US 20100184742A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0184742 A1 Uhr et al. (43) Pub. Date: Jul. 22, 2010 (54) POLYMORPHISMS IN ABCB1 ASSOCIATED Related U.S. Application Data WITH A LACK OF CLINICAL RESPONSE TO (60) Provisional application No. 60/943,335, filed on Jun. MEDCAMENTS 12, 2007. Publication Classification (76) Inventors: Manfred Uhr, Stockdorf (DE): Florian Holsboer, Munchen (DE); (51) Int. Cl. Bertram Miller-Myhsok, A6II 3/55 (2006.01) Munchen (DE) CI2O I/68 (2006.01) C40B 20/00 (2006.01) C40B 40/06 (2006.01) Correspondence Address: A6II 3/343 (2006.01) ROTHWELL, FIGG, ERNST & MANBECK, PC. A63L/35 (2006.01) 1425 KSTREET, N.W., SUITE 800 A6IP 25/00 (2006.01) WASHINGTON, DC 20005 (US) (52) U.S. Cl. .............. 514/214.02:435/6; 506/2:506/16; 514/469; 514/653 (21) Appl. No.: 12/663,997 (57) ABSTRACT The present invention relates to methods, compositions, kits (22) PCT Filed: Jun. 12, 2008 and reagents for determining the prognosis of a clinical response in a human patient to a medicament which acts in the (86). PCT No.: PCT/EP2008/004.737 central nervous system (CNS) and which is a substrate of the ABCB1 protein. Further, the invention relates to a combina S371 (c)(1), tion of medicaments for the treatment of human patients (2), (4) Date: Dec. 10, 2009 having specific polymorphisms in the ABCB1 gene. Patent Application Publication Jul. 22, 2010 Sheet 1 of 4 US 2010/0184742 A1 Figure 1 Cital Opram Venlafaxine S00 500 450 abcb1ab (-f-) 450 abcb1ab (--) o controls o controls 400 400 S 350 S 350 5 300 5 300 on 250 250 200 20 O C SQ 1SO g 150 100 100 50 SO O O cer spl kid liv tes lun cer spi kid liv tes lun 500 Mirtazapine 500 D-Venlafaxine 450 abcb1ab (--) 450 abcb1ab (--) to controls to controls 400 400 S 350 S 350 5 300 5 300 s c 250 dy 250 c t- 200 t- 200 4- 5 150 150 100 50 cer spl kid liv tes lun cer spl kid liv tes lun Patent Application Publication Jul. 22, 2010 Sheet 2 of 4 US 2010/0184742 A1 Figure 2 A substrates of P-gp B Non-substrates of P-gp 00 100 80. 80 6 O 60 4. O 40 20 20 non-remitters remitters non-remitters remitters genotype rs2032583 genotype rs2032583 Patent Application Publication Jul. 22, 2010 Sheet 3 of 4 US 2010/0184742 A1 Figure 3 A All patients D All patients 100 100 Š. 80 s 80 C O 60 O 60 p l gE 40 gE 40 5 20 5 20 C-carriers (N-91) T-carriers (N=125) O - - - non-carriers (N-344) O - - - non-carriers (N-286) O 1 2 3 4 5 6 O 1 2 3 4. 5 6 time weeks time weeks B Substrates of P-glycoprotein E Substrates of P-glycoprotein 100 100 g 80 s 8O - 5 60 9 60 E 40 E 40 se s 5 20 a 20 C C-carriers (N-23) T-carriers (N-36) --- non-carriers (N=110) --- non-carriers (N=96) O 1 2 3 4. 5 6 O 1 2 3 4. s 6 time weeks time weeks C Non-substrates of P-glycoprotein F Non-substrates of P-glycoprotein 100 100 se 80 is 80 C 9 60 9 60 3. 8 E 40 E 40 g 5 20 5 20 C C-carriers (N-26) C T-carriers (N-34) --- non-carriers (N=72) --- non-carriers (N-62) O 1 2 3 4 5 6 O 2 3 4 5 6 time weeks time weeks) Patent Application Publication Jul. 22, 2010 Sheet 4 of 4 US 2010/O184742 A1 Figure 4 US 2010/0184742 A1 Jul. 22, 2010 POLYMORPHISMS IN ABCB1 ASSOCATED 0007 WO 2005/108605 relates to polymorphisms in the WITH A LACK OF CLNICAL RESPONSE TO ABCB1 gene which are associated with an insufficient clini MEDCAMENTS cal response to a CNS active medicament which is a substrate of the ABCB1 protein. Seven single nucleotide polymor phisms (SNPs) in the ABCB1 gene are described, which are 0001. The present invention relates to methods, composi associated with clinical response to antidepressant drugs. tions, kits and reagents for determining the prognosis of a However, there is no evidence in this document that beside the clinical response in a human patient to a medicament which specific polymorphisms disclosed any further polymor acts in the central nervous system (CNS) and which is a phisms in the ABCB1 gene might be associated with a clinical substrate of the ABCB1 protein. Further, the invention relates response to CNS-active medicaments. to a combination of medicaments for the treatment of human 0008 Thus, there is still a need for identifying polymor patients having specific polymorphisms in the ABCB1 gene. phisms of the ABCB1 gene involved in regulating intracere 0002 Major depression constitutes one of the greatest dis bral concentrations of CNS-active medicaments. It was the ease burdens world-wide and is anticipated to be the second object of the present invention to determine new single nucle leading global disease burden by the year 2020 trailing only otide polymorphisms in the ABCB1 gene which are predic cardiovascular disease (Murray and Lopez, 1996). Antide tive for treatment course and outcome of CNS-active medi pressants are the first line treatment of major depression, but caments, which are ABCB1 transporter substrates. their overall clinical efficacy is unsatisfactory as remission, 0009. In the studies on which the present application is i.e. full resolution of depressive symptoms, occurs in only based the inventors surprisingly were able to identify several about half of the patients after a trial with an adequately dosed new polymorphisms in the ABCB1 gene, which have a clear single drug. Remission rates even decline following Succes and statistically relevant association with an insufficient clini sive treatment failures (Trivedi et al., 2006)). cal response to CNS-active medicaments. The inventors suc 0003. One of the possible reasons for poor antidepressant ceeded in identifying the SNPs rs4148740, rs10280101, response is their inadequate penetration into the central ner rs7787.082, rs4148739, rs1 1983225, rs10248420 and Vous system, which depends on the drug's ability to pass the rs 12720067 as particularly responsible for this association. blood-brain barrier (BBB). This barrier includes active trans The presence of these particular SNPs proved highly predic porters that are expressed at the luminal membrane of the tive for treatment course and outcome of CNS-active medi endothelial cells lining the small blood capillaries that form Caments. the blood-brain barrier. These molecules actively transport 0010. A first aspect of the invention relates to a method for their substrates against a concentration gradient out of the determining the prognosis of a clinical response in a human cells back into the blood circulation, thus potentially keeping patient to a central nervous system (CNS)-active medicament brain drug concentrations low. One of the best-studied trans which is a substrate of the ABCB1 protein wherein the pres porter molecules is P-glycoprotein (P-gp) (Cordon-Cardo et ence of at least one first polymorphism in the ABCB1 gene of al., 1989: Thiebaut et al., 1987). P-gp is a member of the said patient is determined, wherein said first polymorphism is highly conserved super-family of ATP-binding cassette selected from the group consisting of rS4148740. (ABC) transporter proteins (Ambudkar et al., 1999). In rs 10280101, rs7787.082, rs4148739, rs1 1983225, humans, this 170-kDa glycoprotein is encoded on chromo rS10248420 and rs12720067 and combinations thereof. some 7 by the ABCB1 gene, also known as the multidrug 0011. A further aspect of the invention relates to a diag resistance 1 (MDR1) gene (Callen et al., 1987; Chin et al., nostic composition or kit for the prognosis of a clinical 1989). P-gp acts as an active efflux pump for a wide range of response in a human patient to a CNS-active medicament compounds including a number of drugs and steroid hor which is a substrate of the ABCB1 protein, comprising at least mones (Schinkel et al., 1996: Uhr et al., 2000, 2002, 2004, one primer or probe for determining at least one first poly 2005). P-gp at the BBB thus regulates intracerebral concen morphism in the ABCB1 gene in said patient, wherein said trations and, by extension, may affect the clinical response of first polymorphism is selected from the group consisting of CNS-targeting drugs that are substrates of this transporter. rs4148740, rs1028O101, rs7787.082, rs4148739, rs1 1983225, 0004. It was speculated that inter-individual differences in rs 10248420, rs12720067 and combinations thereof. the activity of the ABCB1 gene can account in part for the 0012. A still further aspect of the invention relates to a great variation in clinical response to antidepressants in psy microarray for the prognosis of a clinical response in a human chiatric patients, even at comparable plasma levels (Uhr and patient to a CNS-active medicament which is a substrate of Grauner, 2003). A further study showed different enhance the ABCB1 protein comprising a carrier having immobilized ment of penetration of the antidepressants doxepin, Venlafax thereto at least one probe for determining at least one first ine and paroxetine in the brain of mice with an ABCB1ab polymorphism in the ABCB1 gene in said patient, wherein knockout mutation (Uhr, Grauer and Holsboer, 2003). said first polymorphism is selected from the group consisting 0005 Numerous papers describe polymorphisms in of rs4148740, rs1028O101, rs7787.082, rs4148739, ABCB1 (Kioka et al., 1989: Stein et al., 1994; Mickley et al., rs 11983225, rs10248420, rs12720067 and combinations 1998; Hoffmeyer et al., 2000; Kimetal., 2001; Ito et al., 2001; thereof.