TW201828989A - 用於非酒精性脂性肝炎（nash）及肝纖維化之組合療法 - Google Patents
用於非酒精性脂性肝炎（nash）及肝纖維化之組合療法 Download PDFInfo
- Publication number
- TW201828989A TW201828989A TW106146349A TW106146349A TW201828989A TW 201828989 A TW201828989 A TW 201828989A TW 106146349 A TW106146349 A TW 106146349A TW 106146349 A TW106146349 A TW 106146349A TW 201828989 A TW201828989 A TW 201828989A
- Authority
- TW
- Taiwan
- Prior art keywords
- ccr5
- ccr2
- oca
- antagonist
- nash
- Prior art date
Links
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 title claims abstract description 47
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 title claims abstract description 44
- 208000019425 cirrhosis of liver Diseases 0.000 title claims description 10
- 238000002648 combination therapy Methods 0.000 title description 8
- ZXERDUOLZKYMJM-ZWECCWDJSA-N obeticholic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCC(O)=O)CC[C@H]21 ZXERDUOLZKYMJM-ZWECCWDJSA-N 0.000 claims abstract description 109
- 229960001601 obeticholic acid Drugs 0.000 claims abstract description 108
- 239000003067 chemokine receptor CCR5 antagonist Substances 0.000 claims abstract description 39
- 239000002604 chemokine receptor CCR2 antagonist Substances 0.000 claims abstract description 33
- 230000001404 mediated effect Effects 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 27
- 201000010099 disease Diseases 0.000 claims abstract description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
- 229940121360 farnesoid X receptor (fxr) agonists Drugs 0.000 claims abstract description 19
- 102000005962 receptors Human genes 0.000 claims abstract description 13
- 108020003175 receptors Proteins 0.000 claims abstract description 13
- GSNHKUDZZFZSJB-QYOOZWMWSA-N maraviroc Chemical compound CC(C)C1=NN=C(C)N1[C@@H]1C[C@H](N2CC[C@H](NC(=O)C3CCC(F)(F)CC3)C=3C=CC=CC=3)CC[C@H]2C1 GSNHKUDZZFZSJB-QYOOZWMWSA-N 0.000 claims abstract description 5
- 229960004710 maraviroc Drugs 0.000 claims abstract description 5
- CNPVJJQCETWNEU-CYFREDJKSA-N (4,6-dimethyl-5-pyrimidinyl)-[4-[(3S)-4-[(1R)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl]-3-methyl-1-piperazinyl]-4-methyl-1-piperidinyl]methanone Chemical compound N([C@@H](COC)C=1C=CC(=CC=1)C(F)(F)F)([C@H](C1)C)CCN1C(CC1)(C)CCN1C(=O)C1=C(C)N=CN=C1C CNPVJJQCETWNEU-CYFREDJKSA-N 0.000 claims abstract 2
- 229950009860 vicriviroc Drugs 0.000 claims abstract 2
- 208000027866 inflammatory disease Diseases 0.000 claims description 24
- 125000004030 farnesyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 13
- 102000004274 CCR5 Receptors Human genes 0.000 claims description 9
- 108010017088 CCR5 Receptors Proteins 0.000 claims description 9
- 239000000556 agonist Substances 0.000 claims description 9
- 230000003176 fibrotic effect Effects 0.000 claims description 7
- SRWQVWAIVQXPJY-QGZVFWFLSA-N 4-[(2r)-4-tert-butylpiperazine-2-carbonyl]-n-(4-chloro-3-fluorophenyl)piperazine-1-carboxamide Chemical compound C1N(C(C)(C)C)CCN[C@H]1C(=O)N1CCN(C(=O)NC=2C=C(F)C(Cl)=CC=2)CC1 SRWQVWAIVQXPJY-QGZVFWFLSA-N 0.000 claims description 4
- LUUMLYXKTPBTQR-UHFFFAOYSA-N 4-chloro-n-[5-methyl-2-(7h-pyrrolo[2,3-d]pyrimidine-4-carbonyl)pyridin-3-yl]-3-(trifluoromethyl)benzenesulfonamide Chemical compound C=1C(C)=CN=C(C(=O)C=2C=3C=CNC=3N=CN=2)C=1NS(=O)(=O)C1=CC=C(Cl)C(C(F)(F)F)=C1 LUUMLYXKTPBTQR-UHFFFAOYSA-N 0.000 claims description 4
- PJTGSIKANITYOO-RCOXNQKVSA-N N-[(1R,2S,5R)-5-[methyl(propan-2-yl)amino]-2-[(3S)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]methanesulfonamide Chemical compound CC(C)N(C)[C@@H]1CC[C@@H]([C@@H](C1)NS(C)(=O)=O)N1CC[C@H](Nc2ncnc3ccc(cc23)C(F)(F)F)C1=O PJTGSIKANITYOO-RCOXNQKVSA-N 0.000 claims description 4
- MCRWZBYTLVCCJJ-DKALBXGISA-N [(1s,3r)-3-[[(3s,4s)-3-methoxyoxan-4-yl]amino]-1-propan-2-ylcyclopentyl]-[(1s,4s)-5-[6-(trifluoromethyl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]methanone Chemical compound C([C@]1(N(C[C@]2([H])C1)C(=O)[C@@]1(C[C@@H](CC1)N[C@@H]1[C@@H](COCC1)OC)C(C)C)[H])N2C1=CC(C(F)(F)F)=NC=N1 MCRWZBYTLVCCJJ-DKALBXGISA-N 0.000 claims description 4
- MTMDXAIUENDNDL-RJSMDTJLSA-N [(1s,3r)-3-[[(3s,4s)-3-methoxyoxan-4-yl]amino]-1-propan-2-ylcyclopentyl]-[3-(trifluoromethyl)-7,8-dihydro-5h-1,6-naphthyridin-6-yl]methanone Chemical compound CO[C@@H]1COCC[C@@H]1N[C@H]1C[C@](C(=O)N2CC3=CC(=CN=C3CC2)C(F)(F)F)(C(C)C)CC1 MTMDXAIUENDNDL-RJSMDTJLSA-N 0.000 claims description 4
- VALRCWBOFWDEDE-UHFFFAOYSA-N [4-[(3,4-dichlorobenzoyl)amino]phenyl]methyl-dimethyl-(oxan-4-yl)azanium;chloride Chemical compound [Cl-].C1COCCC1[N+](C)(C)CC(C=C1)=CC=C1NC(=O)C1=CC=C(Cl)C(Cl)=C1 VALRCWBOFWDEDE-UHFFFAOYSA-N 0.000 claims description 4
- NXZNYBUBXWWKCP-JMOWIOHXSA-N n-[2-[[(3r)-1-[4-hydroxy-4-(6-methoxypyridin-3-yl)cyclohexyl]pyrrolidin-3-yl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide Chemical compound C1=NC(OC)=CC=C1C1(O)CCC(N2C[C@@H](CC2)NC(=O)CNC(=O)C=2C=C(C=CC=2)C(F)(F)F)CC1 NXZNYBUBXWWKCP-JMOWIOHXSA-N 0.000 claims description 4
- 208000034189 Sclerosis Diseases 0.000 claims description 3
- ZNSVOHSYDRPBGI-CBQRAPNFSA-N n-[2-[(3s)-3-[[4-hydroxy-4-(5-pyrimidin-2-ylpyridin-2-yl)cyclohexyl]amino]pyrrolidin-1-yl]-2-oxoethyl]-3-(trifluoromethyl)benzamide Chemical compound C([C@@H](C1)NC2CCC(CC2)(O)C=2N=CC(=CC=2)C=2N=CC=CN=2)CN1C(=O)CNC(=O)C1=CC=CC(C(F)(F)F)=C1 ZNSVOHSYDRPBGI-CBQRAPNFSA-N 0.000 claims description 3
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 3
- 201000002793 renal fibrosis Diseases 0.000 claims description 3
- 102100031151 C-C chemokine receptor type 2 Human genes 0.000 claims 9
- 101710149815 C-C chemokine receptor type 2 Proteins 0.000 claims 9
- 230000000694 effects Effects 0.000 abstract description 38
- 239000005557 antagonist Substances 0.000 abstract description 25
- 210000004185 liver Anatomy 0.000 abstract description 19
- 239000003795 chemical substances by application Substances 0.000 abstract description 11
- 208000003251 Pruritus Diseases 0.000 abstract description 9
- 230000009467 reduction Effects 0.000 abstract description 8
- 108090000790 Enzymes Proteins 0.000 abstract description 5
- 102000004190 Enzymes Human genes 0.000 abstract description 5
- 102000001902 CC Chemokines Human genes 0.000 abstract 2
- 108010040471 CC Chemokines Proteins 0.000 abstract 2
- 229940122206 Farnesoid X receptor antagonist Drugs 0.000 abstract 1
- 229940000425 combination drug Drugs 0.000 abstract 1
- GSNHKUDZZFZSJB-HLMSNRGBSA-N 4,4-Difluoro-N-[(1S)-3-[(1R,5S)-3-[3-methyl-5-(propan-2-yl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]octan-8-yl]-1-phenylpropyl]cyclohexane-1-carboximidic acid Chemical compound CC(C)C1=NN=C(C)N1C1C[C@H](N2CC[C@H](NC(=O)C3CCC(F)(F)CC3)C=3C=CC=CC=3)CC[C@H]2C1 GSNHKUDZZFZSJB-HLMSNRGBSA-N 0.000 description 32
- 241000699670 Mus sp. Species 0.000 description 16
- 206010016654 Fibrosis Diseases 0.000 description 15
- 230000004761 fibrosis Effects 0.000 description 15
- 102100038495 Bile acid receptor Human genes 0.000 description 12
- 101000603876 Homo sapiens Bile acid receptor Proteins 0.000 description 12
- 238000010172 mouse model Methods 0.000 description 11
- 230000007863 steatosis Effects 0.000 description 10
- 231100000240 steatosis hepatitis Toxicity 0.000 description 10
- 238000013234 NASH mouse model Methods 0.000 description 9
- 238000011161 development Methods 0.000 description 7
- 210000003494 hepatocyte Anatomy 0.000 description 6
- 102000004497 CCR2 Receptors Human genes 0.000 description 5
- 108010017312 CCR2 Receptors Proteins 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 230000002411 adverse Effects 0.000 description 4
- 208000006454 hepatitis Diseases 0.000 description 4
- 231100000283 hepatitis Toxicity 0.000 description 4
- 239000000902 placebo Substances 0.000 description 4
- 229940068196 placebo Drugs 0.000 description 4
- 229940044601 receptor agonist Drugs 0.000 description 4
- 239000000018 receptor agonist Substances 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 3
- 206010004659 Biliary cirrhosis Diseases 0.000 description 3
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000374 effect on fibrosis Effects 0.000 description 3
- 231100000304 hepatotoxicity Toxicity 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000008961 swelling Effects 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 2
- 102000019034 Chemokines Human genes 0.000 description 2
- 108010012236 Chemokines Proteins 0.000 description 2
- 206010019708 Hepatic steatosis Diseases 0.000 description 2
- 206010019851 Hepatotoxicity Diseases 0.000 description 2
- 101000797762 Homo sapiens C-C motif chemokine 5 Proteins 0.000 description 2
- 206010058667 Oral toxicity Diseases 0.000 description 2
- -1 PF- 4136309 Chemical compound 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 210000000013 bile duct Anatomy 0.000 description 2
- 238000010876 biochemical test Methods 0.000 description 2
- 208000003167 cholangitis Diseases 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 230000007686 hepatotoxicity Effects 0.000 description 2
- 235000009200 high fat diet Nutrition 0.000 description 2
- 206010020718 hyperplasia Diseases 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 231100000418 oral toxicity Toxicity 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical class C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 102100023702 C-C motif chemokine 13 Human genes 0.000 description 1
- 102100023700 C-C motif chemokine 16 Human genes 0.000 description 1
- 102100032366 C-C motif chemokine 7 Human genes 0.000 description 1
- 108091008927 CC chemokine receptors Proteins 0.000 description 1
- 102000005674 CCR Receptors Human genes 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 108010055166 Chemokine CCL5 Proteins 0.000 description 1
- 102000001327 Chemokine CCL5 Human genes 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- 206010019668 Hepatic fibrosis Diseases 0.000 description 1
- 101000978379 Homo sapiens C-C motif chemokine 13 Proteins 0.000 description 1
- 101000978375 Homo sapiens C-C motif chemokine 16 Proteins 0.000 description 1
- 101000797758 Homo sapiens C-C motif chemokine 7 Proteins 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 206010023421 Kidney fibrosis Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
- 241000167562 Pittosporum tobira Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000003510 anti-fibrotic effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- PNDKCRDVVKJPKG-WHERJAGFSA-N cenicriviroc Chemical compound C1=CC(OCCOCCCC)=CC=C1C1=CC=C(N(CC(C)C)CCC\C(=C/2)C(=O)NC=3C=CC(=CC=3)[S@@](=O)CC=3N(C=NC=3)CCC)C\2=C1 PNDKCRDVVKJPKG-WHERJAGFSA-N 0.000 description 1
- 229950011033 cenicriviroc Drugs 0.000 description 1
- 229960001091 chenodeoxycholic acid Drugs 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 239000002835 hiv fusion inhibitor Substances 0.000 description 1
- 229960004716 idoxuridine Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 230000007056 liver toxicity Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 102000006255 nuclear receptors Human genes 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 229940055679 ocaliva Drugs 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 231100001271 preclinical toxicology Toxicity 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 238000004383 yellowing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/5545—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having eight-membered rings not containing additional condensed or non-condensed nitrogen-containing 3-7 membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Emergency Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Urology & Nephrology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本發明係針對一種治療諸如非酒精性脂性肝炎(NASH)之CCR5/CCR2介導之疾病的方法，其包含投與有效量之C-C趨化介素受體5 (CCR5)拮抗劑(例如馬拉維若或維克維若)及或有效量之C-C趨化介素受體2 (CCR2)拮抗劑(CCR5/CCR2)及有效量之法尼酯X受體(FXR)促效劑(例如奧貝膽酸(OCA))。「有效量」可為任一單獨藥劑之常規臨床劑量，或該FXR受體促效劑或該CCR5/CCR2拮抗劑之減小之劑量。組合對治療NASH有效，並伴以(1)功效增強及(2)副作用，尤其與投與OCA或其類似物相關之副作用顯著減少，亦即對於肝臟酶升高之影響較少，及搔癢病之嚴重程度及頻率較低。固定劑量組合提供較佳功效及安全形態。
Description
非酒精性脂性肝炎(NASH)係明顯影響生活品質之隱伏且慢性進行性的疾病。其最終可導致肝臟之肝硬化、代償失調性肝臟疾病及/或肝細胞癌瘤。必要特徵係來自脂肪變性之持續損傷、發炎性趨化介素之釋放、發炎及纖維化。與發炎相關之纖維化係疾病進程之關鍵驅動者。在臨床試驗中已測試具有不同機制之多種藥物，然而，尚無有效治療得以認可。 目前在臨床顯現NASH之不同階段存在多個新穎分子，但僅報導微小/適度影響(1，2)。 首先研發CCR5拮抗劑作為HIV進入抑制劑用以治療HIV。馬拉維若(Maraviroc)係批准用於此適應症之第一分子。已展示肝臟脂肪變性與包括CCL5/rantes及其受體CCR5 (3)之趨化介素升高相關。用於CCR5之其他配位體包括CCL3、CCL4、CCL7、CCL13及CCL16。已展示在動物模型中藉由馬拉維若抑制CCR5對於降低NAS分值及纖維化(4)有效。在併發HCV感染之HIV患者中，在接受馬拉維若治療的同時已觀察到肝纖維化降低(5)。近期研究指示靶向CCR5與CCR2之森尼維若(cenicriviroc)對NASH具有微小影響且對纖維化具有相對更明顯的影響(2，6)。森尼維若正處於用於NASH之2期研發中。另一臨床階段CCR5拮抗劑係維克維若(vicroviroc)。CCR5拮抗劑對NASH之主要功效主要反映於其對纖維化之影響且對NAS分值之影響減小(參考2)。已報導CCR2亦係肝纖維化之重要參與者(7)。 奧貝膽酸(Obeticholic acid，OCA)係具有化學結構6 a-乙基-鵝脫氧膽酸之半合成膽酸類似物。作用機制經由活化法尼酯X受體(farnesoid X receptor，FXR)實現。其經歷臨床研發作為用於若干肝病及相關病症之醫藥劑。2016年US FDA已批准其抗用於治療原發性膽道膽管炎(8)。用於NASH之臨床程式正處於3期研發中。 臨床前毒理學研究已展示OCA毒性之目標系統係肝膽系統。在大鼠之26週經口毒性研究中，用OCA處理產生臨床化學參數變化(例如ALT、AST及ALP增加)，肝臟重量增加及膽管增生(9)。在犬之9個月經口毒性研究中，OCA產生可與肝功能相關之毒性臨床症狀(皮膚、黏膜及眼變黃)及使ALT含量升高。在臨床試驗中亦報導肝臟毒性；在肝臟生物化學測試中，經暴露調節之所有嚴重及原本臨床上明顯之肝臟相關之不良反應及獨立隆起之發病率在每100個患者暴露年(PEY)係：與在安慰劑群組中2.4相比，在10 mg群組中5.2，在25 mg群組中19.8%及在50 mg群組中54.5% (10)。 已展示OCA產生劑量相關副作用，包括搔癢病及HDL減少。搔癢病係一種最常見的OCA之不良事件；已報導頻率達至80%；亦報導因搔癢病所致之劑量相關之中斷。在OCA之美國藥品說明書中將重度搔癢病列為一種警告及防範；有時需要劑量減少及/或暫時給藥中斷(8)。在研發之不同階段存在靶向FXR之幾個其他新穎分子實體。 臨床與臨床前資料指示，存在經由CCR5拮抗劑靶向CCR5路徑或使用OCA作為FXR促效劑靶向FXR路徑達成之適度至中等功效(1，2)。此可為OCA為何仍處於臨床測試之一個原因，其中2000個NASH患者(10)在18個月治療之後讀取。臨床前，功效亦適度。臨床前及人類資料指示，在減輕纖維化中使用CCR5拮抗劑靶向CCR5有效，但在NAS分值或脂肪變性下觀察到有效性較差(2)。NASH係慢性疾病且大多數患者具有該疾病之良性疾病；因此，必須具有除有效以外極安全之治療選擇。因此，需要治療NASH/肝纖維化之改良方法以增加總體功效且改良安全形態。
目前已發現在治療NASH中CCR5/CCR2拮抗劑及FXR促效劑之組合比任一藥劑單獨更有效，且副作用較少。 特定言之，在NASH之小鼠模型中CCR5抑制劑馬拉維若及FXR促效劑奧貝膽酸(OCA)各單獨及組合投與時獲得以下觀察結果(參見範例)： • 在減小NAS分值中組合療法比任一單一藥劑單獨更有效(圖1A)。 • 在減輕肝纖維化中組合療法比任一單一藥劑單獨更有效(圖3A)。 • 在減小肝炎分值中組合療法比任一單一藥劑單獨更有效(圖4A)。 • 在減小肝臟肝細胞膨大分值中組合療法比任一單一藥劑單獨更有效(圖5A)，且展示對膨大具有協同效應。此外，當投與一半劑量之兩種藥劑時觀察到無膨大。 • 在減小肝臟脂肪變性分值中組合療法比任一單一藥劑單獨更有效(圖6A)。 • 在全劑量CCR5/CCR2拮抗劑下減少劑量之OCA(一半劑量或更少劑量之OCA)可產生適當功效，但在長期慢性治療設定中毒性減小。 此外，在用OCA處理之小鼠中觀察到之AST及ALP肝臟酶升高在用MVC與OCA處理之小鼠中未觀測到(圖7A-8A)，指示由OCA所產生之不合需要的肝臟毒性可藉由與MVC並行處理而減輕。根據此等發現，用CCR5拮抗劑(及/或CCR2拮抗劑)及FXR促效劑(諸如OCA)治療NASH及其他C-C趨化介素受體5 (CCR5)介導(及/或CCR2介導)之發炎性疾病之方法揭示於本文中。當替代CCR5拮抗劑MVC投與CCR2拮抗劑MK 0812(圖7B及8B)或由於使用CCR5抑制劑馬拉維若及CCR2拮抗劑MK 0812之組合進行治療(資料未示出)時指出類似觀察結果。 本發明之一個實施例係治療患有C-C趨化介素受體5 (CCR5)介導之發炎性疾病、CCR2受體介導之發炎性疾病或CCR2/5受體介導之發炎性疾病的人類患者之方法。該方法包含向患者投與有效量之CCR5拮抗劑(諸如馬拉維若、維克維若或森尼維若)、或CCR2拮抗劑(諸如MLN-1202 (AB)、CCX-140、PF- 4136309、JNJ-17166864、AZD-2423、INCB-003284、BMS-741672、MK-0812、PF-04634817)、或CCR2/5拮抗劑(諸如森尼維若)及有效量之法尼酯X受體(FXR)促效劑。 本發明之另一實施例係治療患有C-C趨化介素受體5 (CCR5)介導之發炎性疾病的人類患者之方法，其包含向患者投與有效量之CCR5拮抗劑及有效量之法尼酯X受體促效劑。本發明之另一實施例係治療患有C-C趨化介素受體2 (CCR2)介導之發炎性疾病的人類患者之方法，其包含向患者投與有效量之CCR2拮抗劑及有效量之法尼酯X受體促效劑。本發明之另一實施例係治療患有C-C趨化介素受體CCR2/5介導之發炎性疾病的人類患者之方法，其包含向患者投與有效量之CCR2/CCR5拮抗劑及有效量之法尼酯X受體促效劑。 本發明之另一實施例係治療患有C-C趨化介素受體5 (CCR5)介導之發炎性疾病的人類患者之方法，其包含向患者投與有效量之CCR5拮抗劑、CCR2拮抗劑或CCR2/CCR5拮抗劑及有效量之法尼酯X受體促效劑。 本發明之另一實施例係CCR5拮抗劑(諸如馬拉維若、維克維若或森尼維若)與法尼酯X受體(FXR)促效劑(諸如OCA)組合用於治療患有C-C趨化介素受體5 (CCR5)介導之發炎性疾病之人類患者。 本發明之另一個實施例係CCR2拮抗劑與法尼酯X受體(FXR)促效劑組合用於治療患有C-C趨化介素受體2 (CCR2)介導之發炎性疾病之人類患者。 本發明之另一實施例係CCR2/5拮抗劑與法尼酯X受體(FXR)促效劑組合用於治療患有C-C趨化介素受體2/5 (CCR2/5)介導之發炎性疾病之人類患者。 本發明之另一實施例係藉由FXR促效劑治療NASH或膽道肝硬化或適用適應症之方法。該方法包含投與有效量之法尼酯X受體(FXR)促效劑以及有效量之CCR5拮抗劑，以改良FXR促效劑之安全形態及/或功效。 本發明之另一實施例係藉由FXR促效劑治療NASH或膽道肝硬化或適用適應症之方法。該方法包含投與有效量之法尼酯X受體(FXR)促效劑以及有效量之CCR2拮抗劑，以改良FXR促效劑之安全形態及/或功效。 本發明之另一實施例係藉由FXR促效劑治療NASH或膽道肝硬化或適用適應症之方法。該方法包含投與有效量之法尼酯X受體(FXR)促效劑以及有效量之CCR2/5拮抗劑，以改良FXR促效劑之安全形態及/或功效。 所揭示之組合療法對治療CCR5及/或CCR2介導之發炎性疾病或FXR介導之疾病(諸如NASH)有效，並伴以(1)功效增強及(2)副作用，尤其與投與OCA或其類似物相關之副作用顯著減少，亦即對於肝臟酶升高之影響較少，及搔癢病之嚴重程度及頻率較低；及(3)FXR促效劑之全劑量減小，以在副作用減少時獲得組合功效。在所揭示之組合療法下，預期將需要較低劑量之OCA以獲得與當單獨投與OCA時相比類似的功效。
相關申請
本申請案主張2016年12月28日申請之美國臨時申請案第62/439,666號之權益，該申請案之全部教示內容以引用的方式併入本文中。 「C-C趨化介素受體5 (CCR5)介導之發炎性疾病」係指以至少部分由CCR5軸線(包括CCR5之配位體，諸如CCL3、CCL4、CCL5、CCL X及CCR5受體)之活性異常造成之發炎為特徵或其症狀可至少部分由抑制CCR5緩解之疾病或病狀。CCR5介導之發炎性病症之實例包括非酒精性脂性肝炎(NASH)、纖維化疾病(例如肝纖維化、腎纖維化及肺纖維化)及原發性膽道硬化。「C-C趨化介素受體2 (CCR2)介導之發炎性疾病」係指以至少部分由CCR2軸線之活性異常造成之發炎為特徵之疾病或病狀。「CCR5/CCR2介導之發炎性疾病」係指以至少部分由CCR5軸線及/或CCR2軸線之活性異常造成之發炎為特徵之疾病或病狀。 「CCR5/CCR2拮抗劑」意謂抑制CCR5及/或CCR2之化合物，「CCR5拮抗劑」意謂抑制CCR5之高度同源物種特異性拮抗劑之家族，包括馬拉維若(MVC)、維克維若及森替維若(centiviroc)。 馬拉維若目前藉由Pfizer, New York, NY以商標名Selentry特許用於治療HIV適應症。 維克維若係已由傳統Schering-Plough研發且目前由Merck/MSD, Kenilworth NJ擱置之CCR5拮抗劑。 森尼維若係Tobira, South San Francisco, CA 94080研發中之用於治療NASH及HIV之CCR5及CCR2雙重拮抗劑。 此專利亦涵蓋CCR5拮抗劑之氘化型式，諸如馬拉維若及維克維若。此等氘化CCR5拮抗劑具有經由CCR5拮抗作用之作用機制，其與CCR5拮抗劑之對應非氘化型式類似。 CCR2拮抗劑意謂抑制CCR2之高度同源物種特異性拮抗劑家族，其包括：MLN-1202 (AB)、CCX-140、PF-4136309、JNJ-17166864、AZD-2423、INCB-003284、BMS-741672、MK-0812或PF-04634817。 FXR促效劑包括奧貝膽酸(OCA)，一種由Intercept Pharmaceuticals, 450 W 15th
street, Suite 505, floor 5, New York, NY 10011批准用於原發性膽道膽管炎之臨床階段化合物，OCA處於用於NASH之3期臨床研發中。亦包括PX104，一種Phenex, Ludwigshafen, Germany, partnered with Gilead, Forest City, CA研發中之FXR促效劑；及AKN-083，其由Akarna Therapeutics研發由Allergan, Irvine, CA獲得。 「有效量」係指CCR5拮抗劑之量、CCR2拮抗劑之量或CCR5/CCR2拮抗劑之量及FXR促效劑之量，其在向患有CCR5/CCR2介導之發炎性疾病之人類患者投與時實現所需治療效果，例如投與不同劑量之不同CCR5拮抗劑：對於馬拉維若，劑量在每天兩次每次100與300 mg之間，或每天一次每次200與600之間；對於維克維若，劑量在每天一次每次5與50 mg之間；森替維若係每天一次每次50 mg至400 mg；且MK 0812係每天一次或兩次每次2 mg至50 mg。或者，為確定有效量，熟習此項技術者可參考各經批准藥物之產品標籤，例如每天一次經口投與臨床批准劑量或更低劑量之CCR5/CCR2拮抗劑以及OCA。諸如馬拉維若或維克維若之CCR5拮抗劑可單獨或以與OCA之固定劑量組合投與。此等情況亦適用於靶向CCR2或CCR2/5藥劑。 臨床上批准之10 mg的OCA以10 mg之起始劑量或滴定劑量投與與劑量相關副作用相關。最明顯不良事件係搔癢病及HDL之減少。與來自安慰劑組之38%相比，在每天一次每次10 mg及滴定療法中分別報導56%及70%之搔癢病。在大致19-23%之接受OCA之患者中報導重度搔癢病(7)。亦報導劑量相關之HDL減少。在組合CCR5拮抗劑、CCR2拮抗劑或CCR5/CCR2之情況下，預期需要較小劑量之OCA以在單獨投與OCA時獲得類似功效。在此情況下，2-10 mg、2-8 mg、2-7 mg、4-6 mg或5 mg每日劑量或小於10 mg之每日劑量之連同CCR5拮抗劑、CCR2拮抗劑或CCR5/CCR2拮抗劑一起投與之OCA將為未來臨床劑量。 本文中所有引用之參考文獻均以全文引用的方式併入本文中。範例
吾人利用充分驗證之小鼠模型，其中NASH及纖維化藉由依序誘發糖尿病及高脂膳食來誘發。在第2天，C59BL/6J小鼠注射鏈脲菌素，接著第4週直至第9週用高脂膳食進行處理。干預處理由第5週開始直至第9週。在第9週，使此等小鼠安樂死。對NASH及其後續疾病過程之干預藉由以單獨或組合形式每天一次經口投與劑量係45 mg/kg之CCR5拮抗劑馬拉維若及每天一次30 mg/kg之OCA進行，持續4週。 如圖1A中所示，單獨CCR5拮抗劑馬拉維若對NAS分值之影響有限，且單獨OCA僅致使NAS分值適度減小。CCR5拮抗劑與OCA之組合致使NAS分值明顯減小且在減小NAS分值上比任何單一藥劑單獨更有效。NAS分值根據共識藉由非酒精性脂性肝炎臨床研究網路(Nonalcoholic Steatohepatitis Clinical Research Network)確定(13)。 如圖2A中所示，CCR5拮抗劑馬拉維若與OCA對減輕纖維化有效，如藉由膠原蛋白染色所證明(圖2A)。根據此證據，在減輕纖維化上馬拉維若比OCA更有效。組合CCR5拮抗劑與OCA致使明顯影響纖維化之減輕。纖維化分值根據共識藉由非酒精性脂性肝炎臨床研究網路確定(13)。如圖3A中所示，對纖維化之影響亦藉由纖維化分值定量，且馬拉維若及OCA之組合致使纖維化分值減小大致80%。如圖4A中所示，單獨OCA及MVC之組合與肝炎減輕相關，但當組合投與OCA與MVC時觀察到更顯著影響。如圖5A中所示，MVC與肝細胞膨大分值減小相關，但當組合投與OCA與MVC時觀察到更顯著影響。指出OCA對肝細胞膨大僅具有微小影響。如圖6A中所示，OCA與脂肪變性之適度減輕相關，然而在MVC下指出僅對脂肪變性具有微小影響。當組合投與OCA與MVC時獲得對脂肪變性之更顯著影響。當使用諸如MK 0812之CCR2拮抗劑時獲得類似結果(圖3B至7B)。 在臨床前動物研究中單獨用OCA處理會產生臨床化學參數變化(例如ALT、AST及ALP增加)、肝臟重量增加及膽管增生，且相對於建議之人類劑量安全裕度僅係2.3倍(8)。在臨床試驗中亦報導肝臟毒性；在肝臟生物化學測試中，經暴露調節之所有嚴重及原本臨床上明顯之肝臟相關之不良反應及獨立隆起之發病率在每100個患者暴露年(PEY)係：與在安慰劑群組中2.4相比，在10 mg群組中5.2，在25 mg群組中19.8%及在50 mg群組中54.5% (9)。在此研究中，用OCA處理產生AST及ALP升高，但在用MVC與OCA處理之小鼠中未觀測到此升高(圖7A-8A)，且在CCR2拮抗劑MK 0812下觀察到類似研究結果，指示藉由OCA之不當肝臟毒性可藉由用MVC或MC 0812並行處理減輕。非專利引用
參考文獻： 1. Neuschwander-Tetri BA, Sanyal AJ, Lavine JE, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic,non-alcoholic steatohepatitis (FLINT):a multicentre, randomised, placebo-controlled trial. Lancet 2015; 385: 956-65. 2.http://www.businesswire.com/news/home/20160725005384/en/ Tobira-Therapeutics-Announces-Clinically-Statistically-Significant-Improvement
3.Seki E 1
,De Minicis S
,Gwak GY
,Kluwe J
,Inokuchi S
,Bursill CA
,Llovet JM
, Brenner DA,Schwabe RF
, CCR1 and CCR5 promote hepatic fibrosis in mice.J Clin Invest.
2009 Jul;119(7):1858-70 4. Laura Pérez-Martínez, Patricia Pérez-Matute, Javier Aguilera-Lizarraga, et e al: Maraviroc, a CCR5 antagonist, ameliorates the development of hepatic steatosis in a mouse model of non-alcoholic fatty liver disease (NAFLD), J. Antimicrob. Chemother. (2014)doi: 10.1093/jac/dku071 5. Gonzalez EO, Boix V, Deltoro MG, Aldeguer JL, Portilla J, et al:The effects of Maraviroc on liver fibrosis in HIV/HCV co-infected patients.See comment in PubMed Commons belowJ Int AIDS Soc.
2014 Nov 2;17(4 Suppl 3):19643. doi: 10.7448/IAS.17.4.19643. 6. Lefebvre E, Moyle G, Reshef R, Richman LP, Thompson M, Hong F, Chou HL, Hashiguchi T, Plato C, Poulin D, Richards T, Yoneyama H, Jenkins H, Wolfgang G, Friedman SL.Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis.PLoS One. 2016 Jun 27;11 (6):e0158156. doi: 10.1371/journal.pone.0158156. 7. Seki E, de Minicis S, Inokuchi S, Taura K, Miyai K, van Rooijen N, Schwabe RF, Brenner DA.CCR2 promotes hepatic fibrosis in mice Hepatology.
2009 Jul;50(1):185- 97. doi: 10.1002/hep.22952 8. US label of Obeticholic Acid (Oacliva).http://www.accessdata.fda.gov/ drugsatfda docs/nda/2016/207999Orig1s000Lbl.pdf
9. Summary of Pharmacology Review for Obeticholic Acid (Ocaliva) http://www.accessdata.fda.gov/mwg internal/de5fs23hu73ds/progress? id=WFZ3PwF4uCkU8lF_46n3pQy0kvZdamy5gZ6 wtD5mqUk, 10. Summary of Medical Review for Obeticholic Acid (Ovaliva).http://www.accessdata.fda.gov/mwg-internal/de5fs23hu73ds/progress?id= mus83V849Br8KocyHQk176o-VDoGe2hfO7NzsYxAC7M
, 11. Randomized Global Phase 3 Study to Evaluate the Impact on NASH With Fibrosis of Obeticholic Acid Treatment (REGENERATE): https://clinicaltrials.gov/ct2/show/NCT02548351 12. Obeticholicacid phase 3 study in NASH:https://clinicaltrials.gov/ ct2/show/NCT02548351
13. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ; Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease.Hepatology. 2005 Jun;41 (6):1313-21. 14. Machado MV, Michelotti GA, Xie G, de Almeida TP, Boursier J, Bohnic B, et al. (2015) Mouse Models of Diet-Induced Nonalcoholic Steatohepatitis Reproduce the Heterogeneity of the Human Disease. PLoS ONE 10(5): e0127991. doi:10.1371/journal.pone.01279
圖1A係條形圖，展示在NASH之小鼠模型中單獨投與之OCA及MVC與NAS分值適度減小相關，但當以諸如全劑量組合及半劑量組合之組合投與OCA與MVC時獲得更顯著影響。圖1B係條形圖，展示在NASH之小鼠模型中單獨投與之OCA及CCR2拮抗劑(MR 0812)與NAS分值適度減小相關，但當組合投與OCA與MK 0812時獲得更顯著影響。考慮到單獨CCR2拮抗劑或一半劑量之OCA影響甚微，當替代30 mg/kg投與15 mg/kg之一半劑量之OCA與MK 0812 (10 mg，每天兩次)時指出尤其值得注意的影響。 圖2A係展示藉由膠原蛋白染色證明之在NASH之小鼠模型中單獨投與之OCA及MVC與纖維化減輕相關之肝臟組織學，但當組合投與OCA與MVC時觀察到更顯著影響。圖2B係展示在NASH之小鼠模型中單獨投與之OCA及MK 0812與纖維化減輕相關之肝臟組織學，如藉由單獨或組合膠原蛋白染色證明。 圖3A係條形圖，展示在NASH之小鼠模型中單獨投與之OCA及MVC與纖維化分值減小相關，但當組合投與OCA與MVC時觀察到更顯著影響。圖3B係條形圖，展示在NASH之小鼠模型中單獨投與之OCA及MK 0812與纖維化分值減小相關，但在組合投與OCA與MK 0812中觀察到更顯著影響。值得注意的是，投與一半劑量之OCA (在15 mg/kg下而非30 mg/kg)與MK 0812 (10 mg，每天兩次)。 圖4A係條形圖，展示在NASH之小鼠模型中單獨投與之OCA及MVC與肝炎減輕相關，但當組合投與OCA與MVC時獲得更顯著影響。圖4B係條形圖，展示在NASH之小鼠模型中單獨投與之OCA及MK 0812與肝炎減輕相關，但在組合投與OCA與MK 0812時呈現更顯著影響。 圖5A係條形圖，展示在NASH之小鼠模型中MVC與肝細胞膨大分值減小相關，但當組合投與OCA與MVC時觀察到更顯著影響。指出OCA對肝細胞膨大僅具有微小影響。當使用MVC與OCA時，對膨大之影響大於單獨單一藥劑，甚至當投與一半劑量之MVC與OCA時，未偵測到膨大。圖5B係條形圖，展示在NASH之小鼠模型中MK 0812與OCA與肝細胞膨大分值減小相關。 圖6A係條形圖，展示在NASH之小鼠模型中OCA與脂肪變性減輕相關，然而在單獨MVC下觀察到對脂肪變性僅有微小影響。當組合投與OCA與MVC時獲得對脂肪變性之更顯著影響。圖6B係條形圖，展示在NASH之小鼠模型中OCA與脂肪變性減輕相關，然而在單獨MK 0812下或在一半劑量之OCA下觀察到對脂肪變性無明顯影響。但一半劑量之OCA與MK 0812之組合與全劑量之OCA一般有效。 圖7A係條形圖，展示在NASH之小鼠模型中單獨投與OCA與肝臟酶AST升高相關。在用單獨MVC或OCA與MVC處理之小鼠中未觀測到此不良影響。用OCA處理之小鼠與用OCA/MVC處理之小鼠之間的AST差在統計學上顯著。圖7B係條形圖，展示在NASH之小鼠模型中單獨投與OCA與肝臟酶AST升高相關。在用單獨MK 0812或OCA與MK 0812處理之小鼠中未觀測到此不良影響。用OCA處理之小鼠與用OCA/MK 0812處理之小鼠之間的AST差在統計學上顯著。 圖8A係條形圖，展示在NASH之小鼠模型中單獨投與之OCA與肝臟酶ALP升高相關，但在用MVC或用OCA及MVC處理之小鼠中無升高。用OCA處理之小鼠與用OCA/MVC處理之小鼠之間的ALP差在統計學上顯著。圖8B係條形圖，展示在NASH之小鼠模型中單獨投與之OCA與肝臟酶升高相關，但在用MK 0812處理之小鼠中無升高。
Claims (20)
- 一種治療患有C-C趨化介素受體5 (CCR5)及/或CCR2介導之發炎性疾病(「CCR5/CCR2介導之發炎性疾病」)的人類患者之方法，其包含向患者投與有效量之CCR5/CCR2拮抗劑及有效量之法尼酯X受體(FXR)促效劑。
- 如請求項1之方法，其中該CCR5/CCR2介導之發炎性疾病係非酒精性脂性肝炎(NASH)。
- 如請求項1之方法，其中該CCR5/CCR2介導之發炎性疾病係纖維化疾病。
- 如請求項1之方法，其中該纖維化疾病係肝纖維化。
- 如請求項1之方法，其中該CCR5/CCR2介導之疾病係原發性膽道硬化。
- 如請求項3之方法，其中該纖維化疾病係肺纖維化或腎纖維化。
- 如請求項1至6中任一項之方法，其中該CCR5/CCR2拮抗劑係馬拉維若(maraviroc)、維克維若(vicriviroc)、森尼維若(cenicriviroc)、MLN-1202 (AB)、CCX-140、PF-4136309、JNJ-17166864、AZD-2423、INCB-003284、BMS-741672、MK-0812或PF-04634817。
- 如請求項1至7中任一項之方法，其中該FXR促效劑係奧貝膽酸(OCA)、PX104或AKN-083。
- 如請求項1至7中任一項之方法，其中該CCR5拮抗劑係馬拉維若且該FXR促效劑係OCA。
- 如請求項8或9之方法，其中每天向該患者投與2與10 mg之間的OCA。
- 一種CCR5/CCR2拮抗劑，其與法尼酯X受體(FXR)促效劑組合用於治療患有CCR5/CCR2介導之發炎性疾病的人類患者。
- 如請求項11之CCR5/CCR2拮抗劑，其中該CCR5/CCR2介導之發炎性疾病係非酒精性脂性肝炎(NASH)。
- 如請求項11之CCR5/CCR2拮抗劑，其中該CCR5/CCR2介導之發炎性疾病係纖維化疾病。
- 如請求項11之CCR5/CCR2拮抗劑，其中該纖維化疾病係肝纖維化。
- 如請求項11之CCR5/CCR2拮抗劑，其中該CCR5/CCR2介導之發炎性疾病係原發性膽道硬化。
- 如請求項13之CCR5/CCR2拮抗劑，其中該纖維化疾病係肺纖維化或腎臟纖維化。
- 如請求項11至16中任一項之CCR5/CCR2拮抗劑，其中該CCR5/CCR2拮抗劑係馬拉維若、維克維若、森尼維若、MLN-1202 (AB)、CCX-140、PF-4136309、JNJ-17166864、AZD-2423、INCB-003284、BMS-741672、MK-0812或PF-04634817。
- 如請求項11至17中任一項之CCR5/CCR2拮抗劑，其中該FXR促效劑係奧貝膽酸(OCA)、PX104或AKN-083。
- 如請求項11至17中任一項之CCR5/CCR2拮抗劑，其中該CCR5拮抗劑係馬拉維若且該FXR促效劑係OCA。
- 如請求項18或19之CCR5/CCR2拮抗劑，其中每天一次向患者投與2與10 mg之間的OCA。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662439666P | 2016-12-28 | 2016-12-28 | |
| US62/439,666 | 2016-12-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TW201828989A true TW201828989A (zh) | 2018-08-16 |
Family
ID=61074511
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW106146349A TW201828989A (zh) | 2016-12-28 | 2017-12-28 | 用於非酒精性脂性肝炎（nash）及肝纖維化之組合療法 |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US11160813B2 (zh) |
| EP (1) | EP3562490A1 (zh) |
| JP (1) | JP7175897B2 (zh) |
| KR (1) | KR20190103246A (zh) |
| CN (1) | CN110352059A (zh) |
| AU (1) | AU2017386648A1 (zh) |
| CA (1) | CA3047591A1 (zh) |
| IL (1) | IL267647A (zh) |
| MA (1) | MA47166A (zh) |
| MX (1) | MX2019007789A (zh) |
| PH (1) | PH12019501528A1 (zh) |
| TW (1) | TW201828989A (zh) |
| WO (1) | WO2018126016A1 (zh) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3876944A4 (en) * | 2018-11-08 | 2022-08-10 | Intercept Pharmaceuticals, Inc. | METHOD OF USE OF OBETICHOLIC ACID |
| CA3139750A1 (en) * | 2019-07-18 | 2021-01-21 | Jacky Vonderscher | Improved treatment using eyp001 |
| WO2021037702A1 (en) * | 2019-08-28 | 2021-03-04 | Poxel | Pharmaceutical combination of a specific thienopyridone derivative with an fxr agonist for the treatment of liver diseases |
| JP2023538533A (ja) * | 2020-08-07 | 2023-09-08 | ブリストル－マイヤーズ スクイブ カンパニー | 線維症の処置のための、ｃｃｒ２／５拮抗剤と組み合わせたｆｇｆ２１ |
| US20240325336A1 (en) * | 2020-12-22 | 2024-10-03 | Northsea Therapeutics B.V. | Combination therapies comprising oxygen-containing structurally enhanced fatty acids for treatment of non-alcoholic steatohepatitis |
| KR102591787B1 (ko) * | 2021-01-13 | 2023-10-20 | 한국과학기술원 | 키토산-빌리루빈 접합체를 포함하는 입자 및 이를 포함하는 약제학적 조성물 |
| AU2022244585A1 (en) * | 2021-03-23 | 2023-09-21 | Dimerix Bioscience Pty Ltd | Treatment of inflammatory diseases |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20170319548A1 (en) * | 2014-09-12 | 2017-11-09 | Tobira Therapeutics, Inc. | Cenicriviroc combination therapy for the treatment of fibrosis |
| RU2018113437A (ru) | 2015-09-16 | 2019-10-17 | Тобира Терапьютикс, Инк. | Комбинированная терапия с использованием ценикривирока для лечения фиброза |
-
2017
- 2017-12-28 EP EP17835977.4A patent/EP3562490A1/en not_active Withdrawn
- 2017-12-28 JP JP2019536198A patent/JP7175897B2/ja active Active
- 2017-12-28 TW TW106146349A patent/TW201828989A/zh unknown
- 2017-12-28 AU AU2017386648A patent/AU2017386648A1/en not_active Abandoned
- 2017-12-28 CA CA3047591A patent/CA3047591A1/en not_active Abandoned
- 2017-12-28 US US16/473,706 patent/US11160813B2/en not_active Expired - Fee Related
- 2017-12-28 MX MX2019007789A patent/MX2019007789A/es unknown
- 2017-12-28 MA MA047166A patent/MA47166A/fr unknown
- 2017-12-28 WO PCT/US2017/068728 patent/WO2018126016A1/en not_active Ceased
- 2017-12-28 KR KR1020197022095A patent/KR20190103246A/ko not_active Ceased
- 2017-12-28 CN CN201780081189.3A patent/CN110352059A/zh active Pending
-
2019
- 2019-06-25 IL IL267647A patent/IL267647A/en unknown
- 2019-06-28 PH PH12019501528A patent/PH12019501528A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CA3047591A1 (en) | 2018-07-05 |
| JP2020504129A (ja) | 2020-02-06 |
| WO2018126016A1 (en) | 2018-07-05 |
| EP3562490A1 (en) | 2019-11-06 |
| CN110352059A (zh) | 2019-10-18 |
| JP7175897B2 (ja) | 2022-11-21 |
| MX2019007789A (es) | 2019-10-21 |
| AU2017386648A1 (en) | 2019-07-18 |
| US20190321377A1 (en) | 2019-10-24 |
| WO2018126016A8 (en) | 2018-08-09 |
| US11160813B2 (en) | 2021-11-02 |
| KR20190103246A (ko) | 2019-09-04 |
| MA47166A (fr) | 2021-05-19 |
| PH12019501528A1 (en) | 2020-09-14 |
| IL267647A (en) | 2019-08-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TW201828989A (zh) | 用於非酒精性脂性肝炎（nash）及肝纖維化之組合療法 | |
| Gawrieh et al. | Saroglitazar, a PPAR‐α/γ agonist, for treatment of NAFLD: a randomized controlled double‐blind phase 2 trial | |
| Anstee et al. | Tropifexor plus cenicriviroc combination versus monotherapy in nonalcoholic steatohepatitis: Results from the phase 2b TANDEM study | |
| Alam et al. | Safety, tolerability, and efficacy of vortioxetine (Lu AA21004) in major depressive disorder: results of an open-label, flexible-dose, 52-week extension study | |
| Hegade et al. | Drug treatment of pruritus in liver diseases | |
| Jongen et al. | Neuropathic pain and pharmacological treatment | |
| Düll et al. | Management of chronic hepatic itch | |
| Vijayvargiya et al. | Systematic review with meta‐analysis: efficacy and safety of treatments for opioid‐induced constipation | |
| AU2020203316B2 (en) | Novel regimes of FXR agonists | |
| Carrion et al. | Understanding and treating pruritus in primary biliary cholangitis | |
| Ooi et al. | Efficacy and safety of vedolizumab in ulcerative colitis in patients from Asian countries in the GEMINI 1 study | |
| AU2020201980A1 (en) | Combination of FXR agonists | |
| Gilday et al. | Clinical pharmacology of paliperidone palmitate a parenteral long-acting formulation for the treatment of schizophrenia | |
| Lee et al. | Efficacy and safety of tamsulosin for treating lower urinary tract symptoms associated with benign prostatic hyperplasia: a multicenter, randomized, controlled, open-label non-inferiority study | |
| Trivella et al. | Safety considerations for the management of cholestatic itch | |
| AU2019301134A1 (en) | Treatment of the pruritic symptoms of liver disease | |
| Frias et al. | Clinical trial: A Phase 2 Randomised Platform Study to Assess Monotherapy and Combination Treatment Regimens in Metabolic Dysfunction–Associated Steatohepatitis | |
| CN112203658A (zh) | 包含卓匹非索和塞尼韦洛的组合 | |
| Dignass et al. | T1146 Maintenance Therapy with Once-Daily 2g Mesalazine (Pentasa) Treatment Improves Remission Rates in Subjects with Ulcerative Colitis Compared to Twice Daily 1g Mesalazine: Data from a Randomised Controlled Trial | |
| Rubin et al. | T1147 Twice-Daily Balsalazide Tablets Improve Patient Quality of Life After 2 and 8 Weeks of Treatment: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study | |
| Nishiba et al. | Naldemedine for the management of opioid-induced constipation in patients with cancer pain: A narrative review | |
| Niwa et al. | Placebo-induced severe diarrhea in a patient with metastatic castration-resistant prostate cancer participating in a double-blind, randomized, Phase III international trial | |
| Hicks et al. | Tu1405 the kappa-opioid receptor agonist asimadoline remains peripherally restricted at supra-therapeutic plasma exposures | |
| Walker | Digestive Disease Week 2016. San Diego, California, USA-May 21-24, 2016 | |
| Pruitt et al. | T1148 Safety and Tolerability of Twice-Daily Balsalazide Tablets: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study |