[go: up one dir, main page]

WO2013143581A1 - Polythérapie pour le traitement d'une infection par le vhc dans une sous-population de sous-génotype de patients spécifique - Google Patents

Polythérapie pour le traitement d'une infection par le vhc dans une sous-population de sous-génotype de patients spécifique Download PDF

Info

Publication number
WO2013143581A1
WO2013143581A1 PCT/EP2012/055453 EP2012055453W WO2013143581A1 WO 2013143581 A1 WO2013143581 A1 WO 2013143581A1 EP 2012055453 W EP2012055453 W EP 2012055453W WO 2013143581 A1 WO2013143581 A1 WO 2013143581A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
patient
ribavirin
Prior art date
Application number
PCT/EP2012/055453
Other languages
English (en)
Inventor
Wulf Otto Boecher
Gerhard Nehmiz
Wiebke SAUTER
Gerhard G. Steinmann
Heike Zimdahl-Gelling
Original Assignee
Boehringer Ingelheim International Gmbh
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 Boehringer Ingelheim International Gmbh filed Critical Boehringer Ingelheim International Gmbh
Priority to JP2015502107A priority Critical patent/JP2015512900A/ja
Priority to PCT/EP2012/055453 priority patent/WO2013143581A1/fr
Priority to PCT/EP2013/056499 priority patent/WO2013144193A1/fr
Publication of WO2013143581A1 publication Critical patent/WO2013143581A1/fr

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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines 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
    • A61K31/70—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
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention relates to therapeutic combinations comprising Compound (1) as herein described, an interferon alfa and ribavirin.
  • the present invention also relates to methods of using such therapeutic combinations for treating HCV infection or alleviating one or more symptoms thereof in a patient that has been identified as having genetic variations located near the IL28B gene, including SNP rs 12979860 with a non-CC genotype and SNP rs 8099917 with a non-TT genotype.
  • the present invention also provides kits comprising the therapeutic combinations of the present invention.
  • Patent 7,585,845, and as Compound # 1008 in U.S. Patent 7,514,557 Compound (1), and pharmaceutical formulations thereof, can be prepared according to the general procedures found in the above-cited references, all of which are herein incorporated by reference in their entirety.
  • Preferred forms of Compound (1) include the crystalline forms, in particular the crystalline sodium salt form, which can be prepared as described in U.S. Patent Application Publication No. 2010/0093792, also incorporated herein by reference.
  • Combination therapy regimens directed to administering Compound (1) with an interferon- alpha and ribavirin for the treatment of HCV infection are described in U.S. Patent Application Publication Nos. 2010/0068182 and 2011/0268700. It is known in the art that particular HCV subtypes and patient subgenotypes may respond differently to HCV therapy. HCV Genotype la is traditionally more difficult to treat and are less responsive to antiviral therapy than Genotype lb. See, e.g., Ghany, Marc et al. "An Update on Treatment of Genotype 1 Chronic Hepatitis C Virus Infection: 2011 Practice Guideline by the American Association for the Study of Liver Diseases",
  • S Ps single nucleotide polymorphisms located on the long arm of chromosome 19 within the gene cluster of IL-28B (Interleukin (IL) 28B, also called lambda interferon), of the patient undergoing therapy can directly effect the IL-28B (Interleukin (IL) 28B, also called lambda interferon), of the patient undergoing therapy can directly effect the IL-28B (Interleukin (IL) 28B, also called lambda interferon), of the patient undergoing therapy can directly effect the IL-28B (Interleukin (IL) 28B, also called lambda interferon).
  • IL Interleukin
  • IL28B genotype associations have also been found with early viral kinetics during interferon free treatment of HCV patients. See Chu et al., "Effect of IL28B Genotype on Early Viral Kinetics During Interferon-Free Treatment of Patients With Chronic Hepatitis C", Gastroenterology (2012), currently in press, available online January 13, 2012.
  • the present invention provides a method of treating HCV infection or alleviating one or more symptoms thereof in a patient comprising the step of administering to the patient a therapeutic combination comprising a Compound (1) as defined herein, or a
  • the present invention further provides for a packaged pharmaceutical composition comprising a packaging containing one or more doses of Compound (1), or a
  • HCV infection means infection by any subtype of the Hepatitis C Virus, including subtypes 1-6, and includes both acute and chronic HCV infection.
  • Interferon means a member of a family of highly homologous species-specific proteins that inhibit viral replication and cellular proliferation and modulate immune response. Human interferons are grouped into three classes based on their cellular origin and antigenicity: a-interferon (leukocytes), ⁇ -interferon (fibroblasts) and ⁇ -interferon (B cells). Recombinant forms of each group have been developed and are commercially available. Subtypes in each group are based on antigenic/structural characteristics. At least 24 interferon alfas (grouped into subtypes A through H) having distinct amino acid sequences have been identified by isolating and sequencing DNA encoding these peptides.
  • alfa-interferon alfa-interferon
  • interferon alfa interferon alfa
  • Suitable interferon-alfas for the present invention include, but are not limited to, recombinant interferon alfa-2b such as INTRON®-A interferon and VIRAFERON®; recombinant interferon alfa-2a such as ROFERON® interferon; recombinant interferon alfa-2c such as BEROFOR® alfa 2 interferon; interferon alfa-nl, a purified blend of natural alfa interferons such as SUMIFERON® or WELLFERON® interferon alfa-nl (INS); or a consensus alfa interferon such as those described in U.S. Pat. Nos. 4,897,471 and 4,695,623; or interferon alfa-n3, a mixture of natural alfa interferons such as
  • interferon alfa is further intended to include those "pegylated” analogs meaning polyethylene glycol modified conjugates of interferon alfa, preferably interferon alfa-2a and -2b.
  • the preferred polyethylene-glycol-interferon alfa-2b conjugate is PEG12000 - interferon alfa 2b.
  • PEG12000-IFN alfa as used herein means conjugates such as are prepared according to the methods of International Application No. WO 95/13090 and containing urethane linkages between the interferon alfa-2a or -2b amino groups and polyethylene glycol having an average molecular weight of 12000.
  • the preferred PEGi2ooo-interferon alfa-2b is prepared by attaching a PEG polymer to the epsilon amino group of a lysine residue in the IFN alfa-2b molecule.
  • a single PEG12000 molecule is conjugated to free amino groups on an IFN alfa-2b molecule via a urethane linkage. This conjugate is characterized by the molecular weight of PEG12000 attached.
  • the PEG12000-IFN alfa-2b conjugate is formulated as a lyophilized powder for injection.
  • the objective of conjugation of IFN alfa with PEG is to improve the delivery of the protein by significantly prolonging its plasma half-life, and thereby provide protracted activity of IFN alfa.
  • interferon alfa that may be used in the present invention are pegylated alfa-interferons, e.g., pegylated interferon alfa-2a, pegylated interferon alfa- 2b, pegylated consensus interferon or pegylated purified interferon alfa product.
  • pegylated interferon alfa-2a is described, e.g., in European Patent No. EP 0 593 868 and
  • Pegylated interferon alfa-2b is described, e.g., in U.S. Patent No. 5,908,621 and WO 98/48840 and commercially-available, e.g., under the tradename PEG-INTRON® A (Schering Plough).
  • Pegylated consensus interferon is described in WO 96/11953.
  • the preferred pegylated alfa interferons are pegylated interferon alfa-2a and pegylated interferon alfa-2b. Also preferred is pegylated consensus interferon.
  • interferon alfa further includes other interferon alfa conjugates that can be prepared by coupling an interferon alfa to a water-soluble polymer.
  • a non-limiting list of such polymers includes other polyalkylene oxide homopolymers such as polyethylene glycol (PEG), polypropylene glycols, polyoxyethylenated polyols, copolymers thereof and block copolymers thereof.
  • PEG polyethylene glycol
  • polypropylene glycols polypropylene glycols
  • polyoxyethylenated polyols copolymers thereof
  • block copolymers thereof block copolymers thereof.
  • polyalkylene oxide-based polymers effectively non-antigenic materials such as dextran, polyvinylpyrrolidones,
  • polyacrylamides polyvinyl alcohols, carbohydrate-based polymers and the like can be used.
  • interferon alfa-polymer conjugates are described in U.S. Pat. No. 4,766, 106, U.S. Pat. No. 4,917,888, European Patent Application No. 0 236 987, European Patent Application Nos. 0510 356, 0 593 868 and 0 809 996 (pegylated interferon alfa-2a) and International Publication No. WO 95/13090.
  • interferon alfa further includes fusion proteins of an interferon alfa, for example fusion proteins of interferon-a-2a, interferon- a-2b, consensus interferon or purified interferon-a product, each of which is fused with another protein.
  • Certain preferred fusion proteins comprise an interferon (e.g., interferon-a-2b) and an albumin as described in U.S. Patent 6,972,322 and international publications WO2005/003296 and WO2005/077042.
  • consensus interferons such as INFERGEN®.
  • pharmaceutically acceptable salt means a salt of a Compound of formula (1) which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, generally water or oil- soluble or dispersible, and effective for their intended use.
  • pharmaceutically-acceptable acid addition salts and pharmaceutically- acceptable base addition salts. Lists of suitable salts are found in, e.g., S. M. Birge et al, J. Pharm. Sci., 1977, 66, pp. 1-19.
  • pharmaceutically-acceptable acid addition salt means those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, butyric acid, camphoric acid,
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, and the like
  • organic acids such as acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, butyric acid, camphoric acid,
  • camphorsulfonic acid cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphoric acid, hemisulfic acid, hexanoic acid, formic acid, fumaric acid, 2-hydroxyethane-sulfonic acid (isethionic acid), lactic acid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid, mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid, pectinic acid, phenylacetic acid, 3-phenylpropionic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-tolu
  • pharmaceutically-acceptable base addition salt means those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable, formed with inorganic bases such as ammonia or hydroxide, carbonate, or bicarbonate of ammonium or a metal cation such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts.
  • Salts derived from pharmaceutically-accepta- ble organic nontoxic bases include salts of primary, secondary, and tertiary amines, quaternary amine compounds, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion- exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N- ethylpiperidine, tetramethylammonium compounds, tetraethyl
  • organic nontoxic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • Rabavirin refers to l-P-D-ribofuranosyl-lH-l,2,4-triazole-3-carboxamide, available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif, and is described in the Merck Index, compound No. 8199, Eleventh Edition. Its manufacture and formulation is described in U.S. Pat. No. 4,211,771. Preferred marketed ribavirin products include REBETOL® and COPEGUS®. The term further includes derivatives or analogs thereof, such as those described in U.S. Pat. Nos. 6,063,772, 6,403,564 and 6,277,830.
  • derivatives or analogs include modified ribavirins such as 5'-amino esters, ICN Pharmaceutical's L- enantiomer of ribavirin (ICN 17261), 2'-deoxy derivatives of ribavirin and 3- carboxamidine derivatives of ribavirin, viramidine (previously known as ribamidine) and the like.
  • modified ribavirins such as 5'-amino esters, ICN Pharmaceutical's L- enantiomer of ribavirin (ICN 17261), 2'-deoxy derivatives of ribavirin and 3- carboxamidine derivatives of ribavirin, viramidine (previously known as ribamidine) and the like.
  • therapeutic combination means a combination of one or more active drug substances, i.e., compounds having a therapeutic utility.
  • each such compound in the therapeutic combinations of the present invention will be present in a pharmaceutical composition comprising that compound and a pharmaceutically acceptable carrier.
  • the compounds in a therapeutic combination of the present invention may be administered simultaneously or separately, as part of a regimen.
  • the present invention provides for a method of treating HCV infection or alleviating one or more symptoms thereof in a patient comprising the step of administering to the patient a therapeutic combination comprising a Compound (1) as defined herein, or a pharmaceutically acceptable salt thereof, together with an interferon alfa and ribavirin and wherein the patient has a non-CC genotype of S P rsl2979860 or a non-TT genotype of S P rs 8099917 located near the IL28B gene.
  • the present invention teaches the use of a Compound (1) as defined herein, or a pharmaceutically acceptable salt thereof, an interferon alfa, and ribavirin for the preparation of a pharmaceutical kit to treat a hepatitis C viral (HCV) infection or alleviating one or more symptoms thereof in a patient and wherein the patient has a non-CC genotype of SNP rsl2979860 or a non-TT genotype of SNP rs 8099917 located near the IL28B gene.
  • HCV hepatitis C viral
  • each active agent can be administered together at the same time or separately at different times in separate dosage administrations.
  • the present invention contemplates and includes all such dosage regimens when administering the triple therapeutic combinations as defined herein.
  • HCV genotype 1 infection including subtypes la and lb, and also having a non-CC genotype of SNP rsl2979860 or a non-TT genotype of SNP rs 8099917 located near the IL28B gene.
  • Particular embodiments include the following patient sub-populations:
  • HCV subtype lb and G/G genotype of SNP rs8099917 A preferred embodiment is directed to the treatment of patients have the HCV subtype la and either the C/T or T/T genotype of SNP 12979860 or the G/T or G/G genotype of SNP rs 8099917 located near the IL28B gene, which represent particularly diffi cult-to-treat HCV-infected patient populations.
  • the patient has first been identified as having a non-CC genotype of S P rsl2979860 or a non-TT genotype of SNP rs 8099917 located near the IL-28B gene prior to the step of administering the therapeutic combination of the present invention. Methods for such genotypic identification as are set forth in detail herein.
  • the patient population to be treated with the combination therapy of the present invention can be further classified into "treatment-naive" patients, i.e., those patient who have not received any prior treatment for HCV infection and "treatment experienced” patients, i.e, those patients who have undergone prior treatment for HCV. Either of these classes of patients may be treated with the combination therapy of the present invention.
  • the clinical data presented hereinafter is directed to treatment naive patients only. Nevertheless, there is an expectation that similar efficacy results will be seen in treatment experienced patients.
  • a particular class of patients that are preferably treated are those treatment experienced patients that have undergone prior interferon plus ribavirin therapy but are non-responsive to said therapy (herein "non-responders").
  • non-responders include three distinct groups of patients: (1) those who experienced ⁇ lx logio maximum reduction in HCV RNA levels during treatment with interferon plus ribavirin ("null responders"), (2) those who experienced > lx logio maximum reduction in HCV RNA levels during treatment with interferon plus ribavirin but never achieve HCV RNA levels below level of detection (“partial responders”), and (3) those who achieved undetectable HCV RNA levels with and during interferon plus ribavirin therapy but had a viral load rebound after treatment has completed (“relapser”).
  • Another treatment experienced patient population to be treated with the combination therapy of the present invention includes those who achieved an initial virologic response with (pegylated) interferon plus ribavirin but had viral load rebound during treatment other than due to nonadherence to the treatment.
  • the present invention provides a method of reducing HCV-RNA levels in a patient in need thereof, comprising the step of
  • the method of the present invention reduces the HCV-RNA levels in a patient to a level below the lower limit of quantification (or "BLQ").
  • a BLQ level of HCV RNA as used in the present invention means a level below 25 International Units (IU) per ml of serum or plasma of a patient as measured by quantitative, multi-cycle reverse transcriptase PCR methodology according to the WHO international standard (Saladanha J, Lelie N and Heath A, Establishment of the first international standard for nucleic acid amplification technology (NAT) assays for HCV RNA. WHO Collaborative Study Group. Vox Sang 76: 149-158, 1999). Such methods are well known in the art.
  • the method of the present invention reduces the HCV-RNA levels in a patient to less than 25 R7 per ml of serum or plasma. In another embodiment the method of the present invention reduces the HCV-RNA levels in a patient to less than a detectible level.
  • the method of the present invention reduces the HCV-RNA levels in a patient to less than 25 IU per ml of serum, even more preferably to less than 10 IU per ml of serum.
  • the method of the present invention reduces the HCV-RNA levels in a patient to less than a detectible level (below the limit of detection, BLD).
  • Treatment decisions for duration of HCV therapy can be made based on BLD, and combinations of BLQ and BLD HCV RNA at subsequent timepoints during initial treatment. Typical time points include HCV RNA measurements at 4, 8, and 12 weeks after initiation of therapy, and results are utilized to guide further treatment duration "response-guided therapy". Cure from HCV infection is typically inferred if HCV RNA remained BLD 12-24 weeks after end of HCV treatment.
  • the method of the present invention results in an HCV-RNA level in the patient that is less than a detectible level at 12 weeks, preferably 24 weeks, after the end of all treatment.
  • the usual duration of the treatment for standard interferon plus ribavirin therapy is at least 48 weeks, and up to 72 weeks, for chronic infection with HCV genotype 1 or 4; 48 weeks for the majority of patients with chronic HCV genotype 2 or 3 infection.
  • a few patients with chronic HCV genotype 2 and 3 infection may be treated with 24 weeks of interferon alpha and ribavirin.
  • Compound (1), or a pharmaceutically acceptable salt thereof, in the triple combination therapy of the present invention it may be possible to have a much shorter duration of treatment.
  • the contemplated durations of treatment include at least 4 weeks, preferably at least 12 weeks, e.g., from about 12 weeks to about 24 weeks, although treatment up to and even beyond 48 weeks is possible as well.
  • further embodiments include treatment for at least 24 weeks and for at least 48 weeks.
  • the duration of treatment of chronic HCV infection may vary depending upon the specific HCV genotype. For example, the typical duration of treatment will be longer for genotypes 1 and 4, than for genotypes 2 and 3.
  • the treatment duration will be shorter for the treatment of acute infection as compared to chronic infection.
  • an initial treatment regimen with the triple combination therapy of the present invention followed by a continuation of only the interferon plus ribavirin double combination therapy.
  • possible scenarios for the initial triple and then double combination therapy include, for example: (1) 4 weeks of the triple combination therapy, followed by 8 to 44 weeks of the interferon plus ribavirin only therapy; (2) 12 weeks of the triple combination therapy, followed by 0 to 36 weeks of the interferon plus ribavirin only therapy; and (3) 24 weeks of the triple combination therapy, followed by 0 to 24 weeks of the interferon plus ribavirin only therapy.
  • the first component of the therapeutic combination namely, Compound (1) or a pharmaceutically acceptable salt thereof is comprised in a composition.
  • composition comprises Compound (1), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant or carrier.
  • Typical pharmaceutical compositions that may be used for Compound (1), or a pharmaceutically acceptable salt thereof, are as described in U.S. Patent 7,585,845, WO 2010/059667 and WO 2011/005646.
  • the Compound (1) or a pharmaceutically acceptable salt thereof may be administered at a maintenance dosage of at least 40 mg/day (in single or divided doses). Additional embodiments for dosage amounts and ranges may include (in single or divided doses):
  • Compound (1) or a pharmaceutically acceptable salt thereof may be administered in single or divided daily doses, once a day administration (QD) of the daily dose is preferred. As the skilled artisan will appreciate, however, lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combinations (co- medications), the severity and course of the infection, the patient's disposition to the infection and the judgment of the treating physician.
  • a loading dose amount of Compound (1) is administered for the first administration dose of the treatment.
  • the loading dose amount is higher than the dose amount administered for subsequent administrations in the treatment, which are referred to as maintenance doses.
  • the loading dose amount is about double in quantity, by weight, of the amount in subsequent administrations in the treatment.
  • the first dose of Compound (1) administered at a loading dosage of about 240 mg and subsequent maintenance doses of Compound (1) are administered at a dosage of about 120 mg.
  • the first dose of Compound (1) administered at a loading dosage of about 480 mg and subsequent maintenance doses of Compound (1) are administered at a dosage of about 240 mg.
  • the second component of the therapeutic combination namely interferon-alfa
  • a pharmaceutical composition is comprised in a pharmaceutical composition.
  • such compositions are injectible formulations comprising interferon-alfa and a pharmaceutically acceptable adjuvant or carrier and are well known in the art, including in a number of marketed interferon-alfa formulations. See, e.g., the various marketed interferon-alfa products and various patent and other literature related to interferon-alfa cited hereinabove.
  • interferon-alfas that may be used in the combination are as outlined hereinabove in the definitions section.
  • the interferon alfa is a pegylated interferon alfa.
  • the interferon alfa is a pegylated interferon alfa-2a or pegylated interferon alfa-2b.
  • the interferon alfa is PEGASYS® or PEG-INTRON®.
  • interferon alfa products When using known, marketed interferon alfa products, such products may be administered at their labeled dosage levels indicated for interferon plus ribavirin combination therapy for the treatment of HCV infection.
  • triple combination therapy of the present invention it may be possible to use a lower dosage of interferon alfa, e.g., significantly lower than is used the current standard interferon plus ribavirin therapy, while delivering the same or better efficacy than the current standard therapy with less side- effects usually associated with such therapy.
  • the interferon alfa may be administered parenterally one to three times per week, preferably once or twice a week.
  • pegylated interferon alfas these are typically administered once per week and the total weekly dose ranges, e.g., from about 0.5 ⁇ g /kg/week to about 2 ⁇ g /kg/week in case of pegylated interferon alfa-2b, and with respect to pegylated interferon alfa-2a the dosage is independent from the body weight of the host and is typically about 90 to 200 ⁇ g/week, more preferably about 160 to about 200 ⁇ g/week.
  • a standard dosage of pegylated interferon alfa-2b is about 1.5 ⁇ g/kg/week and a standard dosage of pegylated interferon alfa-2a is about 180 ⁇ g/week, together with ribavirin, which is preferably dosed once or twice daily according to body weight and with a total daily dose of about 200-1800 mg/day, in particular, 800- 1200 mg/day of oral ribavirin.
  • the pegylated interferon alfa-2b may be administered at dosages of:
  • the pegylated interferon alfa-2a may be administered at dosages of:
  • the third component of the therapeutic combination namely ribavirin
  • ribavirin is comprised in a pharmaceutical composition.
  • compositions comprise ribavirin and a pharmaceutically acceptable adjuvant or carrier and are well known in the art, including in a number of marketed ribavirin formulations.
  • Formulations comprising ribavirin are also disclosed, e.g., in US Patent 4,211,771.
  • ribavirin The types of ribavirin that may be used in the combination are as outlined hereinabove in the definitions section.
  • the ribavirin is either REBETOL® or COPEGUS® and they may be administered at their labeled dosage levels indicated for interferon plus ribavirin combination therapy for the treatment of HCV infection.
  • the triple combination therapy of the present invention it may be possible to use a lower dosage of ribavirin, e.g., lower than is used the current standard interferon plus ribavirin therapy, while delivering the same or better efficacy than the current standard therapy with less side-effects usually associated with such therapy.
  • the ribavirin may be administered at dosages of (in single or divided doses):
  • the ribavirin composition comprises ribavirin in a formulation suitable for dosing once a day or twice daily.
  • a therapeutic combination comprises about 1000 mg/day dosage of ribavirin, and a dosing of two times a day is desired, then the therapeutic combination will comprise ribavirin in a formulation, e.g., a tablet, containing, e.g., about 200 mg of ribavirin, with the first dose of 600 mg (or 400 mg), followed by a second dose of 400 mg (or 600 mg) at least 6 hours apart.
  • the present invention contemplates and includes all combinations of the various preferred embodiments and sub-embodiments as set forth hereinabove.
  • the present invention contemplates a method of treating hepatitis C viral (HCV) infection or alleviating one or more symptoms thereof in a patient that has the non-CC genotype of S P rs 12979860 or a non-TT genotype of S P rs 8099917 located near the IL28B gene comprising the step of administering to the patient a therapeutic combination comprising: (a) Compound (1) or a pharmaceutically acceptable salt thereof at a dosage
  • pegylated interferon alfa -2a at a dosage of about 160 to about 200 ⁇ g/week or pegylated interferon alfa -2b at a dosage of about 0.5 ⁇ g/kg/week to about 2 ⁇ g/kg/week;
  • ribavirin at a dosage of between about 1000 mg/day to about 1200 mg/day.
  • the present invention contemplates a method of treating hepatitis C viral (HCV) infection or alleviating one or more symptoms thereof in a patient that has the non-CC genotype of SNP rsl2979860 or a non-TT genotype of SNP rs 8099917 located near the IL28B gene comprising the step of administering to the patient a therapeutic combination comprising:
  • ribavirin at a dosage of between about 1000 mg/day to about 1200 mg/day.
  • the HCV infection is genotype 1, preferably genotype la, and the patient is a treatment-naive patient; or
  • the HCV infection is genotype 1, preferably genotype la
  • the patient is a treatment-experienced patient who is non-responsive to a combination therapy of interferon plus ribavirin.
  • the patient has first been identified as having a non-CC genotype of SNP rsl2979860 or a non-TT genotype of SNP rs 8099917 located near the IL-28B gene prior to the step of administering the therapeutic combination of the present invention.
  • Further embodiments include any of the above-mentioned embodiments, and where the Compound (1) or a pharmaceutically acceptable salt thereof is administered once a day, the interferon alpha is administered once a week and the ribavirin is administered twice a day.
  • the present invention contemplates and includes all combinations of the various preferred embodiment
  • the therapeutic regimen of the present invention comprises administering to a patient for at least about 4 weeks, more preferably either at least about 12 weeks or at least about 24 weeks:
  • An additional embodiment is directed to a packaged pharmaceutical composition
  • a packaged pharmaceutical composition comprising a packaging containing one or more doses of Compound (1) or a
  • compositions of Compound (1) or a pharmaceutically acceptable salt thereof can be in the form of any of the standard pharmaceutical dosage forms, e.g. tablets, capsules, and packaged within any of the standard types of
  • packaging materials e.g. bottles, blister-packs, etc.
  • an outer packaging material such as a paper/cardboard box.
  • the written instructions will typically be provided either on the packaging material(s) itself or on a separate paper (a so-called "package insert") that is provided together with the dosage forms within the outer packaging material. All such packaging embodiments and variations thereof are embraced by the present invention.
  • HCV RNA quantification HCV subtyping
  • IL28B genotyping Specific methods that have been used for HCV RNA quantification, HCV subtyping and IL28B genotyping are as detailed below. To the extent that other methods may be known and available in the art, and all are considered embraced within the present invention and can be used in connection therewith.
  • a plasma sample of about 6 ml is obtained from the patients and processed by using the Roche COBAS® TaqMan HCV/HPS assay.
  • the assay has a linear range from 25 to 2000,000,000 IU/ml (2.0 E8 IU/ml) with a lower limit of quantification of 25 IU/ml and a lower limit of detection of 10 IU/ml.
  • the HCV subtype was determined by using the TRUGENE® HCV Genotyping Assay.
  • the assay directly amplifies and sequences the virus allowing direct examination of the viral RNA by producing bi-directional sequences using two fluorescently-labeled DNA primers.
  • the library includes viral isolates to allow determination of the 6 major hepatitis C genotypes and 41 sub-types.
  • Genotype analysis was performed on DNA extracted from blood samples of the patients by using TaqMan PCR based test assays established by Beckman Coulter Genomics
  • genotype analysis consisted of the extraction of genomic DNA from blood samples, the application of established molecular genetic techniques to amplify the specific genetic target sites and the detection and analysis of emission data of the fluorescent TaqMan probes employed in the amplification processes.
  • Three kinds of controls were used for each product: a) one water control included prior to DNA isolation, b) one water control included after DNA isolation and c) one heterozygous and/or one homozygous (wild-type or variant) genotyping control.
  • One example of a pharmaceutical formulation of Compound (1) include an oral solution formulation as disclosed in WO 2010/059667. Additional examples include capsules containing a lipid-based liquid formulation, as disclosed in WO 2011/005646. III. Clinical Results
  • Compound (1) drug product was administered as a softgel capsule filled with a lipid-based formulation containing Compound (1) sodium salt. All references to "Compound (1)" in the below clinical study is the sodium salt form.
  • HCV protease inhibitor Compound (1) results in high and consistent SVR rates- results from SILEN-Cl in treatment naive patients across different baseline factors
  • Compound (1) is a highly potent and specific HCV NS3/4A protease inhibitor given once daily (QD) with strong antiviral activity in chronic HCV genotype-1 (GTl) infection. This study presents a sub-group analyses of difficult-to-treat patients.
  • Viral load was measured by Roche TaqMan (lower limit of quantification 25 IU/mL), Subtype was assessed by NS3/4A sequencing, and IL-28B genotype (from the SNP rs 12979860 ) was collected retrospectively on approximately 50% of patients. Based on slightly reduced response rates in both LI groups of Compound (1), the 240mg QD dose has been selected for phase III evaluation (along with 120mg QD). Comparison of this dose to PR across important patient characteristics are presented here. Main inclusion criteria
  • IL28B genotype collected retrospectively on 50% of patients
  • the percentage of patients achieving eRVR and thus eligible for 24 weeks overall treatment duration was 87.3% with consistently high rates across all subgroups including non-CC patients.
  • a eRVR HCV RNA ⁇ 25 IU/mL at Week 4 and undetectable at Weeks 8-20
  • ALT alanine transaminase
  • GGT gamma-glutamyl transpeptidase
  • ULN upper limit of norm
  • BL VL baseline HCV RNA in IU/mL
  • polymorphism are less likely to achieve SVR with PeglFN/RBV treatment.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Zoology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Analytical Chemistry (AREA)
  • Virology (AREA)
  • Wood Science & Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Oncology (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Communicable Diseases (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne des combinaisons thérapeutiques comprenant (a) le composé (1) ou son sel pharmaceutiquement acceptable tel que décrit ici, (b) un interféron alfa, et (c) de la ribavirine. Ledit composé (1) est un puissant inhibiteur sélectif de la sérine protéase NS3 du VHC. La présente invention porte en outre sur des procédés d'utilisation de ces combinaisons thérapeutiques dans le traitement d'une infection par le VHC ou l'atténuation d'un ou de plusieurs de ses symptômes, chez des patients présentant des variations génétiques situées à proximité du gène IL28B, dont SNP rs 12979860 avec un génotype non-CC et SNP rs 8099917 avec un génotype non-TT.
PCT/EP2012/055453 2012-03-28 2012-03-28 Polythérapie pour le traitement d'une infection par le vhc dans une sous-population de sous-génotype de patients spécifique WO2013143581A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2015502107A JP2015512900A (ja) 2012-03-28 2012-03-28 特別な患者の遺伝子亜型分集団のｈｃｖ感染症を治療するための併用療法
PCT/EP2012/055453 WO2013143581A1 (fr) 2012-03-28 2012-03-28 Polythérapie pour le traitement d'une infection par le vhc dans une sous-population de sous-génotype de patients spécifique
PCT/EP2013/056499 WO2013144193A1 (fr) 2012-03-28 2013-03-27 Thérapie combinée destinée au traitement d'une infection par le vhc dans une sous-population de sous-génotype de patients spécifique

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2012/055453 WO2013143581A1 (fr) 2012-03-28 2012-03-28 Polythérapie pour le traitement d'une infection par le vhc dans une sous-population de sous-génotype de patients spécifique

Publications (1)

Publication Number Publication Date
WO2013143581A1 true WO2013143581A1 (fr) 2013-10-03

Family

ID=48013997

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/EP2012/055453 WO2013143581A1 (fr) 2012-03-28 2012-03-28 Polythérapie pour le traitement d'une infection par le vhc dans une sous-population de sous-génotype de patients spécifique
PCT/EP2013/056499 WO2013144193A1 (fr) 2012-03-28 2013-03-27 Thérapie combinée destinée au traitement d'une infection par le vhc dans une sous-population de sous-génotype de patients spécifique

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/EP2013/056499 WO2013144193A1 (fr) 2012-03-28 2013-03-27 Thérapie combinée destinée au traitement d'une infection par le vhc dans une sous-population de sous-génotype de patients spécifique

Country Status (2)

Country Link
JP (1) JP2015512900A (fr)
WO (2) WO2013143581A1 (fr)

Citations (26)

* Cited by examiner, † Cited by third party
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
US4530901A (en) 1980-01-08 1985-07-23 Biogen N.V. Recombinant DNA molecules and their use in producing human interferon-like polypeptides
EP0236987A2 (fr) 1986-03-10 1987-09-16 F. Hoffmann-La Roche Ag Protéines chimiquement modifiées et leur production
US4695623A (en) 1982-05-06 1987-09-22 Amgen Consensus human leukocyte interferon
US4766106A (en) 1985-06-26 1988-08-23 Cetus Corporation Solubilization of proteins for pharmaceutical compositions using polymer conjugation
US4917888A (en) 1985-06-26 1990-04-17 Cetus Corporation Solubilization of immunotoxins for pharmaceutical compositions using polymer conjugation
EP0510356A1 (fr) 1991-03-25 1992-10-28 F. Hoffmann-La Roche Ag Conjugués polyéthylène glycol-protéine
EP0593868A1 (fr) 1992-08-26 1994-04-27 F. Hoffmann-La Roche Ag Conjugués PEG-interféron
WO1995013090A1 (fr) 1993-11-10 1995-05-18 Enzon, Inc. Produits de conjugaison ameliores d'un interferon avec un polymere
WO1996011953A1 (fr) 1994-10-12 1996-04-25 Amgen Inc. Compositions de proteines ayant subi une modification chimique a l'extremite n-terminale et procedes
EP0809996A2 (fr) 1996-05-31 1997-12-03 F. Hoffmann-La Roche Ag Conjugués de l'interféron
WO1998048840A1 (fr) 1997-04-29 1998-11-05 Schering Corporation Conjugues polyethyleneglycol-interferon alpha, pour la therapie des infections
US6063772A (en) 1996-01-23 2000-05-16 Icn Pharmaceuticals, Inc. Specific modulation of Th1/Th2 cytokine expression by ribavirin in activated T-lymphocytes
US6277830B1 (en) 1998-10-16 2001-08-21 Schering Corporation 5′-amino acid esters of ribavirin and the use of same to treat hepatitis C with interferon
US6323180B1 (en) 1998-08-10 2001-11-27 Boehringer Ingelheim (Canada) Ltd Hepatitis C inhibitor tri-peptides
US6403564B1 (en) 1998-10-16 2002-06-11 Schering Corporation Ribavirin-interferon alfa combination therapy for eradicating detectable HCV-RNA in patients having chronic hepatitis C infection
WO2005003296A2 (fr) 2003-01-22 2005-01-13 Human Genome Sciences, Inc. Proteines hybrides d'albumine
WO2005077042A2 (fr) 2004-02-09 2005-08-25 Human Genome Sciences, Inc. Proteines hybrides d'albumine
US6972322B2 (en) 1992-01-31 2005-12-06 Aventis Behring L.L.C. Interferon and albumin fusion protein
US7514557B2 (en) 2004-05-25 2009-04-07 Boehringer Ingelheim International Gmbh Process for preparing acyclic HCV protease inhibitors
US7585845B2 (en) 2003-05-21 2009-09-08 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor compounds
US20100068182A1 (en) 2008-09-17 2010-03-18 Boehringer Ingelheim International Gmbh Combination therapy for treating hcv infection
US20100093792A1 (en) 2008-09-16 2010-04-15 Boehringer Ingelheim International Gmbh Crystalline forms of a potent hcv inhibitor
WO2010059667A1 (fr) 2008-11-21 2010-05-27 Boehringer Ingelheim International Gmbh Composition pharmaceutique d'un inhibiteur puissant du vhc pour une administration orale
WO2011005646A2 (fr) 2009-07-07 2011-01-13 Boehringer Ingelheim International Gmbh Composition pharmaceutique pour un inhibiteur de protéase virale de l'hépatite c
WO2011053617A1 (fr) * 2009-10-30 2011-05-05 Boehringer Ingelheim International Gmbh Régimes posologiques pour une thérapie en combinaison contre le vhc comprenant bi201335, l'interféron alpha et la ribavirine

Patent Citations (30)

* Cited by examiner, † Cited by third party
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
US4530901A (en) 1980-01-08 1985-07-23 Biogen N.V. Recombinant DNA molecules and their use in producing human interferon-like polypeptides
US4897471A (en) 1982-05-06 1990-01-30 Amgen Consensus human leukocyte interferon
US4695623A (en) 1982-05-06 1987-09-22 Amgen Consensus human leukocyte interferon
US4917888A (en) 1985-06-26 1990-04-17 Cetus Corporation Solubilization of immunotoxins for pharmaceutical compositions using polymer conjugation
US4766106A (en) 1985-06-26 1988-08-23 Cetus Corporation Solubilization of proteins for pharmaceutical compositions using polymer conjugation
EP0236987A2 (fr) 1986-03-10 1987-09-16 F. Hoffmann-La Roche Ag Protéines chimiquement modifiées et leur production
EP0510356A1 (fr) 1991-03-25 1992-10-28 F. Hoffmann-La Roche Ag Conjugués polyéthylène glycol-protéine
US6972322B2 (en) 1992-01-31 2005-12-06 Aventis Behring L.L.C. Interferon and albumin fusion protein
EP0593868A1 (fr) 1992-08-26 1994-04-27 F. Hoffmann-La Roche Ag Conjugués PEG-interféron
WO1995013090A1 (fr) 1993-11-10 1995-05-18 Enzon, Inc. Produits de conjugaison ameliores d'un interferon avec un polymere
WO1996011953A1 (fr) 1994-10-12 1996-04-25 Amgen Inc. Compositions de proteines ayant subi une modification chimique a l'extremite n-terminale et procedes
US5908621A (en) 1995-11-02 1999-06-01 Schering Corporation Polyethylene glycol modified interferon therapy
US6063772A (en) 1996-01-23 2000-05-16 Icn Pharmaceuticals, Inc. Specific modulation of Th1/Th2 cytokine expression by ribavirin in activated T-lymphocytes
EP0809996A2 (fr) 1996-05-31 1997-12-03 F. Hoffmann-La Roche Ag Conjugués de l'interféron
WO1998048840A1 (fr) 1997-04-29 1998-11-05 Schering Corporation Conjugues polyethyleneglycol-interferon alpha, pour la therapie des infections
US6323180B1 (en) 1998-08-10 2001-11-27 Boehringer Ingelheim (Canada) Ltd Hepatitis C inhibitor tri-peptides
USRE40525E1 (en) 1998-08-10 2008-09-30 Boehringer Ingelheim (Canada) Ltd. Hepatitis C inhibitor tri-peptides
US6277830B1 (en) 1998-10-16 2001-08-21 Schering Corporation 5′-amino acid esters of ribavirin and the use of same to treat hepatitis C with interferon
US6403564B1 (en) 1998-10-16 2002-06-11 Schering Corporation Ribavirin-interferon alfa combination therapy for eradicating detectable HCV-RNA in patients having chronic hepatitis C infection
WO2005003296A2 (fr) 2003-01-22 2005-01-13 Human Genome Sciences, Inc. Proteines hybrides d'albumine
US7585845B2 (en) 2003-05-21 2009-09-08 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor compounds
WO2005077042A2 (fr) 2004-02-09 2005-08-25 Human Genome Sciences, Inc. Proteines hybrides d'albumine
US7514557B2 (en) 2004-05-25 2009-04-07 Boehringer Ingelheim International Gmbh Process for preparing acyclic HCV protease inhibitors
US20100093792A1 (en) 2008-09-16 2010-04-15 Boehringer Ingelheim International Gmbh Crystalline forms of a potent hcv inhibitor
US20100068182A1 (en) 2008-09-17 2010-03-18 Boehringer Ingelheim International Gmbh Combination therapy for treating hcv infection
WO2010059667A1 (fr) 2008-11-21 2010-05-27 Boehringer Ingelheim International Gmbh Composition pharmaceutique d'un inhibiteur puissant du vhc pour une administration orale
WO2011005646A2 (fr) 2009-07-07 2011-01-13 Boehringer Ingelheim International Gmbh Composition pharmaceutique pour un inhibiteur de protéase virale de l'hépatite c
WO2011053617A1 (fr) * 2009-10-30 2011-05-05 Boehringer Ingelheim International Gmbh Régimes posologiques pour une thérapie en combinaison contre le vhc comprenant bi201335, l'interféron alpha et la ribavirine
US20110268700A1 (en) 2009-10-30 2011-11-03 Boehringer Ingelheim International Gmbh Dosage regimens for hcv combination therapy

Non-Patent Citations (18)

* Cited by examiner, † Cited by third party
Title
AKUTA ET AL., HEPATOLOGY, vol. 52, 2010, pages 421 - 429
ANONYMOUS: "BI 201335 demonstrates potential to shorten HCV treatment duration while achieving high sustained virological response rates in difficult to treat patients", 8 November 2011 (2011-11-08), pages 1 - 2, XP002684160, Retrieved from the Internet <URL:http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2011/08_november_2011hcv.html> [retrieved on 20120924] *
BALAGOPAL, GASTROENTEROLOGY, vol. 139, 2010, pages 1865 - 1876
BERG ET AL., HEPATOL, vol. 52, 2010
CHU ET AL.: "Effect of IL28B Genotype on Early Viral Kinetics During Interferon-Free Treatment of Patients With Chronic Hepatitis C", GASTROENTEROLOGY, 13 January 2012 (2012-01-13)
G. CAIRNS, GENE VARIANT THAT HELPS HEPATITIS C TREATMENT MAY HINDER HIV TREATMENT, 2011
G. CAIRNS, GENE VARIANT THAT HELPS HEPATITIS C TREATMENT MAY HINDER HIV TREATMENT, 2011, Retrieved from the Internet <URL:http://www.bhiva.org/News.aspx?NewsID=a7503829-94b9-4d2f-bd91-ld2fbaad6e8d>
GE ET AL., NATURE, vol. 461, 2009, pages 399 - 401
GHANY, MARC ET AL.: "An Update on Treatment of Genotype 1 Chronic Hepatitis C Virus Infection: 2011 Practice Guideline by the American Association for the Study of Liver Diseases", HEPATOLOGY, vol. 54, no. 4, 2011, pages 1433 - 44, XP055039092, DOI: doi:10.1002/hep.24641
LIU SHAN ET AL: "New protease inhibitors for the treatment of chronic hepatitis C: a cost-effectiveness analysis.", ANNALS OF INTERNAL MEDICINE 21 FEB 2012 LNKD- PUBMED:22351713, vol. 156, no. 4, 21 February 2012 (2012-02-21), pages 279 - 290, XP009163082, ISSN: 1539-3704 *
M.S. SULKOWSKI ET AL: "66 SILEN-C2: SUSTAINED VIROLOGIC RESPONSE (SVR) AND SAFETY OF BI201335 COMBINED WITH PEGINTERFERON ALFA-2A AND RIBAVIRIN (P/R) IN CHRONIC HCV GENOTYPE-1 PATIENTS WITH NON-RESPONSE TO P/R", JOURNAL OF HEPATOLOGY, vol. 54, 1 March 2011 (2011-03-01), pages S30, XP055038944, ISSN: 0168-8278, DOI: 10.1016/S0168-8278(11)60068-8 *
S. M. BIRGE ET AL., J PHARM. SCI., vol. 66, 1977, pages 1 - 19
S. POL ET AL: "1231 SVR AND PHARMACOKINETICS OF THE HCV PROTEASE INHIBITOR BI201335 WITH PEGIFN/RBV IN HCV GENOTYPE-1 PATIENTS WITH COMPENSATED LIVER CIRRHOSIS AND NON-RESPONSE TO PREVIOUS PEGIFN/RBV", JOURNAL OF HEPATOLOGY, vol. 54, 1 March 2011 (2011-03-01), pages S486, XP055038942, ISSN: 0168-8278, DOI: 10.1016/S0168-8278(11)61233-6 *
SALADANHA J; LELIE N; HEATH A: "Establishment of the first international standard for nucleic acid amplification technology (NAT) assays for HCV RNA. WHO Collaborative Study Group", VOX SANG, vol. 76, 1999, pages 149 - 158
SULKOWSKI MARK S ET AL: "TREATMENT WITH THE SECOND GENERATION HCV PROTEASE INHIBITOR BI201 335 RESULTS IN HIGH AND CONSISTENT SVR RATES - RESULTS FROM SILEN-C1 IN TREATMENT-NAiVE PATIENTS ACROSS DIFFERENT BASELINE FACTORS", HEPATOLOGY, vol. 54, no. Suppl. 1, October 2011 (2011-10-01), & 62ND ANNUAL MEETING OF THE AMERICAN-ASSOCIATION-FOR-THE-STUDY-OF-LIVER-DISEASES (AASLD); SAN FRANCISCO, CA, USA; NOVEMBER 04 -08, 2011, pages 473A, XP009163085 *
SULKOWSKI MS ET AL., HEPATOL, vol. 50, 2009, pages 2A
SULKOWSKI MS ET AL., J HEPATOL, vol. 52, no. 1, 2010, pages S462 - S463
WHITE PW ET AL., ANTIMICROB AGENTS CHEMOTHER, vol. 54, no. 11, 2010, pages 4611 - 4618

Also Published As

Publication number Publication date
JP2015512900A (ja) 2015-04-30
WO2013144193A1 (fr) 2013-10-03

Similar Documents

Publication Publication Date Title
JP5539363B2 (ja) インターフェロンおよびリバビリンとのｈｃｖｎｓ３プロテアーゼ阻害剤の組合せ
US20020127203A1 (en) Ribavirin-pegylated interferon alfa HCV combination therapy
EP2061513B1 (fr) Procédé de traitement de patients atteints de l&#39;hépatite c
US8822496B2 (en) Dosage regimens for HCV combination therapy
CA2380653A1 (fr) Mofetilmycophenolate associe a peg-ifn-alpha
US20170224765A1 (en) Treatments of hepatitis c virus infection
US20150147295A1 (en) Combination therapy for treating hcv infection in specific patient subgenotype sub-population
US20010046957A1 (en) Method for treating hepatitis C
WO2013143581A1 (fr) Polythérapie pour le traitement d&#39;une infection par le vhc dans une sous-population de sous-génotype de patients spécifique
US20150164975A1 (en) Combination therapy for treating hcv infection in an hcv-hiv coinfected patient population
WO2013137869A1 (fr) Polythérapie pour le traitement d&#39;une infection par le hcv dans une population de patients co-infectés hcv-hiv
WO2014138374A1 (fr) Polythérapie par voie orale pour le traitement d&#39;une infection par le vhc chez une sous-population spécifique de patients

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12713654

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2015502107

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12713654

Country of ref document: EP

Kind code of ref document: A1