Treatment of hepatitis delta virus infection with interferon lambda.

Abstract

Methods for treating hepatitis delta virus (HDV) infection in a human patient are provided. In some embodiments, the methods comprise administering a therapeutically effective amount of interferon lambda to the patient for at least four weeks.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 297,759, filed February 19, 2016, the entire contents of which are incorporated herein by reference.

[0002] The present invention provides methods for treating viral hepatitis caused by Hepatitis Delta Virus (HDV) infection and relates to the fields of chemistry, medicinal chemistry, medicine, molecular biology and pharmacology. [Background technology]

[0003] Hepatitis delta virus (HDV) causes the most severe form of chronic viral hepatitis, for which there is no effective drug therapy. HDV always presents as a coinfection with hepatitis B virus (HBV). Chronic HDV and HBV coinfection exacerbates pre-existing HBV-associated liver damage, leading to cirrhosis, hepatic decompensation and hepatocellular carcinoma. See Negro, Cold Spring Harb Perspect Med, 2014, 4:a021550; Hoener zu Siederdissen, Visc Med, 2016, 32:86-94; Lau, Hepatology, 1999, 30:546-549. Patients coinfected with both HDV and HBV are more likely to die from complications of liver disease compared to patients infected with HBV alone. See Alavian et al., J Res Med Sci, 2012, 17:967-974. Summary of the Invention [Problem to be solved by the invention]

[0004] Interferon alpha therapy has been described as a treatment for HDV. However, sustained virological responses with interferon alpha therapy are achieved in only about 30% of patients, and only a minority of patients clear HDV infection. See Giersch and Dandri, Journal of Clinical and Translational Hepatology, 2015, 3:220-229; Bahcecioglu et al., Hepat Mon., 2015, 15(e):e24366. Interferon alpha conveys its effects by signaling through the interferon alpha receptor, which is widely expressed by many different cell types. In contrast to interferon alpha, interferon lambda signals through a different type of receptor, the interferon lambda receptor, which has a restricted cellular expression pattern. Interferon lambda also exhibits different antiviral activity than interferon alpha, due in part to differences in expression of the interferon receptor. In a comparative study of pegylated interferon alpha and pegylated interferon lambda for the treatment of HBV (Chan et al., J. Hepatology, 2016, 64:1011-1019), it was found that pegylated interferon lambda produced a more significant reduction in viremia compared to pegylated interferon alpha at the midpoint of treatment (24 weeks), but by the end of the treatment period, there was no difference between pegylated interferon alpha and pegylated interferon lambda treatment, and after treatment, there was a greater virological rebound in the pegylated interferon lambda treatment group. HBV / HDV coinfected mice administered pegylated interferon alpha for 4 weeks showed a 2.2 log reduction in HDV-RNA levels, while mice administered pegylated interferon lambda for 4 weeks showed a 1.5 log reduction in HDV-RNA levels (Giersch et al., 2013). To date, the efficacy of long-term pegylated interferon lambda therapy for the treatment of HDV has not been described. There remains a need for agents to treat HDV infection. [Means for solving the problem]

[0005] In one aspect, a method for treating hepatitis delta virus (HDV) infection in a human patient is provided. In some embodiments, the method comprises administering a therapeutically effective amount of interferon lambda to the patient for at least 4 weeks. In some embodiments, the method comprises administering a therapeutically effective amount of interferon lambda-1a to the patient for at least 4 weeks. In some embodiments, the method comprises administering a therapeutically effective amount of pegylated interferon lambda (e.g., pegylated interferon lambda-1a) to the patient for at least 4 weeks.

[0006] In some embodiments, the interferon lambda (e.g., pegylated interferon lambda, e.g., pegylated interferon lambda-1a) is administered subcutaneously. In some embodiments, the interferon lambda (e.g., pegylated interferon lambda, e.g., pegylated interferon lambda-1a) is administered weekly by subcutaneous injection. In some embodiments, the interferon lambda (e.g., pegylated interferon lambda, e.g., pegylated interferon lambda-1a) is administered at a dose of 120 μg / week. In some embodiments, the interferon lambda (e.g., pegylated interferon lambda, e.g., pegylated interferon lambda-1a) is administered at a dose of 180 μg / week.

[0007] In some embodiments, the patient undergoing treatment has compensated liver disease with or without cirrhosis.In some embodiments, the patient undergoing treatment has compensated liver disease with cirrhosis.

[0008] In some embodiments, the interferon lambda (e.g., pegylated interferon lambda, e.g., pegylated interferon lambda-1a) is administered to the patient for a course of treatment that lasts for at least 30 days, at least 60 days, at least 90 days, at least 120 days, at least 150 days, or at least 180 days; or at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks. In some embodiments, the interferon lambda (e.g., pegylated interferon lambda, e.g., pegylated interferon lambda-1a) is administered to the patient for at least 6 months, at least 9 months, at least 1 year, at least 18 months, at least 2 years, or longer. In some embodiments, the interferon lambda (e.g., pegylated interferon lambda, e.g., pegylated interferon lambda-1a) is administered for at least 48 weeks, at least 60 weeks, at least 72 weeks, at least 84 weeks, or at least 96 weeks.

[0009] In some embodiments, interferon lambda (e.g., interferon lambda-1a) is administered by subcutaneous injection to a patient with chronic HDV infection at a dose of 120 μg per week for at least 12 weeks. In some embodiments, interferon lambda (e.g., interferon lambda-1a) is administered by subcutaneous injection to a patient with chronic HDV infection at a dose of 120 μg per week for at least 24 weeks. In some embodiments, interferon lambda (e.g., interferon lambda-1a) is administered by subcutaneous injection to a patient with chronic HDV infection at a dose of 120 μg per week for 48 weeks. In some embodiments, interferon lambda (e.g., interferon lambda-1a) is administered by subcutaneous injection to a patient with chronic HDV infection at a dose of 120 μg per week for 96 weeks. In some embodiments, a patient with chronic HDV infection has compensated liver disease.

[0010] In some embodiments, interferon lambda (e.g., pegylated interferon lambda, e.g., pegylated interferon lambda-1a) is administered by subcutaneous injection to patients with chronic HDV infection at a dose of 120 μg per week for at least 12 weeks. In some embodiments, interferon lambda (e.g., pegylated interferon lambda, e.g., pegylated interferon lambda-1a) is administered by subcutaneous injection to patients with chronic HDV infection at a dose of 120 μg per week for at least 24 weeks. In some embodiments, interferon lambda (e.g., pegylated interferon lambda, e.g., pegylated interferon lambda-1a) is administered by subcutaneous injection to patients with chronic HDV infection at a dose of 120 μg per week for 48 weeks. In some embodiments, interferon lambda (e.g., pegylated interferon lambda, e.g., pegylated interferon lambda-1a) is administered subcutaneously to patients with chronic HDV infection at a dose of 120 μg per week for 96 weeks. In some embodiments, the patient with chronic HDV infection has compensated liver disease.

[0011] In some embodiments, interferon lambda (e.g., interferon lambda-1a) is administered by subcutaneous injection to a patient with chronic HDV infection at a dose of 180 μg per week for at least 12 weeks. In some embodiments, interferon lambda (e.g., interferon lambda-1a) is administered by subcutaneous injection to a patient with chronic HDV infection at a dose of 180 μg per week for at least 24 weeks. In some embodiments, interferon lambda (e.g., interferon lambda-1a) is administered by subcutaneous injection to a patient with chronic HDV infection at a dose of 180 μg per week for 48 weeks. In some embodiments, interferon lambda (e.g., interferon lambda-1a) is administered by subcutaneous injection to a patient with chronic HDV infection at a dose of 180 μg per week for 96 weeks. In some embodiments, a patient with chronic HDV infection has compensated liver disease.

[0012] In some embodiments, pegylated interferon lambda (e.g., pegylated interferon lambda-1a) is administered by subcutaneous injection to patients with chronic HDV infection at a dose of 180 μg per week for at least 12 weeks. In some embodiments, pegylated interferon lambda (e.g., pegylated interferon lambda-1a) is administered by subcutaneous injection to patients with chronic HDV infection at a dose of 180 μg per week for at least 24 weeks. In some embodiments, pegylated interferon lambda (e.g., pegylated interferon lambda-1a) is administered by subcutaneous injection to patients with chronic HDV infection at a dose of 180 μg per week for 48 weeks. In some embodiments, pegylated interferon lambda (e.g., pegylated interferon lambda-1a) is administered by subcutaneous injection to patients with chronic HDV infection at a dose of 180 μg per week for 96 weeks. In some embodiments, the patient with chronic HDV infection has compensated liver disease.

[0013] In some embodiments, the treatment course results in an HDV viral load of less than 100 copies per mL of serum or less than 100 IU per mL of serum. In some embodiments, the HDV viral load remains less than 100 copies per mL of serum or less than 100 IU per mL of serum for at least 12 weeks after treatment ends. In some embodiments, the HDV viral load remains less than 100 copies per mL of serum or less than 100 IU per mL of serum for at least 24 weeks after treatment ends.

[0014] In some embodiments, the course of treatment results in an HDV viral load below detection levels. In some embodiments, the HDV viral load remains below detection levels for at least 12 weeks after treatment has ended. In some embodiments, the HDV viral load remains below detection levels for at least 24 weeks after treatment has ended.

[0015] In some embodiments, the treatment course results in an improvement in the patient's liver function. In some embodiments, the improvement in liver function is an improvement in one or more serum markers selected from the group consisting of serum albumin, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), prothrombin, alpha2-macroglobulin, apolipoprotein A1, haptoglobin, and gamma-glutamyltranspeptidase (GGT). In some embodiments, the improvement in liver function is an improvement in liver fibrosis.

[0016] In some embodiments, the method further comprises administering to the patient an additional antiviral therapeutic agent as a co-therapy. In some embodiments, interferon lambda therapy is the only or first antiviral therapy administered to the patient. In some embodiments, interferon lambda (e.g., pegylated interferon lambda, e.g., pegylated interferon lambda-1a) therapy is the only or first anti-HDV therapy administered to the patient. In some embodiments, interferon lambda (e.g., pegylated interferon lambda, e.g., pegylated interferon lambda-1a) therapy is the only or first antiviral therapy administered to the patient. In some embodiments, the patient receives one or more antiviral or anti-HDV therapeutic agents in addition to interferon lambda (e.g., pegylated interferon lambda, e.g., pegylated interferon lambda-1a).

[0017] These and other aspects and embodiments of the invention are described in more detail below. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] I. Definition The scope of the present invention is limited only by the appended claims, and therefore the terms used herein are for the purpose of describing only specific embodiments and are not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In this specification and the claims that follow, reference is made to a number of terms that shall be defined to have the following meanings unless a contrary intention is apparent. In some cases, terms that have commonly understood meanings are defined herein for clarity and / or ready reference, and the inclusion of such definitions herein should not be interpreted as representing a substantial difference to the definition of the term as commonly understood in the art.

[0019] Although any method and material similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices and materials are described herein.All technical and patent literature cited herein is incorporated herein by reference in its entirety.Nothing in this specification should be construed as an admission that the present invention is not entitled to antedate such disclosure by prior invention.

[0020] All numerical designations, e.g., pH, temperature, time, concentration, and molecular weight, including ranges, are approximations which are varied (+) or (-) by increments of 0.1 or 1.0, as appropriate. All numerical designations should be understood as being preceded by the term "about," even if not always explicitly stated.

[0021] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of compounds.

[0022] The term "administration" refers to the introduction of the disclosed compound, composition or agent into a host, such as human.In the context of the present invention, one preferred administration route for administration of agent is subcutaneous administration.Other routes are intravenous administration and oral administration.

[0023] The term "baseline" refers to measurements (eg, of viral load, patient status, ALT level) made before a course of treatment, unless otherwise specified or apparent from the context.

[0024] The term "comprising" is intended to mean that the compounds, compositions, and methods include the recited elements, but do not exclude other elements. "Consisting essentially of," when used to define compounds, compositions, and methods, is intended to mean excluding other elements that would materially affect the basic and novel characteristics of the claimed invention. Embodiments defined by each of these transitional phrases are within the scope of the invention.

[0025] The terms "course of treatment" and "course of therapy" are used interchangeably herein and refer to medical intervention after a patient has been diagnosed, for example, with HDV infection and requires medical intervention. Medical intervention includes, but is not limited to, administration of medication for a period of time, typically at least one month, typically several months, or even months or years, for an HDV-infected patient.

[0026] The term "HDV RNA viral load" or "viral load" of a human serum or plasma sample refers to the amount of HDV RNA in a given volume of human serum or plasma sample. HDV RNA is generally detected by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) assays. In such assays, the amount of signal generated during the assay is proportional to the amount of HDV RNA in the sample. The signal from the test sample is compared to the signal of a dilution series of quantified hepatitis delta RNA standards, and the copy number of genome copies is calculated. See, for example, Kodani et al., 2013, J. Virol. Methods, 193(2), 531; Karatayli et al., 2014, J. Clin. Virol, 60(1), 11. HDV RNA viral load may be reported in RNA copies per mL serum (or plasma) or International Units (IU) per mL serum (or plasma). See Chudy et al., 2013, Collaborative Study to Establish World Health Organization International Standards for Hepatitis D Virus RNA for Nucleic Acid Amplification Technology (NAT)-Based Assays, WHO Expert Committee on Biological Standardization WHO / BS / 2013.2227. Commercial assays are available from ARUP Laboratories (Salt Lake City, UT). The detection limit of the ARUP HDV RNA assay is reported to be 31 IU / mL. Analytik Jena AG (Germany) offers the RoboGene® HDV RNA Quantitation Kit 2.0, which is CE-IVD certified with WHO standards to assess response to antiviral treatment. The detection limit of the RoboGene® assay is reported to be 6 IU / mL. "Viral load" without a specific unit (e.g., "viral load less than 100") refers to copies of HDV RNA per mL of serum unless otherwise indicated or clear from the context. Unless otherwise specified, reference to "below the level of detection" means less than 15 IU / mL.

[0027] HDV levels are generally calculated as log 10 The HDV RNA level is presented using units. HDV RNA levels can be presented in units of "RNA copies per mL" or "International Units (IU) per mL". See Chudy et al., 2013, Collaborative Study to Establish World Health Organization International Standards for Hepatitis D Virus RNA for Nucleic Acid Amplification Technology (NAT)-Based Assays" WHO Expert Committee on Biological Standardization WHO / BS / 2013.2227. Both units are used herein. As used herein, a statement of "HDV RNA copies per mL" (e.g., as shown in the Examples, unless otherwise specified and without discussion related to clinical trial results) should be read as "HDV RNA copies / mL or [alternatively] HDVIU / mL" for purposes of description or basis of the specification. When a specific amount of HDV RNA copies per mL is described, a multiplier of 1.2 can be applied to convert the amount of HDV RNA copies / mL to an amount of IU / mL for description and support of the specification. For example, "120 HDV RNA copies per mL" should be read as "120 copies / mL or 100 IU / mL."

[0028] Changes in HDV RNA levels can be expressed as "log reductions" following the usual conventions of virology. For example, a 1 log reduction (i.e., -1 log) in viral load (e.g., from 7 log to 6 log) is a 10-fold reduction, and a 2 log reduction (i.e., -2 log) in viral load (e.g., from 7 log to 5 log) is a 100-fold reduction. A reduction from 4 log RNA copies / mL to 3 log RNA copies / mL is equivalent to a reduction from 4 log IU / mL to 3 log IU / mL.

[0029] The term "HDV infection" with respect to a human (host) refers to the fact that the host is suffering from HDV infection. Typically, a HDV-infected human host has at least about 2 log HDV RNA copies per mL of host serum or plasma, or 10 HDV-RNA copies per mL of host serum or plasma. 2 copies, often at least about 3 log HDV RNA copies per mL of host serum or plasma, or 10 3 copies, and in many cases, especially for patients not receiving any treatment, at least about 4 log HDV RNA copies per mL of host serum or plasma, or 10 4 copies, for example, about 4 log HDV RNA copies per mL of host serum or plasma to 8 log HDV RNA copies per mL of host serum or plasma, or 10 4 ~10 8 The human host has an HDV RNA viral load, such as copies. As used herein, the term "chronic HDV infection" refers to a HDV infection that has persisted in the human host for at least 6 months, as described by a positive HDV antibody (Ab) test and / or detectable by qRT-PCR. The diagnosis and pathogenesis of HDV are described, for example, in Wedemeyer et al., Nat.Rev.Gastroenterol.Hepatol, 2010,7:31-40.

[0030] The term "lower limit of quantification" refers to the lowest concentration of a substance of an analyte (e.g., viral titer) that can be reliably quantified by a particular assay within given confidence limits.

[0031] The terms "patient," "host," or "subject" are used interchangeably and refer to a human infected with HDV, including patients who have been previously infected with HDV and have been cleared of the virus.

[0032] The term "pharmaceutical composition" is meant to encompass compositions suitable for administration to a subject. Generally, a "pharmaceutical composition" is preferably sterile and free of contaminants that may induce an undesired reaction in a subject (e.g., one or more compounds in the pharmaceutical composition are of pharmaceutical grade). Pharmaceutical compositions can be designed for administration to a subject or patient in need thereof by a number of different routes of administration, including oral, intravenous, buccal, rectal, parenteral, intraperitoneal, intradermal, intratracheal, intramuscular, subcutaneous, inhalation, and the like.

[0033] The term "therapeutically effective amount," as used herein, refers to an amount of an embodiment of an agent (e.g., a compound, inhibitor, or drug) being administered that treats to some extent a disease, disorder, or condition, e.g., alleviates one or more of the symptoms of the disease or infection being treated, and / or prevents to some extent one or more of the symptoms of the disease or infection that the subject being treated has or is at risk of developing.

[0034] The terms "treatment", "treating" and "treat" are defined as addressing a disease, disorder or condition with an agent to reduce or ameliorate the pharmacological and / or physiological effects of the disease, disorder or condition and / or its symptoms. "Treatment" as used herein includes any treatment of disease in a human subject, and includes (a) reducing the risk of disease development in a subject determined to be susceptible to the disease but not yet diagnosed as infected with the disease, (b) preventing the development of the disease, and / or (c) relieving the disease, i.e., causing regression of the disease and / or relieving one or more disease symptoms. "Treatment" is also meant to include delivery of inhibitory agents that provide a pharmacological effect even in the absence of disease or condition. For example, "treatment" includes delivery of agents that provide enhanced or desirable effects in a subject (e.g., reduced viral load, reduced disease symptoms, etc.).

[0035] The term "undetectable" or "below the level of detection" as used with respect to HDV RNA levels means that no HDV RNA copies are detected by the assay method used. In some embodiments, the assay is quantitative RT-PCR.

[0036] II. Treatment Method In one aspect, a method for treating HDV infection is provided, wherein HDV-infected patients are treated by administering interferon lambda.In some embodiments, pegylated forms of interferon lambda are administered.In some embodiments, patients undergoing interferon lambda therapy (e.g., pegylated interferon lambda therapy) are also treated with antiviral nucleotide or nucleoside analogs (e.g., anti-HBV nucleotide or nucleoside analogs).

[0037] In another aspect, a method for treating HBV is provided, in which an HBV-infected patient is treated by administering interferon lambda. In some embodiments, a pegylated form of interferon lambda is administered. In some embodiments, an HBV-infected patient undergoing interferon lambda therapy (e.g., pegylated interferon lambda therapy) is also treated with an antiviral nucleotide or nucleoside analog (e.g., an anti-HBV nucleotide or nucleoside analog). In some embodiments, the patient infected with HBV is not co-infected with HDV.

[0038] Interferon-lambda therapy Interferons are polypeptides that inhibit viral replication and cell proliferation and regulate immune responses. Based on the type of receptor through which they signal, human interferons have been classified into three major types (type I, type II, and type III). All type I IFNs bind to a specific cell surface receptor complex known as the IFN-alpha receptor (IFNAR), which consists of the IFNAR1 and IFNAR2 chains. The type I interferons present in humans are IFN-alpha, IFN-beta, IFN-epsilon, and IFN-omega. Type II IFNs bind to the IFN-gamma receptor (IFNGR), which consists of the IFNGR1 and IFNGR2 chains. The type II interferon in humans is IFN-gamma. The type III interferon group consists of three IFN-lambda molecules, termed IFN-lambda 1, IFN-lambda 2, and IFN-lambda 3 (also called IL29, IL28A, and IL28B, respectively). These IFNs signal through a receptor complex consisting of IL10R2 (also called CRF2-4) and IFNLR1 (also called CRF2-12).

[0039] As used herein, the term "interferon-lambda" or "IFN-lambda" includes natural IFN-lambda; synthetic IFN-lambda; derivatized IFN-lambda (e.g., PEGylated IFN-lambda, glycosylated IFN-lambda, etc.); and analogs of natural or synthetic IFN-lambda. In some embodiments, IFN-lambda encompasses derivatives of IFN-lambda that have been derivatized (e.g., chemically modified compared to the native peptide) to alter certain properties, such as serum half-life. Thus, the term "IFN-lambda" includes IFN-lambda that have been derivatized with polyethylene glycol ("PEGylated IFN-lambda"), and the like. PEGylated IFN-lambda (e.g., PEGylated IFN-lambda-1a) and methods for making same are described, for example, in U.S. Patent Nos. 6,927,040, 7,038,032, 7,135,170, 7,157,559, and 8,980,245; and WO 2005 / 097165, WO 2007 / 012033, WO 2007 / 013944, and WO 2007 / 041713; all of which are incorporated herein by reference in their entirety. In some embodiments, the PEGylated IFN-lambda-1a has the structure described in U.S. Patent No. 7,157,559, which is incorporated herein by reference in its entirety.

[0040] In some embodiments, the interferon for use in the treatment methods described herein is pegylated IFN-λ1 (eg, pegylated IFN-λ-1a), pegylated IFN-λ-2, or pegylated IFN-λ-3.

[0041] In some embodiments, the pegylated IFN-λ1 has the amino acid sequence shown below (the lines indicate the intrachain disulfide bonds): (SEQ ID NO:1) : [ka]

[0042] Patient population In some embodiments, the patient treated with the interferon lambda therapy described herein is a patient with chronic HDV infection. In some embodiments, the patient treated has a persistent chronic HDV infection for at least 6 months, documented by a positive HDV antibody (Ab) test and / or detectable HDV RNA by qRT-PCR. In some embodiments, the patient treated with the therapeutic method described herein is a patient with an acute HDV infection that is newly diagnosed or otherwise considered to have been absent in the patient for 6 months or more. The diagnosis and pathogenesis of HDV are described, for example, in Wedemeyer et al., Nat. Rev. Gastroenterol. Hepatol, 2010, 7:31-40. HDV is known to exist in various subtypes. The methods described herein are suitable for treating all HDV patients, regardless of HDV subtype. In some embodiments, the patient is an adult (18 years or older).

[0043] In some embodiments, the patient being treated has at least 10 2 HDV RNA copies or at least 10 per mL of serum or plasma 2 IU, e.g., at least 10 per mL of serum or plasma 3 HDV RNA copies or at least 10 3 IU, at least 10 per mL of serum or plasma 4 HDV RNA copies or at least 10 4 IU, at least 10 per mL of serum or plasma 5 HDV RNA copies or at least 10 5 At least 10 IU per mL of serum or plasma 6 HDV RNA copies or at least 10 6 IU, at least 10 per mL of serum or plasma 7 HDV RNA copies or at least 10 7 IU, at least 10 per mL of serum or plasma 8 HDV RNA copies or at least 108 The patient has a baseline viral load of 1000 mg / kg / day, ...

[0044] In some embodiments, the patient to be treated exhibits one or more symptoms of liver dysfunction. In some embodiments, the patient exhibits one or more liver function parameters that are outside the normal parameters of healthy controls (e.g., subjects not infected with HDV or HBV). In some embodiments, the liver function parameters are selected from the group consisting of serum albumin, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and prothrombin activity. In some embodiments, the patient has a serum ALT level that is at least twice (e.g., at least twice, at least three times, at least four times, at least five times, at least six times, at least seven times, at least eight times, at least ten times, or more) the upper limit of normal (ULN). Liver function parameters are described in the art. See, for example, Limdi et al., Postgrad Med J, 2003, 79:307-312. Methods for measuring these liver function parameters are known in the art and are commercially available.

[0045] In some embodiments, the patient has compensated liver disease (e.g., classified according to the Child-Turcotte-Pugh classification system) with or without cirrhosis. Those skilled in the art will recognize that the Child-Turcotte-Pugh classification system is used to classify the severity of liver disease and is determined by evaluating serum albumin levels, bilirubin levels, international normalized ratio of prothrombin time levels, ascites formation, and encephalopathy. In some embodiments, the patient has a Child-Turcotte-Pugh score of 5 to 6 (Class A). In some embodiments, the patient has compensated liver disease with cirrhosis. In some embodiments, the patient has compensated liver disease without cirrhosis.

[0046] In some embodiments, the patient is diagnosed with chronic hepatitis determined by liver biopsy within 6 months prior to treatment. In some embodiments, the patient has evidence of chronic hepatitis based on liver biopsy within 6 months prior to screening. In some embodiments, the patient has serum alanine aminotransferase (ALT) levels above the upper limit of normal (ULN) within 24 weeks prior to treatment and / or at the start of treatment. In various embodiments, the patient meets one or more independently selected eligibility criteria in Example 1.

[0047] Treatment duration and treatment endpoints The patient may receive interferon lambda therapy for a predetermined period of time, an indefinite period of time, or until an endpoint is reached. Treatment may be continued continuously daily for at least 2-3 months. In some embodiments, treatment is for at least 30 days, at least 60 days, at least 90 days, at least 120 days, at least 150 days, or at least 180 days. In some embodiments, treatment is continued for at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 1 year, at least 15 months, at least 18 months, or at least 2 years. In some embodiments, treatment is for at least 6 weeks, 12 weeks, 18 weeks, 24 weeks, 30 weeks, 36 weeks, 42 weeks, 48 ​​weeks, 60 weeks, 72 weeks, 84 weeks, or 96 weeks. In other embodiments, treatment is continued for the remainder of the patient's life or until administration is no longer effective in maintaining the virus at a sufficiently low level to provide a meaningful therapeutic benefit.

[0048] According to the methods of the present invention, some HDV patients respond to the treatment described herein by clearing the virus to undetectable levels, after which treatment may be discontinued unless and until HDV levels return to detectable levels. Other patients experience a reduction in viral load and improvement in symptoms, but never clear the virus to undetectable levels, and remain on "long-term treatment" for a limited period of time (e.g., about one year or about two years), or as long as it provides therapeutic benefit.

[0049] In some embodiments, treatment with interferon lambda therapy results in a reduction in HDV viral load in the patient of at least 1.5 log HDV RNA copies / mL serum when measured after 8 weeks of treatment. In some embodiments, treatment with interferon lambda therapy results in a reduction in HDV viral load in the patient of at least 2.0 log HDV RNA copies / mL serum when measured after 8 weeks of treatment. In some embodiments, treatment with interferon lambda therapy results in a reduction in HDV viral load in the patient of at least 2.5 log HDV RNA copies / mL serum when measured after 8 weeks of treatment.

[0050] In some embodiments, treatment with interferon lambda therapy results in a sustained reduction in HDV viral load (e.g., a reduction to at least 1.5 log HDV RNA copies per mL of serum, at least 2.0 log HDV RNA copies per mL of serum, or at least 2.5 log HDV RNA copies per mL of serum, or a reduction to undetectable levels of HDV RNA) that persists for a period of time while the treatment course is still in progress (e.g., 1 month, 3 months, 6 months, 1 year, or longer). In some embodiments, treatment with interferon lambda therapy results in a sustained reduction in HDV viral load that persists for a period of time after the treatment course has ended (e.g., 1 month, 3 months, 6 months, 1 year, or longer). In some embodiments, the treatment course results in an HDV RNA level (e.g., serum HDV RNA level or plasma HDV RNA level) of less than 1,000 copies / mL. In some embodiments, the HDV RNA level remains less than 1,000 copies / mL for at least 1 month, at least 3 months, at least 1 year, or longer. In some embodiments, the course of treatment results in an HDV RNA level (e.g., serum HDV RNA level or plasma HDV RNA level) of less than 100 copies / mL. In some embodiments, the HDV RNA level remains less than 100 copies / mL for at least one month, at least three months, at least one year or more. The phrase "remains less than" an initial measurement (e.g., 100 copies / mL or 100 IU / mL) for one month (or another specified period) means that viral load measurements taken are not higher than the initial value for at least one month (or another specified period) after the measurement of the initial measurement. In some embodiments, the patient does not receive interferon lambda therapy for a specified period. In some embodiments, the patient does not receive any anti-HDV therapy for a specified period.

[0051] In some embodiments, the treatment described herein is continued for a period of time until HDV RNA levels are less than 3 log HDV RNA copies / mL (less than 1,000 copies / mL), or sometimes until HDV RNA levels are less than 2 log HDV RNA copies / mL (less than 100 copies / mL) or below detection levels. In some cases, treatment may be continued for a period of time (such as 1-3 months or more) after viral load has fallen to an acceptably low level (e.g., undetectable). In some embodiments, treatment is continued until HDV viral load has fallen to undetectable levels.

[0052] In some embodiments, patients treated according to the methods described herein exhibit a reduction in HDV viral load to undetectable levels during the course of treatment and maintain the reduction in HDV viral load to undetectable levels for at least 12 weeks after treatment ends. In some embodiments, patients treated according to the methods described herein exhibit a reduction in HDV viral load to undetectable levels during the course of treatment and maintain the reduction in HDV viral load to undetectable levels for at least 24 weeks after treatment ends.

[0053] In some embodiments, the patient's HDV titer rises from baseline before dropping below baseline during the course of treatment. In some embodiments, the patient's HDV levels rise to more than 150% above baseline, or more than 200% above baseline. In some embodiments, the rise in titer occurs within 2 weeks of initiating treatment. In some embodiments, the patient's elevated HDV titer drops below baseline within 2 weeks, or within 3 weeks of initiating treatment.

[0054] In some embodiments, patients treated according to the methods described herein show improvement in one or more liver function parameters. In some embodiments, the improvement in liver function is improvement in one or more serum markers (e.g., one, two, three, four, five, six or more markers), such as serum albumin, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), prothrombin, alpha2-macroglobulin, apolipoprotein A1, haptoglobin, gamma-glutamyl transpeptidase (GGT). In some embodiments, patients treated according to the methods described herein show improvement in liver fibrosis (e.g., as assessed by histological analysis, biopsy by transient ultrasound elastography (e.g., FibroScan) or magnetic resonance elastography). In some embodiments, the treatment results in at least 10%, at least 20%, at least 30%, at least 40%, at least 50% or more improvement in one or more of the patient's liver function parameters (e.g., improvement of serum markers or improvement of liver fibrosis) compared to before the start of treatment. In some embodiments, the treatment results in improvement of one or more of the liver function parameters (e.g., improvement of serum markers or improvement of liver fibrosis) to the level of healthy control subjects not infected with HDV or HBV. In some embodiments, the patient shows improvement of serum ALT level to a level within the upper normal limit.

[0055] In some embodiments, patients treated according to the methods described herein exhibit a reduction in HBV viral load compared to baseline levels at the start of treatment and / or compared to similarly infected patients who have not received a treatment effective to reduce the patient's HDV viral load. In some embodiments, the treatment results in at least a 1 log reduction in HBV viral load.

[0056] In some embodiments, patients treated according to the methods described herein show improvement in one or more of the parameters described in Example 1. In some embodiments, patients treated according to the methods of the present invention show a reduction in HDV and / or HBV viral load. Prior to treatment, the patient's HDV and / or HBV viral load is measured to determine a baseline viral load. After a period of treatment (e.g., after 12 weeks of treatment), the patient's viral load is reduced compared to the baseline. In some embodiments, after a period of treatment (e.g., after 12 weeks of treatment), the patient's viral load is substantially reduced, such as to a very low level or to an undetectable level, compared to the baseline. In some embodiments, the treatment results in at least a 2 log reduction in HBV viral load. In some embodiments, patients treated according to the methods described herein show a reduction in HBsAg levels or improved clearance of HBsAg antigen. Prior to treatment, the patient's HBsAg level is measured to determine a baseline. After a period of treatment (e.g., after 12 weeks of treatment), the patient's HBsAg level is reduced compared to the baseline. In some embodiments, patients treated according to the methods described herein show the presence of anti-HBs antibodies.

[0057] Dose escalation and deescalation In some embodiments, patients treated for HDV infection undergo an adjustment in the dosing regimen of interferon lambda therapy during the course of treatment. In some embodiments, patients receive an escalating dosing regimen of interferon lambda, where one or more subsequent doses are higher than one or more prior doses. In some embodiments, the escalating dosing regimen can increase the patient's tolerance to the drug and minimize side effects. In some embodiments, the dose escalation includes administering interferon lambda at a dose of 120 μg / week for a first treatment period, followed by administering interferon lambda at a dose of 180 μg / week for a second treatment period. In some embodiments, the length of time of the first treatment period is the same as the length of time of the second treatment period. In some embodiments, the first treatment period and the second treatment period are of different lengths of time. In some embodiments, the dose escalation further includes administering one or more additional doses of interferon lambda for one or more additional treatment periods.

[0058] In some embodiments, the patient receives a dose reduction of interferon lambda, with one or more subsequent doses being lower than one or more previous doses. In some embodiments, if the patient exhibits unacceptable side effects, a dose reduction is prescribed. In some embodiments, the interferon lambda therapy comprises administering interferon lambda at a dose of 180 μg / week in a first treatment period, followed by administering interferon lambda at a dose of 120 μg / week in a second treatment period. In some embodiments, the interferon lambda therapy comprises administering interferon lambda at a dose of 120 μg / week in a first treatment period, followed by administering interferon lambda at a dose of 80 μg / week in a second treatment period. In some embodiments, the length of time of the first treatment period is the same as the length of time of the second treatment period. In some embodiments, the first treatment period and the second treatment period are of different lengths of time.

[0059] Formulation and Administration Interferon lambda may be administered in any therapeutically appropriate dose. In some embodiments, interferon lambda is administered in a dose of 80 μg (mcg) QW. In some embodiments, interferon lambda is administered in a dose of 120 mcg QW. In some embodiments, interferon lambda is administered in a dose of 180 mcg QW.

[0060] Interferon lambda can be formulated for administration by any therapeutically appropriate route. In some embodiments, interferon lambda is formulated for administration by intravenous or subcutaneous administration. Other routes suitable for drug delivery can be used, including systemic and local administration routes.

[0061] In certain embodiments, interferon lambda is administered by subcutaneous injection, including but not limited to injection into the thigh or abdomen.The present invention provides pharmaceutical formulations in which interferon lambda can be formulated into the injectable preparation according to the present invention by dissolving, suspending or emulsifying in aqueous or non-aqueous solvents such as vegetable or other similar oils, synthetic fatty acid glycerides, esters of higher fatty acids or propylene glycol, and optionally with conventional additives such as solubilizers, isotonicity agents, suspending agents, emulsifiers, stabilizers and preservatives.The unit dosage form for injection or intravenous administration can be included in the composition as a solution in sterile water, saline or another pharmacologically acceptable carrier.The appropriate amount of active pharmaceutical ingredient for the unit dosage form of interferon lambda is provided herein.

[0062] In some embodiments, interferon lambda (e.g., interferon lambda 1, such as interferon lambda 1a) or an analog thereof is formulated and / or administered and / or modified as described in one of the following patent publications, which are incorporated herein by reference: U.S. Patent Nos. 6,927,040, 7,038,032, 7,135,170, 7,157,559, and 8,980,245; U.S. Patent Application Publication Nos. 2009 / 0326204, 2010 / 0222266, 2011 / 0172170, or 2012 / 0036590. EXAMPLES

[0063] III. Examples The following examples are offered to illustrate, but not to limit, the claimed invention.

[0064] Example 1. Protocol Overview for Treating HDV Patients with Pegylated Interferon Lambda This example describes a Phase 2 clinical trial protocol to evaluate the safety, tolerability, and pharmacodynamics of pegylated interferon lambda monotherapy in patients with chronic HDV infection.

[0065] [Table 1]

[0066] [Table 2]

[0067] [Table 3]

[0068] [Table 4]

[0069] [Table 5]

[0070] At least one patient from a cohort of patients who receive at least 80% of the total study drug dose over the entire 48-week treatment period and have HDV viral load data available at day 1 (baseline) and end of treatment (week 48) shows improvement in one or more of the endpoints described in the protocol at the study visit. In some embodiments, the patient shows a reduction in HDV viral load at end of treatment compared to baseline. In some embodiments, the patient shows a reduction in HBV viral load at end of treatment compared to baseline. In some embodiments, the interferon lambda therapy substantially reduces HDV virus, e.g., to undetectable levels, as measured 12 weeks after the end of treatment. In some embodiments, the patient shows a reduction in HBsAg levels at end of treatment compared to baseline. In some embodiments, the patient shows improved clearance of HBsAg antigen.

[0071] Example 2. Treatment of HDV with pegylated interferon lambda monotherapy In this study, patients with chronic HDV infection are randomly assigned to receive either 120mcg or 180mcg of pegylated interferon lambda 1-a as weekly subcutaneous injections for 48 weeks. To date, one enrolled patient has reached 8 weeks of treatment (Patient 1). The change in HDV RNA levels from baseline in patients over 8 weeks of treatment as a result of interferon lambda therapy is summarized below in Table 2.

[0072] [Table 6]

[0073] As shown in Table 2 , after an initial increase in HDV RNA levels, the patient's HDV viral load declined to levels below the lower limit of quantification of the assay (<15 IU / mL).

[0074] All publications and patents cited in this specification are incorporated by reference herein to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference, and are incorporated by reference herein to disclose and describe the methods and / or materials in connection with which the publications are cited.

[0075] While the present invention is specifically disclosed by certain aspects, embodiments and optional features, it should be understood that modifications, improvements and variations of such aspects, embodiments and optional features may be made by those skilled in the art, and such modifications, improvements and variations are considered to be within the scope of the present disclosure.

[0076] The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. Also, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention thereby also relates to any individual member or subgroup of members of the Markush group. Furthermore, the present invention includes the following aspects. 1. A method for treating hepatitis delta virus (HDV) infection in a human patient, comprising administering to said patient a therapeutically effective amount of interferon lambda for at least four weeks. 2. The method according to item 1, wherein the patient has compensated liver disease with or without cirrhosis. 3. The method according to item 2, wherein the patient has compensated liver disease accompanied by cirrhosis. 4. The method of claim 1, wherein the interferon lambda is pegylated. 5. The method of claim 4, wherein the interferon lambda is pegylated interferon lambda-1a. 6. The method according to any one of items 1 to 5, wherein the interferon lambda is administered at a dose of 120 μg per week. 7. The method according to any one of items 1 to 5, wherein the interferon lambda is administered at a dose of 180 μg per week. 8. The method according to any one of items 1 to 7, wherein the interferon lambda is administered subcutaneously. 9. The method according to any one of items 1 to 8, wherein the interferon lambda is administered for at least 6 months. 10. The method of claim 9, wherein the interferon lambda is administered for at least 48 weeks. 11. The method according to any one of paragraphs 1 to 10, wherein the treatment course results in an HDV viral load of less than 100 copies per mL of serum or less than 100 IU per mL of serum. 12. The method of claim 11, wherein the HDV viral load remains less than 100 copies per mL of serum or less than 100 IU per mL of serum for at least 12 weeks after treatment ends. 13. The method of claim 12, wherein the HDV viral load remains less than 100 copies per mL of serum or less than 100 IU per mL of serum for at least 24 weeks after treatment ends. 14. The method according to any one of claims 1 to 10, wherein the treatment course results in an HDV viral load below the detection level. 15. The method of claim 14, wherein the HDV viral load remains below detectable levels for at least 12 weeks after treatment ends. 16. The method of claim 15, wherein the HDV viral load remains below detectable levels for at least 24 weeks after treatment ends. 17. The method of any one of paragraphs 1 to 16, wherein prior to the initiation of the treatment, the patient has a serum alanine aminotransferase (ALT) level above the upper limit of normal (ULN), and the course of treatment results in an improvement in the patient's serum ALT level to a level within the ULN. 18. The method of any one of paragraphs 1 to 17, wherein the course of treatment results in a reduction in the HBV viral load in the patient compared to the patient's baseline HBV viral load at the start of treatment. 19. The method according to any one of paragraphs 1 to 18, wherein the course of treatment results in an improvement in liver function of the patient. 20. The method according to item 19, wherein the improvement in liver function is an improvement in one or more serum markers selected from the group consisting of serum albumin, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), prothrombin, alpha2-macroglobulin, apolipoprotein A1, haptoglobin, and gamma-glutamyl transpeptidase (GGT). 21. The method according to item 19, wherein the improvement in liver function is improvement in liver fibrosis. 22. The method of any one of items 1 to 21, wherein the method further comprises administering to the patient another anti-viral or anti-HDV agent. 23. The method of any one of paragraphs 1 to 21, wherein interferon lambda is the only or first anti-viral treatment, or the only or first anti-HDV treatment.

Claims

1. A pharmaceutical for the treatment of hepatitis delta virus (HDV) infection comprising interferon lambda, administered for at least 8 weeks to a patient who is not co-infected with hepatitis C virus (HCV) and who does not show evidence of another liver disease selected from the group consisting of autoimmune liver disease, biliary cirrhosis, primary sclerosing cholangitis, Wilson's disease, alcoholic liver disease, nonalcoholic steatohepatitis and hemochromatosis, and who is being concurrently treated with an anti-HBV nucleotide or nucleoside analogue.

2. The method of claim 1, wherein the patient has compensated liver disease with or without cirrhosis.

3. The method of claim 2, wherein the patient has compensated liver disease accompanied by cirrhosis.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the interferon lambda is pegylated.

5. The method of claim 4, wherein the interferon lambda is pegylated interferon lambda-1a.

6. Interferon lambda is administered at a dose of 120 μg per week; or Interferon lambda is administered at a dose of 180 μg per week; The pharmaceutical composition according to any one of claims 1 to 5.

7. The method according to any one of claims 1 to 6, wherein interferon lambda is administered subcutaneously.

8. Interferon lambda is administered for at least 12 weeks; Interferon lambda has been administered for at least 6 months; or Interferon lambda is administered for at least 48 weeks; The pharmaceutical composition according to any one of claims 1 to 7.

9. The medicament according to any one of claims 1 to 8, wherein the course of treatment results in an HDV viral load of less than 100 copies per mL of serum or less than 100 IU per mL of serum.

10. The pharmaceutical composition of claim 9, wherein the HDV viral load remains below 100 copies / mL of serum or below 100 IU / mL of serum for at least 12 weeks after treatment has ended.

11. The pharmaceutical composition of claim 10, wherein the HDV viral load remains below 100 copies / mL of serum or below 100 IU / mL of serum for at least 24 weeks after treatment has ended.

12. The method of any one of claims 1 to 8, wherein the course of treatment results in an HDV viral load below detection levels.

13. The method of claim 12, wherein the HDV viral load remains below detectable levels for at least 12 weeks after treatment has ended.

14. The method of claim 13, wherein the HDV viral load remains below detectable levels for at least 24 weeks after treatment has ended.

15. The pharmaceutical agent of any one of claims 1 to 14, wherein prior to the initiation of treatment, the patient has a serum alanine aminotransferase (ALT) level above the upper limit of normal (ULN), and the course of treatment results in an improvement in the patient's serum ALT level to a level within the ULN.

16. The method of any one of claims 1 to 15, wherein the course of treatment results in a reduction in the HBV viral load in the patient compared to the patient's baseline HBV viral load at the start of treatment.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the course of treatment results in an improvement of the patient's liver function.

18. the improvement in liver function is an improvement in one or more serum markers selected from the group consisting of serum albumin, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), prothrombin, alpha2-macroglobulin, apolipoprotein A1, haptoglobin, gamma-glutamyl transpeptidase (GGT); or the improvement in liver function is an improvement in liver fibrosis. The pharmaceutical composition according to claim 17.

19. A medicament according to any one of claims 1 to 18, wherein the patient is also receiving another anti-viral or anti-HDV agent.

20. The method of any one of claims 1 to 18, wherein interferon lambda is the only or first line anti-HDV treatment.

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