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WO2015008223A1 - Traitement du virus de l'hépatite c avec l'alisporivir et la ribavirine - Google Patents

Traitement du virus de l'hépatite c avec l'alisporivir et la ribavirine Download PDF

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Publication number
WO2015008223A1
WO2015008223A1 PCT/IB2014/063125 IB2014063125W WO2015008223A1 WO 2015008223 A1 WO2015008223 A1 WO 2015008223A1 IB 2014063125 W IB2014063125 W IB 2014063125W WO 2015008223 A1 WO2015008223 A1 WO 2015008223A1
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Prior art keywords
alisporivir
treatment
day
hcv
twice
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Clifford BRASS
Nikolai Naoumov
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Novartis AG
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Novartis AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the present disclosure relates to non-immunosuppressive cyclosporin derivatives and non-cyclosporin derived cyclophilin inhibitors which bind to cyclophilin, which are cyclophilin inhibitors, in particular to their pharmaceutical use of in the treatment of Hepatitis C virus infection.
  • the cyclosporins comprise a class of structurally distinctive, cyclic, poly-N-methylated undecapeptides, commonly possessing pharmacological, in particular, immunosuppressive, or anti -inflammatory activity.
  • the first of the cyclosporins to be isolated was the naturally occurring fungal metabolite Ciclosporin or Cyclosporine, also known as cyclosporin A (CsA).
  • Non-immunosuppressive cyclophilin inhibitors have been generated by purposely designed chemical modification (amino acid substitution) of cyclosporine A, to increase the binding to cellular cyclophilins and to abolish the immunosuppressive activity.
  • PCT/EP 2004/009804, WO 2005/021028, or WO 2006/071619 (which are incorporated by reference herein in their entirety) disclose non-immunosuppressive cyclosporins which bind to cellular cyclophilins and have also been found to have an inhibitory effect on Hepatitis C virus (HCV) replication.
  • HCV Hepatitis C virus
  • Alisporivir (Debio-025 or DEB025 or DEB) is a cyclophilin (Cyp) inhibitor and its mode of action as an anti -HCV agent is via inhibition of host proteins, in particular of cyclophilin A, that are directly involved in HCV replication.
  • Cyp cyclophilin
  • HCV hepatitis C virus
  • HCV GT 3 The World Health Organization (WHO) estimates that approximately 170 million people, 3% of the world's population are infected with hepatitis C; and that 3-4 million new infections occur each year.
  • GT HCV genotypes
  • the prevalence rates are between 5-10% of all cases with chronic hepatitis C infection in the USA, 50% in some European countries, and reaching values above 50% in countries such as India (Amarapurkar D et al. (2001) Prevalence of hepatitis C genotypes in Indian patients and their clinical significance. J Assoc Physicians India. 49:983-5, Chandra M, et al.
  • GT 3 (31%) and GT 2 (17%) comprise nearly 50% of the HCV infected population (Westin J, Lindh M, Lagging LM, Norkrans G, et al (1999) Chronic hepatitis C in Sweden: genotype distribution over time in different epidemiological settings. Scand J Infect Dis.;31(4):355-8).
  • the SVR to peg-IFNa/RBV in GT 2 patients is about 85% and in GT 3 patients is approximately 70% (Shiffman MLet al, (2007). ACCELERATE Investigators. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med. 12;357(2): 124-34; Zeuzem S, Hultcrantz R, Bourliere M, et al (2004) Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol; 40: 993-9).
  • anti-HCV agents with novel mechanisms of antiviral action have moved into clinical development.
  • anti-HCV agents - direct acting antiviral agents (DAAs), such as NS3 protease, or NS5A or NS5B (nucleoside/nucleotide and non-nucleoside) polymerase inhibitors, and host targeting antiviral agents (HTAs), such as Cyclophilin Inhibitors.
  • DAAs direct acting antiviral agents
  • HTAs host targeting antiviral agents
  • sofosbuvir and ribavirin was approved for the treatment HCV G2 and G3 as an interferon- firee regimen.
  • the main difference between DAA and HTA drugs is their mechanism of action.
  • DAA agents work by blocking specific binding sites in the viral replication complex, thus making them susceptible to viral mutation and resistance
  • HTA drugs work via modifying host factors that are essential for virus replication and in the life cycle of the virus. As these agents do not block a specific location on the virus, these agents should be less susceptible to emergent viral resistance and efficacious against HCV of all genotypes.
  • DEB025 has been found in vitro to be active against all common resistance variants to polymerase inhibitors, protease inhibitors and NS5a inhibitors (Tiongyip C et al. (2011) Host targeting cyclophilin inhibitor alisporivir presents a high barrier to resistance with no cross-resistance to direct acting antivirals.
  • DEB025 acts indirectly on the NS5a region of the virus, resistance variants to DEB025 when they do occur are in domain II of NS5a whereas resistance variants to direct NS5a inhibitors are found in domain I.
  • Alisporivir also known as Debio 025 or DEB025
  • Cyp cyclophilin
  • STAT-C Specifically Targeted Antiviral Therapy for HCV
  • the cyclophilin inhibitor Debio-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus. Hepatology; 47:817-826; Flisiak R, Pawlotsky JM, Crabbe R, et al. (2011) Once-daily alisporivir (DEB025) plus pegifnalfa2a/ribavirin Results in Superior Sustained Virologic Response (SVR24) in Chronic Hepatitis C Genotype 1 Treatment Naive Patients. Presented at European Association for Study of the Liver (EASL) Congress, Berlin, March 2011). DEB025 has shown to be active against HCV GT 1, 2, 3 and 4, with an additive antiviral effect when combined with peg-IFNa2a
  • Host targeting cyclophilin inhibitor alisporivir presents a high barrier to resistance with no cross-resistance to direct acting antivirals. 6th International Workshop on Hepatitis C, Resistance and New Compounds. Cambridge, MA, June 24th, 2011).
  • interferon interferon
  • DEB025 hematologic toxicities, hypertriglyceridemia and pancreatitis
  • the focus of development plans for DEB025 -based therapy for chronic HCV infection has shifted from regimen(s) with an IFN/RBV backbone, to regimens that are IFN free. Therefore, it is important to explore the full potential of adequate doses of DEB025 (plus RBV) to treat GT 2/3 patients with chronic HCV.
  • the rapid development of a number of direct acting anti-viral agents may be suitable and effective to use in combination with DEB025 without IFN.
  • VITAL-1(CDEB025A2211) study a Phase 2 study with HCV treatment-naive GT 2/3 patients.
  • IFN-free DEB025 therapy up to half of the patients achieved undetectable HCV RNA by week 6 (49% in DEB025 600 mg QD+ RBV, 46% in DEB025 800 mg QD +RBV and 32% in DEB025 1000 mg QD)
  • SVR24 sustained HCV clearance
  • IFN-free or IFN-add-on regimen in treatment naive patients with HCV GT2 or GT3 Final results from VITAL- 1 study.
  • IFN interferon
  • cyclophilin inhibitors in particular alisporivir
  • alisporivir can provide an effective alternative to the standard of care in treatment of HCV.
  • efficacious treatment of Hepatitis C virus genotype 2 and 3 infection in treatment naive patients can be achieved when using alisporivir in the absence of or without interferon, thereby avoiding the side effects of the current standard of care treatment and thus improving patient compliance.
  • the present disclosure provides new anti-HCV treatments using alisporivir, in particular methods of treating hepatitis C virus genotype 2 and 3 infection in a treatment naive patient comprising administering to the patient alisporivir in an amount of about 200 mg to 400 mg twice a day, preferably of about 400 mg twice per day.
  • the disclosure further provides alisporivir for use in the treatment or prevention of Hepatitis C virus genotype 2 and 3 infections or HCV induced disorders in a treatment naive patient.
  • a method for treating Hepatitis C virus genotype 2 and 3 infections or HCV induced disorders in a patient comprising administering to the patient alisporivir in an amount of about 200 mg to about 400 mg twice a day in the absence of interferon.
  • a method for preventing or delaying the recurrence of HCV genotype 2 and 3 infection in a transplant recipient comprising administering to the recipient alisporivir in an amount of about 200 mg to about 400 mg twice a day, preferably of about 400 mg twice per day in the absence of interferon.
  • a method for treating Hepatitis C virus genotype 2 and 3 infections or for treating HCV induced disorders in a treatment naive patient comprising administering to the patient alisporivir in an amount of about 200 mg to about 400 mg twice a day, preferably of about 400 mg twice per day with ribavirin for a treatment duration of at least 12 weeks in the absence of interferon.
  • a method for treating Hepatitis C virus genotype 2 and 3 infections or for treating HCV induced disorders in a treatment naive patient comprising administering to the patient alisporivir in an amount of about 200 mg to about 400 mg twice a day, preferably of about 400 mg twice per day with a ribavirin for a treatment duration of 12 to 24 weeks in the absence of interferon.
  • a method for treating Hepatitis C virus genotype 2 and 3 infections or for treating HCV induced disorders in a treatment naive patient comprising administering to the patient alisporivir in an amount of about 200 mg to about 400 mg twice a day, preferably of about 400 mg twice per day for a treatment duration of at least 12 weeks in the absence of interferon.
  • a method for treating Hepatitis C virus genotype 2 and 3 infections or for treating HCV induced disorders in a treatment naive patient comprising administering to the patient alisporivir in an amount of about 200 mg to about 400 mg twice a day, preferably of about 400 mg twice per day for a treatment duration of 12 to 24 weeks in the absence of interferon.
  • a therapeutic regimen comprising administering alisporivir in an amount of about 200 mg to about 400 mg twice per day, preferably of about 400 mg twice per day in combination with a ribavirin in the absence of interferon.
  • a package comprising the pharmaceutical composition comprising alisporivir as defined above, in combination with instructions to administer the pharmaceutical composition in an amount of about 200 mg to about 400 mg twice a day, preferably of about 400 mg twice per day.
  • a kit for the treatment of chronic hepatitis C virus genotype 2 and 3 infection 7.
  • Also contemplated herein are methods of reducing the HCV genotype 2 and 3 R A in a treatment naive patient comprising administering to the patient: alisporivir in an amount of about 200 mg to about 400 mg twice a day, preferably of about 400 twice per day in the absence of interferon.
  • Additional embodiments of the present disclosure relate to methods of treating hepatitis C genotype 2 and 3 infections in a treatment naive patient comprising administering to the patient: alisporivir in an amount of about 200 mg to about 400 mg twice a day, preferably of about 400 mg twice per day in the absence of interferon.
  • Additional embodiments of the present disclosure relate to methods of treating hepatitis C genotype 2 and 3 infections in a treatment naive patient comprising administering to the patient: alisporivir in combination with ribavirin, wherein alisporivir is administered in an amount of about 200 mg to about 400 mg twice a day in the absence of interferon.
  • Figure 1 shows the DEB025A2222 trial design.
  • Figure 2 is a graph illustrating HCV RNA decline during the first 12 weeks of treatment (triple therapy with DEB025+ peg-IFNa2a +RBV) in treatment-experienced GT1 patients.
  • MPA MPA Molecular Profiling Analysis
  • UGTlAl UGTlA l gene (coding f. glucuronosyltransferase 1 family, polypeptide
  • Epoch The planned stage of the subjects' participation in the study. Each epoch serves a purpose in the study as a whole. Typical epochs are: determination of subject eligibility, wash-out of previous treatments, exposure of subject to treatment or to follow-up on subjects after treatment has ended.
  • Investigational treatment generally does not include other treatments administered as concomitant background therapy required or allowed by the protocol when used within approved indication/dosage
  • composition comprising
  • X may consist exclusively of X or may include something additional, e.g., X + Y.
  • the term "about” in relation to a numerical value x means +/-10% unless the context dictates otherwise.
  • naive or “treatment naive” means that the patient has received no previous treatment for HCV infection.
  • Additional embodiments of the present disclosure relate to method for treating hepatitis C genotype 2 and 3 infections in a patient comprising administering alisporivir to such a level that the level of viral R A in the patient decreases to an undetectable level and that a sustained viral response is achieved at the end of the treatment period.
  • the standard of care treatment is a treatment that is used to treat Hepatitis C infections.
  • the currently used standard of care treatment involves administration of an interferon, in particular pegylated interferon in combination with a ribavirin.
  • the initial phase is a period of about 3, about 4, about 5, about 6, or about 7 days.
  • the initial phase is a period of at least about 3 days, e.g., 3 days, more preferably about 7 days, e.g., 7 days.
  • the second phase is a period of about 11, about 23, about 47 or about 71 weeks.
  • the second phase is a period of about 23 weeks, e.g., 23 weeks.
  • the treatment duration is the duration of the initial and second phases, provided that no other duration is specified.
  • microgram/kilogram means microgram drug per kilogram body weight of the mammal - including man - to be treated.
  • treatment refers to both prophylactic or preventative treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during HCV therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the terms “subject” and “patient” include any human or nonhuman animal.
  • nonhuman animal includes all vertebrates, e.g., mammals and non- mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc.
  • pharmaceutically acceptable means a nontoxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s).
  • administering in relation to a compound, e.g., alisporivir, is used to refer to delivery of that compound to a patient by any route.
  • a "therapeutically effective amount” refers to an amount of alisporivir that is effective, upon single or multiple dose administration to a patient (such as a human) for treating, preventing, preventing the onset of, curing, delaying, reducing the severity of, ameliorating at least one symptom of a disorder or recurring disorder, or prolonging the survival of the patient beyond that expected in the absence of such treatment.
  • a patient such as a human
  • an individual active ingredient e.g., alisporivir
  • the term refers to that ingredient alone.
  • the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
  • treatment refers to both prophylactic or preventative treatment as well as curative or disease modifying treatment, including treatment of a patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a patient having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a patient beyond that expected in the absence of such treatment.
  • therapeutic regimen means the dosing pattern of treatment of an illness, e.g., the dosing protocol used during the treatment of HCV.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • ribavirin is administered at between about 800 to about 1200 mg per day, e.g., 1000 mg to 1200 mg per day. In some embodiments, ribavirin is administered based on the weight of the patient RBV 1000 - 1200 mg/day (1000 mg for patients ⁇ 75kg, 1200 mg/day for patients > 75 kg of body weight at screening). In other embodiments, ribavirin is administered based on the HCV genotype of the patient.
  • alisporivir may be administered with additional agents of the standard of care that promote the antiviral efficacy of the therapy treatment.
  • the standard of care may include additional agents that promote the antiviral efficacy of the therapy treatment, such as substrate-based protease inhibitors of HCV NS3-4A serine protease, non-substrate-based NS3 protease inhibitors; phenanthrenequinones, thiazolidines and benzanilides, nucleosides analogs, antisense molecules directed against HCV genome or any cellular component that is required for viral replication, vaccine or antibody-based approaches to HCV treatment.
  • dosages of the drugs are administered in compositions, i.e. they may be administered together (i.e., simultaneously), but may also be administered separately or sequentially.
  • combination therapy is typically administered together, the rationale being that such simultaneous administration induces multiple simultaneous stresses on the virus.
  • the specific dosages given will depend on absorption, inactivation and excretion rate of the drugs as well as other factors. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated.
  • co-administration or “combined administration” or “administered in combination with” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. Fixed combinations are also within the scope of the present disclosure.
  • the administration of a pharmaceutical combination of the disclosure results in a beneficial effect, e.g. a synergistic or additive therapeutic effect, compared to a monotherapy applying only one of its pharmaceutically active ingredients or as compared to the current standard of care therapy.
  • the treatment used in the methods described herein may be administered by any conventional route.
  • One or more components may be administered parentally, e.g., in the form of injectable solutions or suspensions, or in the form of injectable deposit formulations.
  • alisporivir will be administered orally in the form of solutions or suspensions for drinking, tablets or capsules.
  • Pharmaceutical compositions for oral administration comprising alisporivir typically further comprise one or more pharmaceutically acceptable carrier substances.
  • compositions for parenteral administration typically also include one or more excipients.
  • excipients include an isotonic agent, a buffer or other pH- controlling agent, and a preservative. These excipients may be added for maintenance of the composition and for the attainment of preferred ranges of pH (about 6.5-7.5) and osmolality (about 300 mosm/L).
  • Twice per day or BID means twice in any period of about 24 hour period.
  • alisporivir as described herein is in a single dose form or in more than one dosage form; one or more oral dosage forms may be administered at each time per day.
  • the alisporivir is preferably in a pharmaceutical composition, in unit dosage form such as a gelatin capsule, including 1) alisporivir in an amount of about 15% to about 20% by weight of the composition, 2) a lipophilic component, 3) a surfactant, 4) a polyethylene glycol, and 5) water in an amount of about 2% to about 15% by weight of the composition as disclosed in WO 2012/080176 and incorporated herein by reference.
  • Other alisporivir formulations and dosage forms can also be utilized.
  • Direct acting antiviral agents is used herein to mean agents that interfere with specific steps in the hepatitis C virus (HCV) replication cycle.
  • agents may be, e.g., ribavirin derivatives, protease inhibitors, polymerase inhibitors (e.g., nucleoside/nucleotide and non-nucleoside inhibitors), and cyclophillin inhibitors.
  • Exemplary direct acting antiviral agents include: boceprevir, telaprevir, ABT-072, ABT-450, ABT-333 by Abbott, ACH1625 by Achillion, ANA598 by Anadys Pharmaceuticals, AZD-7295 by AstraZeneca, BI201335, BI207127 by Boehringer Ingelheim Pharma, BMS650032, BMS790052, BMS791325, BMS824383 by Bristol Myers Squibb, Clemizole by Eiger BioPharmacetucials, EDP239 by Enanta/Novartis, Filibuvir by Pfizer, GS9190 (Tegobuvir), GS9256 by Gilead, IDX375 by Idenix, GS-7977 (Sofosbuvir) by Gilead, RG7128 (mericitabine) by Pharmasset/Genentec, PPI-461 by Presidio RG7227 (Danoprevir) by InterMune/Genentech
  • up to 12 or 24 weeks refers to the treatment duration and is intended to mean for about 12 weeks, 16 weeks, or about 24 weeks, respectively. It will be understood that therapy need not end at exactly the 12, 16, or 24 week time period. For example, therapy may end a day or a few days before the 24 week period, and still be an equivalent within the scope and spirit of the current disclosure.
  • the present disclosure further provides a method for treating Hepatitis C virus genotype 2 and 3 infections or HCV induced disorders in a patient, preferably a patient naive to treatment, comprising administering to the patient alisporivir in an amount of about 200 mg to about 400 mg twice a day in the absence of interferon.
  • the present disclosure further provides a method for delaying the recurrence of HCV genotype 2 and 3 infection in a transplant recipient, comprising administering to the recipient alisporivir in an amount of about 200 mg to about 400 mg twice a day, preferably of about 400 mg twice per day in the absence of interferon.
  • the present disclosure further provides a method for treating Hepatitis C virus genotype 2 and 3 infections or for treating HCV induced disorders in a treatment naive patient, comprising administering to the patient alisporivir in an amount of about 200 mg to about 400 mg twice a day, preferably of about 400 mg twice per day with a ribavirin for a treatment duration of at least 12 weeks in the absence of interferon.
  • the present disclosure further provides a method treating Hepatitis C virus genotype 2 and 3 infections or for treating HCV induced disorders in a treatment naive patient, comprising administering to the patient alisporivir in an amount of about 200 mg to about 400 mg twice a day in the absence of interferon, preferably of about 400 mg twice per day with a ribavirin for a treatment duration of 12 to 24 weeks in the absence of interferon.
  • the present disclosure further provides a method for treating
  • Hepatitis C virus genotype 2 and 3 infections or for treating HCV induced disorders in a treatment naive patient comprising administering to the patient alisporivir in an amount of about 200 mg to about 400 mg twice a day in the absence of interferon, preferably of about 400 mg twice per day for a treatment duration of at least 12 weeks in the absence of interferon.
  • the present disclosure further provides a method for treating Hepatitis C virus genotype 2 and 3 infections or for treating HCV induced disorders in a treatment naive patient, comprising administering to the patient alisporivir in an amount of about 200 mg to about 400 mg twice a day in the absence of interferon, preferably of about 400 mg twice per day for a treatment duration of 12 to 24 weeks in the absence of interferon.
  • the present disclosure further provides for the use of alisporivir in the preparation of a pharmaceutical composition for use in any method as defined above.
  • the present disclosure further provides for the use of alisporivir in the preparation of a medicament for use in any method as defined above.
  • the present disclosure further provides a pharmaceutical composition for use in any method as defined above, comprising alisporivir, together with one or more pharmaceutically acceptable diluents or carriers therefor.
  • the present disclosure further provides a therapeutic regimen comprising administering alisporivir in an amount of about 200 mg to about 400 mg twice per day in the absence of interferon, preferably of about 400 mg twice per day in combination with a ribavirin in the absence of interferon.
  • the present disclosure further provides a package comprising the pharmaceutical composition comprising alisporivir as defined above, in combination with instructions to administer the composition in an amount of about 200 mg to about 400 mg twice a day in the absence of interferon, preferably of about 400 mg twice per day in the absence of interferon.
  • the kit can also include ribavirin.
  • the present disclosure further provides a kit for the treatment of chronic hepatitis C virus genotype 2 and 3 infection.
  • Also contemplated herein are methods of reducing the HCV genotype 2 and 3 RNA in a treatment naive patient comprising administering to the patient: alisporivir in an amount of about 200 mg to about 400 mg twice a day, preferably of about 400 twice per day in the absence of interferon.
  • Additional embodiments of the present disclosure relate to methods of treating hepatitis C genotype 2 and 3 infections in a treatment naive patient comprising administering to the patient: alisporivir in an amount of about 200 mg to about 400 mg twice a day in the absence of interferon, preferably of about 400 mg twice per day in the absence of interferon.
  • Additional embodiments of the present disclosure relate to methods of treating hepatitis C genotype 2 and 3 infections in a treatment naive patient comprising administering to the patient: alisporivir in combination with ribavirin in the absence of interferon, wherein alisporivir is administered in an amount of about 200 mg to about 400 mg twice a day and ribavirin is administered in an amount based on the weight of the patient RBV 1000 - 1200 mg/day (1000 mg for patients ⁇ 75kg, 1200 mg/day for patients > 75 kg of body weight at screening).
  • the present disclosure further provides alisporivir for use in treatment of a Hepatitis C virus genotype 2 or 3 infected treatment naive patient characterized in that (i) alisporivir is administered in an amount of between about 200 mg twice a day for about 2 weeks in the absence of interferon, and (ii) if HCV RNA in the patient plasma is detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 200 mg twice a day for up to about 24 weeks in the absence of interferon, and (iii) if HCV RNA in the patient plasma is not detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 200 mg twice a day for up to about 12 weeks in the absence of interferon.
  • the present disclosure further provides alisporivir for use in treatment of a Hepatitis C virus genotype 2 or 3 infected treatment naive patient characterized in that (i) alisporivir is administered in an amount of between about 300 mg twice a day for about 2 weeks in the absence of interferon, and (ii) if HCV RNA in the patient plasma is detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 300 mg twice a day for up to about 24 weeks in the absence of interferon, and (iii) if HCV RNA in the patient plasma is not detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 300 mg twice a day for up to about 12 weeks in the absence of interferon.
  • the present disclosure further provides alisporivir for use in treatment of a Hepatitis C virus genotype 2 or 3 infected treatment naive patient characterized in that (i) alisporivir is administered in an amount of between about 400 mg twice a day for about 2 weeks in the absence of interferon, and (ii) if HCV RNA in the patient plasma is detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 400 mg twice a day for up to about 24 weeks in the absence of interferon, and (iii) if HCV RNA in the patient plasma is not detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 400 mg twice a day for up to about 12 weeks in the absence of interferon.
  • the present disclosure further provides alisporivir for use in treatment of a Hepatitis C virus genotype 2 or 3 infected treatment naive patient characterized in that (i) alisporivir is administered in an amount of between about 200 mg twice a day in combination with ribavirin for about 2 weeks in the absence of interferon, and (ii) if HCV
  • RNA in the patient plasma is detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 200 mg twice a day in combination with ribavirin for up to about 24 weeks in the absence of interferon, and (iii) if HCV RNA in the patient plasma is not detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 200 mg twice a day in combination with ribavirin for up to about 12 weeks in the absence of interferon.
  • the present disclosure further provides alisporivir for use in treatment of a Hepatitis C virus genotype 2 or 3 infected treatment naive patient characterized in that (i) alisporivir is administered in an amount of between about 300 mg twice a day in combination with ribavirin for about 2 weeks in the absence of interferon, and (ii) if HCV RNA in the patient plasma is detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 300 mg twice a day in combination with ribavirin for up to about 24 weeks in the absence of interferon, and (iii) if HCV RNA in the patient plasma is not detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 300 mg twice a day in combination with ribavirin for up to about 12 weeks in the absence of interferon.
  • the present disclosure further provides alisporivir for use in treatment of a Hepatitis C virus genotype 2 or 3 infected treatment naive patient characterized in that (i) alisporivir is administered in an amount of between about 400 mg twice a day in combination with ribavirin for about 2 weeks in the absence of interferon, and (ii) if HCV RNA in the patient plasma is detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 400 mg twice a day in combination with ribavirin for up to about 24 weeks in the absence of interferon, and (iii) if HCV RNA in the patient plasma is not detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 400 mg twice a day in combination with ribavirin for up to about 12 weeks in the absence of interferon.
  • the present disclosure further provides use of alisporivir in the manufacture of a medicament for treatment of a Hepatitis C virus genotype 2 or 3 infected treatment naive patient wherein alisporivir is administered during an initial phase in an amount of about 200 mg to about 400 mg twice per day for between about 12 weeks to about 24 weeks and wherein the alisporivir may be administered in combination with ribavirin in the absence of interferon.
  • the present disclosure further provides use of alisporivir in the preparation of a pharmaceutical composition for treatment of a Hepatitis C virus genotype 2 or 3 infected treatment naive patient wherein alisporivir is administered during an initial phase in an amount of about 200 mg to about 400 mg twice per day for between about 12 weeks to about 24 weeks and wherein the alisporivir may be administered in combination with ribavirin in the absence of interferon.
  • the present disclosure further provides a therapeutic regimen characterized in that that (i) alisporivir is administered in an amount of between about 200 mg twice a day for about 2 weeks in the absence of interferon, and (ii) if HCV RNA in the patient plasma is detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 200 mg twice a day for up to about 24 weeks in the absence of interferon, and (iii) if HCV RNA in the patient plasma is not detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 200 mg twice a day for up to about 12 weeks in the absence of interferon.
  • the present disclosure further provides a therapeutic regimen characterized in that that (i) alisporivir is administered in an amount of between about 300 mg twice a day for about 2 weeks in the absence of interferon, and (ii) if HCV RNA in the patient plasma is detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 300 mg twice a day for up to about 24 weeks in the absence of interferon, and (iii) if HCV RNA in the patient plasma is not detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 300 mg twice a day for up to about 12 weeks in the absence of interferon.
  • the present disclosure further provides a therapeutic regimen characterized in that that (i) alisporivir is administered in an amount of between about 400 mg twice a day for about 2 weeks in the absence of interferon, and (ii) if HCV RNA in the patient plasma is detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 400 mg twice a day for up to about 24 weeks in the absence of interferon, and (iii) if HCV RNA in the patient plasma is not detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 400 mg twice a day for up to about 12 weeks in the absence of interferon.
  • the present disclosure further provides a therapeutic regimen characterized in that that (i) alisporivir is administered in an amount of between about 200 mg twice a day in combination with ribavirin for about 2 weeks in the absence of interferon, and (ii) if HCV RNA in the patient plasma is detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 200 mg twice a day in combination with ribavirin for up to about 24 weeks in the absence of interferon, and (iii) if HCV RNA in the patient plasma is not detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 200 mg twice a day in combination with ribavirin for up to about 12 weeks in the absence of interferon.
  • the present disclosure further provides a therapeutic regimen characterized in that that (i) alisporivir is administered in an amount of between about 300 mg twice a day in combination with ribavirin for about 2 weeks in the absence of interferon, and (ii) if HCV RNA in the patient plasma is detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 300 mg twice a day in combination with ribavirin for up to about 24 weeks in the absence of interferon, and (iii) if HCV RNA in the patient plasma is not detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 300 mg twice a day in combination with ribavirin for up to about 12 weeks in the absence of interferon.
  • the present disclosure further provides a therapeutic regimen characterized in that that (i) alisporivir is administered in an amount of between about 400 mg twice a day in combination with ribavirin for about 2 weeks in the absence of interferon, and (ii) if HCV RNA in the patient plasma is detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 400 mg twice a day in combination with ribavirin for up to about 24 weeks in the absence of interferon, and (iii) if HCV RNA in the patient plasma is not detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of 400 mg twice a day in combination with ribavirin for up to about 12 weeks in the absence of interferon.
  • the present disclosure further provides pharmaceutical compositions comprising alisporivir for uses as defined above.
  • the present disclosure provides a package comprising the pharmaceutical composition comprising alisporivir for uses as defined above in combination with instructions to administer said composition.
  • the present disclosure further provides a use of alisporivir for the manufacture of a medicament for the treatment of a Hepatitis C virus genotype 2 or 3 infected treatment naive patient wherein the medicament is formulated at a dosage comprising one, two, three, four or five dose of about 50 mg to about 200 mg.
  • the present disclosure provides use of alisporivir for the manufacture of a medicament for the treatment of a Hepatitis C virus genotype 2 or 3 infected treatment naive patient wherein the medicament is formulated at a dosage comprising one, two, three or four dose of about 100 mg or about 200 mg in the absence of interferon.
  • the medicament is formulated at a dosage comprising one, two, three, four or five dose of about 50 mg to about 200 mg, further comprising ribavirin.
  • the present disclosure further provides use of alisporivir for the manufacture of a medicament for the treatment of a Hepatitis C virus genotype 2 or 3 infected treatment naive patient wherein the medicament is formulated at a dosage comprising one, two, three, four or five dose of about 50 mg to about 200 mg in the absence of interferon, further comprising ribavirin, wherein the content of ribavirin in the medicament is at between about 800 to about 1200 mg per day, e.g., 1000 mg to 1200 mg per day mg per dosage unit.
  • the present disclosure further provides a pharmaceutical composition comprising alisporivir for any use as defined above.
  • the present disclosure further provides a kit comprising
  • a pharmaceutical composition comprising alisporivir for use in the treatment of a Hepatitis C virus genotype 2 or 3 infected treatment naive patient, optionally in combination with one or more pharmaceutically acceptable excipients, and
  • alisporivir is administered in an amount of between about 200 mg to about 400 mg twice a day in combination with ribavirin for about 2 weeks in the absence of interferon, and (ii) if HCV RNA in the patient plasma is detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of about 200 mg to about 400 mg twice a day in combination with ribavirin for up to about 24 weeks in the absence of interferon, and (iii) if HCV RNA in the patient plasma is not detectable by a HCV-RNA assay following step (ii), then administering alisporivir in an amount of about 200 mg to about 400 mg twice a day in combination with ribavirin for up to about 12 weeks in the absence of interferon.
  • co-administration or “combined administration” or “administered in combination with” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. Fixed combinations are also within the scope of the present disclosure.
  • the administration of a pharmaceutical combination of the disclosure results in a beneficial effect, e.g. a synergistic or additive therapeutic effect, compared to a monotherapy applying only one of its pharmaceutically active ingredients or as compared to the current standard of care therapy.
  • the treatment used in the methods described herein may be administered by any conventional route.
  • One or more components may be administered parentally, e.g., in the form of injectable solutions or suspensions, or in the form of injectable deposit formulations.
  • alisporivir will be administered orally in the form of solutions or suspensions for drinking, tablets or capsules.
  • Pharmaceutical compositions for oral administration comprising alisporivir typically further comprise one or more pharmaceutically acceptable carrier substances. Typically, these compositions are concentrated and need to be combined with an appropriate diluent, e.g., water, prior to administration.
  • Pharmaceutical compositions for parenteral administration typically also include one or more excipients.
  • Optional excipients include an isotonic agent, a buffer or other pH- controlling agent, and a preservative. These excipients may be added for maintenance of the composition and for the attainment of preferred ranges of pH (about 6.5-7.5) and osmolality (about 300 mosm/L).
  • alisporivir as described herein is in a single dose form or in more than one dosage form; one or more oral dosage forms may be administered at each time per day. In some embodiments, alisporivir is administered in doses of 200 mg to 1000 mg.
  • the efficacy of the therapy regimen may be monitored using standard protocols. Treatment may be followed by determinations of HCV in serum and measurement of serum ALT levels. For example, the patients may be assessed for the presence of HCV RNA in their plasma. HCV RNA (IU/mL) can be measured at regular intervals during the treatment, e.g., at Day 1 (pre-dose and 4, 8, and 12 hours post-dose) and pre-dose at Day 2, Day 3, Day 8, Day 15, Day 29, and at Week 12, Week 24, Week 36, Week 48, Week 72 (when applicable), and at follow up. In addition, the HCV strains in the patient can be sequenced and assessed for identification of mutations selecting for resistance.
  • LOD means limit of detection (serum HCV RNA is less than 10 IU/mL) and LOQ means limit of quantification (serum HCV RNA is less than 25 IU/mL).
  • HCV RNA levels can be measured using commercially available methods.
  • the endpoint of treatment is a virological response, i.e., the absence of HCV at the end of a treatment course, several months after initiation of treatment, or several months after completion of treatment.
  • HCV in serum may be measured at the RNA level by methods such as quantitative RT-PCR or northern blots or at the protein level by enzyme immunoassay or enhanced chemiluminescence immunoassay of viral proteins.
  • the endpoint may also include a determination of a serum ALT level in the normal range.
  • the virological response parameters are: rapid virologic response at treatment week 4 (RVR 4) defined by undetectable serum HCV-RNA at treatment week 4; early virological response (EVR), defined by at least 2 log 10 IU/mL reduction in HCV-RNA compared to baseline (partial EVR) or undetectable serum HCV-RNA (complete EVR) at treatment week 12; sustained virological response (SVR24), defined as absence of HCV-RNA from serum by a sensitive Polymerase Chain Reaction (PCR) assay 24 weeks following end of therapy or the HCV RNA is undetectable (by LOD) 24 weeks after end of treatment; End of Treatment Response (ETR): HCV RNA undetectable (by LOD) at treatment end (completed or prematurely discontinued).
  • RVR 4 rapid virologic response at treatment week 4
  • EVR early virological response
  • SVR24 sustained virological response
  • Exemplary therapeutic regimens are given in the Examples.
  • a subject in need of treatment is provided with about 200 mg to about 400 mg alisporivir orally twice daily for 2 weeks, followed by about 200 mg to about 400 mg alisporivir orally twice daily for up to 12 weeks.
  • Ribavirin is a synthetic nucleoside analogue and is also commercially available, e.g., as COPEGUS® from Roche.
  • Example 1 - DEB025A2222 A Phase II, multi center, open-label, randomized, 3 arms, dose exploration phase II study.
  • a total of approximately 150 treatment naive chronic hepatitis C GT2/3 patients will be randomized into one of the 3 treatment groups (A, B or C) in a 1 : 1 : 1 ratio.
  • Randomization will be stratified by the following parameters measured at screening:
  • Viral load at screening > 800,000 IU/mL (5.903 logio) or ⁇ 800,000 IU/mL (5.903 logio)
  • Study epoch The total planned duration of the study is up to 48 weeks from randomization as shown in Figure 1.
  • the main study includes 3 epochs: screening, treatment period 1(DEB025/RBV treatment), and post treatment follow-up 1
  • Screening epoch with duration of 1 to 42 days during which study eligibility will be confirmed.
  • Treatment period 1 (DEB025/RBV treatment) epoch (12 or 24 weeks): Patients will be randomized into one of three parallel treatment arms:
  • Arm A Dual-therapy with response-guided treatment duration with DEB025
  • Arm B Dual-therapy with a response-guided treatment duration with DEB025 300 mg BID and RBV 1000 - 1200 mg/day (1000 mg for patients ⁇
  • Arm C Dual-therapy with a response-guided treatment duration with DEB025 400 mg BID and RBV 1000 - 1200 mg/day (1000 mg for patients ⁇ 75kg, 1200 mg/day for patients > 75 kg of body weight at screening) for 12 or 24 weeks based on week 2 HCV RNA results.
  • the doses/regimens have been chosen based on inferences made from available clinical data, including the use of modeling and simulation. Recently available on-treatment results from the ongoing study CDEB025A2210 were also considered.
  • the target Cmin of 371 ng/mL is the basis for the therapeutic regimen of DEB025 in the treatment of GT1-4 HCV, including treatment-naive and -experienced patients.
  • previously investigated regimens i.e., 600 mg QD and 400 mg BID.
  • twice daily administration does increase in vivo exposure faster than once daily administration and most importantly maintains a higher Cmin.
  • the efficacy and safety of the highest proposed dose, 400 mg BID has been confirmed in a recent interim analysis from the CDEB025A2210 study.
  • the antiviral activity of the 400 mg BID regimen of DEB025 with peg-IFNa2a and RBV (i.e., triple therapy) in treatment- experienced GT1 patients over the first 12 weeks of treatment was greater than that observed with the once daily regimens (including 800 mg dosed QD) or the peg-IFNa2a /RBV control as shown if Figure 2.
  • the rate of HCV-RNA undetectable was superior in the 400 mg BID group (cEVR 72%; p ⁇ 0.01 for all comparisons) compared with peg- IFN(x2a /RBV dual therapy (cEVR 33%) as well as triple therapy regimens in which
  • DEB025 was administered as 600 mg (cEVR 46%) or 800 mg (cEVR 61%) once daily.
  • the safety profile was generally similar across the BID and QD regimens when DEB025 was administered with peg-IFNa2a /RBV, the 400 mg BID regimen was associated with increased frequencies of certain adverse events, notably a higher incidence of benign, reversible jaundice, nausea, vomiting, and neutropenia. Determining the safety and/or tolerability profile of alternative BID regimens of DEB025 will be important in determining the best dosing regimen for IFN free treatment in GT2/3 for future phase III and in planning future combinations with DAA in interferon free regimens. This is particularly relevant in that IFN likely contributes to the nausea, vomiting and neutropenia and alternative BID dosing not been explored in an IFN-free regimen.
  • the IFN-free regimens of DEB 025 + RBV in the planned study are approximately equal to or higher than the DEB025 regimens investigated in the phase 2 study in patients with GT2/3 HCV (VITAL- 1), which included 1,000 mg QD, but do not exceed the highest doses/regimens investigated in GT1 HCV patients (1,200 mg BID).
  • the regimens are expected to comprehensively characterize the antiviral activity and short-term safety
  • DEB025-based dual therapy to further inform and ultimately refine the dose justification for DEB025 based on PK/PD relationships for both safety /tolerability and efficacy.
  • RBV is recommended as a fixed dose of 800mg daily for HCV G2 or 3 treatment-naive patients in combination with peglFN for 24 weeks.
  • the recommended dose of RBV is 1000-1200 mg/day (weight-based) with peglFN over 48 weeks of treatment.
  • ribavirin dosing has primarily been toxicity limited (anemia) with higher responses seen with greater ribavirin exposure.
  • For therapy of Gl patients it has been common practice to utilize weight-based ribavirin when used in combination with interferon, direct acting anti-virals or in combination with both.
  • VITAL- 1 GT2/3 treatment naive patients

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Abstract

La présente invention concerne l'utilisation de l'alisporivir inhibiteur de la cyclophiline en combinaison avec la ribavirine en l'absence d'interféron pour le traitement de l'infection du génotype 2 ou 3 du virus de l'hépatite C dans le traitement de patients naïfs.
PCT/IB2014/063125 2013-07-17 2014-07-15 Traitement du virus de l'hépatite c avec l'alisporivir et la ribavirine Ceased WO2015008223A1 (fr)

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WO2006038088A1 (fr) 2004-10-01 2006-04-13 Debiopharm Sa Utilisation de cyclosporine dans le traitement d'infections a hepatite c et composition pharmaceutique contenant ladite cyclosporine
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