Claims for Patent: 10,086,072

Summary for Patent: 10,086,072

Title:	Methods of disease activity profiling for personalized therapy management
Abstract:	The present invention provides methods for personalized therapeutic management of a disease in order to optimize therapy and/or monitor therapeutic efficacy. In particular, the present invention comprises measuring an array of one or a plurality of biomarkers at a plurality of time points over the course of therapy with a therapeutic agent to determine a mucosal healing index for selecting therapy, optimizing therapy, reducing toxicity, and/or monitoring the efficacy of therapeutic treatment. In certain instances, the therapeutic agent is a TNF.alpha. inhibitor for the treatment of a TNF.alpha.-mediated disease or disorder.
Inventor(s):	Singh; Sharat (Rancho Santa Fe, CA), Hoe; Nicholas (San Diego, CA), Lockton; Steve (San Diego, CA), Hauenstein; Scott (San Diego, CA), Ohrmund; Linda (San Diego, CA)
Assignee:	Nestec S.A. (Vevey, CH)
Application Number:	14/072,746
Patent Claims:	1. A method for monitoring therapeutic efficiency in an individual receiving therapy having inflammatory bowel disease (IBD), wherein the IBD comprises Crohn's disease, the method comprising: (a) measuring the levels of an array of mucosal healing markers in a sample from the individual at a plurality of time points over the course of therapy; (b) applying a statistical algorithm to the level of the one or more markers determined in step (a) to generate a mucosal healing index; (c) comparing the individual's mucosal healing index to that of a control, wherein the control is an endoscopic score; (d) determining whether the therapy is appropriate for the individual to promote mucosal healing; and (e) administering an appropriate therapy. 2. The method of claim 1, wherein the mucosal healing marker is a member selected from the group consisting of AREG, EREG, HB-EGF, HGF, NRG1, NRG2, NRG3, NRG4, BTC, EGF, IGF, TGF-.alpha., VEGF-A, VEGF-B, VEGF-C, VEGF-D, FGF1, FGF2, FGF7, FGF9, TWEAK and combinations thereof. 3. The method of claim 1, wherein the markers are measured in a sample selected from the group consisting of serum, plasma, whole blood, stool, peripheral blood mononuclear cells (PBMC), polymorphonuclear (PMN) cells, and a tissue biopsy. 4. The method of claim 1, wherein the appropriate therapy is selected from the group consisting of TNF.alpha. inhibitor therapy, an immunosuppressive agent, a corticosteroid, a drug that targets a different mechanism, nutrition therapy, and combinations thereof. 5. The method of claim 4, wherein the TNF.alpha. inhibitor therapy comprises an anti-TNF.alpha. antibody. 6. The method of claim 5, wherein the anti-TNF.alpha. antibody is a member selected from the group consisting of REMICADE.TM. (infliximab), ENBREL.TM. (etanercept), HUMIRA.TM. (adalimumab), CIMZIA.RTM. (certolizumab pegol), and combinations thereof. 7. The method of claim 4, wherein the immunosuppressive agent is a member selected from the group consisting of azathioprine, 6-mercaptopurine, methotrexate, and combinations thereof. 8. The method of claim 4, wherein the drug that targets a different mechanism is a member selected from the group consisting of an IL-6 receptor inhibiting antibody, an anti-integrin molecule, a JAK-2 inhibitor, a tyrosine kinase inhibitor, and combinations thereof. 9. The method of claim 4, wherein the nutrition therapy comprises a special carbohydrate diet. 10. The method of claim 1, wherein the array of mucosal healing markers further comprises at least one member selected from the group consisting of an anti-TNF.alpha. antibody, an anti-drug antibody (ADA), an inflammatory marker, an anti-inflammatory marker, a mucosal healing marker, and combinations thereof. 11. The method of claim 10, wherein the anti-TNF.alpha. antibody is a member selected from the group consisting of REMICADE.TM. (infliximab), ENBREL.TM. (etanercept), HUMIRA.TM. (adalimumab), CIMZIA.RTM. (certolizumab pegol), and combinations thereof. 12. The method of claim 10, wherein the anti-drug antibody (ADA) is a member selected from the group consisting of a human anti-chimeric antibody (HACA), a human anti-humanized antibody (HAHA), a human anti-mouse antibody (HAMA), and combinations thereof. 13. The method of claim 10, wherein the mucosal healing marker is a member selected from the group consisting of AREG, EREG, HB-EGF, HGF, NRG1, NRG2, NRG3, NRG4, BTC, EGF, IGF, TGF-.alpha., VEGF-A, VEGF-B, VEGF-C, VEGF-D, FGF1, FGF2, FGF7, FGF9, TWEAK and combinations thereof. 14. The method of claim 10, wherein the inflammatory marker is a member selected from the group consisting of GM-CSF, IFN-.gamma., IL-1.beta., IL-2, IL-6, IL-8, TNF-.alpha., sTNF RII, and combinations thereof. 15. The method of claim 10, wherein the anti-inflammatory marker is a member selected from the group consisting of IL-12p70, IL-10, and combinations thereof. 16. The method of claim 1, wherein: (i) the marker is a cytokine selected from the group consisting of GM-CSF, IFN-.gamma., IL-1.beta., IL-2, IL-6, IL-8, TNF-.alpha., soluble tumor necrosis factor-.alpha. receptor II (sTNF RII), TNF-related weak inducer of apoptosis (TWEAK), osteoprotegerin (OPG), IFN-.alpha., IFN-.beta., IL-1.alpha., IL-1 receptor antagonist (IL-1ra), IL-4, IL-5, soluble IL-6 receptor (sIL-6R), IL-7, IL-9, IL-12, IL-13, IL-15, IL-17, IL-23, and IL-27; or (ii) the marker is selected from the group consisting of MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, MT1-MMP-1, and combinations thereof; or (iii) the marker is selected from the group consisting of C-reactive protein (CRP), D-dimer protein, mannose-binding protein, alpha 1-antitrypsin, alpha 1-antichymotrypsin, alpha 2-macroglobulin, fibrinogen, prothrombin, factor VIII, von Willebrand factor, plasminogen, complement factors, ferritin, serum amyloid P component, serum amyloid A (SAA), orosomucoid (alpha 1-acid glycoprotein (AGP)), ceruloplasmin, haptoglobin, and combinations thereof; or (iv) the marker is selected from the group consisting of TGF-.alpha., TGF-.beta., TGF-.beta.2, and TGF-.beta.3; or (v) the marker selected from the group consisting of AREG, EREG, HB-EGF, HGF, HRG, NRG1, NRG2, NRG3, NRG4, BTC, EGF, IGF-1, TGF, VEGF-A, VEGF-B, VEGF-C, VEGF-D, FGF1, FGF2, FGF7, FGF9, and TWEAK; or (vi) the marker selected from the group consisting of IL-10, SCF, ICAM, VCAM, IL-12p40, and VEGFA. 17. The method of claim 1, wherein the array of markers are members selected from the group consisting of C-reactive protein (CRP), IL 7, MMP 1, MMP 2, MMP 3, MMP 9, serum amyloid A (SAA), TGF.alpha., VCAM and a combination thereof. 18. A method for reducing or minimizing the risk of surgery in an individual being administered a therapy regimen diagnosed with Crohn's disease, said method comprising: (a) measuring an array of mucosal healing markers at a plurality of time points over the course of therapy with a therapeutic antibody; (b) generating the individual's mucosal healing index comprising a representation of the presence and/or concentration levels of each of the markers over time; (c) comparing the individual's mucosal healing index to that of a control, wherein the control is an endoscopic score; (d) selecting an appropriate therapy regimen to reduce or minimize the risk of surgery; and (e) administering an appropriate therapy regimen. 19. The method of claim 18, wherein: (i) the marker is a cytokine selected from the group consisting of GM-CSF, IFN-.gamma., IL-1.beta., IL-2, IL-6, IL-8, TNF-.alpha., soluble tumor necrosis factor-.alpha. receptor II (sTNF RII), TNF-related weak inducer of apoptosis (TWEAK), osteoprotegerin (OPG), IFN-.alpha., IFN-.beta., IL-1.alpha., IL-1 receptor antagonist (IL-1ra), IL-4, IL-5, soluble IL-6 receptor (sIL-6R), IL-7, IL-9, IL-12, IL-13, IL-15, IL-17, IL-23, and IL-27; or (ii) the marker is selected from the group consisting of MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, MT1-MMP-1, and combinations thereof; or (iii) the marker is selected from the group consisting of C-reactive protein (CRP), D-dimer protein, mannose-binding protein, alpha 1-antitrypsin, alpha 1-antichymotrypsin, alpha 2-macroglobulin, fibrinogen, prothrombin, factor VIII, von Willebrand factor, plasminogen, complement factors, ferritin, serum amyloid P component, serum amyloid A (SAA), orosomucoid (alpha 1-acid glycoprotein (AGP)), ceruloplasmin, haptoglobin, and combinations thereof; or (iv) the marker is selected from the group consisting of TGF-.alpha., TGF-.beta., TGF-.beta.2, and TGF-.beta.3; or (v) the marker selected from the group consisting of AREG, EREG, HB-EGF, HGF, HRG, NRG1, NRG2, NRG3, NRG4, BTC, EGF, IGF-1, TGF, VEGF-A, VEGF-B, VEGF-C, VEGF-D, FGF1, FGF2, FGF7, FGF9, and TWEAK; or (vi) the marker selected from the group consisting of IL-10, SCF, ICAM, VCAM, IL-12p40, and VEGFA. 20. The method of claim 18, wherein the array of markers are members selected from the group consisting of C-reactive protein (CRP), IL 7, MMP 1, MMP 2, MMP 3, MMP 9, serum amyloid A (SAA), TGF.alpha., VCAM and a combination thereof. 21. The method of claim 18, wherein the appropriate therapy regimen is selected from the group consisting of TNF.alpha. inhibitor therapy, an immunosuppressive agent, a corticosteroid, a drug that targets a different mechanism, nutrition therapy, and combinations thereof.

Details for Patent 10,086,072

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Janssen Biotech, Inc.	REMICADE	infliximab	For Injection	103772	08/24/1998		2031-05-10
Immunex Corporation	ENBREL	etanercept	For Injection	103795	11/02/1998		2031-05-10
Immunex Corporation	ENBREL	etanercept	For Injection	103795	05/27/1999		2031-05-10