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WO 2013/045505 Al 4 April 2013 (04.04.2013) P O P C T

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WO 2013/045505 Al 4 April 2013 (04.04.2013) 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 2013/045505 Al 4 April 2013 (04.04.2013) P O P C T (51) International Patent Classification: Orly [US/US]; Department of Pharmacy, 1040 Ronnebo- C12Q 1/68 (2006.01) A61K 31/00 (2006.01) hm Hall, 777 Highland Avenue, Madison, Wisconsin A61K 38/00 (2006.01) 53705-2222 (US). SOLOMON, Scott David [US/US]; c/o The Brigham And Women's Hospital, Inc., 75 Francis (21) International Application Number: Street, Boston, Massachusetts 021 15 (US). PCT/EP2012/068985 (74) Agent: FRIGOLA-DEULOFEU, Carmen; NOVARTIS (22) Date: International Filing PHARMA AG, Patent Department, CH-4002 Basel (CH). 26 September 2012 (26.09.2012) (81) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of national protection available): AE, AG, AL, AM, (26) Publication Language: English AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (30) Priority Data: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 61/540,141 28 September 201 1 (28.09.201 1) US HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (71) Applicants (for all designated States except US) : NO- KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, VARTIS AG [CH/CH]; Lichtstrasse 35, CH-4056 Basel ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (CH). THE BRIGHAM AND WOMEN'S HOSPITAL, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, INC. [US/US]; 75 Francis Street, Boston, Massachusetts RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, 021 15 (US). TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (72) Inventors; and (71) Applicants (for US only): LI, Yali [CN/US]; c/o Novartis (84) Designated States (unless otherwise indicated, for every Institutes for BioMedical Research, Inc., 45 Sidney Street, kind of regional protection available): ARIPO (BW, GH, Cambridge, Massachusetts 02139 (US). PRESCOTT, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, Margaret Forney [US/US]; c/o Novartis Pharmaceuticals UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, Corporation, One Health Plaza, East Hanover, New Jersey TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, 07936 (US). ROCHA, Ricardo [CO/CH]; c/o Novartis MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, Pharma AG, Posfach, CH-4002 Basel (CH). VARDENY, [Continued on nextpage] (54) Title: BIOMARKERS FOR RAAS COMBINATION THERAPY Aliskiren Losartan Combination o ■REN -5312 CC □ REN -5312 CT TT © Figure 1 (57) Abstract: A method of predicting whether a subject having a cardiovascular, renal, and/or metabolic disease has an increased o likelihood of benefiting from a combination treatment comprising at least two RAAS agents selected from renin inhibitors, ACEi and ARBs. This method comprises analysing a biological sample from the subject to determine the identity of the nucleotide pair at o position -5312 of the renin gene, wherein the presence of a CC genotype at position -53 12 indicates that the subject has an increased likelihood of benefiting from such a combination treatment. TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Published: ML, MR, NE, SN, TD, TG). -with international search report (Art. 21(3)) Declarations under Rule 4.17: — as to the applicant's entitlement to claim the priority of the earlier application (Rule 4.17(Hi)) BIOMARKERS FOR RAAS COMBINATION THERAPY FIELD OF THE INVENTION This invention relates generally to the analytical testing of biological samples in vitro, and more particularly to aspects of genotyping indicative of the efficacy of a RAAS combination therapy for treating particular disorders. BACKGROUND OF THE INVENTION The renin aldosterone angiotensin system (RAAS) plays an important role in the regulation of blood pressure and volume homeostasis, and pivotal roles in the pathophysiology of cardiovascular, renal, and metabolic diseases. Renin is secreted by the kidney in response to a decrease in circulating volume and blood pressure, and cleaves the substrate angiotensinogen to form the inactive decapeptide angiotensin I (Ang I). Ang I is converted to the active octapeptide angiotensin II (Ang II) by angiotensin converting enzyme (ACE). Ang II interacts with cellular receptors, in particular ATI receptors, inducing vasoconstriction and release of catecholamines from the adrenal medulla and pre-junctional nerve endings. It also promotes aldosterone secretion and sodium reabsorption. In addition, Ang II inhibits renin release, thus providing a negative feedback to the system. Accordingly, Ang II acts at various levels (e.g. vasculature, sympathetic nervous system, cortex and medulla of the adrenal gland) to increase vascular resistance and blood pressure. The RAAS can be blocked at various levels. Renin inhibitors, ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs) represent major drug classes that block the RAAS. Each individual drug class has a different mode of action and thus blocks the RAAS at a different level: Renin inhibitors block the first, rate-limiting step of RAAS cascade by competitively inhibiting the enzyme renin, thereby preventing the formation of Ang I from angiotensinogen. ACEi block the second step of the RAAS cascade by competitively inhibiting the enzyme ACE, thereby preventing the formation of Ang II. Finally, ARBs block the third and last step of the RAAS cascade by binding to and occupying the ATI receptors without activating them. Thereby, ARBs prevent binding and activation of said ATI receptors by Ang II. It has been disclosed that certain gene polymorphisms reflecting on cardiovascular systems are useful as biomarkers for predicting disease susceptibility or progression, or as a guide for individualised therapy, including drug therapy. Renin has an important role in the regulation of electrolyte homeostasis and blood pressure (Corvol et al, Pathol. Biol., 45:229-239, 1997). A single nucleotide polymorphism, REN- 5312C/T, located in the distal enhancer region and upstream of the transcription start side of the coding region of the renin gene, had been reported to be associated with higher expression of renin (Fuchs et al, Journal of Hypertension, 20(12):2391-2398, 2002), increased susceptibility to hypertension (Moore et al, Hypertension, 50:340-347, 2007), and elevated diastolic BP (Vangjeli, et al., Circ. Cardiovasc. Genet. 3(l):53-59, 2010). Carriage of the - 5312T allele, a specific marker for a single renin haplotype, is associated with both elevated ambulatory and elevated clinic blood pressure (BP) levels in healthy humans. Furthermore, Moore et al found evidence that this polymorphism may predict BP lowering responses to RAAS blockade in hypertensive patients, and that this prediction is additional to that of plasma renin activity. Specifically, it was found that BP lowering with losartan among T allele carriers was more than twice that of CC homozygotes, whereas with aliskiren BP lowering was greatest among CC homozygotes. On the other hand, a more recent study found that CC homozygotes of REN C-5312T showed greater BP reduction with valsartan treatment than T allele carriers (Konoshita et al, Diabetes Care, 32(8):1485-1490, 2009). Given the complexity of RAAS, there is still a need for providing therapeutic approaches that target more complete inhibition of this system and which offer additional clinical benefits for patients such as enhanced efficacy (i.e. enhance blood pressure lowering efficacy, decrease aldosterone levels, decrease proteinuria, and increase heart and kidney function), decreased drug toxicity, improved response rate and hence, a more consistent response in the appropriate patient, and consequently decreased disease-related mortality and morbidity. Thus, an object of the present invention is to provide a method to predict which subjects will be more responsive to a combination treatment with RAAS agents. SUMMARY OF THE INVENTION In a first aspect, the invention relates to a method of predicting whether a subject having a cardiovascular, renal, and/or metabolic disease has an increased likelihood of benefiting from a particular treatment, comprising: analyzing a biological sample from the subject to determine the identity of the nucleotide pair at position -5312 of the renin gene, wherein the presence of a CC genotype at position -5312, or a GG genotype at its complement, indicates that the subject has an increased likelihood of benefiting from a combination treatment comprising therapeutically effective amounts of at least two RAAS agents selected from renin inhibitors, ACEi and ARBs. In another aspect, the invention relates to a method of selecting a subject having a cardiovascular, renal, and/or metabolic disease for a treatment with a combination of RAAS agents, comprising: (a) analyzing a biological sample from the subject to determine the identity of the nucleotide pair at position -5312 of the renin gene; and (b) selecting said subject when the identity of this nucleotide pair is CC, or a GG genotype at its complement, for a combination treatment comprising therapeutically effective amounts of at least two RAAS agents selected from renin inhibitors, ACEi and ARBs. In another aspect, the invention relates to a method of treating a subject having a cardiovascular, renal, and/or metabolic disease, or at risk of developing a cardiovascular, renal, and/or metabolic disease, comprising: (a) analyzing a biological sample from the subject to determine the identity of the nucleotide pair at position -5312 of the renin gene; and (b) either (i) administering a combination of at least two RAAS agents selected from renin inhibitors, ACEi and ARBs if the identity of this nucleotide pair is CC, or a GG genotype at its complement, or (ii) administering an alternative therapy to the subject if the nucleotide pair at position -53 12 of the renin gene is CT or TT, or GA or AA at its complement.
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