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Predicting Clinical Response to Treatment with a Soluble Tnf-Antagonist Or Tnf, Or a Tnf Receptor Agonist

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Predicting Clinical Response to Treatment with a Soluble Tnf-Antagonist Or Tnf, Or a Tnf Receptor Agonist (19) TZZ _ __T (11) EP 2 192 197 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 02.06.2010 Bulletin 2010/22 C12Q 1/68 (2006.01) (21) Application number: 08170119.5 (22) Date of filing: 27.11.2008 (84) Designated Contracting States: (72) Inventor: The designation of the inventor has not AT BE BG CH CY CZ DE DK EE ES FI FR GB GR yet been filed HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR (74) Representative: Habets, Winand Designated Extension States: Life Science Patents AL BA MK RS PO Box 5096 6130 PB Sittard (NL) (71) Applicant: Vereniging voor Christelijk Hoger Onderwijs, Wetenschappelijk Onderzoek en Patiëntenzorg 1081 HV Amsterdam (NL) (54) Predicting clinical response to treatment with a soluble tnf-antagonist or tnf, or a tnf receptor agonist (57) The invention relates to methods for predicting a clinical response to a therapy with a soluble TNF antagonist, TNF or a TNF receptor agonist and a kit for use in said methods. EP 2 192 197 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 192 197 A1 Description [0001] The invention relates to methods for predicting a clinical response to a treatment with a soluble TNF antagonist, with TNF or a TNF receptor agonist using expression levels of genes of the Type I INF pathway and a kit for use in said 5 methods. In another aspect, the invention relates to a method for evaluating a pharmacological effect of a treatment with a soluble TNF antagonist, TNF or a TNF receptor agonist. Anti-tumour necrosis factor- (TNF-) therapies represent an important advancement in therapy for RA. However, there remains a proportion of patients who do not improve despite therapy. Although TNF antagonists have been shown to be highly efficient and safe for the treatment of RA patients, clinical complications have been reported for a subgroup 10 of the treated patients. These include the reactivation of tuberculosis (Gomez-Reino A&R 48, 2003), the induction of anti-dsDNA autoantibodies (15;16) and development of symptoms of SLE (15). Increased anti-dsDNA autoantibodies have been observed in approximately 15% and SLE-like symptoms in about 0.2% of treated RA patients. The SLE symptoms are reversible upon discontinuation of anti-TNF treatment. These drugs are expensive and have the potential of serious toxicity. Therefore, it would be ideal to predict the patients who will respond, so that the use of these drugs 15 can be targeted. Methods of predicting a TNF response known in the art are based on observational, habitual or demo- graphic variables (age, sex, disease activity score (DAS28) or health assessment questionnaire (HAQ) scores (Hydrich et al. Rheum 2006: 1558-1565). There is a need is for improved methods using personalised biological parameters. Administration of TNF or a TNF receptor agonist has been implied as a therapy for Type I diabetes (Ban L, et al, PNAS 2008;105(36):13644-9). It is desirable to predict whether a patient will respond to a therapy with TNF or a receptor agonist. 20 [0002] The invention relates to a method for prognosticating a clinical response of a patient to a treatment with a soluble TNF-antagonist, TNF or TNF receptor agonist, said method comprising determining the level of an IFN-I type response in at least two samples of said individual, wherein a first of said samples has not been exposed to a soluble TNF-antagonist, TNF or TNF receptor agonist and wherein at least a second of said samples has been exposed to said soluble TNF-antagonist, TNF or TNF receptor agonist prior to determining said level, said method further comprising 25 comparing said levels and prognosticating said clinical response from said comparison. [0003] The term "patient" refers to any subject (preferably human) afflicted with a disease likely to benefit from a treatment with soluble TNF-antagonist, TNF or TNF receptor agonist, in particular a TNF -related disease. Two types of TNF related diseases exist. One type is a disease wherein high expression of TNF is a problem. In another type of a TNF related disease, low expression of TNF is a problem. Problems with high expression of TNF can be treated with 30 a TNF antagonist. Problems with low expression of TNF can be treated with TNF or a TNF receptor agonist. In a preferred embodiment, said TNF-related disease comprises a disease which is likely to benefit from a treatment with a soluble TNF-antagonist. Preferably, said TNF -related disease comprises an autoimmune disorder, an infectious disease, trans- plant rejection or graft-versus-host disease, malignancy, a pulmonary disorder, an intestinal disorder, a cardiac disorder, sepsis, a spondyloarthropathy, a metabolic disorder, anemia, pain, a hepatic disorder, a skin disorder, a nail disorder, 35 and vasculitis. In one embodiment, the autoimmune disorder is selected from the group consisting of rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, allergy, multiple sclerosis, autoimmune diabetes, autoimmune uveitis, and nephrotic syndrome. In another embodiment, said TNF -related disease is selected from the group consisting of inflammatory bone disorders, bone resorption disease, alcoholic hepatitis, viral hepatitis, fulminant hepatitis, coagu- lation disturbances, burns, reperfusion injury, keloid formation, scar tissue formation, pyrexia, periodontal disease, obes- 40 ity, and radiation toxicity. In still another embodiment, said TNF -related disease is selected from the group consisting of Behcet’s disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disorder (COPD), idiopathic pulmo- nary fibrosis (IPF), restenosis, diabetes, anemia, pain, a Crohn’s disease-related disorder, juvenile rheumatoid arthritis (JRA), a hepatitis C virus infection, psoriatic arthritis, and chronic plaque psoriasis. [0004] In one embodiment of the invention, the TNF related disease is Crohn’s disease. In another embodiment, the 45 disease is ulcerative colitis. In still another embodiment, the disease is psoriasis. In still another embodiment, the disease is psoriasis in combination with psoriatic arthritis (PsA). [0005] In another preferred embodiment, said TNF-related disease comprises a disease which is likely to benefit from a treatment with TNF or TNF receptor agonist. Preferably, said disease comprises type I diabetes. [0006] In a preferred embodiment, said patient is an individual suffering from at risk or suffering from Rheumatoid 50 Arthritis (RA)" With the term an individual suffering from at risk or suffering from Rheumatoid Arthritis (RA) is meant an individual who is diagnosed with RA or is suspected by a doctor of suffering from RA or of developing the symptoms of RA within 10 years. Predominant symptoms of RA comprise pain, stiffness, and swelling of peripheral joints. The clinical manifestation of the disorder is very variable, ranging from mild, self-limiting arthritis to rapidly progressive multi-system inflammation with profound morbidity and mortality (Lee & Weinblatt 2001; Sweeney & Firestein 2004). RA symptoms 55 may also comprise joint damage, which typically occurs early in the course of rheumatoid arthritis; 30 percent of patients have radiographic evidence of bony erosions at the time of diagnosis, and this proportion increases to 60 percent by two years (van der Heijde 1995; BrJ. Rheumatol., vol. 34 Suppl 2, pp. 74-78). Typically, RA is a polyarthritis, which involves many joints (six or more), although for example in the early stages of the disease, only one or a few joints might 2 EP 2 192 197 A1 be afflicted. Virtually all peripheral joints can be affected by the disease; however, the most commonly involved joints are those of the hands, feet and knees (Smolen et al. 1995; Arthritis Rheum., vol. 38, no. 1, pp. 38-43). In addition, RA can affect the spine, and atlanto-axial joint involvement is common in longer- standing disease, and constitutes a directly joint-related cause of mortality. Extra-articular involvement is another hallmark of RA, and this can range from rheumatoid 5 nodules to life-threatening vasculitis (Smolen & Steiner 2003; Nat.Rev.Drug Discov., vol. 2, no. 6, pp. 473-488). RA can be classified using history, physical examination, laboratory and radiographic findings and this is usually performed according to criteria as described in Arnett FC, et al.: Arthritis Rheum 31:315, 1988. Preferably, said individual has a DAS28 score of 3.2 or higher. More preferably, said DAS28 score is 4.6 or higher. Most preferably, said DAS28 score is 5.1 or higher. 10 [0007] Patients who are resistant to methotrexate (MTX), usually considered first-line therapy for the treatment of RA, are a further preferred group of patients for whom the method of the invention can be particularly useful. [0008] More generally, patients who already receive a basic treatment for their TNF -related disease, e.g. with MTX, azathioprine or leflunomide, are particularly good candidates for the test method of the invention. [0009] With the term "clinical response" is meant the clinical result of a treatment with a soluble TNF-antagonist, TNF 15 or TNF receptor agonist. Said clinical response can be a positive or a negative clinical response. With a positive clinical response is meant that the severity of symptoms or the number of symptoms is reduced as a result of a treatment with said soluble TNF-antagonist, TNF or TNF receptor agonist. Preferably, said clinical result is the result of a treatment with a soluble TNF antagonist. When the disease is RA, it is preferred that a positive clinical response comprises at least reduction of swelling of joints. Preferably, an assessment of a clinical response is based on standardized and 20 preferably validated clinical response criteria such as provided by the guidelines of organisations such as the National Institute for Health and Clinical Excellence (NICE), EULAR and/or ACR.
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