HRP20000808A2 - Use of peg-ifn-alpha and ribavirin for the treatment of chronic hepatitis c - Google Patents
Use of peg-ifn-alpha and ribavirin for the treatment of chronic hepatitis c Download PDFInfo
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- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 title claims description 40
- 229960000329 ribavirin Drugs 0.000 title claims description 33
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 title claims description 33
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
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- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 11
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Classifications
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- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
- A61K38/212—IFN-alpha
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/642—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the peptide or protein in the drug conjugate being a cytokine, e.g. IL2, chemokine, growth factors or interferons being the inactive part of the conjugate
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- A—HUMAN NECESSITIES
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- 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
Description
Predloženi izum odnosi se na područje liječenja infekcije s kroničnim hepatitisom C upotrebom količine PEG-IFN-α konjugata zajedno s Ribavirinom koja količina je učinkovita u liječenju hepatitisa C.
Interferoni (IFN) su proteini koji nastaju prirodnim putem i koji imaju antivirusno, antiproliferativno i imunoregulacijsko djelovanje, Poznato je da u ljudima postoje četiri različita razreda interferona (Pestka et al. (1987) Ann. Rev. Biochem. 56, 727-777 i Emanual & Pestka (1993) J. Biol. Chem. 268, 12565-12569). Porodica IFN predstavlja pretežni razred IFN kojeg proizvode stimulirani leukociti periferne krvi (Pestka et al., loc. cit.; Havell et al. (1975) Proc. Natl. Acad. Sci. USA 72, 2185-2187; Cavalieri et al. (1977) Proc. Natl. Acad. Sci. USA 74, 3287-3291), te limfoblastoidne i mijeloblastoidne stanične linije (Familletti et al. (1981) Antimicrob. Agents. Chemother. 20. 5-9). Antivirusni učinak IFNα postiže se ne samo izravnim utjecajem na sami virus, već i djelovanjem na njegove ciljne stanice u smislu zaštite od virusne infekcije. Interferoni mogu pokazati učinke na kanceroznim tumorima i mogu djelovati na imunosni sistem tijela tako da, na primjer, aktiviraju makrofage NK stanice i intenziviraju ekspresiju raznih imunološki značajnih konstituenata stanične membrane. Pojedinosti pripravljanja interferon-cDNA i njena izravna ekspresija, posebno u E. coli, bila je tema mnogih publikacija. Tako, na primjer, pripravljanje rekombinantnih interferona je poznato, na primjer, iz Nature 295 (1982), 503-508, Nature 284 (1980), 326-320, Nature 290 (1981), 20-26, Nucleic Acids Res. 8 (1980), 4057-4074, kao i iz europskih patenata br. 32134, 43980 i 211148.
Bila je predložena kombinirana terapija s IFN-α i Ribavirinom u liječenju infekcija s kroničnim hepatitisom C (europska patentna prijava br. 707855), međutim to liječenje nije uvijek učinkovito.
Stoga kombinirana terapija s PEG-IFN-a konjugatima i Ribavirinom može biti mnogo učinkovitija od kombinirane terapije s IFN-α i Ribavirinom.
Opaženo je da u slučaju IFN-α, PEG-ilacija povećava vrijeme trajanja cirkulacije i vrijeme zadržavanja u plazmi, smanjuje imunogenost, skraćuje čišćenje i povećava djelovanje in vivo.
Predloženi izum osigurava stoga upotrebu PEG-IFN-α konjugata zajedno s Ribavirinom za proizvodnju lijekova za liječenje infekcija s kroničnim hepatitisom C. K tome, s predloženim izumom data je metoda za liječenje kroničnih infekcija s hepatitisom C pacijenata kojima je potrebno takovo liječenje davanjem količine PEG-IFN-α konjugata zajedno s količinom Ribavirina koja je učinkovita za liječenje kroničnog hepatitisa C.
Pojam "PEG-IFN-α konjugata", kako se ovdje rabi, uključuje IFN-a derivirane od bilo kojeg prirodnog materijala (npr. leukocita, fibroblasta, limfocita) ili materijala deriviranog iz njih (npr. iz staničnih linija), ili onih koji su proizvedeni tehnologijom rekombinantne DNA.
Pojedinosti kloniranja IFNα i njegova izravna ekspresija, posebno u E. coli, bila je predmet mnogih publikacija. Pripravljanje rekombinantnih IFNα je poznato, na primjer iz Goeddel et al. (1980) Nature 284, 316-320 i (1981), Nature 290, 20-26, i europskih patenata br. 32134, 43980 u 211148. Postoji mnogo tipova IFNα, kao IFNαI, IFNα2; te, nadalje, njihovih podtipova koji uključuju ali nisu ograničeni samo na IFNα2A, IFNα2B, IFNα2C i IFNαII (koji se također označava kao IFNαII ili (d-ifn) . Pojam "IFNα" također uključuje opće prihvaćeni IFNα koji se može dobiti od Amgena ili mješavine prirodnih i/ili rekombinantnih IFNα. Prednost se daje upotrebi IFNα2A. Proizvodnja IFNα2A opisana je u europskim patentima br. 43980 i 211148.
IFN-α se konjugira s polimerom kao što je polialkilen glikol (supstituiran ili nesupstituiran), na primjer polietilen glikol, čime se dobije PEG-IFN-α konjugat. Konjugaciju se može provesti pomoću raznih linkera poznatih u struci, posebno pomoću linkera kao što su oni opisani i europskim patentnim prijavama br. 0510356, 593868 i 809996. Molekulska masa polimera, koji je ponajprije polietilen glikol, može se kretati u rasponu od 300 do 70.000 daltona, a jedan ili više, ponajprije jedan do tri polimera mogu biti konjugirani s IFN-α. Prednosni PEG-IFN-α konjugat ima formulu:
[image]
u kojoj R i R' predstavljaju metil, X je NH, a n i n' su pojedinačno ili obadva jednaki 420 ili 520.
Ribavirin, 1-β-D-ribofuranozil-lH-l,2,4-triazol-3-karboksamid, je opisan u Merckovom indeksu, kao spoj 8199, 11. izdanje. Njegova proizvodnja i formuliranje opisani su u U.S. patentnu br. 4,211,771.
U skladu s ovim izumom, PEG-IFN-α konjugat i Ribavirin se daju pacijentu koji pati od infekcije s kronične hepatitisom C u kombiniranim količinama koje su učinkovite tako da odstrane ili da barem ublaže jedan ili više znakova ili simptoma kroničnog hepatitisa C, uključiv povišen ALT, pozitivan test za anti-HIV antitijela, prisutnost HCV-a koja se vidi kao pozitivan testom na HCV-RNA, klinički stigmatizam kronične bolesti jetre i hepatocelularno oštećenje.
Doziranje PEG-IFN-α konjugata za provedbu kombinirane terapije ovog izuma je otprilike 33 do 540 mikrograma (mcg) tjedno, bez obzira na tjelesnu težinu, pri čemu se lijek uzima jednom ili dva puta tjedno.
Doziranje Ribavirina za provedbu ovog izuma je otprilike 400 do 1200 mg dnevno najmanje pet dan tjedno, ponajprije sedam dana tjedno. Na temelju procjene da pacijent ima težinu između 40 i 150 kg, raspon doziranja je time između 10 i 30 mg po kilogramu tjelesne težine dnevno. U više specifičnoj izvedbi, dnevno doziranje Ribavirina je 800 - 1200 mg. To se dnevno doziranje može dati jednom dnevno u jednostrukoj dozi ili podijeljeno u dvije ili tri doze dnevno. Ribavirin se daje ponajprije dnevno podijeljen u dvije doze.
U skladu s ovim izumom, Ribavirin se daje pacijentu zajedno s PEG-IFN-α konjugatom, to jest doza PEG-IFN-α konjugata daje se tijekom istog ili drugog vremenskog perioda pacijentu koji prima Ribavirin. U izvedbi ovog izuma, daje se najmanje jedna dnevna doza Ribavirina u istom tjednu kad i najmanje jedna doza PEG-IFN-a konjugata. U više specifičnoj izvedbi glavnina Ribavirina aplicira se tijekom istog tjedna kad se PEG-IFN-α konjugat daje jednom ili više puta. U drugoj specifičnoj izvedbi, sav ili gotovo sav Ribavirin daje se u istom tjednu kad se PEG-IFN-α konjugat aplicira jednom ili više puta. Za sada formulacije PEG-IFN-α konjugata nisu učinkovite ako se daju oralno, tako da je prednosna metoda davanja PEG-IFN-α konjugata parenteralna; ponajprije subkutanom (sc) ili intramuskularnom (in) injekcijom. Ribavirin se može dati oralno u obliku kapsula ili tableta zajedno s parenteralnim davanjem PEG-IFN-α konjugata. Naravno, kad je to dostupno, obadva lijeka mogu se dati na obadva načina, kao s nazalnim sprejem, transdermalno, sa čepićem, doziranjem s usporenim oslobađanjem, itd. Svaki oblik davanja dobar je tako dugo dok se pravilno doziranje isporučuje bez razgradnje aktivne tvari.
Učinkovitost liječenja može se utvrditi pomoću kontroliranih kliničkih pokusa u usporedbi s monoterapijom i/ili kombiniranom terapijom IFN-α i Ribavirina. Učinkovitost kombinirane terapije u ublažavanju znakova ili simptoma infekcije s kroničnim hepatitisom i učestalost i ozbiljnost sporednih učinaka uspoređuje se s prethodnom IFN-α monoterapijom i/ili kombiniranom terapijom s IFN-α i Ribavirinom. Za procjenu su relevantne tri skupine ljudi koji pate od infekcije kroničnog hepatitisa. Promatra se jednu ili sve tri skupine pacijenata s kombinacijom
1. pacijenata koji ranije nisu bili liječeni,
2. pacijenata koji su prethodno liječeni s IFN-α i /ili Ribavirinom ili s bilo kojim drugim lijekom i koji su zatim ponovno oboljeli,
3. pacijenata koji nisu reagirali na prethodno liječenje s IFN-α i/ili Ribavirinom ili s nekim drugim lijekom.
Učinkovitost kombinirane terapije utvrđuje se opsegom do kojeg su ublaženi prethodno opisani znakovi i simptomi kroničnog hepatitisa.
Primjer
Faza III. Nasumično. U više centara. Proučavanje učinkovitosti i sigurnosti usporedbom kombinacije pegiliranog interferona α2A i Ribavirina prema REBETRONU!!!! u liječenju pacijenata s kroničnom HCV infekcijom (CHC).
Primarna svrha ove studije je usporedba učinkovitosti i sigurnosti kombinacije PEG-IFN-α i Ribavirina s REBETRONOM [Intron A + Rebetol (Schering/ICN, zaštićen naziv Ribavirin)] u liječenju CHC. Jednake skupine pacijenata (330) primale su kombinaciju PEG-IFN-α i Ribavirina ili REBETRONA tijekom 48 tjedana. Treća skupina pacijenata (165 pacijenta) primala je PEG-IFN-α plus placebo 48 tjedana. Sigurnosti i učinkovitosti za kombinaciju PEG-IFN-α uspoređene su prema monoterapiji.
Doza Introna je 3 Mio. u 0,5 ml otopine, koju se je davalo subkutano (sc) tri puta tjedno (tiw) tijekom 48 tjedana.
Doza PEG-IFN-α je 180 μg, a data je sc jednom tjedno u kombinaciji s Ribavirinom ili s placebom tijekom 48 tjedana.
Doza Ribavirina i Rebetola je 1000 mg ili 1200 mg, računato prema tjelesnoj težini, koja je data svaki dan u podijeljenoj dozi. Pacijenti težine <75 kg /165 Ibs) primili su 100 mg dnevno, 400 mg ujutro i 600 mg uvečer) , dok su pacijenti težine >75 kg primili 1200 mg dnevno (600 mg ujutro i 600 mg uvečer).
Primarni parametri učinkovitosti kombinirani su trajno virološki [tj. ne-dokaziva HCV-RNA, kako je bila izmjerena pokusom PCR pomoću AMPLICORA!!!! (osjetljivost ≥100 kopija/ml], a biokemijske (normalizacija koncentracije ALT u serumu) reakcije na završetku slijedećeg perioda neliječena. Smatralo se je, da su pacijenti reagirali ako su imali normalnu aktivnost amino tranferaze alanina u serumu (ALT) u obadva tjedna, 68 i 72, a u tjednu 72 nije smjelo biti dokazivog virusa.
Ispitivanje sigurnosti provedeno je tijekom pretraživanja, načelno, u tjednima 1, 2, 4, 6 i 8 i 10, svaka 4 tjedna, i nakon toga po isteku perioda liječenja od 48 tjedana. Ocjenjivanje sigurnosti nastavljeno je zatim 24 tjedna slijedećeg perioda. Mjerenje sigurnosti uključuje nepoželjne slučajeve, vitalne znakove, te laboratorijska ispitivanja, kao i prikazivanje u tablicama namještenih doza i prerani prestanak liječenja zbog sigurnosnih i razloga podnošljivosti.
Populaciju pacijenata predstavljali su muškarci i žene, starosti 18 godina ili stariji, sa CHC, koji prethodno nisu bili liječeni s nekim drugim oblikom IFN-α ili Ribavirina. Pacijenti su morali imati mjerljivu HCV-RNA, stalno nenomalan ALT i biopsiju jetre koja je u roku od 12 mjeseci stalno pokazivala CHC.
Isključeni su bili pacijenti s drugim oblicima bolesti jetre, anemijom, infekcijom s humanim virusom imunodeficijencije (HIV), hepatocelularnim karcinomom, ranijim postojanjem teške depresije ili druge psihijatrijske bolesti, s kardijalnom bolešću, bubrežnom bolešću, poremećajima s napadima, ili s ozbiljnom retinopatijom.
Period pretraživanja (vrijeme od prvog pretražnog ispitivanja do prvog davanja ispitnog lijeka) od 35 dana prethodio je dijelu pokusnog liječenja (48 tjedana). Pacijenti koji su ispunili sve odabrane kriterije podvrgnuti tu nasumično jednom od tri režima liječenja.
Pacijenti u svim skupinama koje nisu pokazivale reakcije 2 tjedna [definirane kao smanjenje najmanje jedne (1) jedinice od log 10 u titru HCV-RNA, u usporedbi prema osnovnim, ili najmanje 50%-tno smanjenje (ili normalizaciju) njihovog ALT u serumu, u usporedbi s osnovnim] prekinuli s terapijom i smatrani su pacijentima koji ne reagiraju. Pacijenti koji su u tjednu 12 ispunili definiciju reakcije, prekinuli terapiju u tjednu 24 ako nisu pokazali nikakvu dokazivu HCV-RNA (<100 kopija/ml) ili normalizaciju ALT. Pacijenti koji su prekinuli liječenje, promatrani su nakon toga samo u pogledu sigurnosti. Svi pacijenti koji su ispunili kriterije reakcije u tjednima 12 i 24, liječeni su 48 tjedana. Primarni parametar učinkovitosti je kombinirani virološki i biokemijski odgovor (HCV-RNA <100 kopija/ml i normalizacija ALT) na kraju liječenja koje je nastavljeno još tijekom 24 tjedna).
Dolje su zbirno prikazani za sada poznatih trajnih stupnjeva viroloških odgovora na kombiniranu terapiju s Intronom A plus Rebetol i utvrđivanje stupnjeva trajnih viroloških odgovora na PEG-IFN-a monoterapiju za 48 tjedana (računato iz podataka dobivenih iz studije II faze) i PEG-IFN-α plus Ribavirin.
Poznate i utvrđene mjere virološkog odgovora,
[image] *) Postoci u zagradama su mjere odgovora utvrđene na osnovi poznatih mjera odgovora prikazanih u ostatku tablice.
EOT: Mjera virološkog odgovora na kraju liječenja (čišćenje virusa).
EOF: Mjera virološkog odgovora na kraju nastavljenog liječenja (čišćenje virusa).
Claims (10)
1. Upotreba PEG-IFN-a konjugata, , naznačena time, da se koristi zajedno s Ribavirinom za proizvodnju lijeka za liječenje infekcije s kroničnim hepatitisom C.
2. Upotreba prema zahtjevu 1, naznačena time, da je količina PEG-IFN-α konjugata otprilike 33 do 540 mg tjedno.
3. Upotreba prema zahtjevu 1, naznačena time, da je količina Ribovirina 400 do 1200 mg dnevno.
4. Upotreba prema zahtjevima 1 do 3, naznačena time, da PEG-IFN-α konjugat je konjugat PEG-IFN-α2A koji ima formulu
[image]
u kojoj R i R' predstavljaju metil, X je NH, a n i n' su pojedinačno ili obadva jednaki 420 ili 520.
5. Metoda za liječenje infekcija s kroničnim hepatitisom C, naznačena time, da uključuje davanje količine PEG-IFN-α konjugata zajedno s količinom Ribovirina koje količine su učinkovite za liječenje kroničnog hepatitisa C.
6. Metoda prema zahtjevu 5, naznačena time, da količina PEG-IFN-a konjugata data po ovoj metodi iznosi otprilike 33 do 540 mcg tjedno.
7. Metoda prema zahtjevu 5, naznačena time, da količina Ribavirina data po ovoj metodi iznosi otprilike 400 do 1200 mg dnevno.
8. Metoda prema bilo kojem zahtjevu 5 do 7, naznačena time, da dati PEG-IFN-α konjugat je PEG-IFN-α2A konjugat definiran kao gore.
9. Upotreba PEG-IFN-α konjugata i Ribavirina, naznačena time, da se oni koriste za liječenje infekcija s kroničnim hepatitisom C.
10. Izum, naznačen time, da je u skladu s gornjim opisom.
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PCT/EP1999/003746 WO1999064016A1 (en) | 1998-06-08 | 1999-05-29 | Use of peg-ifn-alpha and ribavirin for the treatment of chronic hepatitis c |
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Families Citing this family (70)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1087778B1 (en) * | 1998-06-08 | 2005-10-26 | F. Hoffmann-La Roche Ag | Use of peg-ifn-alpha and ribavirin for the treatment of chronic hepatitis c |
MY164523A (en) * | 2000-05-23 | 2017-12-29 | Univ Degli Studi Cagliari | Methods and compositions for treating hepatitis c virus |
CN1315862C (zh) | 2000-05-26 | 2007-05-16 | 艾登尼科斯(开曼)有限公司 | 处理黄病毒和瘟病毒的方法和组合物 |
US7208167B2 (en) | 2000-08-07 | 2007-04-24 | Sciclone Pharmaceuticals, Inc. | Treatment of hepatitis C with thymosin and peptide combination therapy |
MXPA03001145A (es) * | 2000-08-07 | 2004-08-02 | Sciclone Pharmaceuticals Inc | Composicion farmaceutica para el tratamiento de la hepatitis c con timocina, interferon y ribavirin. |
US7179791B2 (en) | 2001-01-11 | 2007-02-20 | Duke University | Inhibiting GS-FDH to modulate NO bioactivity |
KR100480429B1 (ko) * | 2001-12-04 | 2005-04-06 | 선바이오(주) | 인터페론-알파와 폴리에틸렌글리콜 유도체의 배합체 |
US7608600B2 (en) | 2002-06-28 | 2009-10-27 | Idenix Pharmaceuticals, Inc. | Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections |
US7456155B2 (en) | 2002-06-28 | 2008-11-25 | Idenix Pharmaceuticals, Inc. | 2′-C-methyl-3′-O-L-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections |
NZ537662A (en) * | 2002-06-28 | 2007-10-26 | Idenix Cayman Ltd | 2'-C-methyl-3'-O-L-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections |
CN103319554A (zh) | 2002-06-28 | 2013-09-25 | 埃迪尼克斯医药公司 | 用于治疗黄病毒感染的修饰的2’和3’-核苷前药 |
EP1576138B1 (en) | 2002-11-15 | 2017-02-01 | Idenix Pharmaceuticals LLC. | 2'-methyl nucleosides in combination with interferon and flaviviridae mutation |
KR20050109918A (ko) * | 2002-12-12 | 2005-11-22 | 이데닉스 (케이만) 리미티드 | 2'-분지형 뉴클레오시드의 제조 방법 |
WO2004058792A1 (en) * | 2002-12-23 | 2004-07-15 | Idenix (Cayman) Limited | Process for the production of 3'-nucleoside prodrugs |
ES2726998T3 (es) | 2003-05-30 | 2019-10-11 | Gilead Pharmasset Llc | Análogos de nucleósidos fluorados modificados |
BRPI0512360A (pt) * | 2004-06-23 | 2008-03-11 | Idenix Cayman Ltd | derivados de 5-aza-7-deazapurina para o tratamento de flaviviridae |
US7857760B2 (en) | 2004-07-13 | 2010-12-28 | Dexcom, Inc. | Analyte sensor |
NZ554442A (en) | 2004-09-14 | 2011-05-27 | Pharmasset Inc | Preparation of 2'fluoro-2'-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives |
WO2006056464A2 (en) | 2004-11-26 | 2006-06-01 | Pieris Ag | Compound with affinity for the cytotoxic t lymphocyte-associated antigen (ctla-4) |
CA2617958A1 (en) * | 2005-08-15 | 2007-02-22 | F. Hoffmann-La Roche Ag | Peg-ifn alpha and ribavirin for hbv treatment |
US9201979B2 (en) * | 2005-09-14 | 2015-12-01 | Millennial Media, Inc. | Syndication of a behavioral profile associated with an availability condition using a monetization platform |
EP1976382B1 (en) * | 2005-12-23 | 2013-04-24 | IDENIX Pharmaceuticals, Inc. | Process for preparing a synthetic intermediate for preparation of branched nucleosides |
US7964580B2 (en) | 2007-03-30 | 2011-06-21 | Pharmasset, Inc. | Nucleoside phosphoramidate prodrugs |
TW200946541A (en) | 2008-03-27 | 2009-11-16 | Idenix Pharmaceuticals Inc | Solid forms of an anti-HIV phosphoindole compound |
EP3381933B1 (en) | 2008-06-24 | 2020-06-03 | Technische Universität München | Muteins of hngal and related proteins with affinity for a given target |
CN102159245B (zh) * | 2008-09-17 | 2013-07-24 | 贝林格尔.英格海姆国际有限公司 | Hcv ns3蛋白酶抑制剂与干扰素和利巴韦林的组合 |
CN102325783A (zh) | 2008-12-23 | 2012-01-18 | 法莫赛特股份有限公司 | 嘌呤核苷的合成 |
PA8855601A1 (es) | 2008-12-23 | 2010-07-27 | Forformidatos de nucleósidos | |
CA2748034A1 (en) | 2008-12-23 | 2010-07-01 | Pharmasset, Inc. | Purified 2'-deoxy'2'-fluoro-2'-c-methyl-nucleoside-phosphoramidate prodrugs for the treatment of viral infections |
WO2010129947A2 (en) | 2009-05-08 | 2010-11-11 | Sciclone Pharmaceuticals, Inc. | Alpha thymosin peptides as vaccine enhancers |
US8618076B2 (en) | 2009-05-20 | 2013-12-31 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
TWI576352B (zh) | 2009-05-20 | 2017-04-01 | 基利法瑪席特有限責任公司 | 核苷磷醯胺 |
RU2012107812A (ru) | 2009-08-05 | 2013-09-10 | Аллерган, Инк. | Препараты мутеинов липокалинов с контролируемым высвобождением |
BR112012010110A2 (pt) | 2009-10-30 | 2019-09-24 | Boehringer Ingelheim Int | regimes de dosagem para terapia combinada para hcv compreendendo bi201335, interferon alfa e ribavirina |
RU2707126C2 (ru) | 2009-12-07 | 2019-11-22 | Пирис Аг | МУТЕИНЫ ЛИПОКАЛИНА 2 ЧЕЛОВЕКА (Lcn2, hNGAL) С АФФИННОСТЬЮ ДЛЯ ОПРЕДЕЛЕННОЙ МИШЕНИ |
SG184323A1 (en) | 2010-03-31 | 2012-11-29 | Gilead Pharmasett Llc | Stereoselective synthesis of phosphorus containing actives |
US8986951B2 (en) | 2010-06-08 | 2015-03-24 | Pieris Ag | Tear lipocalin in muteins binding IL-4 R alpha |
CN103154023B (zh) | 2010-08-16 | 2017-04-05 | 皮里斯制药有限公司 | 铁调素的结合蛋白 |
US9260492B2 (en) | 2010-11-15 | 2016-02-16 | Pieris Ag | Muteins of human lipocalin 2 with affinity for glypican-3 (GPC-3) |
CA2818853A1 (en) | 2010-11-30 | 2012-06-07 | Gilead Pharmasset Llc | 2'-spirocyclo-nucleosides for use in therapy of hcv or dengue virus |
US9221885B2 (en) | 2010-12-02 | 2015-12-29 | Pieris Ag | Muteins of human lipocalin 2 with affinity for CTLA-4 |
MX354958B (es) | 2011-09-16 | 2018-03-27 | Gilead Pharmasset Llc | Metodos para el tratamiento de vhc. |
US8889159B2 (en) | 2011-11-29 | 2014-11-18 | Gilead Pharmasset Llc | Compositions and methods for treating hepatitis C virus |
CN103998053B9 (zh) | 2011-12-13 | 2020-07-21 | 皮里斯制药有限公司 | 通过抑制il-4和/或il-13与其各自的受体结合来预防或治疗某些障碍的方法 |
US9522940B2 (en) | 2012-05-23 | 2016-12-20 | Pieris Pharmaceuticals Gmbh | Lipocalin muteins with binding-affinity for glypican-3 (GPC-3) and use of lipocalin muteins for target-specific delivery to cells expressing GPC-3 |
US20140039923A1 (en) * | 2012-08-03 | 2014-02-06 | AxelaCare Health Solutions, Inc. | Computer program, method, and system for receiving and managing patient data gathered during patient treatments |
PL2950786T3 (pl) | 2013-01-31 | 2020-05-18 | Gilead Pharmasset Llc | Formulacja skojarzona dwóch związków przeciwwirusowych |
EP2968490A1 (en) | 2013-03-14 | 2016-01-20 | Daiichi Sankyo Co., Ltd. | Novel binding proteins for pcsk9 |
CA2891557A1 (en) | 2013-03-26 | 2014-05-22 | Pieris Ag | Novel specific-binding polypeptides and uses thereof |
PL3038601T3 (pl) | 2013-08-27 | 2020-08-24 | Gilead Pharmasset Llc | Formulacja złożona dwóch związków przeciwwirusowych |
EP3094650A2 (en) | 2014-01-13 | 2016-11-23 | Pieris Pharmaceuticals GmbH | Multi-specific polypeptide useful for localized tumor immunomodulation |
US10774119B2 (en) | 2014-05-22 | 2020-09-15 | Pieris Pharmaceuticals Gmbh | Specific-binding polypeptides and uses thereof |
BR112017015773A2 (pt) | 2015-01-28 | 2018-03-27 | Pieris Pharmaceuticals Gmbh | muteína de lipocalina, muteína de hngal, molécula de ácido nucleico, célula hospedeira, método para produzir a muteína de hngal, composição farmacêutica, kit, uso da muteína de hngal, uso da muteína de hngal, método para ligar ang-2 em um indivíduo, método para inibir angiogênese em um indivíduo, método para tratar, prevenir ou melhorar uma doença e método para inibir ou reduzir angiogênese em um indivíduo |
TN2017000348A1 (en) | 2015-02-18 | 2019-01-16 | Sanofi Sa | Novel proteins specific for pyoverdine and pyochelin |
SG11201708334RA (en) | 2015-05-04 | 2017-11-29 | Pieris Pharmaceuticals Gmbh | Anti-cancer fusion polypeptide |
RU2736312C2 (ru) | 2015-05-04 | 2020-11-13 | ПИЕРИС ФАРМАСЬЮТИКАЛС ГмбХ | Белки, специфичные в отношении cd137 |
US10273275B2 (en) | 2015-05-18 | 2019-04-30 | Pieris Pharmaceuticals Gmbh | Muteins of human lipocalin 2 with affinity for glypican-3 (GPC3) and methods of use thereof |
ES2938525T3 (es) | 2015-05-18 | 2023-04-12 | Pieris Pharmaceuticals Gmbh | Polipéptido de fusión anticanceroso |
EP3115371A1 (en) | 2015-07-07 | 2017-01-11 | Sanofi | Fusion molecules |
JP7108535B2 (ja) | 2015-07-15 | 2022-07-28 | ピエリス ファーマシューティカルズ ゲーエムベーハー | Lag-3に特異的な新規タンパク質 |
AU2016363668A1 (en) | 2015-11-30 | 2018-05-24 | Pieris Australia Pty Ltd. | Novel anti-angiogenic fusion polypeptides |
TW201725212A (zh) | 2015-12-10 | 2017-07-16 | 第一三共股份有限公司 | 特異性於降鈣素基因相關胜肽的新穎蛋白 |
WO2018087108A1 (en) | 2016-11-09 | 2018-05-17 | Pieris Pharmaceuticals Gmbh | Proteins specific for cd137 |
CN110402252A (zh) | 2017-01-18 | 2019-11-01 | 皮里斯制药有限公司 | 对lag-3具有结合亲和力的脂质运载蛋白突变蛋白 |
CA3100119A1 (en) | 2018-07-31 | 2020-02-06 | Pieris Pharmaceuticals Gmbh | Fusion protein specific for cd137 and pd-l1 |
US20220153864A1 (en) | 2019-02-26 | 2022-05-19 | Pieris Pharmaceuticals Gmbh | Novel Fusion Proteins Specific for CD137 and GPC3 |
WO2021245240A1 (en) | 2020-06-05 | 2021-12-09 | Pieris Pharmaceuticals Gmbh | Multimeric immunomodulator targeting 4-1bb |
JP2024515564A (ja) | 2021-04-08 | 2024-04-10 | ピエリス ファーマシューティカルズ ゲーエムベーハー | 結合組織増殖因子(ctgf)に特異的な新規リポカリンムテイン |
WO2022243341A1 (en) | 2021-05-18 | 2022-11-24 | Pieris Pharmaceuticals Gmbh | Lipocalin muteins with binding affinity for ox40 |
WO2024064713A1 (en) | 2022-09-21 | 2024-03-28 | Seagen Inc. | Novel fusion protein specific for cd137 and cd228 |
Family Cites Families (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4211771A (en) * | 1971-06-01 | 1980-07-08 | Robins Ronald K | Treatment of human viral diseases with 1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide |
EP0098110B1 (en) * | 1982-06-24 | 1989-10-18 | NIHON CHEMICAL RESEARCH KABUSHIKI KAISHA also known as JAPAN CHEMICAL RESEARCH CO., LTD | Long-acting composition |
US4681848A (en) * | 1982-09-22 | 1987-07-21 | Takeda Chemical Industries, Ltd. | Novel peptide and use thereof |
GB8430252D0 (en) * | 1984-11-30 | 1985-01-09 | Beecham Group Plc | Compounds |
US4766106A (en) * | 1985-06-26 | 1988-08-23 | Cetus Corporation | Solubilization of proteins for pharmaceutical compositions using polymer conjugation |
DE3719046A1 (de) * | 1987-06-06 | 1988-12-15 | Basf Ag | Verwendung von salzen von sulfonamidcarbonsaeuren als korrosionsinhibitoren in waessrigen systemen |
US5122614A (en) * | 1989-04-19 | 1992-06-16 | Enzon, Inc. | Active carbonates of polyalkylene oxides for modification of polypeptides |
US5238915A (en) * | 1991-02-08 | 1993-08-24 | Wakunaga Seiyaku K.K. | Aromatic composition and method for controlling aroma |
US5595732A (en) * | 1991-03-25 | 1997-01-21 | Hoffmann-La Roche Inc. | Polyethylene-protein conjugates |
US5281698A (en) * | 1991-07-23 | 1994-01-25 | Cetus Oncology Corporation | Preparation of an activated polymer ester for protein conjugation |
US5382657A (en) * | 1992-08-26 | 1995-01-17 | Hoffmann-La Roche Inc. | Peg-interferon conjugates |
US5359030A (en) * | 1993-05-10 | 1994-10-25 | Protein Delivery, Inc. | Conjugation-stabilized polypeptide compositions, therapeutic delivery and diagnostic formulations comprising same, and method of making and using the same |
US5919455A (en) * | 1993-10-27 | 1999-07-06 | Enzon, Inc. | Non-antigenic branched polymer conjugates |
US5643575A (en) * | 1993-10-27 | 1997-07-01 | Enzon, Inc. | Non-antigenic branched polymer conjugates |
WO1995013090A1 (en) * | 1993-11-10 | 1995-05-18 | Enzon, Inc. | Improved interferon polymer conjugates |
US5932462A (en) * | 1995-01-10 | 1999-08-03 | Shearwater Polymers, Inc. | Multiarmed, monofunctional, polymer for coupling to molecules and surfaces |
TW426523B (en) * | 1995-04-06 | 2001-03-21 | Hoffmann La Roche | Interferon solution |
US5695760A (en) * | 1995-04-24 | 1997-12-09 | Boehringer Inglehiem Pharmaceuticals, Inc. | Modified anti-ICAM-1 antibodies and their use in the treatment of inflammation |
US6387365B1 (en) * | 1995-05-19 | 2002-05-14 | Schering Corporation | Combination therapy for chronic hepatitis C infection |
EP0858343B1 (en) * | 1995-11-02 | 2004-03-31 | Schering Corporation | Continuous low-dose cytokine infusion therapy |
US5908621A (en) * | 1995-11-02 | 1999-06-01 | Schering Corporation | Polyethylene glycol modified interferon therapy |
TW517067B (en) * | 1996-05-31 | 2003-01-11 | Hoffmann La Roche | Interferon conjugates |
US6172046B1 (en) * | 1997-09-21 | 2001-01-09 | Schering Corporation | Combination therapy for eradicating detectable HCV-RNA in patients having chronic Hepatitis C infection |
EP1087778B1 (en) * | 1998-06-08 | 2005-10-26 | F. Hoffmann-La Roche Ag | Use of peg-ifn-alpha and ribavirin for the treatment of chronic hepatitis c |
-
1999
- 1999-05-29 EP EP99927804A patent/EP1087778B1/en not_active Expired - Lifetime
- 1999-05-29 DK DK99927804T patent/DK1087778T3/da active
- 1999-05-29 NZ NZ508249A patent/NZ508249A/xx not_active IP Right Cessation
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2000
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2004
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2007
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