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
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • 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
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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 is co-infected with the Human
• HIV Immunodeficiency Virus
• kits comprising the therapeutic combinations of the present invention.
• B is ; L° is MeO-; L 1 is Br; and R 2 is and having the chemical name: l- ⁇ [4-[8-Bromo-2-(2-isopropylcarbamoyl-thiazol-4-yl)-7- methoxy-quinolin-4-yloxy]-l-(R)-(2-cyclopentyloxycarbonyl amino-3,3-(S)-dimethyl- butyryl)-pyrrolidine-(S)-2-carbonyl]-amino ⁇ -2-(S)-vinyl-cyclopropane-(R)-carboxylic acid, is known as a selective and potent inhibitor of the HCV NS3 serine protease and useful in the treatment of HCV infection.
• Compound (1) falls within the scope of the acyclic peptide series of HCV inhibitors disclosed in U.S. Patents RE 40,525, 7,514,557 and 7,585,845.
• Compound (1) is disclosed specifically as Compound # 1055 in U.S. 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.
• HIV/HCV coinfected persons tend to have higher HCV viral loads and are less likely to clear the HCV spontaneously.
• the urgency for treatment of persons who are coinfected is greater than it is for those with HCV infection alone.
• the course of liver disease is more rapid in HIV/HCV-coinfected persons, including an approximately 2-fold increased risk of cirrhosis, more rapid progression to decompensated liver disease and increased risk for hepatocellular carcinoma (Graham CS, et al., Clin Infect Dis (2001 );33:562-569) .
• HCV infection increases the risk of mitochondrial toxicity and hepatotoxicity from HAART (Sulkowski MS, et al., JAMA (2000);283:74-80; Lafeuil!ade A, et al., Lancet (2001);357:280-281 ).
• the present invention provides a method of treating HCV infection or alleviating one or more symptoms thereof in a patient that is co-infected with HIV 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, as defined herein.
• the three actives of the combination can be administered simultaneously or separately, as part of a regimen.
• the present invention further provides for a packaged pharmaceutical composition
• 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 PEG12 000 - interferon alfa 2b.
• PEG12 000 -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 PEG ⁇ ooo-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 PEG 12 000 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 PEG12 000 attached.
• the PEG12 000 -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.
• Especially preferred conjugates of 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.
• the term includes 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., /. Pharm. Set, 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, 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, mal
• 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- -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 in a that is co-infected with HIV 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.
• 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 in a patient that is co-infected with HIV.
• 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.
• a preferred embodiment is directed to the treatment of patients have the HCV subtype 1 a which represent particularly difficult- to-treat HCV-infected patient populations.
• 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.
• 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 a virologic response 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 IU per ml of serum or plasma, or less than 10 IU 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 (below the limit of detection, BLD).
• BLD detectible level
• 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 pegylated interferon plus ribavirin therapy in HIV/HCV coinfected patients is at least 48 weeks, and up to 72 weeks for chronic HCV infection with HCV genotype 1 or 4; 48 weeks for the majority of HIV/HCVcoinfected 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 pegylated 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 specificHCV 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 patient to be treated with the combination therapy of the present invention is a patient that is co-infected with the Human Immunodeficiency Virus (HIV), including HIV-1 or HIV-2 infection.
• HIV infection is chronic HIV-1 infection, as documented by seroconversion and presence of detectable anti-HIV antibodies.
• Patients that can be treated include those that are anti-retroviral naive or on stable anti-retroviral therapy.
• the patient is diagnosed as having chronic HIV infection using the standard diagnostic testing methods known in the art, e.g. HIV-l/HIV-2 antibody ELISA for screening, HIV Western blot for confirmation of a positive screening result, and quantitative assay for detection of HIV-1 or HIV-2 plasma RNA, which may detect HIV RNA early after HIV infection and before anti-HIV antibodies have developed.
• standard diagnostic testing methods e.g. HIV-l/HIV-2 antibody ELISA for screening, HIV Western blot for confirmation of a positive screening result, and quantitative assay for detection of HIV-1 or HIV-2 plasma RNA, which may detect HIV RNA early after HIV infection and before anti-HIV antibodies have developed.
• patients with active AIDS defining illnesses as defined by CDC Centers for Disease Control and Prevention, 1992 MMWR, 41(RR17), should not undergo triple therapy for HCV until AIDS defining illness has been sufficiently treated and has resolved.
• the HCV-infected patient to be treated is first tested to confirm the presence of an HIV co-infection in the patient.
• one embodiment is directed to a method of treating HCV infection or alleviating one or more symptoms thereof in a patient in comprising the step of administering to the patient a therapeutic combination comprising a Compound (1) as defined herein, or a
• the first component of the therapeutic combination namely, Compound (1) or a pharmaceutically acceptable salt thereof is comprised in a composition.
• a 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 concomitant medications (co-medications), the severity and course of the infection, the patient's disposition to the infection and the judgment of the treating physician. Specific factors affecting dosing may include, for example, individual patient factors which modify the adsorption, distribution, metabolism and excretion of Compound (1); the specific HCV Genotype; the specific IL28B genotype of the patient; the patient's
• the compound is most desirably administered at a concentration level that will generally afford antivirally effective results without causing any harmful or deleterious side effects.
• Typical dosing for HIV/HCV coinfected adults will be 120mg QD and 240mg QD. In the presence of a strong enzyme-inducer comedication, dosing higher than 240mg QD may be possible. In the presence of a strong CYP3A inhibitor such as ritonavir or cobicistat as part of HIV therapy, a daily dose of less than 120mg QD, for example in certain patients, may be possible (40 or 80mg). Dosing for children starting at ages 3-5 may be
• 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 loading dosage of about 240 mg and subsequent maintenance doses of Compound (1) are administered at a daily 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 daily dosage of about 240 mg.
• interferon- alfa 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®.
• 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 180 ⁇ g/week, more preferably about 135 to aboutl80 ⁇ 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 to 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 is co-infected with HIV comprising the step of administering to the patient a therapeutic combination comprising: (a) Compound (1) or a pharmaceutically acceptable salt thereof at a dosage between about 40 mg per day and about 480 mg per day;
• pegylated interferon alfa -2a at a dosage of about 135 to about 180 ⁇ 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 200 mg/day to about 1800 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 is co- infected with HIV 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 present invention contemplates a method of treating hepatitis C viral (HCV) infection or alleviating one or more symptoms thereof in a patient that is co- infected with HIV 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 and the patient is a treatment-naive patient;
• the HCV infection is genotype 1 and the patient is a treatment-experienced patient.
• 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 pharmaceutical packaging materials, e.g. bottles, blister-packs, etc., that may themselves be contained within 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.
• the patient is diagnosed as having chronic HIV infection using standard diagnostic testing methods known in the art, e.g. HIV-l/HIV-2 antibody ELISA for screening, HIV Western blot for confirmation of a reactive screening test, and quantitative assay for HIV-1 or HIV- 2 plasma RNA that detects HIV during the "window period" following acute infection, during which anti-HIV antibodies have not yet developed. HIV plasma RNA quantitative assays further aide in the decision regarding which specific antiretroviral therapy to start, and for monitoring the effectiveness of antiretroviral therapy.
• standard diagnostic testing methods known in the art e.g. HIV-l/HIV-2 antibody ELISA for screening, HIV Western blot for confirmation of a reactive screening test, and quantitative assay for HIV-1 or HIV- 2 plasma RNA that detects HIV during the "window period" following acute infection, during which anti-HIV antibodies have not yet developed. HIV plasma RNA quantitative assays further aide in the decision regarding which specific antiretroviral therapy to start, and for monitoring the effectiveness of antiretroviral therapy
• One example of a pharmaceutical formulation of Compound (1) include an oral solution formulation as disclosed in WO 2010/059667. Additional examples include soft-gelatin capsules containing a lipid-based liquid formulation, as disclosed in WO 2011/005646.
• the Compound (1) drug product will be administered as a softgel capsule lipid-based formulation containing Compound (1) sodium salt. All references to "Compound (1)" in the below clinical study is the sodium salt form.
• HCV Human Immunodeficiency Virus
• the aim of this trial is to evaluate the efficacy and the safety of Compound (1) given for 12 or 24 weeks in combination with PeglFN/RBV given for 24 or up to48 weeks in HCV treatment-naive or relapsers patients coinfected with HIV.
• Patients who achieve reduction of HCV viral load according to Early Treatment Success (ETS) criteria will be randomized 1 : 1 to stop triple therapy at 24 weeks, or continue PeglFN/RB V for 48 week treatment duration. Patients without ETS continue PeglFN/RBV for 48 week treatment duration.
• ETS Early Treatment Success
• SVR Sustained Virological Response
• HCV Plasma Hepatitis C Virus
• RNA Ribonucleic Acid
• HCV hepatitis C
• HIV Human Immunodeficiency Virus
• HBV infection with presence of HBs-Ag
• Active autoimmune disease including autoimmune hepatitis

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• 2012
  • 2012-03-14 JP JP2015500406A patent/JP2015509980A/ja active Pending
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• 2013
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