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WO 2017/077391 A2 11 May 2017 (11.05.2017) P O P C T

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WO 2017/077391 A2 11 May 2017 (11.05.2017) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/077391 A2 11 May 2017 (11.05.2017) P O P C T (51) International Patent Classification: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, C07K 16/28 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, PCT/IB20 16/00 1726 MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (22) International Filing Date: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 3 November 20 16 (03 .11.20 16) SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (25) Filing Language: English ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 62/250,691 4 November 2015 (04. 11.2015) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (71) Applicant: ASTRAZENECA AB [SE/SE]; SE-15 1 85 TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, Sodertalje (SE). DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (72) Inventors: NEWBOLD, Paul; C/o Medlmmune, LLC, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, One Medlmmune Way, Gaithersburg, MD 20878 (US). GW, KM, ML, MR, NE, SN, TD, TG). KOUSTUBH, Ranade; C/o Medlmmune, LLC, One Medlmmune Way, Gaithersburg, MD 20878 (US). Published: (74) Agent: TTOFI, Evangelia, K.; Medimmune Limited, Mil- — without international search report and to be republished stein Building, Granta Park, Cambridge CB21 6GH (GB). upon receipt of that report (Rule 48.2(g)) (81) Designated States (unless otherwise indicated, for every — with sequence listing part of description (Rule 5.2(a)) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, < (54) Title: DIPEPTIDYL PEPTIDASE-4 AND PERIOSTIN AS PREDICTORS OF CLINICAL RESPONSE TO EOSINO- PHIL-TARGETED THERAPEUTIC AGENTS IN EOSINOPHILIC DISEASES (57) Abstract: The present disclosure relates to the use of protein and/or gene expression levels of dipeptidyl peptidase-4 o (DPP4/CD26) and periostin (POSTN) as peripheral biomarkers for eosinophilic diseases or disorders, e.g., moderate to severe asthma. Levels of the DPP4 and/or POSTN above or below predetermined DPP4 or POSTN threshold levels can be used, e.g., (i) to o determine a patient's eligibility for a certain treatment with an IL-5R antagonist, e.g., an anti-IL- 5R antibody such as benralizumab (MEDI-563), (ii) to determine whether a certain treatment of an eosinophilic disease or disorder with a specific IL-5R antagonist should commence, be suspended, or be modified, (iii) to diagnose whether an eosinophilic disease or disorder is treatable or not o treatable with a specific IL-5R antagonist, (iv) to prognosticate the outcome of treating an eosinophilic disease or disorder with a specific IL-5R antagonist, etc. DIPEPTIDYL PEPTIDASE-4 AND PERIOSTIN AS PREDICTORS OF CLINICAL RESPONSE TO EOSINOPHIL-TARGETED THERAPEUTIC AGENTS IN EOSINOPHILIC DISEASES REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY [0001] The content of the electronically submitted sequence listing in ASCII text file (Name: DPP4_sequence listing_ST25_ascii.txt; Size: 52,739 bytes; and Date of Creation: November 4, 2015) filed with the application is incorporated herein by reference in its entirety. BACKGROUND [0002] Eosinophils are implicated in various diseases including allergic diseases, and are thought to play an important role in generating morbidity of allergic diseases such as chronic bronchial asthma and atopic dermatitis. Adv. Immunol., 39, 177(1986), Immunol. Today, 13, 501(1992)]. In addition to the above diseases, eosinophils are also implicated in diseases generally referred to as hypereosinophilic syndrome (HES), such as eosinophilia, eosinophilic enterogastritis, eosinophilic leukemia, eosinophilic granuloma and Kimura's disease. Ann. Intern. Med., 97, 78 (1982). [0003] Bronchial asthma is a common persistent inflammatory disease of the lung characterized by airways hyper-responsiveness, mucus overproduction, fibrosis, and raised serum IgE levels. Airways hyper-responsiveness (AHR) is the exaggerated constriction of the airways to non-specific stimuli such as cold air. Both AHR and mucus overproduction are thought to be responsible for the variable airway obstruction that leads to the shortness of breath characteristic of asthma attacks (exacerbations) and which is responsible for the mortality associated with this disease. [0004] Current British Thoracic Society (BTS) and Global Initiative for Asthma (GINA) guidelines suggest a stepwise approach to the treatment of asthma (Society, B. T., Thorax, 2003. 58 Suppl 1:1-94; GINA, Global Strategy for Asthma Management and Prevention. 2002, National Institute of Health). Mild to moderate asthma can usually be controlled by the use of inhaled corticosteroids, in combination with beta-agonists or leukotriene inhibitors. However, due to the documented side effects of corticosteroids, patients tend not to comply with the treatment regime, which reduces the effectiveness of treatment (Milgrom, H. et al. Ann Allergy Asthma Immunol, 2002. 88:429-31; Fish, L. and C. L. Lung, Ann Allergy Asthma Immunol, 2001. 86:24-30; Bender, B. G. J. Allergy Clin. Immunol, 2002. 109:S554- 9). Asthma presents significant heterogeneity in response to various treatments, thereby highlighting the need to develop more effective therapies for this disease or identify biomarkers that predict response to specific therapies. [0005] The terms "precision medicine," "personalized health care," or "targeted therapeutics" are often used interchangeably to describe efforts geared to tailor therapies for patient subgroups with a diverse collection of molecular and clinical characteristics, such as asthma. Current treatment of asthma is dominated by inhaled and oral corticosteroids in combination with bronchodilators. Although very effective in most patients, about 10 to 20% of the patients with asthma remain poorly controlled with current standard of care (Bousquet et al., Allergy Clin Immunol 126, 926-938 (2010)). Recently, much progress has been made through the discovery of new biomarkers using "omics" approaches, linking clinical phenotypes with molecular biomarkers and referred to as asthma "endotypes" (Anderson, Lancet 372, 1107-1119 (2008); Lotvall et al. J Allergy Clin Immunol 127, 355-360 (2011); Wenzel, Pulm Pharmacol Ther 26, 710-715 (2013)). [0006] In some cases, these biomarkers are useful predictors of treatment response. For example, patients with elevated IgE, eosinophilic inflammation or high levels of periostin, a surrogate marker for interleukin (IL)-13 activity in asthma, preferentially respond to monoclonal antibodies targeting immunoglobulins E (Di Domenico et al., Inflamm Allergy Drug Targets 10, 2-12 (2011)), IL-5/IL-5RCC (Castro et al., Lancet Respir Med 3, 355-366 (2015)), or IL-13/IL-4RCC (Wenzel, Pulm Pharmacol Ther 26, 710-715 (2013)), respectively. However, a better appreciation of the dynamic changes of endotypes over time and with treatment, associations with clinical phenotypes and ultimately the discovery of new endotypes, which allow for the development of new and tailored treatments for patients whose asthma remains poorly controlled, is needed (Holgate et al., Nat Rev Drug Discov 14, 367-368 (2015)). BRIEF SUMMARY [0007] The present disclosure provides a method of treating an eosinophilic disease or disorder in a patient in need thereof, comprising administering an eosinophil-targeted therapeutic agent to the patient if the patient is determined or identified to have lower or decreased dipeptidyl peptidase-4 (DPP4) and/or periostin (POSTN) levels in one or more samples taken from the patient compared to predetermined DPP4 or POSTN threshold levels, or compared to DPP4 or POSTN threshold levels in one or more control samples. [0008] Also provided are methods of treating a patient having an eosinophilic disease or disorder comprising suspending or not initiating the administration of an eosinophil-targeted therapeutic agent to the patient if the patient is determined or identified to have higher or increased DPP4 and/or POSTN levels in one or more samples taken from the patient compared to predetermined DPP4 or POSTN threshold levels, or compared to DPP4 or POSTN threshold levels in one or more control samples. [0009] The disclosure provides also methods of treating an eosinophilic disease or disorder in a patient in need thereof, wherein the patient failed, was non-responsive or intolerant to treatment with a therapeutic agent comprising administering an eosinophil- targeted therapeutic agent to the patient if the patient is determined or identified to have lower or decreased DPP4 and/or POSTN levels in one or more samples taken from the patient compared to predetermined DPP4 or POSTN threshold levels, or compared to DPP4 or POSTN threshold levels in one or more control samples. [0010] Also provided are methods of determining whether to treat a patient having an eosinophilic disease or disorder with an eosinophil-targeted therapeutic agent, comprising determining to treat the patient if the patient is determined
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