CONJOINT THERAPY FOR TREATING FIBROTIC DISEASES

• US 20100111898A1
• Filed: 12/04/2007
• Published: 05/06/2010
• Est. Priority Date: 12/04/2006
• Status: Active Grant

• Current Assignee: Promedior, Inc. (Roche Holding AG)
• Original Assignee: Promedior, Inc. (Roche Holding AG)
• Inventors: Pelura, Timothy J.
• Granted Patent: US 8,247,370 B2
• Time in Patent Office: Days
• US Class Current: 424/85.200
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/1716 Amyloid plaque core protein
• CPC Class Codes: A61K 38/208 IL-12
• CPC Class Codes: A61K 38/217 IFN-gamma
• CPC Class Codes: A61K 38/39 Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 : for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 27/00 : Drugs for disorders of the senses
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/12 : for cataracts
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 29/02 : without antiinflammatory effect
• CPC Class Codes: A61P 3/14 : for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/20 : for DNA viruses
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 39/02 : Antidotes
• CPC Class Codes: A61P 39/06 : Free radical scavengers or antioxidants
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/12 : Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention relates to improved methods of treating fibrotic or fibroproliferative disorders. Conjoint therapies are provided comprising the combination of one or more fibrocyte suppressors and one or more profibrotic factor antagonists or anti-fibrotic agents.

Claims

1. A method of treating a fibrotic or fibroproliferative disorder in patient, the method comprising administering to a patient in need thereof a combination of one or more fibrocyte suppressors and one or more profibrotic factor antagonists or anti-fibrotic agents.

3. The method of claim 1, wherein the fibrocyte suppressor and profibrotic factor antagonist are co-formulated.

4. The method of claim 1, wherein the fibrocyte suppressor and profibrotic factor antagonist are administered simultaneously.

5. The method of claim 1, wherein the fibrocyte suppressor and profibrotic factor antagonist are administered within a time of each other to produce overlapping therapeutic concentrations in the patient.

6. The method of claim 1, wherein the fibrocyte suppressor is selected from SAP, SAP analogs, IL-12, Laminin-1, an anti-Fcγ

R antibody, an aggregated IgG antibody, a cross-linked IgG antibody, and combinations thereof.

7. The method of claim 1, wherein the fibrocyte suppressor is an agent that causes Fcγ

R-dependent activation of Syk- and Src-related tyrosine kinases in monocytes, or causes Feγ

R-independent activation of a Syk- and Src-related tyrosine kinase in monocytes in a manner that suppresses fibrocyte formation.

8. The method of claim 1, wherein the fibrocyte suppressor is an agent that causes aggregation and/or cross-linking of Fcγ

R on monocytes.

9. The method of claim 1, wherein the fibrocyte suppressor induces apoptosis of fibroblast precursors, such as CD14+ monocytes.

10. The method claim 9, wherein the fibrocyte suppressor is an IL-15 antagonist.

11. The method of claim 1, wherein the profibrotic factor antagonist is an antagonist of a peptide growth factor or cytokine selected from TGF-β

, VEGF, EGF, RANTES, a profibrotic interleukin, TNF-α

, PDGF, IGF, bFGF, MCP-1, a macrophage inflammatory protein, CTGF, endothelin-1, angiotensin-II, leptin, a profibrotic chemokines, SLC/CCL21, IL-1, IL-4, IL-5, IL-6, IL-8, IL-13, CCL2, CCL12, CXCL12, CXCR4, CCR3, CCR5 or CCR7.

15. The method of claim 11, wherein the TGF-β

antagonist is selected from an antibody directed against one or more isoforms of TGF-β

;

a TGF-β

receptor;

an antibody directed against one or more TGF-β

receptors;

a latency associated peptide;

a large latent TGF-β

a TGF-β

inhibiting proteoglycan;

somatostatin;

mannose-6-phosphate;

mannose-1-phosphate;

prolactin;

insulin-like growth factor 11;

IP-10;

an arg-gly-asp containing peptide;

a plant, fungal, or bacterial extract,;

an antisense oligonucleotide; and

a TGF-β

signaling protein.

16. The method of claim 15, wherein said TGF-β

inhibiting proteoglycan is selected from fetuin;

decorin;

biglycan;

fibromodulin;

lumican; and

endoglin.

17. The method of claim 1, wherein the fibrotic or fibroproliferative disorder is selected from rheumatoid arthritis, lupus, pathogenic fibrosis, fibrosing disease, fibrotic lesion, radiation damage, autoimmune disease, lyme disease, chemotherapy induced fibrosis, HIV, infection-induced focal sclerosis, failed back syndrome, abdominal adhesion post surgery scarring, and fibrocystic formation, alcohol-induced cirrhosis, drug-induced cirrhosis, chemically-induced cirrhosis, ischemia-reperfusion, injury after hepatic transplant, necrotizing hepatitis, hepatitis B, hepatitis C, primary biliary cirrhosis, primary sclerosing cholangitis, proliferative glomerulonephritis, sclerosing glomerulonephritis, nephrogenic fibrosing dermopathy, diabetic nephropathy, renal tubulointerstitial fibrosis, focal segmental glomerulosclerosis, pulmonary interstitial fibrosis, drug-induced sarcoidosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, diffuse alveolar damage disease, pulmonary hypertension, neonatal bronchopulmonary dysplasia, chronic asthma, emphysema, myocardial fibrosis, atherosclerosis, coronary artery restenosis, congestive cardiomyopathy, heart failure, exopthalmos of Grave'"'"'s disease, proliferative vitroretinopathy, anterior capsule cataract, corneal fibrosis, corneal scarring due to surgery, trabeculectomy-induced fibrosis, Depuytren'"'"'s contracture, scleroderma, keloid scarring, psoriasis, hypertrophic scarring, atherosclerosis, restenosis, pseudoscleroderma, periodontal disease scarring, gingival hypertrophy, pancreatic fibrosis, stromal remodeling pancreatitis, stromal fibrosis, collagenous colitis, villous atrophy, crypt hyperplasia, polyp formation, fibrosis of Crohn'"'"'s disease, healing gastric ulcer, glial scar tissue, fibrocystic disease, desmoplastic reaction to breast cancer, myelodysplasia, neoplastic diseases, rheumatoid pannus formation, endometriosis, uterine fibroids, or ovarian fibroids.

32. The method of claim 1, wherein the profibrotic factor antagonist is an anti-fibrotic cytokine.

33. The method of claim 1, wherein the profibrotic factor antagonist is a calcium channel blocker.

34. The method of claim 1, wherein the profibrotic factor antagonist is an Angiotensin-Converting Enzyme (ACE) inhibitor.

35. The method of claim 1, wherein the ACE inhibitor is enalapril.

36. The method of claim 1, wherein the profibrotic factor antagonist is selected from an anti-oxidant, a PPAR gamma agonist, an integrin antagonist, a TIMP-1 or TIMP-2 inhibitor, a Farnesoid X receptor agonist, a caspase inhibitor, an AGE inhibitor, a RAGE inhibitor, LMW heparin, a PKC inhibitor, an ADAM-10 inhibitor, a copper chelator, or a rho kinase inhibitor.

37. The method of claim 32, wherein the anti-fibrotic cytokine is HGF, BMP-7, or IL-10.

2. A kit comprising;

(i) a fibrocyte suppressor; and

(ii) a profibrotic factor antagonist or anti-fibrotic agent,

wherein the fibrocyte suppressor and profibrotic factor antagonist or anti-fibrotic agent are formulated to be administered conjointly.

12-14. -14. (canceled)

18-31. -31. (canceled)