EP1881828A1 - Traitement de l'hepatite c (hcv) au moyen de doses sous-therapeutiques de ribavirine - Google Patents

Traitement de l'hepatite c (hcv) au moyen de doses sous-therapeutiques de ribavirine

Info

Publication number
EP1881828A1
EP1881828A1 EP06759554A EP06759554A EP1881828A1 EP 1881828 A1 EP1881828 A1 EP 1881828A1 EP 06759554 A EP06759554 A EP 06759554A EP 06759554 A EP06759554 A EP 06759554A EP 1881828 A1 EP1881828 A1 EP 1881828A1
Authority
EP
European Patent Office
Prior art keywords
ribavirin
amount
antiviral agent
less
administered
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06759554A
Other languages
German (de)
English (en)
Other versions
EP1881828A4 (fr
Inventor
Zhi Hong
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Valeant Research and Development
Original Assignee
Valeant Research and Development
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Valeant Research and Development filed Critical Valeant Research and Development
Publication of EP1881828A1 publication Critical patent/EP1881828A1/fr
Publication of EP1881828A4 publication Critical patent/EP1881828A4/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K31/33—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
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • 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

Definitions

  • the present invention relates to the field of antiviral therapy with nucleic acid analogues, more specifically it relates to combination drug therapies for the treatment of hepatitis C.
  • Ribavirin has been used for many years as a first-line therapy for the treatment of hepatitis C.
  • the combination of ribavirin with interferon alpha, and more recently in combination with PEG-interferon alpha have been the standard of care for treatment of hepatitis C infections. M. Fried et al, N. E. J. Med. 347:975-982 (2003).
  • ribavirin is directly toxic to red blood cells, and interferon causes bone marrow suppression, so that the maximum dose of ribavirin is typically limited by anemia, and the dose of interferon is limited by thrombocytopenia and neutropenia.
  • these hematologic side effects of ribavirin- interferon therapy have been managed through dose reduction or even cessation of treatment.
  • the present invention provides combinations of ribavirin with other antiviral drugs, wherein what would normally be a sub-therapeutic dose of ribavirin is rendered effective by a synergistic interaction with one or more other antiviral agents.
  • doses of ribavirin below about 800 mg which would ordinarily be without antiviral effect in humans, are found to have an antiviral effect against hepatitis C when combined with a viral protease inhibitor and/or a viral polymerase inhibitor.
  • the resulting combination treatment keeps the dose of ribavirin below levels that might induce anemia, but is nonetheless effective against HCV.
  • Ribavirin has been shown to exhibit synergy with drugs other than interferon alpha, including didanosine (M. Klein et al, AIDS, 17:1001-1008 (2003)); quercetin (W. Li et al, Oncol. Res. 11:243-247 (1999)); pokeweed antiviral protein (E. Weaver and G. Aron, Can. J. Microbiol./Rev. Can. Microbiol. 44:702-705 (1998)); neuraminidase inhibitors (D. Smee et al, Chemotherapy 48:88-93 (2002)); docosanol (J. Marcelletti, Antiviral Res.
  • didanosine M. Klein et al, AIDS, 17:1001-1008 (2003)
  • quercetin W. Li et al, Oncol. Res. 11:243-247 (1999)
  • pokeweed antiviral protein E. Weaver and G. Aron, Can. J. Microbiol./Rev
  • the invention provides methods for treating an HCV infection in a mammal, which comprise administering an amount of ribavirin that is normally ineffective for treating HCV infection when administered alone.
  • This sub-therapeutic dose is rendered effective by also admim ' stering at least one additional antiviral agent.
  • additional agents include, but are not limited to, NS 3/4 A protease inhibitors, RNA-dependent RNA polymerase (NS 5 B) inhibitors, and inosine monophosphate dehydrogenase (IMPDH) inhibitors.
  • the combination of the additional agent with ribavirin is more effective for treating HCV infection than an identical amount of the additional antiviral agent when administered alone.
  • the additional antiviral agent is administered in an amount that is ineffective for treating HCV infection when the agent is administered alone.
  • the ribavirin and the additional antiviral agent or agents may be administered at one time, for convenience, or they may be administered separately on separate dosing schedules, to accommodate differing absorption, distribution, metabolism, and excretion kinetics.
  • the method of the invention encompasses the separate administration of ribavirin and an additional antiviral agent, and also encompasses the use of combination compositions.
  • Combination compositions comprise ribavirin and at least one additional antiviral agent, and are preferably prepared in advance in unit dose formulations such as tablets or capsules.
  • the combination composition is administered at therapeutically effective single or divided daily doses.
  • an interferon to enhance the therapeutic effects of high doses of ribavirin is known in the art.
  • This enhancement extends to the low-dose ribavirin combination therapies of the present invention.
  • the invention also provides the methods described above, further comprising the administration of an interferon, preferably an interferon alpha, at therapeutically effective doses.
  • Suitable interferon alphas include, but are not limited to, recombinant interferon-alpha and PEGylated interferon alpha.
  • the amount of ribavirin administered according to the methods of the invention is less than 800 mg per day for a human patient. In certain embodiments, the amount of ribavirin administered is less than 600 mg per day, and in other embodiments it is less than 400. In certain embodiments the amount of ribavirin administered may be less than 200 mg per day.
  • compositions comprising ribavirin as a first antiviral agent, and at least one additional antiviral agent selected from the group consisting of NS3/4A protease inhibitors, RNA-dependent RNA polymerase (NS5B) inhibitors, and IMPDH inhibitors, are provided.
  • the amount of ribavirin is an amount ineffective for treating HCV infection when administered alone, and the combination is more effective for treating an HCV infection than the additional antiviral agent when administered alone at the same dose.
  • the amount of the additional antiviral agent is an amount ineffective for treating HCV infection when administered alone.
  • the amount of ribavirin in the compositions of the invention will be such that a daily dose will total less than 800 mg, less than 600, less than 400, or less than 200 mg, as desired by the practitioner.
  • the daily dose may be contained in a single unit dose intended for once-daily administration, or it may be divided into two or more unit doses for administration at intervals over the course of a day.
  • Suitable NS3/4A protease inhibitors include, but are not limited to, compounds 1 and 2
  • R 1 is an aryl or 5- or 6-membered heteroaryl ring optionally substituted with lower alkyl, amino, or lower acylamino
  • R 2 is H or lower alkyl
  • R 3 is lower alkyl
  • X is OH, NH 2 , NHCOR 4 , or NHSO 2 R 4 , where R 4 is aryl or lower alkyl.
  • lower alkyl encompasses linear, branched, and cyclic C 1 to C 6 hydrocarbon radicals
  • the term “lower acyl” encompasses (lower alkyl)carbonyl radicals.
  • Other suitable compounds are 3 and 4
  • X is N or CH
  • Y is CH 2 or SO 2
  • R 1 is halogen or lower acyl
  • R 2 is H or lower alkyl
  • R 3 is phenyl or naphthyl optionally substituted with lower alkoxy or lower alkoxycarbonyl
  • R 4 is lower alkyl or allyl
  • L is -CH 2 -CH 2 -CH 2 - or -NH-CO-NH-;
  • R 1 is cyclohexyl, cyclopentyl, or isopropyl
  • R 2 is t-butyl or isopropyl
  • R 3 is methyl, ethyl, or propyl
  • R is benzyl or 1-phenylethyl
  • L is CH 2 or CO
  • R 5 is phenyl, 2-naphthyl, or l,2,3,4-tetrahydroisoquinolin-2-yl; and compounds 7 and 8
  • R 1 and R 2 are independently lower alkyl, and X is O or NH.
  • RNA-dependent RNA polymerase inhibitors include, but are not limited to, compounds of structures 9 and 10
  • Ar is a 5- or 6-membered heterocyclic group such as a furan, thiophene, or pyrazine ring;
  • Ar' is indoly-3-yl or phenyl, optionally substituted with hydroxyl, carboxyl, or carboxymethoxy groups; and
  • R 1 and R 2 are independently H, CH 3 , or CO 2 H; any of structures 13 - 15
  • R is an aryl or heteroaryl ring such as phenyl or thiazole, optionally substituted with hydroxyl;
  • L is a linker such as CH2CH2 or C ⁇ C;
  • R' is aminomethyl or carboxyl, L' is NH or NHCO, and
  • X and Y are independently halogen or aminomethyl;
  • R and R' are independently propyl, isopropyl, butyl, or isobutyl; and compounds 20, 21 and 22
  • Ar and Ar' are independently phenyl substituted with one or more halogen, nitrile, thiazol-2-yl, or lower alkyl groups
  • X represents one or more halogen or lower alkyl groups
  • R 1 is optionally substituted alkyl, aryl, or heteroaryl
  • R 2 is optionally substituted cyclopentyl
  • n 0-6.
  • Suitable IMPDH inhibitors include but are not limited to VX-497 (23), mycophenylate mofetil' (24), and analogues thereof.
  • HCV hepatitis C virus
  • a convenient surrogate for use in anti-HCV drug evaluation utilizes bovine viral diarrhea virus (BVDV), a representative pestivirus, for antiviral evaluations.
  • BVDV bovine viral diarrhea virus
  • YFV yellow fever virus
  • Antiviral evaluations using GBV-B virus, phylogenetically the most closely-related virus to HCV, can be used in assays. There is a high level of sequence identity between GBV-B and HCV viruses.
  • HCV RNA Replicons An HCV RNA replicon that contains a stable luciferase reporter is used to measure HCV RNA levels. The activity of the luciferase reporter is directly proportional to HCV RNA levels and antiviral compounds behave comparably using either the luciferase activity or RNA levels as endpoints.
  • GBV-B Virus Ribavirin-drug mixtures are evaluated for antiviral activities and cytoxicities with GBV-B grown in primary hepatocyte cultures. Virus is measured using quantitative RT-PCR. The use of this virus as a surrogate model is desirable due to the.
  • Virion infectivity If ribavirin-drug combinations are mutagenic, or if their incorporation into virion RNA blocks further incorporation of ribonucleotides into the growing RNA strand, the infectivity of the viruses produced under these conditions is reduced dramatically.
  • HCV chronically-infected chimpanzees and GBV-B infected marmosets can be treated with various ribavirin-drug combinations.
  • Solid pharmaceutical compositions according to the invention may be prepared by methods of compounding and tablet and capsule formation well-known in the pharmaceutical arts.
  • a typical unit dose composition will comprise ribavirin, in an amount less than 800 mg, and optionally less than 600 mg, or less than 400 mg, or less than 200 mg.
  • the composition will also comprise a second antiviral agent, in a therapeutically effective amount, or in certain embodiments, in a sub-therapeutic amount.
  • composition may also include pharmaceutically acceptable carriers, including but not limited to solvents, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • pharmaceutically acceptable carriers including but not limited to solvents, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington's Pharmaceutical Sciences, 15th Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1975) discloses various carriers used in formulating pharmaceutical compositions, and known techniques for their compounding and use. Insofar as any conventional carrier medium is compatible with the antiviral compounds of the invention, its use is contemplated to be within
  • Materials which can serve as pharmaceutically acceptable disintegrants and carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, powdered tragacanth, malt, gelatin, silica, and talc.
  • Suitable excipients include but are not limited to cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; and agar.
  • Buffering agents include materials such as magnesium hydroxide, aluminum hydroxide, monobasic and dibasic phosphate salts, and alginic acid.
  • Other additives include but are not limited to compatible lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating agents, and sweetening, flavoring and perfuming agents. Preservatives and antioxidants can also be present in the composition, at the discretion of the practitioner.
  • Liquid pharmaceutical compositions according to the invention may be prepared for oral or parenteral administration.
  • Suitable carriers for parenteral administration include pyrogen-free water, isotonic saline, Ringer's solution, and phosphate buffer solutions. Solutions and suspensions may be lyophilized for storage and shipment, and reconstituted with saline for injection just prior to administration.
  • Liquid compositions suitable for oral administration may be prepared with any of the carriers listed above, and in addition may comprise oils, emulsifiers, and non-aqueous solvents such as ethyl alcohol.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Zoology (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des combinaisons de ribavirine avec d'autres médicaments antiviraux dans lesquelles une dose sous-thérapeutique normale de ribavirine est rendue efficace par interaction synergique avec un ou plusieurs agents(s) antiviral/antiviraux. L'invention concerne également des combinaisons de ribavirine avec d'autres médicaments antiviraux dans lesquelles une dose sous-thérapeutique normale de l'autre médicament est rendue efficace par interaction synergique avec la ribavirine.
EP06759554A 2005-05-20 2006-05-09 Traitement de l'hepatite c (hcv) au moyen de doses sous-therapeutiques de ribavirine Withdrawn EP1881828A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US68341605P 2005-05-20 2005-05-20
PCT/US2006/018228 WO2006127289A1 (fr) 2005-05-20 2006-05-09 Traitement de l'hepatite c (hcv) au moyen de doses sous-therapeutiques de ribavirine

Publications (2)

Publication Number Publication Date
EP1881828A1 true EP1881828A1 (fr) 2008-01-30
EP1881828A4 EP1881828A4 (fr) 2009-06-03

Family

ID=37452331

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06759554A Withdrawn EP1881828A4 (fr) 2005-05-20 2006-05-09 Traitement de l'hepatite c (hcv) au moyen de doses sous-therapeutiques de ribavirine

Country Status (2)

Country Link
EP (1) EP1881828A4 (fr)
WO (1) WO2006127289A1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8466159B2 (en) 2011-10-21 2013-06-18 Abbvie Inc. Methods for treating HCV
US8492386B2 (en) 2011-10-21 2013-07-23 Abbvie Inc. Methods for treating HCV
CH707029B1 (de) 2011-10-21 2015-03-13 Abbvie Inc Verfahren zur Behandlung von HCV, umfassend mindestens zwei direkt wirkende antivirale Wirkstoffe, Ribavirin, aber nicht Interferon.
AU2013201532B2 (en) 2011-10-21 2014-10-02 Abbvie Ireland Unlimited Company Methods for treating HCV
CA2863645A1 (fr) * 2012-02-01 2013-08-08 Samuel Waksal Traitement une fois par jour de l'hepatite c avec de la ribavirine et de la taribavirine
US11192914B2 (en) 2016-04-28 2021-12-07 Emory University Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998017679A1 (fr) * 1996-10-18 1998-04-30 Vertex Pharmaceuticals Incorporated Inhibiteurs de serines proteases, notamment de ns3 protease du virus de l'hepatite c
WO2000024725A1 (fr) * 1998-10-26 2000-05-04 Vertex Pharmaceuticals Incorporated Composes pentacycliques utiles en tant qu'inhibiteurs de l'helicase de ns3 du virus de l'hepatite c
WO2003101199A1 (fr) * 2002-05-31 2003-12-11 Schering Corporation Therapie combinatoire pour infections de virus d'arn impliquant la ribavirine et des inhibiteurs d'impdh
WO2006007693A1 (fr) * 2004-07-16 2006-01-26 Boehringer Ingelheim International Gmbh Inhibiteurs de la polymerase virale
WO2006039488A2 (fr) * 2004-10-01 2006-04-13 Vertex Pharmaceuticals Incorporated Inhibition de la protease ns3-ns4a du vhc

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MXPA04009672A (es) * 2002-04-01 2004-11-12 Pfizer Inhibidores de la rna polimerasa dependiente del rna del virus de la hepatitis c, y las composiciones y los tratamientos que usan los mismos.

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998017679A1 (fr) * 1996-10-18 1998-04-30 Vertex Pharmaceuticals Incorporated Inhibiteurs de serines proteases, notamment de ns3 protease du virus de l'hepatite c
WO2000024725A1 (fr) * 1998-10-26 2000-05-04 Vertex Pharmaceuticals Incorporated Composes pentacycliques utiles en tant qu'inhibiteurs de l'helicase de ns3 du virus de l'hepatite c
WO2003101199A1 (fr) * 2002-05-31 2003-12-11 Schering Corporation Therapie combinatoire pour infections de virus d'arn impliquant la ribavirine et des inhibiteurs d'impdh
WO2006007693A1 (fr) * 2004-07-16 2006-01-26 Boehringer Ingelheim International Gmbh Inhibiteurs de la polymerase virale
WO2006039488A2 (fr) * 2004-10-01 2006-04-13 Vertex Pharmaceuticals Incorporated Inhibition de la protease ns3-ns4a du vhc

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KATO ET AL: "Steroid-Free Induction and Preemptive Antiviral Therapy for Liver Transplant Recipients With Hepatitis C: A Preliminary Report from a Prospective Randomized Study" TRANSPLANTATION PROCEEDINGS, ORLANDO, FL, US, vol. 37, no. 2, 18 April 2005 (2005-04-18), pages 1217-1219, XP022309764 ISSN: 0041-1345 *
NAKA K ET AL: "Mizoribine inhibits hepatitis C virus RNA replication: Effect of combination with interferon-alpha" BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ACADEMIC PRESS INC. ORLANDO, FL, US, vol. 330, no. 3, 13 May 2005 (2005-05-13), pages 871-879, XP004833719 ISSN: 0006-291X *
See also references of WO2006127289A1 *

Also Published As

Publication number Publication date
WO2006127289A1 (fr) 2006-11-30
EP1881828A4 (fr) 2009-06-03

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