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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • 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
  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
  • C12Q1/70—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving virus or bacteriophage
  • C12Q1/701—Specific hybridization probes
  • C12Q1/706—Specific hybridization probes for hepatitis
  • C12Q1/707—Specific hybridization probes for hepatitis non-A, non-B Hepatitis, excluding hepatitis D
• • 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 Compounds (1) and
• 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 CC or non-CC genotypes and SNP rs 8099917 with a TT or non-TT genotype.
• 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 as described in U.S. Patent Application Publication No. 2010/0093792, also incorporated herein by reference.
• a combination therapy regimen including administering Compound (1) with an interferon- alpha and ribavirin is described in U.S. Patent Application Publication No. 2010/0068182.
• an interferon administered by injection
• Compound (2) is disclosed specifically as Compound # 3085 in U.S. Patent 7,582,770.
• Compound (2), 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 (2) include the crystalline forms, in particular the crystalline sodium salt form which is prepared as herein described.
• HCV Genotype la is traditionally more difficult to treat and is 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", Hepatology, 54(4): 1433-44 (2011)).
• SNPs 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 affect the responsiveness of that patient to the antiviral therapy.
• IL-28B Interleukin (IL) 28B, (also called lambda interferon)
• SNPs 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)
• IL Interleukin
• the SNP that was most strongly associated with SVR in the genome-wide analysis was rs 12979860 followed by rs 8099917. See, e.g., Ge et al., Nature, 461 :399- 401 (2009) and Balagopal, Gastroenterology, 139:1865-1876 (2010). See G. Cairns, "Gene variant that helps hepatitis C treatment may hinder HIV treatment", 2011, at:
• 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.
• this combination therapy has been found to have excellent effectiveness in treating those patients having a CC genotype of SNP rs 12979860 located near IL28B gene, regardless of the HCV Subtype being la or lb. Similar excellent results are to be expected for patients having a TT genotype of SNP rs 8099917, regardless of the HCV Subtype being la or lb.
• 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 an effective amount of a therapeutic combination comprising Compounds (1) and (2) as herein described, or a pharmaceutically acceptable salt thereof, and optionally ribavirin and wherein the patient has a CC or non-CC genotype of SNP rs 12979860 or a TT or non-TT genotype of SNP rs 8099917 located near the IL28B gene, and in more specific embodiments:
• the two or 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 comprising a Compound (1), which is accompanied by written instructions indicating administering Compound (1) with Compound (2) and optionally ribavirin for the treatment of HCV infection wherein the patient has a CC or non-CC genotype of SNP rs 12979860 or a TT or non-TT genotype of rs 8099917 located near the IL28B gene.
• the present invention further provides for a packaged pharmaceutical composition
• a packaged pharmaceutical composition comprising a Compound (2), which is accompanied by written instructions indicating administering Compound (1) with Compound (2) and optionally ribavirin for the treatment of HCV infection in a patient that has a CC or non-CC genotype of SNP rsl2979860 or a TT or non-TT genotype of SNP rs 8099917 located near the IL28B gene.
• Figure 1 depicts the proportion of patients with HCV RNA ⁇ LLOD at Week 12 by viral subtype (GT-la vs GT-lb) in the clinical study described herein.
• Figure 2 depicts the proportion of patients with HCV RNA ⁇ LLOD at Week 12 by IL28B GT (CC vs non-CC) in the clinical study described herein.
• Figure 3 depicts the proportion of patients with HCV RNA ⁇ LLOD at Week 12 by IL28B GT and viral subtype in the clinical study described herein..
• HCV infection means infection by any subtype of the Hepatitis C Virus, including subtypes 1-6, and includes both acute and chronic HCV infection.
• 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.
• 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
• terapéutica combination means a combination of one or more active drug substances, i.e., compounds having a therapeutic utility. Typically, 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 an effective amount of a therapeutic combination comprising a Compound (1) as defined herein, or a pharmaceutically acceptable salt thereof, Compound (2) as defined herein, or a pharmaceutically acceptable salt thereof, optionally together with ribavirin and wherein the patient has a CC or non-CC genotype of SNP rsl2979860 or a TT or non-TT genotype of SNP rs 8099917 located near the IL28B gene.
• An additional embodiment is directed to the use of Compound (1), or a pharmaceutically acceptable salt thereof, and Compound (2) or a pharmaceutically acceptable salt thereof, for the manufacture of pharmaceutical compositions of each compound, for use together, optionally also with ribavirin, in the treatment of HCV infection in a patient that has a CC or non-CC genotype of SNP rsl2979860 or a TT or non-TT genotype of SNP rs 8099917 located near the IL28B gene.
• Additional general embodiments include a packaged pharmaceutical composition
• a packaged pharmaceutical composition comprising a packaging containing one or more doses of Compound (1) or a
• kits for the treatment of HCV infection in a patient comprising: (a) one or more doses of Compound (1) or a pharmaceutically acceptable salt thereof, and (b) one or more doses of Compound (2) or a pharmaceutically acceptable salt thereof, and (c) optionally ribavirin, together with written instructions directing the co-administration of Compound (1), Compound (2) and optionally ribavirin for the treatment of HCV infection wherein the patient has a CC or non-CC genotype of SNP rsl2979860 or a TT or non-TT genotype of SNP rs 8099917 located near the IL28B gene.
• 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 double or triple therapeutic combinations as defined herein.
• This combination therapy has also been demonstrated to be particularly effective in treating HCV genotype 1 infection, specifically subtype la, and also having a CC genotype of SNP rs 12979860 located near the IL28B gene; and it is also expected to effective treating HCV genotype 1 infection, specifically subtype 1 a, in patients having a TT genotype of SNP rs 8099917 located near the IL28B gene.
• Particular embodiments include the following patient sub-populations:
• HCV subtype la and T/T genotype of SNP rs8099917 Another preferred embodiment is directed to the treatment of patients have the HCV Subtype la and either CT or TT (non-CC) genotype of SNP 12979860 or the GT or GG (non-TT) genotype of SNP rs 8099917 located near the IL28B gene, which represent particularly difficult-to-treat HCV-infected patient populations.
• the patient has first been identified as having a CC or non-CC genotype of SNP rsl2979860 or a TT or 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 ⁇ 2x logio maximum reduction in HCV RNA levels during the first 12 weeks of treatment with interferon plus ribavirin ("null responders"), (2) those who experienced > 2x logio reduction in HCV RNA levels from baseline at week 12 (EVR) but not achieving HCV RNA undetectable at end of treatment (“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").
• the present invention provides a method of reducing HCV- RNA levels in a patient in need thereof, comprising the step of administering to said patient a therapeutic combination according to the present invention.
• 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.
• 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 detectable level (below the limit of detection, BLD).
• Treatment decisions for duration of HCV therapy can be made based on the time when HCV RNA level reaches BLD, and combinations of BLQ and BLD HCV RNA at subsequent time- points 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.
• a composition Such 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 7,514,557. Further specific examples of compositions are as set forth in the examples section below.
• 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.
• 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 innate/adaptive immune response to HCV; acute vs. chronic HCV infection; and the disposition of ribavirin based on host factors.
• 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.
• 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.
• a clear advantage is that it is thereby possible to achieve steady state levels of active drug in the patient' s system earlier than would otherwise be achieved.
• a higher blood level is achieved early by using a loading dose preferably double the maintenance dose at first intake. Reaching the targeted steady state level of active drug earlier in therapy also means that there is less possibility of insufficient drug exposure at the beginning of therapy so that resistant viral strains have a smaller chance of emerging.
• the second component of the therapeutic combination namely, Compound (2) or a pharmaceutically acceptable salt thereof is comprised in a composition.
• composition comprises Compound (2), 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 7,582,770.
• the Compound (2) or a pharmaceutically acceptable salt thereof may be administered at dosage amounts and in dose ranges that may include (in single or divided doses):
• Compound (2) or a pharmaceutically acceptable salt thereof may be administered in single or divided daily doses, thrice a day administration (TID) of the divided 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 combination, the severity and course of the infection, the patient's disposition to the infection and the judgment of the treating physician. In general, the compound is most desirably
• Compound (2) is administered for the first administration dose of the treatment.
• the induction dose amount is higher than the dose amount administered for subsequent administrations in the treatment.
• the induction dose amount is about double to triple in quantity, by weight, of the amount in subsequent administrations in the treatment.
• the first dose of Compound (2) administered at dosage of about 1200 mg and subsequent doses of Compound (2) are administered at a dosage of about 600 mg.
• the first dose of Compound (2) administered at a dosage of about 1200 mg and subsequent doses of Compound (2) are administered at a dosage of about 400 mg.
• the optional 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 a method of treating hepatitis C viral (HCV) infection or alleviating one or more symptoms thereof in a patient that has a CC or non-CC genotype of SNP rs 12979860 or a TT or non-TT genotype of SNP rs 8099917 located near the IL28B gene comprising the step of administering to the patient a therapeutic combination comprising:
• (c) optionally ribavirin at a dosage of between about 200 mg/day to about 1800 mg/day.
• the patient is infected with HCV Subtype lb.
• the patient is infected with HCV Subtype la, and the patient has a CC genotype of SNP rs 12979860 or a TT genotype of SNP rs 8099917 located near the IL28B gene.
• the patient is infected with HCV Subtype la, and the patient has a CT or TT genotype of SNP rs 12979860 or a GT or GG genotype of SNP rs 8099917 located near the IL28B gene.
• 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 a CC or non-CC genotype of SNP rs 12979860 or a TT or non-TT genotype of SNP rs 8099917 located near the IL28B gene comprising the step of administering to the patient a therapeutic combination comprising:
• (c) optionally ribavirin at a dosage of between about 1000 mg/day to about 1200 mg/day.
• the patient is infected with HCV Subtype lb.
• the patient is infected with HCV Subtype la, and the patient has a CC genotype of SNP rs 12979860 or a TT genotype of SNP rs 8099917 located near the IL28B gene.
• the patient is infected with HCV Subtype la, and the patient has a CT or TT genotype of SNP rs 12979860 or a GT or GG genotype of SNP rs 8099917 located near the IL28B gene.
• 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 a CC or non-CC genotype of SNP rs 12979860 or a TT or non-TT genotype of SNP rs 8099917 located near the IL28B gene comprising the step of administering to the patient a therapeutic combination comprising:
• (c) optionally ribavirin at a dosage of between about 1000 mg/day to about 1200 mg/day.
• the patient is infected with HCV Subtype lb.
• the patient is infected with HCV Subtype la, and the patient has a CC genotype of SNP rs 12979860 or a TT genotype of SNP rs 8099917 located near the IL28B gene.
• the patient is infected with HCV Subtype la, and the patient has a CT or TT genotype of SNP rs 12979860 or a GT or GG genotype of SNP rs 8099917 located near the IL28B gene.
• the therapy is a triple combination therapy including administration of
• the therapy is a double combination therapy including administration of
• the HCV infection is genotype 1 , preferably genotype 1 a, and the patient is a treatment-naive patient;
• the HCV infection is genotype 1 , preferably genotype 1 a
• 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 CC or non-CC genotype of SNP rsl2979860 or a TT or 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 loading dose concept in used for Compound (1), e.g., the first dose of Compound (1) administered is double in quantity to the subsequent doses. Further embodiments include any of the above-mentioned embodiments, and where the therapeutic regimen of the present invention is administered to the patient for at least about 4 weeks, more preferably at least about 12 weeks, at least about 16 weeks, at least about 24 weeks, at least about 28 weeks or at least about 48 weeks. With respect to the double or triple combination therapies of the present invention, the present invention contemplates and includes all combinations of the various preferred embodiments and sub-embodiments as set forth herein.
• 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
• one or more doses of Compound (1), or a pharmaceutically acceptable salt thereof, and one or more doses of Compound (2), or a pharmaceutically acceptable salt thereof, and optionally ribavirin are placed together in a single packaging forming a so-called "kit", which includes written instructions directing the coadministration of Compound (1), Compound (2) and optionally ribavirin for the treatment of HCV infection in a patient that has a CC or non-CC genotype of SNP rsl2979860 or a TT or non-TT genotype of SNP rs 8099917 located near the IL28B gene.
• the individual doses of Compound (1) or a pharmaceutically acceptable salt thereof, or Compound (2) 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.
• 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.
• Step 1 Synthesis of Isopropyl 3-Cyclopentyl-l-methyl-lH-indole-6-carboxylate Because of the instability of brominated product, methyl 3 -cyclopentyl- 1 -methyl- 1H- indole-6-carboxylate needed to be converted into the more stable isopropyl 3 -cyclopentyl - l-methyl-lH-indole-6-carboxylate via a simple and high yielding operation. The conversion worked the best with stoichiometric amounts of solid lithium isopropoxide. Use of 0.1 eq lithium isopropoxide led to longer reaction times and as a result to more hydrolysis by-product, while lithium isopropoxide solution in THF caused a problematic isolation and required distillation of THF. Procedure:
• the batch was filtered and rinsed with 28 wt% 2-propanol in water (186 g), and water (500 g).
• the wet cake was dried in vacuo ( ⁇ 200 Torr) at 40-45 °C until the water content was ⁇ 0.5% to give isopropyl 3-cyclopentyl-l-methyl-lH-indole-6-carboxylate (52.7 g, 95% yield) in 99.2 A% (240 nm).
• the starting material methyl 3-cyclopentyl-l-methyl-lH-indole-6-carboxylate can be prepared as described in Example 12 of U.S. Patent 7,141,574, and in Example 12 of U.S. Patent 7,642,352, both herein incorporated by reference.
• This process identified the optimal conditions for the synthesis of 2-bromo-3-cyclopentyl- l-methyl-lH-indole-6-carboxylate via bromination of the corresponding 3-cyclopentyl-l- methyl- lH-indole-6-carboxylate with bromine. It's very important to control the reaction temperature and to quench the reaction mixture with a mixture of aqueous sodium thiosulfate and 4-methylmorpholine to minimize the formation of the dibromo- and 2- indolone impurities. Further neutralization of the crude product with NaOH in isopropanol greatly increases the stability of the isolated product.
• the resulting hazy solution was treated with 1.0 M aqueous sodium hydroxide solution (9.1 g) and then with 135.0 g water at a rate to maintain the batch at 75+5°C.
• the suspension was stirred at 75+5°C for at least 30 min, cooled to 15+2 °C over 30-40 min, and held at 15+2 °C for at least 1 h.
• the mixture was heated to 40 - 50 °C and charged with methanol (664 g). After it was stirred at the same temperature for at least 0.5 h, the batch was cooled to 0 - 10 °C and stirred for another 1 hr. The precipitate was filtered, rinsed with 56 wt methanol/ water solution (322 g), and dried in vacuo ( ⁇ 200 Torr) at 50-60 °C until the water content was ⁇ 0.4% to give isopropyl 2-bromo-3- cyclopentyl-l-methyl-lH-indole-6-carboxylate as a beige solid (90-95 g, 80-85 % yield ).
• Step 3a,b Preparation of compound I by one-pot Pd-catalyzed borylation- Suzuki coupling reaction
• the batch was cooled to 20+3 °C over 0.5h and hold at 20+3 °C for at least lh.
• the solid was collected by filtration.
• the wet cake was first rinsed with 62.8 g of 2-propanol, followed by 200 g of H 2 0.
• the solid was dried under vacuum at the temperature below 50 °C.
• the solid product was collected and rinsed with 80 g of NMP/water (1 :3 volume ratio) and then 60 g of water.
• the product was dried under vacuum at the temperature below 50 °C to give II as a pale yellow powder (19 -20 g, purity > 99.0 A% and 88.4 wt , containing 5.4 wt% NMP).
• the yield is about 93-98%.
• the batch was stirred for over 30 min at 70 °C, then cooled to 20 °C over 1 hr and kept for at least 1.0 h.
• the solid product was collected and rinsed with 407 g of isopropanol/water (229 g IPA, 178 g H 2 0).
• the product was dried under vacuum at 80 °C for over 5 hrs to give II as a white powder (61 g, 95% yield).
• intermediate V was developed.
• the first step was the preparation of 4-chloro-2-(methyl)- aminonitrobenzene starting from 2,4-dichloronitrobenzene using aqueous methyl amine in DMSO at 65 °C. Then, a ligandless Heck reaction with n-butyl acrylate in the presence of Pd(OAc) 2 , 'PrzNEt, LiCl, and DMAc at 110 °C was discovered.
• Step 7 Reduction of n-butyl (3-methylamino-4-nitro)-cinnamate
• the filtrate was concentrated under reduced pressure to remove solvents to 50% of the original volume.
• the remained content was heated to 70 °C and charged slowly methyl cyclohexane (335 mL) at the same temperature.
• the mixture was cooled to about 30 - 40 °C and seeded with III seed crystals, then slowly cooled the suspension to— 10 °C.
• the solid was filtered and rinsed with methyl cyclohexane in three portions (3 x 46 mL).
• the wet cake was dried in vacuo at 40 °C to give III (53.3 g, 215 mmol, 86%).
• the mixture was stirred at 25+5 °C for at least 30 min for completion of the amide formation.
• the mixture was distilled at normal pressure to remove ca. 197 mL (171.5 g) of volatiles (Note: the distillation can also be done under reduced pressure).
• the batch was adjusted to 40+5 °C, and MeOH (118.6 g) was added. Water (15.0 g) was added and the mixture was stirred at 40+5 °C until crystallization occurred (typically in 30 min), and held for another 1 h. Water (90 g) was charged at 40+5 °C over 1 h, and the batch was cooled to 25+5 °C in 0.5 h, and held for at least 1 h.
• the resulting solution was cooled to 35 C, and filtered through an in-line filter (0.5 micron), and rinsed with a pre-mixed solution of water (978 g) and MeOH (387 g).
• the solution was heated to 60 ⁇ 4 C, and acetic acid (41.4 g, 689 mmol) was added over 1 h while the mixture was well agitated.
• the resulting suspension was stirred at 60 ⁇ 4 C for 0.5 h.
• Another portion of acetic acid (41.4 g, 689 mmol) was charged in 0.5 h, and batch was stirred at 60 ⁇ 4 C for additional 0.5 h.
• the batch was cooled to 26 ⁇ 4 C over 1 h and held for 1 h.
• the Compound (1) sodium salt (Type A) MEK solvate seeds used in the above process step can be manufactured by the above process except without using seeds and without drying of the solvate. Notes Regarding Crystallization Step 11
• the XRPD pattern on the wet cake confirmed the MEK solvated phase.
• Another experiment was carried out to adapt the process for the slow crystallization kinetics observed in the current crystallization system. A 1/2 hour aging time was included after seeding and the MEK anti-solvent addition time was increased from 2 to 4 hours at 50 °C. All solids were found to have crystallized out of solution within 2 hours of aging.
• Examples of pharmaceutical formulations containing Compound (2) include the tablet formulations described below.
• composition of the solid oral formulation is a composition of the solid oral formulation:
• Two specific solid oral drug product formulations were prepared according to the above general Formulation # 1 , a 50 mg product and a 200 mg product.
• Compound (2) Na salt sodium salt is equivalent to 200 mg and 50 mg of the active moiety, Compound (2) (free acid), respectively.
• Purified water is used as a granulating agent; it does not appear in the final product.
• composition of the solid oral formulation is a composition of the solid oral formulation:
• Two specific solid oral drug product formulations were prepared according to the above general Formulation # 1 , a 200 mg product and a 400 mg product.
• Compound (2) Na salt sodium salt is equivalent to 200 mg and 400 mg of the active moiety, Compound (2) (free acid), respectively.
• Preparation of Formulations 1-2 The drug substance along with the intragranular excipients including the basifier, surfactant, solubilizer/binder, filler are mixed in a dry state in a high shear granulator prior to addition of water.
• the drug substance and the excipients may be screened prior to milling to remove large agglomerates if necessary.
• the mixture is granulated using purified water as a granulating agent in the high shear granulator till a suitable end point is achieved.
• the wet granules are removed and dried at appropriate drying temperatures either in a tray dryer or a fluid bed dryer.
• the dried granules are milled by passing through a high speed mill, such as a Comill. Milled granules are then blended with the extragranular excipients, glidant and lubricant and then table ted in a tablet press.
• the Compound (1) drug product was administered as a softgel capsule filled with a lipid-based formulation containing Compound (1) sodium salt.
• Compound (2) drug product was administered as a tablet formulation containing Compound (2) sodium salt.
• SOUND-C1 Phase lb study
• SOUND-C2 Phase lib study evaluating efficacy and safety of several all-oral combination regimens of these compounds for up to 40 weeks of treatment.
• a loading dose of 240 mg Compound (1) was given on the first day of treatment, followed by 120 mg QD starting on Day 2
• Plasma HCV RNA was measured using the Roche COB AS® TaqMan HCV/HPS assay v2.0, with a lower limit of quantification (LLOQ) of 25 IU/mL, and a lower limit of detection (LLOD) of approximately 15 IU/mL
• IL28B genotype was determined from the SNP rs 12979860 as CC or non-CC
• treatment group D had liver cirrhosis (17%), as compared with treatment groups A-C (9%) and treatment group E
• Antiviral response (HCV RNA ⁇ LLOQ) ranged from 72% to 88% at Week 4 and 57% to 76% at Week 12
• Virologic failure was due to failure to achieve undetectable plasma HCV RNA at Week 6 and Week 8 (3.4%, 1.3% and 4.3% of patients, respectively) or virologic
• the interferon-free oral combination therapy with Compound (1), Compound (2) and RBV provides high virologic response rates in HCV GT-1 TN patients, confirming the potent antiviral activity of this combination.
• the response rate in the RBV-sparing arm was substantial but lower than in other arms at Week 12.
• the safety and tolerability profile was comparable to other direct acting antiviral regimens and more favorable in the Compound (1), + 2BID + RBV arm. Specific results include:
• Compound (2) were the most-difficult-to-treat GT-1 a patients with the unfavorable non-CC IL28B GT
• Host IL28B polymorphism had a major influence on virologic response in GT-1 a patients who, based on earlier clinical studies with Compound (2) plus PeglFN/RBV, have a weaker virologic response to Compound (2)

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