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WO 2011/006169 Al (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 13 January 2011 (13.01.2011) WO 2011/006169 Al (51) International Patent Classification: Eighth Floor, San Francisco, California 941 11-3834 A61K 31/216 (2006.01) C12Q 1/68 (2006.01) (US). A61K 31/51 7 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/US20 10/04 1749 AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (22) International Filing Date: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 12 July 2010 (12.07.2010) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (25) Filing Language: English KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (26) Publication Language: English NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (30) Priority Data: SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, 61/224,839 10 July 2009 (10.07.2009) US TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 61/321,596 7 April 2010 (07.04.2010) US (84) Designated States (unless otherwise indicated, for every (71) Applicant (for all designated States except US): POR- kind of regional protection available): ARIPO (BW, GH, TOLA PHARMACEUTICALS, INC. [US/US]; 270 E. GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, Grand Avenue, Suite 22, South San Francisco, California ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, 94080 (US). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (72) Inventors; and LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, (75) Inventors/Applicants (for US only): GURBEL, Paul A. SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, [US/US]; 2401 W . Belvedere Avenue, Baltimore, Mary GW, ML, MR, NE, SN, TD, TG). land 21215 (US). CONLEY, Pamela B. [US/US]; 116 Lois Lane, Palo Alto, California 94303 (US). ANDRE, Published: Patrick [FR/US]; 950 N. Humboldt Street, San Mateo, — with international search report (Art. 21(3)) California 94401 (US). GRETLER, Daniel D. [US/US]; — before the expiration of the time limit for amending the 230 27th Street, San Francisco, California 9413 1 (US). claims and to be republished in the event of receipt of JUREK, Marzena [US/US]; 1942 Buchanan Street, San amendments (Rule 48.2(h)) Francisco, California 941 15 (US). (74) Agents: HOPKINS, Mark H. et al; Townsend and Townsend and Crew LLP, Two Embarcadero Center, (54) Title: METHODS FOR DIAGNOSIS AND TREATMENT OF THROMBOTIC DISORDERS MEDIATED BY CYP2C19*2 (57) Abstract: Genetic polymorphisms in the 2Cl 9*2 gene are useful as biomarkers for diagnosing an increased risk for high platelet reactivity or increased bleeding in a subject suffering from a cardiovascular disorder. In particular, the invention relates to methods of treating and preventing coronary artery disease using P2Y-12 receptor inhibitors. In addition, the present invention re lates to kits for use in identifying patients with coronary heart disease with an increased risk for high platelet reactivity or in creased bleeding. METHODS FOR DIAGNOSIS AND TREATMENT OF THROMBOTIC DISORDERS MEDIATED BY CYP2C1 9*2 CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims the benefit of priority under 35 U.S.C. 119(e) to U.S. Provisional Application No. 61/224,839 filed on July 10, 2009 and U.S. Provisional Application No. 61/321,596 filed on April 7, 2010, which are herein incorporated in their entirety by reference. FIELD OF THE INVENTION [0002] This invention relates generally to analytical testing, and more particularly to the analysis of gene expression or hematology profiles as biomarkers for predicting the effectiveness of P2Yi inhibitors in treating coronary artery disease or other ischemic events. In addition, the present invention relates to methods of treatment of coronary artery disease or ischemic events as well as kits for use in identifying patients with coronary artery disease at risk for high platelet reactivity or increased bleeding. BACKGROUND OF THE INVENTION [0003] Coronary artery disease is the principal cause of death in the United States, Europe and most of Asia. P2Y ]2 receptor inhibition, together with aspirin therapy, is a major treatment strategy in patients with high risk coronary artery disease. Currently, the only available P2Yi2 inhibitors are the thienopyridines, clopidogrel and ticlopidine (Schomig et al. N Engl J Med. Apr 25 1996;334(17): 1084-1089; Bertrand et al. Circulation. Oct 20 1998;98(16): 1597-1603; Leon et al. N Engl J Med. Dec 3 1998;339(23):1665-1671 ; Urban et al. Circulation. Νov 17 1998;98(20):2126-2132; Lancet. Νov 16 1996;348(9038): 1329-1339; Yusuf et al. N Engl J Med. Aug 16 2001;345(7):494-502; Mehta et al. Lancet. Aug 18 2001;358(9281):527-53; Wiviott et al. N Engl J Med. Νov 15 2007;357(20):200 1-20 15). These compounds are prodrugs (nondirect-acting) which are metabolized in vivo by cytochrome P450 (CYP) isoenzymes to an unstable, highly reactive and short-lived intermediate (Savi et al. Thromb Haemost. Νov 2000;84(5):891-896). This intermediate then irreversibly binds to the P2Yi 2 receptor and prevents adenosine diphosphate (ADP)-induced platelet activation and aggregation. [0004] Clopidogrel is routinely administered as a daily 75 mg dose along with 8 1 -325 mg aspirin in patients treated with coronary artery stents and after acute coronary syndromes. Clopidogrel is also administered in stable patients with prior myocardial infarction or established peripheral arterial disease. However, the recurrence of ischemic events in these patients is still high (Tantry et al. Future Cardiology. 2006;2:343-346). Pharmacodynamic studies have demonstrated wide response variability to clopidogrel therapy and a substantial percentage of patients exhibit non-responsiveness or high on-treatment platelet reactivity (HPR) to ADP as measured by ex-vivo methods. (Gurbel et al. Circulation 2003; 107:2908- 13; Gurbel et al Rev. Cardiovasc. Med. 2006;7 Suppl 4:S20-8). Translational research has demonstrated that clopidogrel nonresponsiveness or HPR is associated with increased risk for recurrent ischemic events including stent thrombosis (Gurbel et al. J Am Coll Cardiol. 2005;46: 1820-26; Gurbel et al. JAm Coll Cardiol. 2005 ;46: 1827-32; Price et al. Eur Heart J. 2008;29:992-1000; Bonello et al. J Thromb Haemost. 2007;5:1630-6). Among persons treated with clopidogrel, carriers of a reduced-function CYP2C19 allele showed significantly lower levels of the active metabolite of clopidogril, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did noncarriers (Mega et al. N . Engl. J. Med. 2009: 360). [0005] Prasugrel, a newer thienopyridine that exhibited better platelet inhibition than clopidogrel in phase II studies, was also associated with lower ischemic event occurrence in a Phase III acute coronary syndrome trial. However, prasugrel therapy is still associated with a recurrent ischemic event rate and an increased bleeding risk. (Gurbel et al. Curr Opin Investig Drugs 2008;9:324-36; Wiviott et al. N Engl J Med. 2007;357:2001-15). Likewise patient response to prasugrel is also related to cytochrome P450 genetic polymorphisms (Mega et al. Circulation May 4, 2009). [0006] In addition, preclinical studies have reported disproportionate effects of the thienopyridines, clopidogrel and prasugrel, on bleeding at high doses. For example, recent preclinical studies performed in rabbits have cautioned against the use of high dose thienopyridines that produce near-to-maximal platelet inhibition, indicating that these doses could significantly increase bleeding complications (Wong et al. Thromb Haemost. Jan 2009;101(1):108-115). Particularly, high doses of clopidogrel providing limited incremental benefits in preventing arterial thrombosis have been associated with disproportionate levels of bleeding in both rabbits and rats (Wong et al. J Cardiovasc Pharmacol. May 2007;49(5):3 16-324; Schumacher et al. 7 Pharmacol Exp. Ther. JuI 2007;322(l):369-377). There was also excessive bleeding reported in patients in the TRITON-TIMI 38 trial (Wiviott et al. N Engl J Med. Nov 15 2007;357(20):2001-2015). [0007] While progress has been made in this field, the totality of the available data indicate that significant non-responsiveness, due to cytochrome P450 genetic polymorphisms is undesirable in patients with high risk cardiovascular disease. Likewise, HPR is undesirable in patients with high risk cardiovascular disease, and irreversible, non-direct acting platelet inhibition associated with thienopyridine treatment is a major limitation in patients. Accordingly, new, safer and more effective methods for treating cardiovascular disease that address high on-treatment platelet reactivity (HPR), irreversible, non-direct acting platelet inhibition, and thienopyridine non-responsive patients with cytochrome P450 genetic polymorphisms are needed, especially for high risk patients. There also remains a need for a P2Yi2 inhibitory treatment that differentially affects thrombosis and hemostasis, specifically one that preferentially inhibits arterial thrombosis resulting in a greater therapeutic index and reduced bleeding. [0008] Elinogrel (Portola Pharmaceuticals Inc, South San Francisco, CA) is a new reversible, direct acting P2Y 2 receptor inhibitor, that is being developed for several indications, including treatment of thrombosis, see, U.S. Pat. Application No. 11/556,490. The present invention solves these problems by providing methods for determining subjects who are at risk for HPR or developing HPR or excessive bleeding associated with thienopyridine treatment in patients with cytochrome P450 (CYP) gene polymorphisms.
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