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Ep 3217179 A1 (19) TZZ¥ ___T (11) EP 3 217 179 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 13.09.2017 Bulletin 2017/37 G01N 33/68 (2006.01) (21) Application number: 17167637.2 (22) Date of filing: 02.10.2013 (84) Designated Contracting States: • LIU, Xinjun AL AT BE BG CH CY CZ DE DK EE ES FI FR GB San Diego, CA 92130 (US) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • HAUENSTEIN, Scott PL PT RO RS SE SI SK SM TR San Diego, CA 92130 (US) • KIRKLAND, Richard (30) Priority: 05.10.2012 US 201261710491 P San Diego, CA 92111 (US) 17.05.2013 US 201361824959 P (74) Representative: Krishnan, Sri (62) Document number(s) of the earlier application(s) in Nestec S.A. accordance with Art. 76 EPC: Centre de Recherche Nestlé 13779638.9 / 2 904 405 Vers-chez-les-Blanc Case Postale 44 (71) Applicant: Nestec S.A. 1000 Lausanne 26 (CH) 1800 Vevey (CH) Remarks: (72) Inventors: This application was filed on 21-04-2017 as a • SINGH, Sharat divisional application to the application mentioned Rancho Santa Fe, CA 92127 (US) under INID code 62. (54) METHODS FOR PREDICTING AND MONITORING MUCOSAL HEALING (57) The present invention provides methods for pre- an individual with a disease such as IBD. Information on dicting the likelihood of mucosal healing in an individual mucosal healing status derived from the use of the with a disease such as inflammatory bowel disease present invention can also aid in optimizing therapy (IBD). In addition, the present invention provides meth- and/or monitoring the therapeutic efficiency of an an- ods for monitoring the progression of mucosal healing in ti-TNFα inhibitor drug. EP 3 217 179 A1 Printed by Jouve, 75001 PARIS (FR) 1 EP 3 217 179 A1 2 Description healing and/or monitoring the progression of mucosal healing in patients with IBD or other inflammatory dis- CROSS-REFERENCES TO RELATED APPLICATIONS eases. This information enables the personalized thera- peutic management of the disease, such as allowing for [0001] This application claims priority to U.S. Provi- 5 appropriate selection and/or administration of therapy. sional Application No. 61/710,491, filed October 5, 2012, The present invention satisfies this need and provides and U.S. Provisional Application No. 61/824,959, filed related advantages as well. May 17, 2013. BRIEF SUMMARY OF THE INVENTION BACKGROUND OF THE INVENTION 10 [0006] Provided herein is a method for predicting the [0002] Inflammatory bowel disease (IBD) which in- likelihood of mucosal healing in a subject. The method cludes Crohn’s disease (CD) and ulcerative colitis (UC) comprises the steps of: (a) measuring a first set of mark- is a chronic idiopathic inflammatory disorder affecting the ers to form an inflammatory phase marker score; (b) gatrointestine tract. Disease progression of CD and UC 15 measuring a second set of markers to form a proliferation includes repeated episodes of inflammation and ulcera- phase marker score; (c) comparing the inflammatory tion of the intestine, leading to complications requiring phase marker score to the proliferation phase marker hospitalization, surgery and escalation of therapy (Pey- score;and (d)predicting thelikelihood ofmucosal healing rin-Biroulet et al., Am. J. Gastroenterol,. 105: 289-297 based upon the comparison in step (c). (2010); Langholz E., Dan. Med. Bull., 46: 400-41520 [0007] In some embodiments, the subject has an in- (1999)). Current treatments such as anti-tumor necrosis flammatory bowel disease (IBD). In some instances, the factor-alpha (TNF-α) biologics e.g.,( infliximab (IFX), inflammatory bowel disease is Crohn’s disease or ulcer- etanercept, adalimumab (ADL) and certolizumab pegol), ative colitis. thiopurine drugs (e.g., azathioprine (AZA), 6-mercaptop- [0008] In some embodiments, the first set of markers urin (6-MP)), anti-inflammatory drugs (e.g., mesalazine), 25 comprises one or more of TWEAK, CRP, ICAM, SAA, and steroids (e.g., corticosteroids) have been shown to VCAM, IL-2, IL-8, IL-12p70, IL-1β, GMCSF, IFNγ, IL-6, reduce disease activity. In some clinical trials of CD, mu- TNFα, ASCA-A, ASCA-G, CBir1, Fla2, FlaX, OmpC, an cosal healing (MH) which is described as the absence of anti-drug antibody (ADA), and combinations thereof. In intestinal ulcers, was induced in patients receiving com- some instances, the first set of markers comprises one bination therapy of corticosteroids and IFX or ADL. Fur- 30 or more of GMCSF, IL-2, and VCAM. thermore, MH was maintained in patients receiving IFX. [0009] In some embodiments, the second set of mark- [0003] Other studies have shown that mucosal healing ers comprises one or more of AREG, EREG, HBEGF, can be a hallmark of suppression of bowel inflammation HGF, HRGB, BTC, EGF, TGFA, FGF1, FGF2, FGF4, and can predict long-term disease remission (Froslie et FGF7, FGF9, FGF19, SCF, PDGFA, PDGFB, PDGFC, al., Gastroenterology, 133: 412-422 (2007); Baert et al., 35 VEGFA, VEGFB, VEGFC, VEGFD, TGFB1, IL-10, and Gastroenterology, (2010)). Long-term mucosal healing an anti-TNFα antibody. In some instances, the second has been associated with a decreased risk of colectomy set of markers comprises HGF. and colorectal cancer in UC patients, a decreased need [0010] In some embodiments, each marker is assigned for corticosteroid treatment in CD patients, and possibly a value of from 0 to 6 based upon the concentration or a decreased need for hospitalization (Dave et al., Gas- 40 level of the marker. troenterology & Hepatology, 8(1): 29-38 (2012)). [0011] In some embodiments, the concentration or lev- [0004] The process of mucosal healing can be divided el of the marker is relative to the level of the same marker into three phase, beginning with bleeding e.g.,( degra- in a patient population without mucosal healing. dation of the endothelial layers of the blood vessels) and [0012] In some embodiments, the value for each mark- inflammation, then progression to cell and tissue prolif- 45 er in the first set of markers is summed to form the in- eration, and finally tissue remodeling. At the inflammation flammatory phase marker score. In some embodiments, stage, cytokines, chemokines and other inflammatory the value for each marker in the second set of markers signaling molecules are secreted by immune cells in the is summed to form the proliferation phase marker score. gut mucosa. During proliferation, tissue repair and re- [0013] In some embodiments, the comparison in step modeling growth factors activate intestinal epithelial cells 50 (c) comprises applying an algorithm incorporating the in- to proliferate, migrate to the sites of injury and repair the flammatory phase marker score and the proliferation damaged tissue. At the remodeling phase, structural and phase marker score. functional improvements occur to the intestinal mucosal [0014] In some embodiments, the algorithm comprises barrier. The present invention is based on the identifica- subtracting the inflammatory phase marker score from tion of novel markers of mucosal healing that are predic- 55 the proliferation phase marker score to form a biomarker tive of the phases of the process. score of the subject. [0005] There is an unmet need in the art for non-inva- [0015] In some embodiments, the subject has an in- sive methods for predicting the likelihood of mucosal creased likelihood of having complete improvement of 2 3 EP 3 217 179 A1 4 mucosal healing without relapse when the biomarker a value of from 0 to 6 based upon the concentration or score of the subject is higher than the biomarker score level of the marker. of a patient population without mucosal healing. [0025] In some embodiments, the concentration or lev- [0016] In some embodiments, the algorithm predicts el of the marker is relative to the level of the same marker the likelihood of mucosal healing independent of clinical 5 in a patient population without mucosal healing. confounders. In some instances, the clinical confounders [0026] In some embodiments, the value for each mark- comprise one or more selected from the group consisting er in the first set of markers is summed to form the in- of age of diagnosis, age of last sample, disease location, flammatory phase marker score. In some embodiments, anal involvement, smoking, and surgery. the value for each marker in the second set of markers [0017] In some embodiments, the algorithm predicts 10 is summed to form the proliferation phase marker score. the likelihood of mucosal healing by excluding serology [0027] In some embodiments, the comparison in step markers. In other words, the algorithm can predict the (c) comprises applying an algorithm incorporating the in- likelihood of mucosal healing without the use of serology flammatory phase marker score and the proliferation markers. In particular embodiments, the excluded serol- phase marker score. ogy markers comprise one or more selected from the 15 [0028] In some embodiments, the algorithm comprises group consisting of ASCA-A, ASCA-G, CBir1, Fla2, FlaX, subtracting the inflammatory phase marker score from and OmpC. the proliferation phase marker score to form a biomarker [0018] In some embodiments, the subject is receiving score of the subject at each time point. an anti-TNFα antibody. In some embodiments, the anti- [0029] In some embodiments, the subject is progress- TNFα antibody comprises one or more of REMICADE™ 20 ing through the phases of mucosal healing when the bi- (infliximab), ENBREL™ (etanercept), HUMIRA™ (adal- omarker score of the subject increases at each time point imumab), and CIMZIA® (certolizumab pegol). over the plurality of time points. In some instances, the [0019] In some embodiments, the marker is measured subject is progressing from a phase of mucosal healing in a sample selected from the group consisting of serum, selected from an inflammatory phase and a proliferation plasma, whole blood, stool, peripheral blood mononu- 25 phase onto the next phase of mucosal healing.
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