IL-1 p of about 50 pM or less.

[0064] In any embodiment of the invention, or any preferred embodiment of the invention said IL- 1 P binding antibody is selected from the group consisting of: an IL-1 p binding antibody directed to an antigenic epitope of human IL-1 p which includes the loop comprising the Glu64 residue of the mature IL-1 p, wherein said IL-1 p binding antibody is capable of inhibiting the binding of IL-1 p to its receptor, and further wherein said IL-1 p binding antibody has a KD for binding to IL-1 p of about 50 pM or less.

[0065] In any embodiment of the invention, or any preferred embodiment of the invention, said IL- 1 P binding antibody is canakinumab. In other embodiments of the invention, said IL-1 p binding antibody or functional fragment thereof is selected from the group consisting of XOMA 052 or gevokizumab, LY-2189102 or AMG-108. In some embodiments described above, the antibody or fragment binds to human IL-1 p with a dissociation constant of about 50 pM or less. In some embodiments, the antibody or fragment binds to human IL-1 with a dissociation constant of about 500 pM or less. In some embodiments, the IL-1 p binding antibody or functional fragment thereof binds to human IL-1 p with a dissociation constant of about 250 pM or less. In some embodiments, the IL-1 p binding antibody or functional fragment thereof binds to human IL-1 p with a dissociation constant of about 100 pM or less. In some embodiments described above, the IL-1 p binding antibody or functional fragment thereof binds to human IL-1 with a dissociation constant of about 5 pM or less. In some embodiments, the IL-1 p binding antibody or functional fragment thereof binds to human IL-1 p with a dissociation constant of about 1 pM or less. In some embodiments, the IL-1 p binding antibody or functional fragment thereof binds to human IL-1 p with dissociation constant of about 0.3 pM or less.

[0066] In some embodiments described above, the IL-1 p binding antibody or functional fragment thereof is a neutralizing antibody.

[0067] In some embodiments described above, said IL-1 p binding antibody or functional fragment thereof is administered subcutaneously or intravenously.

[0068] When administered subcutaneously, canakinumab can be administered in a reconstituted formulation comprising canakinumab at concentration 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.

[0069] When administered subcutaneously, canakinumab can be administered in a liquid formulation comprising canakinumab at concentration: 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.

[0070] When administered subcutaneously, canakinumab or any of said IL-1 p 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.

[0071] In other embodiments, biomarkers other than hsCRP include but are not limited to: IL-1 Ra, IL-6, IL-18, leptin, adiponectin (total and high MW), TNFa, PAI-1 and fibrinogen.

[0072] In a particularly preferred embodiment, said IL-1 p binding antibody is canakinumab.

[0073] In other embodiments, said IL-1 p binding antibody is XOMA 052 or gevokizumab, LY- 2189102 orAMG-108.

[0074] Other embodiments of the invention include the use of an IL-1 p binding antibody or a functional fragment thereof as herein described in any embodiment of the invention, or any preferred embodiment of the invention in a method of treatment for preventing or reducing risk of having a recurrent event of pancreatitis in a patient that has suffered a first acute event of pancreatitis.

[0075] Other embodiments of any aspect described above include a pharmaceutical composition comprising an IL-1 p binding antibody or functional fragment thereof for preventing or reducing risk of having a recurrent event of pancreatitis in a patient that has suffered a first acute event of pancreatitis. Preferably the invention comprises a dosage of about 25 mg to about 300 mg of said pharmaceutical composition for said use. More preferably a patient receiving said dosage of said pharmaceutical composition for said use has a CRP level of about 1 mg / L before receiving said dosage of said pharmaceutical composition for said use.

[0076] Attention is drawn to the publication lnterleukin-1 beta induces autophagy by affecting calcium homeostasis and trypsinogen activation in pancreatic acinar cells by Bin Xu et al - Int J Clin Exp Pathol. 2014; 7(7): 3620-3631 as published (online) on Jun 15, 2014. In the discussion section of this paper there is disclosure concerning possible explanations for the crucial role of autophagy in trypsinogen activation in pancreatitis. Trypsin is a digestive enzyme which breaks down proteins in the small intestine. Trypsin is produced and stored in pancreatic acinar cells as trypsinogen. Trypsinogen is 'inactive' in the sense that it is a proenzyme. Nevertheless it is the trypsinogen rather than the trypsin which has the potential to become problematic in regard to being causative of an attack of acute pancreatitis. This is because of the possibility that the proenzyme trypsinogen in prematurely converted into the active enzyme trypsin in the pancreas rather than in the small intestine. Particularly the first two paragraphs of the discussion section of this paper disclose that IL-1 beta upregulates cellular Ca(2+) ions which results in the premature activation of digestive enzymes in the pancreas. This is because Ca(2+) ions are heavily involved in trypsinogen being activated to the mature active enzyme trypsin. This could 'trigger 'an acute attack of pancreatitis since trypsinogen activation is a known instigating event of pancreatitis. Thus if the amount of active IL-1 beta were reduced through use of the claimed IL-1 beta antibody cellular Ca(2+) ions would not be upregulated which would reduce the risk of having an event of acute pancreatitis in a patient who had had a prior event of acute pancreatitis. In an attack of acute pancreatitis premature activation of digestive enzymes like trypsin results in necrotic cell death which results in the release of damage associated molecular patterns that trigger the inflammatory response. This causes the release of IL-1 beta as part of the inflammatory response. In turn IL-1 beta is an effector of immune mediated pancreatic cell destruction resulting in a feedback loop of more digestive enzyme release into the pancreas which causes more necrotic cell death etc. etc. The bioavailability of IL-1 beta antibody in the patient through the use of regular dosing of the IL-1 beta antibody to reduce the risk of having an event of acute pancreatitis in a patient who had had a prior event of acute pancreatitis would also serve to protect the pancreas during any acute pancreatic attack which unfortunately occurred. This is because the IL-1 beta antibody would reduce the amount of active IL-1 beta released in the pancreas as part of the inflammatory response. In addition the release of IL-1 beta as part of the inflammatory response in the pancreas (see above) could also result in further upregulation of cellular Ca(2+) ions (also see above) in yet a further feed back loop to cause trypsinogen to be activated to the mature active enzyme trypsin. Furthermore there is no requirement that dosing with the IL-1 beta antibody cease once an acute attack of pancreatitis came on so protection of the pancreas would continue. Again release of IL - 1 beta during an attack of acute pancreatitis can result in a systemic inflammatory response which can be fatal due to systemic organ failure. So the use of the IL-1 beta antibody can help mitigate this risk too. Furthermore an acute attack of pancreatitis is a risk factor for further acute attacks of pancreatitis due to the possibility of scar tissue dependent IL-1 beta disregulation.

[0077] Accordingly the IL-1 B binding antibodies of the invention are also useful for the treatment, or amelioration of autoimmune disease and of inflammatory conditions, such as acute pancreatitis.

[0078] In another embodiment, therefore, the subject invention is directed to an IL-1 B binding antibody or functional fragment thereof, preferably canakinumab, for use in treating acute pancreatitis.

[0079] In yet another embodiment, the subject invention is directed to an IL-1 B binding antibody or functional fragment thereof, preferably canakinumab, for use in treating chronic pancreatitis.

[0080] 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.

[0081] 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.

[0082] As used herein, the term “hsCRP” refers to the level of CRP in the blood as measured by high sensitivity CRP testing.

[0083] 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.

[0084] By “IL-1 p binding antibody” is meant any antibody capable of binding to the IL-1 p 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 p 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 p binding antibodies used in the invention to IL-1 p may be shown in a competitive binding assay.

[0085] As used herein the term “antibody” 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, CH1 , 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.

[0086] As used herein, the term “functional fragment” of an antibody, refers to portions or fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., IL- 1 P). 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 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 VH and CH1 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).

[0087] 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.

[0088] As used herein, the terms “monoclonal antibody” or “monoclonal antibody composition” 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.

[0089] As used herein, the term “KD”, is intended to refer to the dissociation constant, which is obtained from the ratio of Kd to Ka (i.e. Kd / Ka) and is expressed as a molar concentration (M). KD values for antibodies can be determined using methods well established in the art. A method for determining the KD of an antibody is by using surface plasmon resonance, or using a biosensor system such as a Biacore® system.

[0090] 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.

[0091] As used herein, an antibody that “inhibits” one or more of these IL-1 p 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 p 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-13 functional activity.

[0092] 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.

[0093] EXAMPLE 1

[0094] Rationale of Dose / Regimen, Duration of Treatment / Safety

[0095] Canakinumab 50 mg and 150 mg Quarterly

[0096] The 50 mg and 150 mg canakinumab dosing schedule has been selected on the basis of anticipated efficacy, safety, and biomarker modeling data. In phase II development, all canakinumab doses up to 300 mg subcutaneous (s.c.) every other week have been found safe, well tolerated, and free of adverse lipid effects. Canakinumab efficacy in lowering hsCRP, IL-6 and fibrinogen was assessed based on studies CACZ885A2213 and CACZ88512202. The maximum efficacy of hsCRP lowering in study CACZ88512202 was at approximately 50-75 mg of canakinumab monthly, with persistent lowering across a wide range of higher doses. Therefore, 50 mg monthly as fully efficacious dose and 15 mg monthly as submaximal dose were selected for further development (see FIG. 3). The optimal dosing interval was examined using data from CACZ885A2213 (diabetes) and from gout studies with canakinumab (see FIG. 3). These studies indicated that canakinumab effect on lowering hsCRP was durable for up to approximately 3 months (see FIG. 2). Further, modeling and simulation methods showed that 150 mg quarterly dosing had similar free IL-1 p suppression compared to 50 mg monthly dosing and 50 mg quarterly dosing had similar free IL-13 suppression compared to 15 mg monthly dosing. This conclusion was reached by comparing the doses and regimens based on both the time for maintenance of suppression and the fraction of patients below a specified suppression threshold of ‘tissue free’ IL-1 p. Therefore, canakinumab 50 mg and 150 mg quarterly administration are safe and efficacious dosages.

[0097] Canakinumab 300 mg Quarterly

[0098] Given evidence of safety across a wide dosing range, a 300 mg quarterly dosing schedule for canakinumab has also been developed. This allows evaluation of a higher canakinumab dose if required. A higher dose may deliver greater efficacy than the other selected dose, 150 mg quarterly. This 300 mg quarterly dosing regimen also includes an induction period over 2 weeks, dosing at randomization (month 0) and at week 2 (month 0.5), in order to assure that auto-induction of IL-13 pathway is adequately inhibited at study initiation. The complete suppression of IL-13 related gene expression achieved with this early high dose administration, coupled with the continuous canakinumab treatment effect which has been proven to last the entire quarterly dosing period, is expected to minimize the potential for IL-1 p rebound. This may be relevant for pathogenesis of acute pancreatitis because it is theorized that IL-1 auto-induction provides a positive feedback mechanism for pancreatitis. In phase II studies in patients with gout, diabetes, and acute inflammatory conditions, safety of canakinumab across a wide range of doses has not emerged as a major clinical issue. Due to long term suppression of inflammatory biomarkers, quarterly dosing of canakinumab is feasible and likely to be clinically effective. In addition, data in the setting of acute inflammation suggests that higher initial doses of canakinumab that can be achieved through induction are safe and provide an opportunity to ameliorate concern regarding potential auto-induction of IL-1 p and to achieve greater early suppression of IL- 1 P related gene expression. IL-13 auto-induction has been shown in human mononuclear blood, human vascular endothelial, and vascular smooth muscle cells in vitro and in rabbits in vivo where IL-1 has been shown to induce its own gene expression and circulating IL-1 p level (Dinarello et al. 1987, Warner et al. 1987a, and Warner et al. 1987b). These studies suggested that IL-1 induced IL-1 gene expression may provide a positive feedback mechanism in the pathogenesis of pancreatitis and promote pancreatitis. This consequently suggests that suppression of this feedback mechanism may provide benefits in pancreatitis. Specifically, data supporting an induction dose of canakinumab includes the following: In CACZ885A2102, a CAPS mechanism of action study of patients with Muckle Wells Syndrome (N=4), canakinumab treatment with 10 mg / kg i.v. (equivalent to 600 mg i.v.) single dose induced clinical (improved skin lesions and conjuctival injection) and biomarker (hsCRP and SAA) responses in 24 hrs which was durable up to 180 days. In contrast, canakinumab doses of 1 mg / kg i.v. without induction were only durable up to 90 days. Support for more sustained and higher dose canakinumab therapy was also seen in the rheumatoid arthritis proof of concept study CACZ885A2101 , where higher doses of canakinumab were required (^3.0 mg / kg i.v.) to achieve a significant clinical response as scored by the ACR system. Furthermore, in the CACZ885A2102 study, analysis of gene expression known to be related to IL-1 p expression, inflammasome activity, and autoinduction of IL-1 , showed more complete response to higher dose (10 mg / kg i.v.) than lower dose (1 mg / kg i.v.) canakinumab. In addition, IL-1 p and inflammasome related gene expression modification began to decrease with the lower dose (1 mg / kg i.v.) compared to the higher dose (10 mg / kg i.v.) between 10 and 12 weeks. Similar results were obtained in a canakinumab rheumatoid arthritis study where IL-1 p related genes were suppressed more with 300 mg s.c. q2 weeks dosing than 150 mg q4 weeks dosing.

[0099] The documented safety record of canakinumab up to doses of 300 mg s.c. every 2 weeks with and without induction dose of 600 mg i.v., in a study in rheumatoid arthritis patients up to 6 months, 300 mg q1 month, in a study in gout patients up to 6 months, and 150 mg q1 month, in a study in T2DM patients up to 4 months supports the use of this higher dose regimen.

[0100] Example 2

[0101] Caspase - 1 silenced mice are obtained. Five are separated into a group hereinafter referred to as 'the group A mice'. Healthy laboratory mice are then obtained and are separated into two groups of five hereinafter respectively referred to as 'the group B mice' and 'the group C mice'.

[0102] Caspase - 1 is known as the 'ICE' enzyme or more fully the Interleukin - 1 converting enzyme. Removal of caspase - 1 in the group A caspase - 1 silenced mice results in the inflammasome not being able to exist in a cell. Infammation is a process that can start at the level of an individual cell and can then cascade through a process of inflammation cellular signalling to more widespread inflammation. Inflammasomes are involved in this signalling process and exist in the cell. When caspase - 1 silenced mice are unable to form the inflammasome compexes in their cells the inflammation process cannot effectively propagate from the level of the individual cell and hence cannot effectively cascade to more widespread inflammation.

[0103] The group A and the group B mice are then dosed with effective doses of canakinumab.

[0104] Mice in each of the 3 groups A, B and C are then fed a diet deficient in choline and supplemented with 0.5% ethionine (CDE diet) over 10 days in an attempt to induce acute pancreatitis in the mice.

[0105] Acute pancreatitis will be seen in each of the group B and the group C mice. However the rate of acute pancreatitis that will be seen in the group B canakinumab treated mice is less than the rate of acute pancreatitis that will be seen in the non canakinumab treated group C mice.

[0106] It will be seen that there is a higher rate of acute pancreatitis in the non canakinumab treated mice and hence that treatment of the mice with canakinumab reduces the risk of them having an event of acute pancreatitis.

[0107] The rate of acute pancreatitis will be significantly reduced in the group A caspase - 1 silenced mice compared to the group B and the group C mice.

Claims

CLAIMS:

1. An IL-1 p binding antibody or functional fragment thereof for use in reducing the risk of having an event of acute pancreatitis in a patient who has had a prior event of acute pancreatitis.

2. The IL-1 p binding antibody or functional fragment thereof of claim 1 for the use of claim 1 , wherein said IL-1 p binding antibody or functional fragment thereof is administered subcutaneously in amounts of from 50 mg to 300 mg every three months.

3. The IL-1 p binding antibody or functional fragment thereof of any preceding claim for the use of any preceding claim wherein said IL-1 p binding antibody or functional fragment thereof is administered to a patient having a hsCRP level of ^2 mg / L before said administration of said antibody or functional fragment thereof.

4. The IL-1 p binding antibody or functional fragment thereof of any preceding claim for the use of any preceding claim, wherein said IL-1 p binding antibody or functional fragment thereof is administered in an amount of 50 mg, preferably 150mg, more preferably 300mg.

5. The IL-1 p binding antibody or functional fragment thereof of any preceding claim for the use of any preceding claim, wherein said IL-1 p binding antibody or functional fragment thereof is capable of inhibiting the binding of IL-1 p to its receptor and has a KD for binding to IL-1 p of 50 pM or less.

6. The IL-1 p binding antibody or functional fragment thereof of any preceding claim for the use of any preceding claim, wherein said IL-1 p binding antibody or functional fragment thereof is administered in an amount of 50 mg every 4 weeks or 150mg every 12 weeks.

7. The IL-1 p binding antibody or functional fragment thereof of any preceding claim for the use of any preceding claim, wherein said IL-1 p binding antibody or functional fragment thereof is canakinumab.

8. The IL-1 p binding antibody or functional fragment thereof of any preceding claim for the use of any preceding claim, wherein the pathology of said pancreatitis in said patient who has had a prior event of acute pancreatitis is not alcohol related and not gall stone related.

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