TW201536297A - New treatments of hepatitis C virus infection - Google Patents

Abstract

The invention concerns the use of cyclophilin inhibitors in the treatment of Hepatitis C virus genotype 2 or 3 infection in treatment naive patients.

Description

New treatment for hepatitis C virus infection

The present invention relates to a non-immunosuppressive cyclosporin derivative which binds to cyclophilin and a non-cyclosporine-derived cyclophilin inhibitor which is a cyclophilin inhibitor, in particular for its infection with hepatitis C virus Medical use in therapy.

Cyclosporin comprises a class of structurally unique cyclic poly-N-methylated undecyl acid polypeptides which generally have pharmacological, in particular immunosuppressive or anti-inflammatory activity. The first cyclosporin to be isolated is the naturally occurring fungal metabolite Ciclosporin or Cyclosporine, also known as cyclosporin A (CsA).

Non-immunosuppressive cyclophilin inhibitors have been generated by specially designed cyclosporin A chemical modifications (amino acid substitutions) to increase binding to cellular cyclophilins and to eliminate immunosuppressive activity. PCT/EP 2004/009804, WO 2005/021028, or WO 2006/071619, which is hereby incorporated by reference in its entirety, discloses the disclosure of the entire entire entire entire entire entire entire entire entire entire entire entire entire disclosure Hepatitis B virus (HCV) replication has an inhibitory effect. WO 2006/038088 (incorporated herein by reference in its entirety) describes the methods and compositions for the use of alisporivir in the treatment of HCV. Apixovir (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 a host protein, particularly cyclophilin A, which is directly involved in HCV replication.

Hepatitis C virus (HCV) chronic infection is a major and growing public health problem question. It is the main cause of liver cirrhosis, liver cancer and other liver related diseases. The World Health Organization (WHO) estimates that approximately 170 million people (3% of the world's population) are infected with hepatitis C; and between 3 million and 4 million new infections occur each year. Among the six major HCV genotypes (GT), HCV GT 3 is the second most common worldwide, second only to GT 1. The prevalence rate is between 5% and 10% in all cases of chronic hepatitis C infection in the United States, 50% in some European countries, and more than 50% in countries such as India (Amarapurkar D, etc.) (2001) Prevalence of hepatitis C genotypes in Indian patients and their clinical significance. J Assoc Physicians India. 49:983-5, Chandra M et al. (2003) Prevalence, risk factors and genotype distribution of HCV and HBV infection in the tribal Population: a community based study in south India. Trop Gastroenterol. 24(4): 193-5). GT 2 is somewhat less widespread, but in some countries such as Italy, approximately 25% of patients are infected with GT 2 (Esteban JI et al. (2008). The changing epidemiology of hepatitis C virus infection in Europe.J Hepatol. 48(1): 148-62. November 5, 2007, electronic publication. Annotations are given in J Hepatol. 2008 49(4): 661-2; the author replies 663). In Sweden, GT 3 (31%) and GT 2 (17%) account for nearly 50% of HCV-infected populations (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).

Currently, the most widely used treatment in patients infected with GT 2 or 3 is weekly peginterferon alfa (Peg-IFNα) plus daily ribavirin (RBV) for 24 weeks (Ghany) MG, Strader DB, Thomas DL et al. (2009) Diagnosis, Management, and Treatment of Hepatitis C: An Update. Hepatology; 49: 1335-1374). The primary goal of treatment is the sustained virological response (SVR12 and SVR24), which is defined as HCV that is not detectable by serum by sensitive polymerase chain reaction (PCR) at weeks 12 and 24 after the end of treatment. Ribonucleic acid (RNA). universal SVR24 was accepted as a synonym for healing (Ghany MG, Strader DB, Thomas DL et al. (2009) Diagnosis, Management, and Treatment of Hepatitis C: An Update. Hepatology; 49: 1335-1374). Treatment of chronic hepatitis C with peg-IFNα plus RBV in previously untreated patients with HCV GT 2 or 3 to achieve SVR24 significantly reduced the risk of liver-related death and all-cause mortality (Backus Li, Boothroyd DB) , Philips BR et al. (2011) A sustained virologic response reduces risk of all-cause mortality in patients with hepatitis C. Clin Gastroenterol hepatol; 9: 509-51). The SVR of peg-IFNα/RBV is approximately 85% in GT 2 patients and approximately 70% in GT 3 patients (Shiffman ML et 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). Although the SVR rate is higher than in patients infected with GT 1, the treatment outcome, especially in GT 3 patients with high initial viral load and/or other exacerbative conditions, is suboptimal. These patients had a recurrence rate of 23% compared to 9% of patients with GT 2 with similar baseline viral load (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). In addition to re-treatment with longer duration PegIFN/RBV, which is suboptimal, there are no other therapies available for GT 2/3 patients who have previously failed peg-IFNα/RBV treatment. (Poynard T, Colombo M, Bruix J et al. (2009) Peginterferon alfa-2b and Ribavirin: Effective in Patients With Hepatitis C Who Failed Interferon-alfa/Ribavirin Therapy. Gastroenterology 2009; 136: 1618-1628).

In recent years, several anti-HCV agents with novel antiviral mechanisms have entered clinical development. There are two main groups of anti-HCV agents: direct acting antiviral agents (DAA), such as NS3 protease or NS5A or NS5B (nucleoside/nucleotide and non-nucleoside) polymerase inhibitors; and host-targeted antiviral agents (HTA), such as a cyclophilin inhibitor. Recently, a combination of sofosbuvir and ribavirin was approved as an interferon-free regimen for the treatment of HCV G2 and G3. The main difference between DAA and HTA drugs is its mechanism of action. DAA agents act by blocking specific binding sites in viral replication complexes, thus making them susceptible to viral mutations and resistance, while HTA drugs alter hostes necessary for viral replication and during the viral life cycle. Factors come to work. Because these agents do not block specific locations on the virus, these agents should be less sensitive to the viral resistance that occurs and are effective against HCV for all genotypes. In fact, DEB025 has been found to be active in vitro against all common variants that are resistant 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. 6th International Workshop on Hepatitis C, Resistance and New Compounds. Cambridge, MA, June 24, 2011). Although DEB025 acts indirectly on the NS5a region of the virus, variants resistant to DEB025 are in domain II of NS5a when it does occur, whereas variants that are resistant to direct NS5a inhibitors are found in domain I in.

Apoloxivir (also known as Debio 025 or DEB025) is an orally available cyclophilin (Cyp) inhibitor in preclinical models (Coelmont L, Kaptein S, Paeshuyse J et al. (2009) Debio 025, a cyclophilin Binding molecule,is highly efficient in clearing HCV replicon containing cells,alone or when combined with specific Targeted Antiviral Therapy for HCV(STAT-C)inhibitors.Antimicrob Agents Chemother;53:967-976,Paeshuyse J,Kaul A,De Clercq E Et al. (2006) The non-immunosuppressive cyclosporin DEBIO-025 is a potent inhibitor of hepatitis C virus replication in vitro. Hepatology; 43: 761-770, Inoue K, Umehara T, Ruegg UT et al. (2007) Evaluation of a cyclophilin inhibitor in hepatitis C virus-infected chimeric mice in vivo.Hepatology; 45: 921-928, Chatterji U, Bobardt M, Selvarajah S et al (2009) The isomerase active site of cyclophilin A is critical for hepatitis C virus replication.J Biol Chem .; 284:16998-17005) and clinical studies (Flisiak R, Feinman SV, Jablkowski M et al. (2009) The cyclophilin inhibitor Debio 025 Combined with PEG IFNa2a significantly reduces viral load in treatment-naive hepatitis C patients. Hepatology; 49: 1460-1468; Flisiak R, Horban A, Gallay P, et al. (2008) 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. Effective anti-HCV activity has been shown in the European Association for Study of the Liver (EASL) conference, Berlin, March 2011). DEB025 has been shown to be active against HCV GT 1, 2, 3 and 4, and in conjunction with peg-IFNα2a (Flisiak R, Feinman SV, Jablkowski M et al. (2009) The cyclophilin inhibitor Debio 025 combined with PEG IFNa2a significantly reduces viral load in Treatment-naive hepatitis C patients. Hepatology; 49: 1460-1468) when combined or in combination with peg-IFNα2a/RBV (Nelson DR, Ghalib RH, Sulkowski M et al. (2009) Efficacy and Safety of the Cyclophilin Inhibitor DEBIO 025 In Combination with Pegylated Interferon alpha-2a and Ribavirin in Previously Null-Responder Genotype 1 HCV Patients.J Hepatol; 50:S40) has an additive antiviral effect when combined. In vitro, the activity against genotypes 2 and 3 appears to be even higher than the activity against genotype 1, which is quite different from protease inhibitors or NS5a inhibitors against genotype 2 and The activity of 3 is relatively poor. DEB025 has also shown a high barrier to the emergence of HCV mutations that cause drug resistance (Tiongyip C et al. (2011) 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 24, 2011).

The poor tolerance of interferon (IFN) and its well-defined toxicity have driven the development of modern drugs for chronic HCV along the IFN-free regime. Due to the recent increase in potential safety issues (ie hematologic toxicity, hypertriglyceridemia and pancreatitis) when IFN is combined with DEB025 for a longer period of time (>12 weeks), chronic on DEB025 The focus of the development plan for HCV infection therapy has shifted from the IFN/RBV scaffolding scheme to the IFN-free regimen. Therefore, it is important to explore the full potential of a suitable dose of DEB025 (plus RBV) for patients with GT 2/3 with chronic HCV. In addition, the rapid development of a variety of direct acting antiviral agents can be suitably and effectively used in combination with DEB025 without IFN.

In the VITAL-1 (CDEB025A2211) study, phase 2 studies were performed in patients with GT 2/3 who were not treated with HCV. Up to half of patients receiving IFN-free DEB025 therapy achieved undetectable HCV RNA by week 6 (49% in DEB025 600mg QD+RBV and 46% in DEB025 800mg QD+RBV, and 32% in DEB025 1000mg QD) (Pawlotsky J, Flisiak R, Rasenack J et al. (2012) Alisporivir plus Ribavirin achieves high rates of sustained HCV clearance (SVR24) as interferon (IFN)-free or IFN-add-on regimen In treatment naive patients with HCV GT2 or GT3: Final results from VITAL-1 study. in the American Association for the Study of Liver Diseases (American Association for the Study of Liver Diseases; AASLD), Boston, November 13, 2012). Most patients with detectable HCV RNA at week 6 experienced a viral load that was 3 logs lower than baseline. Patients with GT2 and GT3 had similar response rates to the DEB025-free IFN regimen. Of the patients with rapid virological response (RVR) who received complete IFN-free DEB025+RBV treatment, 96% achieved a therapeutic response, and 84% achieved SVR12 and SVR24. 4% had a viral breakthrough (3 patients) and 6% had Recurrence after treatment. The findings of this study demonstrate that the IFN-free DEB025+RBV regimen is an effective treatment option for patients with HCV GT2/3, which causes high SVR12 rates, low viral breakthrough, or relapse after treatment. DEB025 without IFN was well tolerated and the rate of adverse events was substantially lower than with additional IFN or with baseline IFN. These positive results indicate that DEB025 may have the potential to be IFN-free oral therapy for most GT 2/3 patients who have not received treatment.

Data from study CDEB025A2210 (2b phase study of GT 1 peg-IFNα2a/RBV relapsers and non-responders) showed that the combination of peg-IFNα2a/RBV with 400 mg BID DEB025 was more effective than DEB025 600 mg QD in GT 1 patients.

Thus, despite existing therapies, there is clearly a need for safer, more tolerable, and more effective methods and compositions for the treatment of HCV without the use of interferon, using DEB025 dose (administered in a BID regimen, respectively). With RBV, the viral type GT 2/3 was treated only in patients who had not received treatment.

Unexpectedly, we have determined that cyclophilin inhibitors, especially alisporivir, are an effective alternative to standard care in the treatment of HCV. In particular, we have found that alisporivir can be used to treat hepatitis C virus genotype 2 and 3 infections in patients who have not received treatment without interferon or interferon-free. This avoids the side effects of current standard care treatments and thus improves patient compliance.

Accordingly, the present invention provides a novel anti-HCV treatment using alisporivir, particularly a method for treating hepatitis C virus genotype 2 and 3 infection in a patient who has not received treatment, The patient is administered alisporivir in an amount of about 200 mg to 400 mg twice a day, preferably about 400 mg twice a day.

The invention further provides alisporivir for the treatment or prevention of hepatitis C virus genotype 2 and 3 infection or HCV induced disorders in patients who have not received treatment.

In addition, describe the following:

1.1 A method for treating a hepatitis C virus genotype 2 and 3 infection or an HCV-induced disorder in a patient, preferably a patient who has not received treatment, comprising twice daily, without interferon The patient is administered alisporivir in an amount from about 200 mg to about 400 mg.

1.2 A method for preventing or delaying the recurrence of HCV genotype 2 and 3 infection in a transplant recipient, comprising, in the absence of interferon, about 200 mg to about 400 mg twice a day, preferably twice a day. The amount of about 400 mg was administered to the recipient in the form of alisporivir.

1.3 A method for treating a hepatitis C virus genotype 2 and 3 infection for a patient who has not received treatment or for treating an HCV-induced condition in a patient who has not received treatment, comprising Approximately 200 mg to about 400 mg twice a day, preferably about 400 mg twice daily, is administered to the patient with ribavirin in an amount of about 400 mg per day for a treatment duration of at least 12 weeks.

1.4 A method for treating a hepatitis C virus genotype 2 and 3 infection for a patient who has not received treatment or for treating an HCV-induced condition in a patient who has not received treatment, comprising Approximately 200 mg to about 400 mg twice a day, preferably about 400 mg twice daily, is administered to the patient along with ribavirin for a duration of treatment of 12 to 24 weeks.

1.5 A method for treating a hepatitis C virus genotype 2 and 3 infection for a patient who has not received treatment or for treating an HCV-induced condition in a patient who has not received treatment, which comprises, without interferon, Administration of alisporivir to the patient is continued from about 200 mg to about 400 mg twice a day, preferably about 400 mg twice a day. Less than 12 weeks of treatment duration.

1.6 A method for treating a hepatitis C virus genotype 2 and 3 infection for a patient who has not received treatment or for treating an HCV-induced condition in a patient who has not received treatment, comprising The patient is administered alisporivir for a duration of treatment of from 12 mg to about 400 mg twice a day, preferably about 400 mg twice daily.

2. Use of alisporivir for the preparation of a pharmaceutical composition for use in any of the methods as defined above.

3. Use of alisporivir for the preparation of a medicament for use in any of the methods as defined above.

4. A pharmaceutical composition for use in any of the methods as defined above, comprising alisporivir together with one or more pharmaceutically acceptable diluents or carriers thereof.

5. A therapeutic regimen comprising administering alisporivir in combination with ribavirin in an amount of from about 200 mg to about 400 mg twice daily, preferably about 400 mg twice daily, without the use of interferon.

6. A package comprising a pharmaceutical composition comprising alisporivir as defined above, and administering the pharmaceutical combination in an amount of from about 200 mg to about 400 mg twice a day, preferably about 400 mg twice daily. Combination of instructions for the object.

7. A kit for treating chronic hepatitis C virus genotype 2 and 3 infection.

Also included herein is a method of reducing HCV genotype 2 and 3 RNA in a patient who has not received treatment, comprising to the patient: from 200 mg to about 400 mg twice daily, preferably twice daily, without interferon. Each time about 400 doses were administered to alisporivir.

An additional embodiment of the invention relates to a method of treating hepatitis C genotype 2 and 3 infections in a patient who has not received treatment, comprising to the patient: about 200 mg to twice a day, without interferon Aparpovir is administered in an amount of about 400 mg, preferably about 400 mg twice a day.

An additional embodiment of the invention relates to a method of treating hepatitis C genotype 2 and 3 infection in a patient who has not received treatment, comprising administering to the patient: a combination of alisporivir and ribavirin, wherein alisporivir is not It is administered in an amount of about 200 mg to about 400 mg twice a day using interferon.

Figure 1 shows the DEB025A2222 test design.

Figure 2 is a graph illustrating HCV RNA attenuation during the first 12 weeks of treatment (using triple therapy with DEB025 + peg-IFNα2a + RBV) in GT1 patients undergoing treatment.

Abbreviated list

AE adverse events

ALT alanine-transaminase

AUC concentration versus time curve area

BID twice a day

cEVR complete early virological response

CHC chronic hepatitis C

Cmax maximum concentration

Cmin minimum concentration

Cyp cyclophilin

DAA direct acting antiviral

End of ETR treatment response

EVR early virological response

Partial early virological response to pEVR

FU tracking (after stopping treatment)

GT genotype

Hb heme

HbsAg hepatitis B surface antigen

HBV hepatitis B virus

HCV hepatitis C virus

HTAs host-targeted antiviral agents

IB Researcher's Handbook

IRT interactive response technology

IU International Unit

LOD detection limit

LOQ quantization limit

MPA Molecular Profiling Analysis (MPA)

PCR polymerase chain reaction

PD pharmacodynamics

PEG polyethylene glycol

Peg-IFNα pegylated interferon alpha

PK pharmacokinetics

PT better term

QD once a day

qPCR quantitative polymerase chain reaction

RBV ribavirin

RNA ribonucleic acid

mRNA messenger RNA

miRNA microRNA

RVR rapid virological response

SAE serious adverse events

SOC standard care

SVR sustained virological response

UGT1A1 UGT1A1 gene (encoding glucuronyltransferase 1 family, peptide (A1))

WHO World Health Organization

Ll microliter

Glossary of terms

Definition of virological response parameters

The term "comprising" encompasses "including" and "consisting of", for example, a composition comprising "including" X may consist exclusively of X, or may include additional items such as X+Y.

The term "about" in relation to the value x means +/- 10% unless the context indicates otherwise.

The term "naive/treatment naive" means that the patient has not received treatment for HCV infection in the past.

An additional embodiment of the present invention relates to a method for treating hepatitis C genotype 2 and 3 infection in a patient, comprising administering alisporivir, such that the amount of viral RNA in the patient is reduced to an undetectable amount, and A sustained viral response is reached at the end of the treatment period.

In the above examples and in the present specification, standard care treatments are treatments for the treatment of hepatitis C infection. The standard treatment currently used involves the administration of interferon in combination with ribavirin, especially pegylated interferon.

In the above embodiments and in the present specification, the initial stage is a period of about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days. The initial phase is preferably a period of at least about 3 days (e.g., 3 days), more preferably about 7 days (e.g., 7 days).

In the above embodiments and in the present specification, the second stage is a period of about 11 weeks, about 23 weeks, about 47 weeks, or about 71 weeks. The second stage is preferably a period of about 23 weeks (e.g., 23 weeks).

In the above embodiments and in the present specification, if no other treatment duration is specified, the duration of treatment is the duration of the initial phase and the second phase.

As used herein, "micrograms per kilogram" means the drug used per kilogram of body weight of a mammal (including a human) to be treated, in micrograms.

As used herein, the term "treatment" refers to prophylactic or preventative treatment as well as curative or disease-modifying treatment, including treatment of a disease at risk of infection or suspected infection. Patients and patients who are ill or have been diagnosed with a disease or medical condition and include inhibition of clinical relapse. The treatment can be administered to an individual having a medical condition or who may eventually suffer from the condition to prevent, cure, or delay the onset of the condition, delay its onset, reduce its severity, or improve one or more symptoms, or prolong the survival of the individual. Exceeding the expected life expectancy in the absence of this treatment.

"Treatment regimen" means a mode of treatment for a disease, such as the mode of administration used during HCV therapy. The treatment regimen can include an induction regimen and a maintenance regimen.

As used herein, the terms "individual" and "patient" include any human or non-human animal. The term "non-human animal" includes all vertebrates, such as mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, and the like.

The term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient.

The term "administered" in connection with a compound (eg, alisporivir) is used to mean that the compound is delivered to a patient by any route.

As used herein, "therapeutically effective amount" refers to the effective use of a single or multiple doses to a patient, such as a human, for the treatment, prevention, or recurrence of a condition, prevention of its onset, cure, delay, reduction of severity thereof. , ameliovir that improves at least one of its symptoms, or prolongs the survival of the patient beyond the expected survival in the absence of the treatment the amount. When applied separately to the individual active ingredients (e.g., alisporivir) administered, the term refers to the ingredient alone. When applied to a combination, the term refers to the combined amount of active ingredient that produces a therapeutic effect, whether administered in combination, sequentially or simultaneously.

The term "treatment" refers to prophylactic or preventative treatment as well as curative or disease-modifying treatment, including treatment of a patient at risk of contracting a disease or suspected already infected disease, and illness. Or a patient who has been diagnosed with a disease or medical condition and includes inhibition of clinical relapse. The treatment can be administered to a patient having a medical condition or ultimately obtaining the condition to prevent, cure, or delay the onset of the condition, delay its onset, reduce its severity, or improve one or more symptoms, or prolong the patient's survival. The period exceeds the expected life expectancy in the absence of this treatment.

The phrase "treatment regimen" means the mode of administration for the treatment of a disease, such as the dosage regimen used during the treatment of HCV. The treatment regimen can include an induction regimen and a maintenance regimen.

In some embodiments, ribavirin is administered between about 800 to about 1200 mg per day, such as between 1000 mg and 1200 mg per day. In some embodiments, ribavirin is RBV 1000-1200 mg/day based on the weight of the patient (1000 mg/day for patients weighing <75 kg at screening, weight for screening) 75 kg of patients were administered 1200 mg/day. In other embodiments, ribavirin is administered based on the HCV genotype of the patient.

In another embodiment, alisporivir can be administered with a standard care supplement that promotes the antiviral efficacy of therapeutic treatment. Standard care may include additional agents that promote antiviral efficacy of therapeutic therapies, such as HCV NS3-4A serine protease based on a protease inhibitor, non-based NS3 protease inhibitor; phenanthrenequinone, thiazole and benzene Anthraquinone, a nucleoside analog, an antisense molecule, a vaccine, or an antibody-based HCV treatment for any cellular component required for HCV genome or viral replication.

In the above treatment, an effective amount of the drug is administered in the form of a composition, that is, it can be administered together (i.e., simultaneously), but it can also be administered separately or sequentially. In general, combination therapies are usually administered together, the basic principle being that the simultaneous administration induces multiple simultaneous stresses on the virus. The given specific dose will depend on the absorption, inactivation and excretion rates of the drug and other factors. It should be noted that the dose value will also vary with the severity of the condition to be alleviated.

The terms "co-administered" or "combined administration" or "in combination with" or the like as used herein are intended to encompass the administration of a selected therapeutic agent to a single patient, and are intended to include that the agent does not necessarily borrow Treatment regimens administered by the same route of administration or concurrently. Fixed combinations are also within the scope of the invention. Administration of a pharmaceutical combination of the invention may have beneficial effects, such as synergistic or additive therapeutic effects, as compared to monotherapy using only one of its pharmaceutically active ingredients or compared to current standard care therapies. The treatments used in the methods described herein can be administered by any conventional means. One or more components can be administered parenterally, e.g., in the form of an injectable solution or suspension, or in the form of an injectable formulation. Preferably, alisporivir will be administered orally in the form of a solution or suspension, lozenge or capsule for drinking. Pharmaceutical compositions for oral administration comprising alisporivir typically further comprise one or more pharmaceutically acceptable carrier materials. These compositions are typically concentrated and need to be combined with a suitable diluent (e.g., water) prior to administration. Pharmaceutical compositions for parenteral administration also typically include one or more excipients. Excipients selected as appropriate include isotonic agents, buffers or other pH controlling agents and preservatives. Such excipients can be added to maintain the composition and achieve a preferred pH range (about 6.5-7.5) and volumetric osmotic concentration (about 300 mosm/L).

As used herein, "twice a day" or BID means twice in any period of about a 24-hour period.

As described herein, alisporivir is administered in a single dosage form or in more than one dosage form; one or more oral dosage forms can be administered per day.

The alisporivir is preferably in a unit dosage form in a pharmaceutical composition, such as a gelatin capsule disclosed in WO 2012/080176 and incorporated herein by reference, including 1) from about 15% to about 20 weight of the composition. Amounts of alisporivir, 2) lipophilic component, 3) surfactant, 4) polyethylene glycol, and 5) water in an amount of from about 2% to about 15% by weight of the composition. Other alisporivir formulations and dosage forms can also be utilized.

As used herein, a direct acting antiviral agent is used to mean an agent that interferes with a particular step in the hepatitis C virus (HCV) replication cycle. Such agents can be, for example, ribavirin derivatives, protease inhibitors, polymerase inhibitors (e.g., nucleoside/nucleotide and non-nucleoside inhibitors), and cyclophilin inhibitors. Exemplary direct acting antiviral agents include: Abbott's boceprevir, telaprevir, ABT-072, ABT-450, ABT-333, Achillion's ACH1625, Anadys Pharmaceuticals' ANA598, AstraZeneca AZD-7295, BI201335 of Boehringer Ingelheim Pharma, BI207127, BMS650032 of Bristol Myers Squibb, BMS790052, BMS791325, BMS824383, Clemizole of Eiger BioPharmacetucials, EDP239 of Enanta/Novartis, Filibuvir of Pfizer Gilead GS9190 (Tegobuvir), GS9256, IDX375 from Idenix, GS-7977 from Gilead, RG7128 from Pharmasset/Genentec (mericitabine), PPI from Presidio 461, InterMune/Genentech's RG7227 (Danoprevir), Merck's SCH900518 (Narlaprevir), Vaniprevir, Medivir/Tibotec's TMC435, Vertex's VX-222, VX-759, VX-500, VX-916.

As used herein, "up to 12 or 24 weeks" refers to the duration of treatment and is intended to mean about 12 weeks, 16 weeks, or about 24 weeks, respectively. It should be understood that the therapy does not need to end at the 12th, 16th or 24th week. For example, the therapy may end one or more days prior to the 24th week period, while still being equivalent within the scope and spirit of the invention.

In one embodiment, the invention further provides a method for treating a hepatitis C virus genotype 2 and 3 infection or an HCV-induced disorder in a patient, preferably a patient who has not been treated, comprising no interference The patient is administered alisporivir in an amount of from about 200 mg to about 400 mg twice a day.

In another embodiment, the present invention further provides a method for delaying transplant recipients A method for recurring infection of HCV genotypes 2 and 3, which comprises administering to the recipient in an amount of from about 200 mg to about 400 mg twice a day, preferably about 400 mg twice a day, without using interferon. With Alappo.

In another embodiment, the invention further provides a method for treating a hepatitis C virus genotype 2 and 3 infection for a patient who has not received treatment or for treating an HCV-induced condition in a patient who has not received treatment, It is administered to the patient for about at least 12 weeks with ribavirin in an amount of from about 200 mg to about 400 mg twice a day, preferably about 400 mg per day, twice daily, without the use of interferon. duration.

In another embodiment, the invention further provides a method for treating a hepatitis C virus genotype 2 and 3 infection for a patient who has not received treatment or for treating an HCV-induced condition in a patient who has not received treatment, It comprises administering to the patient alisporivir in an amount of from about 200 mg to about 400 mg twice a day without interferon, preferably without using interferon, in an amount of about 400 mg twice daily. The patient was administered alisporivir with the ribavirin for a duration of treatment ranging from 12 weeks to 24 weeks.

In another embodiment, the invention further provides a method for treating a hepatitis C virus genotype 2 and 3 infection for a patient who has not received treatment or for treating an HCV-induced condition in a patient who has not received treatment, It comprises administering to the patient alisporivir in an amount of from about 200 mg to about 400 mg twice a day without interferon, preferably without using interferon, in an amount of about 400 mg twice daily. The patient was administered alisporivir for a treatment duration of at least 12 weeks.

In another embodiment, the invention further provides a method for treating a hepatitis C virus genotype 2 and 3 infection for a patient who has not received treatment or for treating an HCV-induced condition in a patient who has not received treatment, It comprises administering to the patient alisporivir in an amount of from about 200 mg to about 400 mg twice a day without interferon, preferably without using interferon, in an amount of about 400 mg twice daily. The patient was administered alisporivir for a duration of treatment ranging from 12 weeks to 24 weeks.

In another embodiment, the invention further provides the use of alisporivir for the preparation of a pharmaceutical composition for use in any of the methods as defined above.

In another embodiment, the invention further provides the use of alisporivir for the preparation of a medicament for use in any of the methods as defined above.

In another embodiment, the invention further provides a pharmaceutical composition for use in any of the methods as defined above, comprising alisporivir together with one or more pharmaceutically acceptable diluents or carriers thereof.

In another embodiment, the invention further provides a therapeutic regimen comprising administering opiatevir in an amount of from about 200 mg to about 400 mg twice daily, without interferon, preferably without interferon. Next, alisporivir was administered in combination with ribavirin in an amount of about 400 mg twice a day.

In another embodiment, the invention further provides a package comprising a pharmaceutical composition comprising alisporivir as defined above, and in the absence of interferon, from about 200 mg to about 400 mg twice a day Preferably, the amount is preferably administered in combination with the instructions of the composition in an amount of about 400 mg twice a day without the use of interferon. The package may also include ribavirin.

In another embodiment, the invention further provides a kit for treating chronic hepatitis C virus genotype 2 and 3 infection.

Also included herein is a method of reducing HCV genotype 2 and 3 RNA in a patient who has not received treatment, comprising to the patient: from 200 mg to about 400 mg twice daily, preferably twice daily, without interferon. Each time about 400 doses were administered to alisporivir.

An additional embodiment of the invention relates to a method of treating hepatitis C genotype 2 and 3 infections in a patient who has not received treatment, comprising to the patient: about 200 mg to twice a day, without interferon In an amount of about 400 mg, it is preferred to administer alisporivir in an amount of about 400 mg twice a day without using interferon.

An additional embodiment of the invention relates to a method of treating hepatitis C genotype 2 and 3 infection in a patient who has not received treatment, comprising administering to the patient: alapoivir in combination with ribavirin without the use of interferon , wherein alisporivir is administered in an amount of from about 200 mg to about 400 mg twice a day, and the ribavirin is RBV 1000-1200 mg/day based on the weight of the patient (1000 mg/day for a patient weighing <75 kg at the time of screening, Weight on screening The dose of 750 mg/day for 75 kg patients was administered.

In one embodiment, the invention further provides alisporivir for treating a patient who has not been treated with a hepatitis C virus genotype 2 or 3 infection, characterized in that (i) alisporivir is not using interferon, Administration in an amount of between about 200 mg twice a day for about 2 weeks, and (ii) if HCV RNA can be detected in the patient's plasma by HCV-RNA analysis after step (i), then Administration of alisporivir in an amount of 200 mg twice daily for up to about 24 weeks without interferon, and (iii) failure to be in the patient's plasma by HCV-RNA analysis after step (i) When HCV RNA is detected, alisporivir is administered for up to about 12 weeks in an amount of 200 mg twice a day without the use of interferon.

In one embodiment, the invention further provides alisporivir for treating a patient who has not been treated with a hepatitis C virus genotype 2 or 3 infection, characterized in that (i) alisporivir is not using interferon, Administration in an amount of between about 300 mg twice a day for about 2 weeks, and (ii) if HCV RNA can be detected in the patient's plasma by HCV-RNA analysis after step (i), then Administration of alisporivir for up to about 24 weeks in an amount of 300 mg twice a day without interferon, and (iii) failure to be in the patient's plasma by HCV-RNA analysis after step (i) When HCV RNA is detected, alisporivir is administered for up to about 12 weeks in an amount of 300 mg twice a day without the use of interferon.

In one embodiment, the invention further provides alisporivir for treating a patient who has not been treated with a hepatitis C virus genotype 2 or 3 infection, characterized in that (i) alisporivir is not using interferon, Investigate in an amount of about 400 mg twice a day Renewal for 2 weeks, and (ii) if HCV RNA can be detected in the patient's plasma by HCV-RNA analysis after step (i), then 400 mg twice daily without interferon The amount administered to alisporivir lasts up to about 24 weeks, and (iii) if HCV RNA cannot be detected in the patient's plasma by HCV-RNA analysis after step (i), then without interferon The alisporivir was administered in an amount of 400 mg twice a day for up to about 12 weeks.

In one embodiment, the invention further provides alisporivir for treating a patient who has not been treated with a hepatitis C virus genotype 2 or 3 infection, characterized in that (i) alisporivir is not using interferon, Administration with ribavirin in an amount of between about 200 mg twice a day for about 2 weeks, and (ii) if HCV-RNA analysis is used after step (i), HCV can be detected in the patient's plasma In the case of RNA, alisporivir is administered in combination with ribavirin in an amount of 200 mg twice a day for up to about 24 weeks without interferon, and (iii) if HCV- is followed by step (i) When RNA analysis is unable to detect HCV RNA in the patient's plasma, alisporivir is administered in combination with ribavirin in an amount of 200 mg twice a day for up to about 12 weeks without the use of interferon.

In one embodiment, the invention further provides alisporivir for treating a patient who has not been treated with a hepatitis C virus genotype 2 or 3 infection, characterized in that (i) alisporivir is not using interferon, Administration in combination with ribavirin in an amount of about 300 mg twice a day for about 2 weeks, and (ii) if HCV-RNA analysis is used after step (i), HCV can be detected in the patient's plasma. In the case of RNA, alisporivir is administered in combination with ribavirin in an amount of 300 mg twice a day for up to about 24 weeks without interferon, and (iii) if HCV- is followed by step (i) When RNA analysis is unable to detect HCV RNA in the patient's plasma, alisporivir is administered in combination with ribavirin in an amount of 300 mg twice a day for up to about 12 weeks without interferon.

In one embodiment, the invention further provides alisporivir for treating a patient who has not been treated with a hepatitis C virus genotype 2 or 3 infection, characterized in that (i) arapa Wei is administered in combination with ribavirin in an amount of about 400 mg twice a day without interferon for about 2 weeks, and (ii) if HCV-RNA analysis is possible after step (i) When HCV RNA is detected in the patient's plasma, the alisporivir is administered in combination with ribavirin in an amount of 400 mg twice a day for up to about 24 weeks without interferon, and (iii) if at the step (i) When HCV RNA is not detected in the patient's plasma by HCV-RNA analysis, alisporivir is administered in combination with ribavirin in an amount of 400 mg twice a day without interferon. Up to about 12 weeks.

In one aspect, the invention further provides the use of alisporivir for the manufacture of an agent for treating a patient who has not been treated for a hepatitis C virus genotype 2 or 3 infection, wherein alisporivir is during the initial phase Administration is carried out in an amount of from about 200 mg to about 400 mg twice daily for about 12 weeks to about 24 weeks, and wherein alisporivir can be administered in combination with ribavirin without the use of interferon.

In one aspect, the invention further provides the use of alisporivir for the preparation of a pharmaceutical composition for treating a patient who has not been treated for a hepatitis C virus genotype 2 or 3 infection, wherein alisporivir is initially The period of administration is administered in an amount of from about 200 mg to about 400 mg twice daily for about 12 weeks to about 24 weeks, and wherein alisporivir can be administered in combination with ribavirin without the use of interferon.

In one aspect, the invention further provides a treatment regimen characterized in that (i) alisporivir is administered in an amount of between about 200 mg twice daily for about 2 weeks without interferon, and (ii) If HCV RNA can be detected in the patient's plasma by HCV-RNA analysis after step (i), then aparpo is administered twice daily at 200 mg without interferon. Wei lasts for up to about 24 weeks, and (iii) if HCV RNA cannot be detected in the patient's plasma by HCV-RNA analysis after step (i), then twice per day without interferon The amount of 200 mg was administered to alisporivir for up to about 12 weeks.

In one aspect, the invention further provides a treatment regimen characterized in that (i) alisporivir is administered in an amount of between about 300 mg twice a day for about 2 weeks without interferon, and (ii) if HCV-RNA analysis is performed after step (i) When HCV RNA can be detected in the patient's plasma, the alisporivir is administered in an amount of 300 mg twice a day for up to about 24 weeks without interferon, and (iii) if in step (i) Thereafter, when HCV RNA could not be detected in the patient's plasma by HCV-RNA analysis, alisporivir was administered in an amount of 300 mg twice a day for up to about 12 weeks without using interferon.

In one aspect, the invention further provides a treatment regimen characterized in that (i) alisporivir is administered in an amount of between about 400 mg twice a day for about 2 weeks without interferon, and (ii) If HCV RNA can be detected in the patient's plasma by HCV-RNA analysis after step (i), then aparpo is administered twice a day, 400 mg per dose without interferon. Wei lasts for up to about 24 weeks, and (iii) if HCV RNA cannot be detected in the patient's plasma by HCV-RNA analysis after step (i), then twice per day without interferon The amount of 400 mg administered to alisporivir lasted for up to about 12 weeks.

In one aspect, the invention further provides a therapeutic regimen characterized in that (i) alisporivir is administered in combination with ribavirin in an amount of between about 200 mg twice a day without interferon. 2 weeks, and (ii) if HCV RNA can be detected in the patient's plasma by HCV-RNA analysis after step (i), then 200 mg twice a day without interferon In combination with ribavirin, alisporivir is administered for up to about 24 weeks, and (iii) if HCV RNA cannot be detected in the patient's plasma by HCV-RNA analysis after step (i), then no interference is used. The alisporivir was administered in combination with ribavirin in an amount of 200 mg twice a day for up to about 12 weeks.

In one aspect, the invention further provides a therapeutic regimen characterized in that (i) alisporivir is administered in combination with ribavirin in an amount of between about 300 mg twice a day without interferon. 2 weeks, and (ii) if the HCV-RNA is subdivided after step (i) When the HCV RNA is detected in the patient's plasma, the alisporivir is administered in combination with ribavirin in an amount of 300 mg twice a day for up to about 24 weeks without interferon, and (iii) If HCV RNA cannot be detected in the patient's plasma by HCV-RNA analysis after step (i), then in combination with ribavirin in an amount of 300 mg twice a day without interferon, Powell lasts for up to about 12 weeks.

In one aspect, the invention further provides a therapeutic regimen characterized in that (i) alisporivir is administered in combination with ribavirin in an amount of between about 400 mg twice a day without interferon. 2 weeks, and (ii) if HCV RNA can be detected in the patient's plasma by HCV-RNA analysis after step (i), then 400 mg twice a day without interferon In combination with ribavirin, alisporivir is administered for up to about 24 weeks, and (iii) if HCV RNA cannot be detected in the patient's plasma by HCV-RNA analysis after step (i), then no interference is used. The alisporivir was administered in combination with ribavirin in an amount of 400 mg twice a day for up to about 12 weeks.

In one aspect, the invention further provides a pharmaceutical composition comprising alisporivir for use as defined above. In other aspects, the invention provides a package comprising a pharmaceutical composition comprising alisporivir for use as defined above in combination with instructions for administering the composition.

In one aspect, the invention further provides the use of alisporivir for the manufacture of a medicament for treating a patient who has not been treated with a hepatitis C virus genotype 2 or 3 infection, wherein the medicament comprises one, Two, three, four or five doses of from about 50 mg to about 200 mg are dosed. In other aspects, the invention provides the use of alisporivir for the manufacture of an agent for treating a patient who has not been treated with a hepatitis C virus genotype 2 or 3 infection, wherein the agent is not using interferon Formulated at a dose comprising one, two, three or four doses of about 100 mg or about 200 mg. In other aspects, the agent is formulated at a dose comprising one, two, three, four or five doses of from about 50 mg to about 200 mg, further comprising ribavirin.

In one aspect, the invention further provides the use of alisporivir for the manufacture of an agent for treating a patient who has not been treated for a hepatitis C virus genotype 2 or 3 infection, wherein the agent is not using interferon Prepared at a dose comprising one, two, three, four or five doses of from about 50 mg to about 200 mg, further comprising ribavirin, wherein the amount of ribavirin in the medicament is between each dosage unit Between about 800 mg to about 1200 mg per day, for example from 1000 mg to 1200 mg per day.

In one aspect, the invention further provides a pharmaceutical composition comprising alisporivir for use in any of the uses as defined above.

In one aspect, the invention further provides a kit comprising a) a pharmaceutical composition comprising alisporivir for treating a patient who has not been treated with a hepatitis C virus genotype 2 or 3 infection, as appropriate In combination with one or more pharmaceutically acceptable excipients, and b) instructions for administering the pharmaceutical composition for treating an untreated patient for treatment of hepatitis C virus genotype 2 or 3 infection, wherein The administration is characterized in that (i) alisporivir is administered in combination with ribavirin in an amount of between about 200 mg to about 400 mg twice daily for about 2 weeks without interferon, and (ii) If HCV RNA can be detected in the patient's plasma by HCV-RNA analysis after step (ii), the virus is administered in an amount of about 200 mg to about 400 mg twice a day without interferon. The combination of azole and alisporivir lasts for up to about 24 weeks, and (iii) if HCV RNA cannot be detected in the patient's plasma by HCV-RNA analysis after step (ii), then without interferon In combination with ribavirin in an amount of about 200 mg to about 400 mg twice a day. Labevir lasts for up to about 12 weeks.

The terms "co-administered" or "combined administration" or "in combination with" or the like as used herein are intended to encompass the administration of a selected therapeutic agent to a single patient, and are intended to include that the agent does not necessarily borrow Treatment regimens administered by the same route of administration or concurrently. Fixed combinations are also within the scope of the invention. Single with one of its medicinal active ingredients Administration of a pharmaceutical combination of the invention may have beneficial effects, such as synergistic or additive therapeutic effects, as compared to or in comparison to current standard care therapies. The treatments used in the methods described herein can be administered by any conventional means. One or more components can be administered parenterally, e.g., in the form of an injectable solution or suspension, or in the form of an injectable formulation. Preferably, alisporivir will be administered orally in the form of a solution or suspension, lozenge or capsule for drinking. Pharmaceutical compositions for oral administration comprising alisporivir typically further comprise one or more pharmaceutically acceptable carrier materials. These compositions are typically concentrated and need to be combined with a suitable diluent (e.g., water) prior to administration. Pharmaceutical compositions for parenteral administration also typically include one or more excipients. Excipients selected as appropriate include isotonic agents, buffers or other pH controlling agents and preservatives. Such excipients can be added to maintain the composition and achieve a preferred pH range (about 6.5-7.5) and volumetric osmotic concentration (about 300 mosm/L).

As described herein, alisporivir is administered in a single dosage form or in more than one dosage form; one or more oral dosage forms can be administered per day. In some embodiments, alisporivir is administered at a dose of from 200 mg to 1000 mg.

The efficacy of the treatment regimen can be monitored using a standard protocol. After treatment, HCV in serum can be measured and serum ALT levels measured. For example, the presence of HCV RNA in the plasma of a patient can be analyzed. HCV RNA (IU/mL) can be measured at regular intervals during treatment, for example on day 1 (before administration and 4, 8 and 12 hours after administration) and on day 2, day 3, day 8 , before the 15th day, the 29th day, and at the 12th week, the 24th week, the 36th week, the 48th week, the 72nd week (if applicable) and at the time of tracking. In addition, HCV strains in patients can be sequenced and analyzed to identify mutations selected for resistance.

As used herein, LOD means detection limit (serum HCV RNA is less than 10 IU/mL), and LOQ means quantitation limit (serum HCV RNA is less than 25 IU/mL). HCV RNA levels can be measured using commercially available methods.

The treatment endpoint is a viral response, that is, at the end of the treatment process, at the beginning of treatment There is no HCV within the next few months or months after the treatment is completed. HCV in serum can be measured at the RNA level by methods such as quantitative RT-PCR or northern blotting, or by enzyme immunoassay of viral proteins or enhanced chemiluminescence immunoassays at the protein level. The endpoint can also include measurements of serum ALT levels within the normal range.

The viral response parameters were: rapid virological response (RVR 4) at week 4 of treatment, defined by serum HCV-RNA that was undetectable at week 4 of treatment; early virological response (EVR), at week 12 of treatment HCV-RNA is reduced by at least 2 log ₁₀ IU/mL (partial EVR) or undetectable serum HCV-RNA (complete EVR) definition compared to baseline; sustained virological response (SVR24) by 24 weeks after the end of therapy Analysis of the absence of HCV-RNA from serum by sensitive polymerase chain reaction (PCR) or undetectable HCV RNA at 24 weeks after treatment (by LOD); end of treatment response (ETR): at the end of treatment HCV RNA is undetectable (by LOD) (complete or premature interruption).

An exemplary treatment regimen is given in the examples. In an exemplary embodiment, an individual in need of treatment is provided with about 200 mg to about 400 mg of alisporivir twice a day for 2 weeks, followed by about 200 mg to about 400 mg of alisporivir for up to 12 weeks. .

The following examples illustrate embodiments of the invention described above.

Instance Compound

Ribavirin is a synthetic nucleoside analog and is also commercially available, for example from COPEGUS® from Roche.

Apravia gelatin capsules.

Example 1-DEB025A2222: Phase II, multicenter, unblinded, randomized, 3-group, dose-exploration Phase II study.

A total of approximately 150 patients who have not received treatment for chronic hepatitis C GT2/3 will be randomized into one of three treatment groups (A, B or C) at a 1:1:1 ratio.

Random packets will be ranked by the following parameters measured at screening.

Virus load at screening time ( 800,000 IU/mL (5.903 log ₁₀ ) or <800,000 IU/mL (5.903 log ₁₀ ))

Study period: The total planned duration of the study was from randomization for up to 48 weeks, as shown in Figure 1. The main study consisted of three periods: screening, treatment period 1 (DEB025/RBV treatment) and follow-up after treatment 1

1. Screening period: The duration is from 1 to 42 days, during which the applicability of the study will be confirmed.

2. Treatment period 1 (DEB025/RBV treatment) period (12 or 24 weeks): Patients will be randomly assigned to one of three parallel treatment groups:

Group A: Dual therapy with duration of treatment-guided treatment with DEB025 200 mg BID and RBV 1000-1200 mg/day (1000 mg/day for patients weighing <75 kg at screening, weight for screening) 75 kg of patients (1200 mg / day), based on the second week of HCV RNA results for 12 or 24 weeks.

DEB025/RBV response-guided treatment duration:

̇A1: Patients with viral load <LOQ at week 2 will discontinue DEB025/RBV study drug treatment after 12 weeks.

̇A2: viral load at week 2 Patients with LOQ will complete a 24-week DEB025/RBV study treatment.

Group B: Dual therapy with response-guided duration of treatment using DEB025 300 mg BID and RBV 1000-1200 mg/day (1000 mg/day for patients weighing <75 kg at screening, weight for screening) 75 kg of patients (1200 mg / day), based on the second week of HCV RNA results for 12 or 24 weeks.

DEB025/RBV response-guided treatment duration:

̇B1: Patients with viral load <LOQ at week 2 will discontinue DEB025/RBV study drug treatment after 12 weeks.

̇B2: viral load at week 2 Patients with LOQ will complete a 24-week DEB025/RBV study treatment.

Group C: Dual therapy with duration of treatment-guided treatment with DEB025 400 mg BID and RBV 1000-1200 mg/day (1000 mg/day for patients weighing <75 kg at screening, weight for screening) 75 kg of patients (1200 mg / day), based on the second week of HCV RNA results for 12 or 24 weeks.

DEB025/RBV response-guided treatment duration:

̇C1: Patients with viral load <LOQ at week 2 will discontinue DEB025/RBV study drug treatment after 12 weeks.

̇C2: viral load at week 2 Patients with LOQ will complete a 24-week DEB025/RBV study treatment.

The initial analysis will be performed when all patients complete 12 weeks of DEB025/RBV treatment or early stop. The interim analysis will be performed in all patients in treatment groups A, B, and C after 12 weeks of treatment followed by 1 or earlier discontinuation. The final analysis for the core of the study will be performed in all of the patients in treatment groups A, B, and C after completing the treatment for 1 period or earlier.

Example 2 Basic Principles, Dosing Mode, and Duration of Dosage/Scheme for Treatment with DEB025

Dosage/scheme has been selected based on inferences made from available clinical data, including using modeling and simulation. The results of the recently available treatment from the ongoing study CDEB025A2210 are also considered.

Clinical observations from multiple early studies of DEB025 with peg-IFNα2a in the presence or absence of RBV revealed Cmin ("valley" exposure) and various antiviral effect measurements (including baselines at week 1) The relationship between changes, RVR, EVR, and SVR). Using data from the ESSENTIAL study (Debio 025-HCV-205), categorical observations based on the Cmin quintile indicate that higher Cmin tends to produce higher response rates regardless of treatment duration.

In the GT1a, 1b, 2a and 3a replicons, the in vitro subgenomic replicon EC50 values (not adjusted for protein binding) ranged from 31 to 70 nM. Recovered by GT1a and 1b The highest IC binding for IC binding was estimated to be 371 ng/ml (305 nM) for GT1a and 366 ng/mL for GT1b. Analysis of clinical data revealed that Cmin (>411 ng/ml) associated with the optimal therapeutic response met the protein binding adjusted IC50 estimated by the GT1a and 1b replicons. It is hypothesized that the concentration-response relationship of cyclophilin inhibition is independent of the HCV genotype. The clinical experience of using DEB025 to date confirms this hypothesis. Therefore, the target Cmin of 371 ng/mL is the basis of the DEB025 treatment regimen in GT1-4 HCV treatment, including patients who have not received treatment and undergoes treatment.

In view of the exposure profile (ie, PK variability) and the variability in viral susceptibility (ie, the change in Cmin required for individual patients), the included BID protocol covers the effective dose range based on previous studies (ie, 600 mg QD and 400 mg). BID). Although the time to reach steady state is less important for DEB025 than DAA, especially considering the higher resistance to resistance, twice daily dosing does increase intravitreal exposure faster than once daily. And most importantly, maintain a high Cmin. The efficacy and safety of the highest dose proposed (400 mg BID) has been confirmed in the most recent mid-term analysis from the CDEB025A2210 study. In the GT1 patients undergoing treatment, the 400 mg BID regimen (ie, triple therapy) of DEB025 with peg-IFNα2a and RBV was greater than the one-time regimen (including 800 mg of QD) after the first 12 weeks of treatment. Or the antiviral activity observed for the peg-IFNα2a/RBV control, as shown in Figure 2.

At the 12th week of treatment, compared with peg-IFNα2a/RBV dual therapy (cEVR 33%) and triple therapy regimen in which DEB025 was administered once daily at 600 mg (cEVR 46%) or 800 mg (cEVR 61%) The ratio of undetectable HCV-RNA in the 400 mg BID group (cEVR 72%; p<0.01 for all comparisons) was superior.

Although the safety profile is generally similar between the BID and QD regimens when DEB025 is administered with peg-IFNα2a/RBV, the 400 mg BID regimen results in an increased frequency of certain adverse events, especially benign, reversible jaundice, nausea, vomiting and The incidence of neutropenia is high. Determining the safety and/or tolerability of alternative BID protocols for DEB025 The state will be critical in determining the optimal dosing regimen for IFN-free therapy in GT2/3 in Phase III and in planning for future combinations with DAA in the interferon-free regimen. This is particularly relevant because IFN may cause nausea, vomiting, and neutropenia, and no alternative BID administration is explored in the IFN-free regimen.

The clinical signs that are available continue to be consistent with the modeled relationship of exposure and response (efficacy) and based on the predictions made, specifically the higher Cmin based on the administered dose translates into better efficacy. The protocol of less than 200 mg BID was not included because it was predicted that it could not maintain the median steady-state trough exposure above the 600 mg QD value steady-state trough exposure.

The IFN-free regimen of DEB025+RBV in the planned study was approximately equal to or higher than the DEB025 regimen (VITAL-1) studied in Phase 2 studies in patients with GT2/3 HCV, including 1,000 mg QD, but not Exceeded the highest dose/scenario (1,200 mg BID) studied in GT1 HCV patients. These protocols are expected to fully characterize the antiviral activity and short-term safety of DEB025-based dual therapies (not accompanied by peg-IFNα2a) to further understand and ultimately based on the PK/PD relationship between safety/tolerance and efficacy. Improve the dose adjustment of DEB025.

RBV weight based dose

For patients with HCV G2 or 3 who have not received treatment, a daily fixed dose of 800 mg of RBV in combination with pegIFN is recommended for 24 weeks. For patients with HCV G2 or 3 who have failed treatment, the recommended dose of RBV is 1000-1200 mg/day (by weight) and is treated with pegIFN for 48 weeks. When used in combination with interferon, ribavirin administration is primarily limited by toxicity (anemia), with higher reactivity seen with larger ribavirin exposure. For the treatment of G1 patients, it is customary to utilize weight-based ribavirin when combined with interferon, a direct acting antiviral agent, or a combination of both. In a VITAL-1 study using a single dose of 800 mg/d for all patients, logistic regression analysis showed that higher RBV concentrations were significantly associated with better efficacy (SVR), with higher weight being inversely related to efficacy. Therefore, in this study, it was proposed to use a combination of RBV and DEB025 based on the appropriate weight to ensure that all patients receive similar and higher mg/kg. RBV dose.

In the absence of myelosuppressive effects of pegIFN, the safety of RBV should be significantly better than the use of pegIFN, although anemia is the major abnormality expected.

Combination DEB025+RBV

The rationale, including RBV and DEB025, comes from a combination of studies using IFN, which have shown that RBV substantially increases SVR rates, primarily by preventing recurrence (McHutchison JG et al., (1998) Interferon alfa-2b alone or in combination with Ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med, 339(21): 1485-92). RBV is associated with peg-IFNα2a and the protease inhibitor traprate (Hézode C, Forestier N, Dusheiko G et al. (2009) Telaprevir and peginterferon with or without ribvarin for chronic HCV infection. N Engl J Med.; 360:1839- 50) or boceprevir (Kwo PY, Lawitz EJ, McCone J et al (2010) Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment naive patients with genotype 1 hepatitis C infection ( SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 2010; 376: 705-16) is also effective in preventing viral breakthrough and recurrence.

Analysis from the VITAL-1 study demonstrated that at higher doses, the response rate was higher in the DEB025 group containing RBV compared to DEB025 monotherapy. To date, all studies using single or dual oral anti-HCV agents appear to indicate the need for concomitant RBV therapy, and subsequently, the development of DEB025 is currently intended to include RBV in the treatment regimen. In this study, the efficacy of three different doses of DEB025 will be studied with the administration of weight-based RBV.

Duration of treatment

One of the areas of concern in the clinical development of anti-HCV drugs is to shorten the overall treatment duration. Therefore, in this study, a reaction-directed method guided by a response to treatment with DEB025/RBV will be studied. The 12 or 24 week treatment duration was based on a pharmacokinetic-viral dynamics (PKVK) model developed using data obtained from GT2/3 who had not received a Phase II study (VITAL-1) in a treated patient. In this model, patients who were treated with DEB025/RBV in the absence of interferon were expected to achieve a very high sustained duration of treatment with only 12 weeks of therapy as of the second week of treatment. Virological response rate. This model demonstrates the use of 400 mg BID DEB025 plus ribavirin, and as of the second week of therapy, 26% of patients will be virus negative. In the VITAL-1 study, approximately half of patients treated with DEB025/RBV achieved non-quantitative levels of HCV-RNA as of the 6th week of treatment or earlier. The viral load of most patients who still have a detectable virus is several logs lower than the baseline. The curve of viral load reduction during the first 6 weeks is clearly differentiated between doses.

Claims (12)

A use of a combination of ribavirin and aliporivir for the preparation of an agent for treatment of hepatitis C genotype 2 and 3 infection in an untreated patient, wherein alisporivir is not used The interferon is administered in an amount of from about 200 mg to about 400 mg twice a day. The use of claim 1, wherein 1000 mg/day of ribavirin is administered to a patient weighing less than 75 kg, and 1200 mg/day of ribavirin is administered to a patient having a body weight of greater than or equal to 75 kg. The use of claim 1 wherein about 200 mg of alisporivir is administered twice a day. The use of claim 1 wherein about 300 mg of alisporivir is administered twice a day. The use of claim 1 wherein about 400 mg of alisporivir is administered twice a day. The use of claim 1 wherein the alisporivir is administered for about 12, 16 or 24 weeks without the use of interferon. A use of a combination of ribavirin and aliporivir for the preparation of a medicament for the treatment of hepatitis C virus genotype 2 or 3 infection in an untreated patient, wherein (i) arapa Wei is administered in combination with ribavirin in an amount between about 200 mg to about 400 mg twice daily for about 2 weeks without interferon, and (ii) if HCV is used after step (i) - RNA analysis can detect HCV RNA in the patient's plasma, and in combination with ribavirin in an amount of about 200 mg to about 400 mg twice a day without interferon, the alisporivir can be administered up to about 24 times. Week, and (iii) if HCV RNA cannot be detected in the patient's plasma by HCV-RNA analysis after step (i), then about 200 mg to about twice a day without interferon The amount of 400 mg is administered in combination with ribavirin for up to about 12 weeks. The use of claim 7 wherein about 200 mg of alisporivir is administered twice a day. The use of claim 7 wherein about 300 mg of alisporivir is administered twice a day. The use of claim 7 wherein about 400 mg of alisporivir is administered twice a day. A pharmaceutical composition comprising alisporivir, for use as claimed in any one of claims 1 to 6. A package comprising a pharmaceutical composition as claimed in claim 11 in combination with instructions for indicating administration of the composition.