WO2024123860A9 - Methods to treat hepatitis delta viral infections - Google Patents

Methods to treat hepatitis delta viral infections Download PDF

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WO2024123860A9
WO2024123860A9 PCT/US2023/082638 US2023082638W WO2024123860A9 WO 2024123860 A9 WO2024123860 A9 WO 2024123860A9 US 2023082638 W US2023082638 W US 2023082638W WO 2024123860 A9 WO2024123860 A9 WO 2024123860A9
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weeks
treatment
patient
hdv
lonafarnib
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WO2024123860A1 (en
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Ingrid Choong
Colin Michael Hislop
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Eiger Biopharmaceuticals, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/70—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving virus or bacteriophage
    • C12Q1/701—Specific hybridization probes
    • C12Q1/706—Specific hybridization probes for hepatitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention provides methods for treating viral hepatitis resulting from hepatitis delta virus infection, and so relates to the fields of chemistry, medicinal chemistry, medicine, molecular biology, and pharmacology.
  • Hepatitis delta virus (HDV) infection is a deadly disease affecting more than 12 million people globally. See, Stockdale et al., J. of Hepatology, 2020, 73:523-32. Approximately half of the patients diagnosed with HDV infection have liver cirrhosis at the time of diagnosis. See, Nourredin et al., Curr. GasteroL Rep., 2014, 16:365.
  • HDV is a deficient virus that relies on another virus, hepatitis B virus (HBV), to supply envelope proteins for infectivity and propagation. Consequently, HBV is always present when HDV is present.
  • HBV-encoded surface proteins small, medium, and large HBsAgs
  • a farnesylated form of the intracellular HDV-encoded large delta antigen (large HDAg) mediates interactions between HDV and the three HBV-encoded surface proteins. See, Glenn et al., 1992, Science, 256:1331-33; Otto and Casey, 1996, J. Biol. Chem., 271:4569-4572.
  • Prenylation is required for this function of the large HDAg because studies have shown that specific mutation of the prenylated site on the large delta antigen prevents both prenylation and HDV particle formation. See, Glenn et al., 1998, J. Virol. 72:9303-06; Bordier et aL, 2002, J. Virol. 76:10465-10472.
  • HDV High-density virus
  • HBV alone with 70% of patients progressing to liver cirrhosis within 5-10 years, compared to 20% of patients infected by HBV alone (within 5 years) and 10-20% of patients infected with HCV (within 20 years).
  • Westbrook et al. J. Hepatology, 2014, 61:S58-S68; Fattovich et al., Seminars in Liver Diseases, 2003, 23:47-58; Nourredin et al., Curr. Gasterol. Rep., 2014, 16:365.
  • HDV can also worsen preexisting HBV-related liver damage, leading to greater risk of developing liver cirrhosis, hepatic decomposition, and hepatocellular carcinoma. See, Negro, Cold Spring Harb. Perspect. Med., 2014, 4:a021550; Honer zu Siederdissen, Vise. Med., 2016, 32:86-94; Lau, Hepatology, 1999, 30:546-549.
  • a method of treating hepatitis delta virus (HDV) infection in a patient comprising administering to the patient a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor.
  • HDV hepatitis delta virus
  • hepatitis delta virus HDV
  • a method of treating hepatitis delta virus (HDV) infection in a patient comprising administering a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor at regular intervals as a chronic therapy.
  • HDV hepatitis delta virus
  • a method of reducing both the viral load and alanine aminotransferase (ALT) levels in a patient with hepatitis delta virus (HDV) infection comprising administering to the patient a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor.
  • FIG. 1 shows a Phase 3 study schematic according to aspects of this disclosure.
  • patients were treated for 48 weeks and further studied during a 24-week post-treatment period.
  • the primary endpoint at 48 weeks was a composite of >2 log decline in HDV RNA and normalization of ALT.
  • One secondary endpoint at week 48 was based on histological data measured as no worsening fibrosis and a >2- point change in Ishak HAI score.
  • FIG. 2 shows a flowchart of the baseline characteristics of patients who were screened and treated in the study shown in FIG. 1 according to aspects of this disclosure.
  • FIG. 3 shows the percentage of patients in each study arm that achieved the primary endpoint of composite >2 log decline in HDV RNA and ALT normalization at week 48 according to aspects of this disclosure.
  • FIG. 4 shows the percentage of patients in each study arm that achieved >2 log decline in HDV RNA at week 48 according to aspects of this disclosure.
  • FIG. 5 shows the percentage of patients in each study arm that achieved alanine aminotransferase (ALT) normalization at week 48 according to aspects of this disclosure.
  • FIG. 6 shows the percentage of patients in each study arm that achieved HDV RNA levels below the lower limit of quantitation (BLQ or below LLOQ.)) at week 48 according to aspects of this disclosure.
  • FIG. 7 shows the mean decline in HDV RNA levels during the 48-week treatment period according to aspects of this disclosure.
  • FIG. 8 shows the mean decline in ALT normalization during the 48-week treatment period according to aspects of this disclosure.
  • FIG. 9 shows the primary endpoint of composite >2 log decline in HDV RNA and ALT normalization at week at the end of the follow-up period (week 72) according to aspects of this disclosure.
  • FIG. 10 shows the percentage of patients in each study arm that achieved >2 log decline in HDV RNA levels at the end of the follow-up period (week 72) according to aspects of this disclosure.
  • FIG. 11 shows the mean HDV RNA decline in each study arm during the treatment and follow-up period (72 weeks). Data regarding HDV RNA levels from week 48 to week 72 are only available for 211 patients according to aspects of this disclosure.
  • FIG. 12 shows the mean decline in ALT normalization in each study during the treatment and follow-up period (72 weeks). Data regarding ALT normalization from week 48 to week 72 are only available for 211 patients according to aspects of this disclosure.
  • FIG. 13 shows the percentage of patients in each study arm who achieve ALT normalization at the end of the follow-up period (week 72). Data is only shown for the 211 patients tested at week 72 according to aspects of this disclosure.
  • FIG. 14 shows proportion of patients achieving composite > 2 logiodecline in HDV RNA plus ALT normalization at week 48.
  • Alfa peginterferon alfa-2a
  • Cl confidence interval
  • LNF lonafarnib
  • RTV ritonavir.
  • FIG. 15 shows proportion of patients achieving > 2 logiodecline in HDV RNA at week 48.
  • Alfa peginterferon alfa-2a
  • LNF lonafarnib
  • RTV ritonavir.
  • FIG. 16 shows proportion of patients achieving ALT normalization at week 48.
  • Alfa peginterferon alfa-2a
  • LNF lonafarnib
  • RTV ritonavir.
  • FIG. 17 shows proportion of patients achieving virologic response (both "target detected” and “target not detected”) below the lower limit of quantitation (LLOQ) at week 48.
  • Alfa peginterferon alfa-2a
  • LNF lonafarnib
  • RTV ritonavir.
  • FIGS. 18A-18B show the composite primary efficacy endpoint response in patients at week 48 and post-treatment week 24.
  • FIG. 18A shows > 2 logiodecline in HDV RNA.
  • FIG. 18B shows BLQ (below limit of quantitation) in HDV RNA.
  • Alfa peginterferon alfa-2a;
  • LNF lonafarnib
  • RTV ritonavir
  • FIG. 19 shows proportion of patients achieving > 2 logiodecline in HDV RNA in patients at week 48 and post-treatment week 24.
  • Alfa peginterferon alfa-2a
  • LNF lonafarnib
  • RTV ritonavir.
  • FIG. 20 shows proportion of patients achieving virologic response (both "target detected” and “target not detected”) below LLOQ at week 48 and post-treatment week 24.
  • Alfa peginterferon alfa-2a
  • LNF lonafarnib
  • RTV ritonavir.
  • FIG. 21 shows proportion of patients achieving virologic response "target detected” below LLOQ at week 48 and post-treatment week 24.
  • Alfa peginterferon alfa-2a
  • LNF lonafarnib
  • RTV ritonavir
  • FIG. 22 shows proportion of patients achieving ALT normalization at week 48 and posttreatment week 24.
  • Alfa peginterferon alfa-2a
  • LNF lonafarnib
  • RTV ritonavir.
  • administration refers to introducing a compound, a composition, or an agent of the present disclosure into a host, such as a human.
  • preferred routes of administration of the agents are oral administration and subcutaneous administration.
  • Other routes of administration include intravenous administration and oral administration.
  • baseline refers to a measurement (of, e.g., viral load, subject condition, ALT level) made prior to the start of a course of therapy.
  • HDV RNA viral load or "viral load” of a human serum or plasma sample refers to the amount of HDV RNA in a given amount of a 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 that of a dilution series of a quantified Hepatitis Delta RNA standard, and a copy number of genome copies is calculated. See, e.g., Kodani et al., 2013, J. Virol.
  • HDV RNA viral load may be reported as RNA copies per mL serum (or plasma) or using International Units (IU) per mL serum (or plasma).
  • IU International Units
  • An assay for measuring HDV RNA viral load is commercially available from ARUP Laboratories (Salt Lake City, UT).
  • HDV levels are generally presented using logio units.
  • HDV RNA levels may be presented in units of "RNA copies per mL” or as "International Units (IU) per mL.” See, Chudy et al., 2013, Collaborative Study to establish a World Health Organization International standard for hepatitis D virus RNA for nucleic acid amplification technique (NAT)-based assays.” WHO Expert Committee on Biological Standardization WHO/BS/2013.2227. Both units are used in this specification.
  • HDV RNA copies per mL should be read, for purposes of written description or basis, as referring to "HDV RNA copies/mL or HDV lU/mL.” Where a specific quantity of HDV RNA copies per mL is recited, a multiplier of 1.2 may be applied, for the purposes of written description and support, to convert the quantity of HDV RNA copies/mL to the quantity of lU/mL. For example, "120 HDV RNA copies per mL” should be read as "100 lU/mL or 120 copies/mL.” Changes in HDV RNA levels may be represented as a "log reduction" following the normal conventions of virology.
  • HDV infection refers to the fact that the host is suffering from HDV infection.
  • an HDV infected human host will have a viral load of HDV RNA of at least about 2 logio HDV RNA copies/mL of host serum or plasma or 10 2 copies of HDV- RNA/mL of host serum or plasma, often at least about 3 log HDV RNA copies/mL of host serum or plasma or 10 3 copies of HDV-RNA/mL of host serum or plasma, and, often, especially for subjects not on any therapy, at least about 4 logio HDV RNA copies/mL of host serum or plasma or 10 4 copies of HDV-RNA/mL of host serum or plasma, such as about 4 logio HDV RNA copies/mL of host serum or plasma to 8 logio HDV RNA copies/mL of host serum or plasma or 10 4 to 10 s copies of HDV-RNA/mL of host serum or plasma.
  • chronic HDV infection refers to an HDV infection that has persisted in the human host for at least 6 months, as documented by a positive HDV antibody (Ab) test and/or HDV RNA detectable by qRT-PCR. Diagnosis and pathogenesis of HDV is described, for example, in Wedemeyer et aL, Nat. Rev. Gastroenterol. Hepatol, 2010, 7:31-40.
  • RNA ribonucleic acid
  • ALT alanine aminotransferase
  • lower limit of quantification refers to the lowest concentration of a substance of analyte (e.g., a viral titer) that can be reliably quantified by a particular assay within a stated confidence limit.
  • analyte e.g., a viral titer
  • subject refers to a human infected with HDV, including subjects previously infected with HDV in whom virus has cleared.
  • a “sustained reduction” or “sustained decrease” of HDV viral load means a reduction of viral load (e.g., a decrease of at least 1.5 logio HDV RNA lU/mL serum, at least 2.0 logio HDV RNA copies/mL serum, or at least 2.5 logio HDV RNA lU/mL serum, or a decrease in HDV RNA to undetectable levels) for a period time (e.g., 1 month, 3 months, 6 months, 1 year or longer).
  • the sustained reduction may be a period of time during which the course of treatment is still ongoing or a period of time after the course of treatment is finished.
  • a "durable virologic response" occurs when HDV RNA below limit of quantification at 24 weeks post-treatment.
  • terapéuticaally effective amount refers to that amount of an embodiment of the agent (e.g., a compound, inhibitory agent, or drug) being administered that will treat to some extent a HDV or a disease, disorder, or condition related to HDV, e.g., relieve one or more of the symptoms of HDV or other disease, i.e., infection, being treated, and/or that amount that will prevent, to some extent, one or more of the symptoms of the HDV or the other disease, i.e., infection, that the subject being treated has or is at risk of developing.
  • the agent e.g., a compound, inhibitory agent, or drug
  • treatment is defined as acting upon a disease, disorder, or condition with an agent to reduce or ameliorate the pharmacologic and/or physiologic effects of HDV or the disease, disorder, or condition and/or its symptoms.
  • treatment encompasses delivery of an agent, such as those disclosed herein, that provides for enhanced or desirable effects in the subject (e.g., reduction of viral load, reduction of disease symptoms, etc.).
  • Treatment covers any treatment of a disease in a human subject, and includes: (a) reducing the risk of occurrence of the disease, such as HDV, in a subject determined to be predisposed to the disease but not yet diagnosed as infected with the disease, (b) impeding the development of the disease, such as HDV, and/or (c) relieving the disease, such as HDV, i.e., causing regression of the disease and/or relieving one or more disease symptoms.
  • Treatment is also meant to encompass delivery of an inhibiting agent to provide a pharmacologic effect, even in the absence of a disease or condition.
  • the terms “undetectable” or “below the level of detection” or “BLD” or “below the lower limit of quantitation” or “BLQ,” as used with reference to HDV RNA levels, means that no HDV RNA copies can be detected by the assay methodology employed or that the RNA levels are below the lower limit of quantitation ("LLOQ").
  • the assay is quantitative RT-PCR.
  • Histologic response is defined as an improvement in Ishak modified histology activity index (HAI) score ("fibrosis score”) of > 2 points relative to baseline and no worsening of fibrosis score.
  • HAI histology activity index
  • the "net proportion with improved fibrosis score” is defined as the proportion of patients with improved fibrosis score relative to baseline minus the proportion of patients with worsened fibrosis score relative to baseline.
  • interferon alpha includes naturally occurring interferon alpha (I FN-alpha); synthetic IFN-alpha; derivatized IFN-alpha (e.g., PEGylated I FN-alpha, glycosylated IFN- alpha, and the like); and analogs of naturally occurring or synthetic IFN-alpha.
  • IFN-alpha interferon alpha
  • ulFN-alpha-Le a pharmaceutical drug composed of natural interferon alpha (IFN-a), obtained from the leukocyte fraction of human blood following induction with Sendai virus.
  • an IFN-alpha is a derivative of IFN-alpha that is derivatized (e.g., chemically modified relative to the naturally occurring peptide) to alter certain properties such as serum half-life.
  • IFN-alpha includes IFN-alpha derivatized with polyethylene glycol ("pegylated IFN-alpha” or "pegylated interferon alpha"), and the like.
  • PEGylated IFN-alpha, and methods for making same are known.
  • pegylated interferon alpha is peginterferon alfa 2a (PEG IFN-alfa-2a or pegylated I FN-alfa-2a).
  • FibroScan® (Echosens, Waltham, Massachusetts) is a non-invasive ultrasound-based test that measures the pressure required to distend the liver (liver elasticity) and can be used to assess the extent of fibrosis. The scores are as follows: Fl: 2-7 KPa (little to no scarring); F2: 7.5-10 KPa (moderate scarring); F3: 10-14 KPa (sever scarring); F4: >14 KPa (cirrhosis).
  • the present disclosure provides methods of treating hepatitis delta virus (HDV) infection.
  • the method of treatment is useful for a patient that has a contraindication to interferon.
  • the methods comprise administering a therapeutically effective amount of lonafarnib and a CYP3A4 inhibitor (e.g., ritonavir or cobicistat).
  • the contraindication is at least one of severe depression, advanced liver disease, leukopenia, severe thrombocytopenia, active autoimmune disease, compensated chronic hepatitis, and/or a severe concomitant disease that precludes IFN therapy.
  • the present disclosure also provides methods of identifying patients likely or not likely to respond to the methods of treatment provided in the present disclosure.
  • Lonafarnib (“LN F”) is a small molecule prenyltransferase inhibitor that has been used to inhibit HDV particle assembly by blocking farnesyltransferase from attaching the 15-carbon farnesyl group onto the prenylation motif of the HDV large delta antigen (HDAg).
  • Lonafarnib therapy for the treatment of HDV has been previously describes, for example, in US 2017/0042862, which is incorporated by reference herein. Previous clinical studies, however, have shown that 100 mg lonafarnib administered BID for 28 days did not reduce HDV viral load sufficiently to be developed as a therapeutic. See, WO 2017/079009. Furthermore, higher doses were poorly tolerated due to gastrointestinal-related adverse effects. Id.
  • methods are provided for treating hepatitis delta virus (HDV) infection by administration of lonafarnib in combination with a CYP3A4 inhibitor.
  • CYP3A4 is a member of the cytochrome P450 family of oxidizing enzymes. Cytochrome P450 is involved in the turnover of other molecules, including lonafarnib.
  • a CYP3A inhibitor such as ritonavir ("RTV”) or cobicistat is also co-administered.
  • the CYP3A inhibitor is ritonavir.
  • a CYP3A inhibitor such as ritonavir
  • a CYP3A inhibitor can boost serum levels of lonafarnib by preventing its degradation.
  • Lonafarnib and ritonavir co-therapy has been previously described, for example, in WO 2015/168648 and in WO 2017/079009, which are incorporated by reference herein.
  • an interferon for use in a therapeutic method as described herein is a pegylated interferon alpha (e.g., pegylated I FN-a lfa-2a).
  • Immune modulators such as interferons may be useful in treating HDV as both the direct cytotoxic effects of HDV and the host's immune response to HDV are known to contribute to the detrimental effects of HDV infection.
  • Interferons are polypeptides that may inhibit viral replication and cellular proliferation and modulate immune response. Based on the type of receptor through which they signal, human interferons have been classified into three major types (Types I, II, and III). All type I IFNs bind to a specific cell surface receptor complex known as the IFN-alpha receptor (IFNAR) that consists of IFNAR1 and IFNAR2 chains. The type I interferons present in humans are IFN-alpha, IFN-beta, IFN-epsilon, and IFN- omega. To date, clinical studies with interferon alpha monotherapy have reported unsatisfactory anti-HDV effects. See, for example, Wedemeyer et al, Lancet Infectious Diseases, 2019.
  • a subject to be treated with a therapy disclosed herein is a subject having an HDV infection, e.g., an acute HDV infection or a chronic HDV infection.
  • the subject to be treated has a chronic HDV infection of at least 6 months in duration as documented by a positive HDV antibody (Ab) test, and/or detectable HDV RNA by qRT-PCR.
  • a subject to be treated with a therapeutic method described herein is a subject having an acute HDV infection, e.g., a newly diagnosed HDV infection or a HDV infection otherwise believed not to have existed in the subject for more than six months.
  • HDV is known to exist in a variety of subtypes; the methods described herein are suitable for treating all HDV subjects, regardless of HDV subtype.
  • the subject is an adult (18 years or older), and in other embodiments, the subject is pediatric.
  • the HDV viral load of the subject is >2 logTM above the lower limit of quantification (LLOQ.) of the HDV RNA assay.
  • the viral load is measured at three pre-treatment points with a mean viral load of >2 logi 0 above the LLOQ, of the HDV RNA assay.
  • Genotype 1 is widely distributed around the world, and genotype 3 is associated with more severe liver disease. See, Shirvani-Dastgerdi and Tacke, 2015, 4:36-41.
  • the patient is infected with a genotype 1 virus.
  • a subject to be treated has a baseline viral load of at least 10 2 HDV RNA copies per mL serum or plasma or at least 10 2 HDV RNA lU/mL serum or plasma, e.g., at least 10 3 HDV RNA copies per mL or at least 10 3 HDV RNA lU/mL serum or plasma, at least 10 4 HDV RNA copies per mL or at least 10 4 HDV RNA lU/mL serum or plasma, at least 10 5 HDV RNA copies per mL or at least 10 5 HDV RNA lU/mL serum or plasma, at least 10 6 HDV RNA copies per mL or at least 10 6 HDV RNA ID/mL serum or plasma, at least 10 7 HDV RNA copies per mL or at least 10 7 HDV RNA lU/mL serum or plasma, or at least 10 8 HDV RNA copies per mL or at least 10 8 HDV RNA lU/mL serum or plasma.
  • HDV viral load is measured using serum samples from the subject. In some embodiments, HDV viral load is measured using plasma samples from the subject. In some embodiments, viral load is measured by quantitative RT-PCR. qRT-PCR assays for quantification of HDV RNA in serum or plasma are known in the art, e.g., as described above. In some embodiments, a subject to be treated has a baseline viral load that is up to about 10 4 HDV RNA copies per mL serum or plasma or up to about 10 4 HDV RNA l U/mL serum or plasma.
  • a subject to be treated has a baseline viral load that is up to about 10 5 HDV RNA copies per mL serum or plasma and/or up to about 10 5 HDV RNA lU/mL serum or plasma. In some embodiments, a subject to be treated has a baseline viral load that is up to about 10 s HDV RNA copies per mL serum or plasma and/or up to about 10 G HDV RNA lU/mL serum or plasma.
  • HDV viral load is measured using serum samples from the subject. In some embodiments, HDV viral load is measured using plasma samples from the subject. In some embodiments, viral load is measured by quantitative RT-PCR. qRT-PCR assays for quantification of HDV RNA in serum or plasma are known in the art, e.g., as described above.
  • a subject to be treated has one or more of: the presence of a nti- HDV in serum; presence of quantifiable HDV RNA in serum at three time pre-treatment points with a mean HDV RNA level greater than 2 logio above the LLOQ. of the HDV RNA assay; the demonstration of chronicity as evidenced by the presence of HDV RNA in serum for at least 6 months; or presence of anti-HDV antibody for at least 6 months.
  • a subject to be treated exhibits one or more symptoms of liver dysfunction.
  • the subject exhibits one or more liver function parameters that are outside the normal parameters for a healthy control (e.g., a subject that is not infected with HDV and/or HBV).
  • the liver function parameter is selected from the group consisting of serum albumin, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and prothrombin activity.
  • the subject has a serum ALT level that is at least two-fold higher than the upper limit of normal (ULN) (e.g., at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 10-fold or higher than the ULN).
  • UPN upper limit of normal
  • Liver function parameters are described in the art. See, e.g., Limdi et al., Postgrad Med J, 2003, 79:307-312. Methods of measuring these liver function parameters are known in the art.
  • the subject has compensated liver disease (e.g., as classified according to the Child-Turcotte-Pugh Classification System) with or without liver cirrhosis.
  • the Child-Turcotte-Pugh Classification System is used to classify the severity of liver disease and is determined by assessing serum albumin levels, bilirubin levels, international normalized ratio of prothrombin time levels, ascites formation, and encephalopathy.
  • the subject has a Child-Turcotte-Pugh score of 5-6 (class A).
  • the subject has a Child-Turcotte-Pugh score of 1-6.
  • the subject has a Child-Turcotte-Pugh score of a sub-range of 1-6, e.g., 1-2, 1-3, 2-4, 3-4, 2-5, 3-5, or 2-6.
  • the subject has compensated liver disease with liver cirrhosis. In some embodiments, the subject has compensated liver disease without liver cirrhosis.
  • the subject is diagnosed with chronic hepatitis as determined by, for example, one or more of: a liver biopsy, a liver function test, an ultrasound, a hepatic venous pressure gradient (HVPG) measurement, an ALT level, one or more other blood tests, or an albumin level.
  • the biopsy is conducted within the 6 months before the initiation of treatment. In some embodiments, the biopsy is conducted within the 18 months before the initiation of treatment, according to the methods provided herein. In some embodiments, the biopsy is conducted within the 1 day to 24 months before the initiation of treatment. In some embodiments, the subject has evidence of chronic hepatitis based on a liver biopsy within 6 months before screening.
  • the subject has a serum alanine aminotransferase (ALT) level that is above the upper limit of normal (ULN) within 24 weeks prior to treatment and/or at the initiation of treatment, within 24 months prior to the initiation of treatment, from 24 months to 1 month prior to the initiation of treatment, or from 12 months to 1 day prior to the initiation of treatment.
  • ALT serum alanine aminotransferase
  • UPN upper limit of normal
  • the subject meets one or more independently selected criteria in Example 1.
  • the subject exhibits > 2 logiodecline in HDV RNA levels at about 12 weeks of treatment according to the methods of the present disclosure.
  • the subject exhibits a decline in HDV RNA levels starting at a first timepoint after the start of the treatment, the decline continuing through at least two additional successive timepoints of the treatment according to the methods of the present disclosure.
  • the at least two additional successive timepoints can be referred to as "second timepoint” and "third timepoint", respectively.
  • the interval between the start of the treatment and the first timepoint maybe referred to as "first interval.”
  • the interval between the first timepoint and the second timepoint may be referred to as “second interval.”
  • the interval between the second timepoint and the third timepoint may be referred to as “third interval.”
  • the durations of the first interval, the second interval, and the third interval may vary.
  • the duration of the first interval may be at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, or at least 20 weeks.
  • the duration of the second interval may be at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks.
  • the duration of the third interval may be at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks.
  • the subject exhibits a decline in HDV RNA levels, in comparison to timepoint at or before the start of the treatment, at the timepoint of 12 weeks after the start of the treatment (first timepoint). The subject then exhibits continued decline in HDV RNA levels at the timepoint of 18 weeks (second timepoint) after the start of the treatment and 22 weeks (third timepoint) after the treatment.
  • the subject exhibits a decline in HDV RNA levels, in comparison to timepoint at or before the start of the treatment, at the timepoint of 16 weeks after the start of the treatment (first timepoint). The subject then exhibits continued decline in HDV RNA levels at the timepoint of 20 weeks (second timepoint) after the start of the treatment and 24 weeks (third timepoint) after the treatment.
  • the patient receiving lonafarnib-ritonavir co-therapy receives lonafarnib at a daily dose of 50 mg/day to 150 mg/day, or at a daily dose of 50 mg/day to 100 mg/day, for example, 25 mg/day, 50 mg/day, 75 mg/day, or 100 mg/day, preferably wherein each administration of lonafarnib is no more than 75 mg, e.g., 25 mg or 50 mg; and ritonavir is at a daily dose of 100 mg/day - 200 mg/day, preferably wherein each administration of ritonavir is no more than 100 mg.
  • the patient may receive 75 mg lonafarnib BID and 100 mg ritonavir BID. In some embodiments, the patient may receive 50 mg lonafarnib BID and 100 mg ritonavir BID, or 25 mg lonafarnib BID and 100 mg ritonavir BID, or 75 mg lonafarnib BID and 100 mg ritonavir QD. In some embodiments, the patient receives a daily dose of 100 mg lonafarnib and 200 mg ritonavir. For example, the patient may receive 50 mg lonafarnib BID and 100 mg ritonavir BID.
  • the patient receives a daily dose of 75 mg lonafarnib and 100 mg ritonavir.
  • the patient may receive 75 mg lonafarnib Q.D and 100 mg ritonavir Q.D.
  • the patient receives a daily dose of 50 mg lonafarnib and 100 mg ritonavir.
  • the patient may receive 50 mg lonafarnib Q.D and 100 mg ritonavir Q.D.
  • the patient receives a daily dose of 50 mg lonafarnib and 200 mg ritonavir.
  • the patient may receive 25 mg lonafarnib BID and 100 mg ritonavir BID.
  • the therapeutic approaches disclosed herein comprise administering lonafarnib at a first dose followed by administering lonafarnib at a second dose, wherein the second dose is lower than the first dose.
  • the therapeutic approaches disclosed herein comprise an escalating dosage regimen comprising administering lonafarnib at a first dose for a first treatment period and then administering lonafarnib at a second dose that is higher than the first dose for a second treatment period.
  • the patient receives lonafarnib at a first dose of 25 mg BID for the first treatment period followed by lonafarnib at a second dose of 50 mg BID for the second treatment period.
  • the therapeutic approach comprises administering the lonafarnib at a first dose for a first treatment period and then administering lonafarnib at a second dose that is higher than the first dose for a second treatment period if the patient does not experiences unacceptable gastrointestinal side effects during the first treatment period, or administering the lonafarnib at a first dose for a first treatment period and then administering lonafarnib at a second dose that is lower than the first dose for a second treatment period if the patient experiences unacceptable gastrointestinal side effects during the first treatment period.
  • a hepatitis flare is an increase in liver inflammation, sometimes detected as an increase in ALT levels so also called an ALT flare. It typically occurs due to the changes in the immune system's response to hepatitis B infection and precedes a decrease in virus levels. See, e.g., Ghany et al.
  • the method comprises administering lonafarnib at a total daily dose in the range of 50 mg to 150 mg for at least 12 weeks and/or until a hepatitis flare is observed.
  • the hepatitis flare is accompanied by a transient increase in the patient's HBV viral load.
  • the method comprises administering lonafarnib-ritonavir co-therapy in which ritonavir is administered at a total daily dose of 100-200 mg.
  • HDV viral load may be reduced by at least 2 logio, by at least 3 logic, or reduced to an undetectable level.
  • inducing immune reactivation in a patient infected with HDV and HBV involves administering lonafarnib at a first dose followed by administering lonafarnib at a second dose, wherein the second dose is lower than the first dose.
  • the first dose is administered for at least 8 weeks and the second dose is administered for at least 2 weeks, and optionally at least 4 weeks.
  • the first dose of lonafarnib is 50 mg BID and the second dose of lonafarnib is 50 mg QD.
  • the first dose of lonafarnib and the second dose of lonafarnib are administered in combination with ritonavir at a dose of 100 mg BID.
  • the lonafarnib and the ritonavir are administered together in a single unit dose form, but in other embodiments, they are administered in two separate, single unit dosage forms, i.e., a unit dosage form comprising lonafarnib and a unit dosage form comprising ritonavir.
  • the unit dose form comprises amorphous lonafarnib.
  • the unit dose form comprises lonafarnib (e.g., amorphous lonafarnib), ritonavir, and a copolymer.
  • the co-polymer is povidone.
  • the lonafarnib and the ritonavir are administered at about the same time as separate unit dose forms.
  • the lonafarnib and the ritonavir are administered together in a liquid formulation containing both lonafarnib and ritonavir.
  • the method comprises treating the patient with lonafarnib, ritonavir, and an interferon (e.g., unpegylated or pegylated interferon alpha or interferon lambda).
  • the method comprises treating the patient with lonafarnib-ritonavir cotherapy for at least 30 days, wherein the patient has a baseline viral load of at least 10 5 lU/mL serum before the initiation of treatment, and treatment results in a reduction of viral load to less than 10 3 lU/mL serum.
  • the lonafarnib component of the therapy is administered at a total daily dose of 50-200 mg per day, e.g., at least 50 mg per day, at least 75 mg per day, at least 100 mg per day, at least 150 mg per day, or at least 200 mg per day.
  • Lonafarnib therapy may be administered once daily (Q.D) or twice daily (BID).
  • lonafarnib is administered at a dose of 25 mg BID, 50 mg BID, 75 mg BID, 100 mg BID, 50 mg QD, 75 mg QD, or 100 mg QD.
  • lonafarnib therapy is initiated at the start of interferon alpha therapy or, alternatively, during the course of interferon alpha therapy.
  • the lonafarnib-ritonavir portion of the therapy is at a total daily dose of 50-200 mg of lonafarnib per day (e.g., at least 50 mg per day, at least 75 mg per day, at least 100 mg per day, at least 150 mg per day, or at least 200 mg per day of lonafarnib) and 100-200 mg of ritonavir per day (e.g., at least 100 mg per day, at least 150 mg per day, or at least 200 mg per day of ritonavir).
  • the lonafarnib and ritonavir portion of the therapy may be administered once daily (QD) or twice daily (BID).
  • the lonafarnib is at a dose of 25 mg BID, 50 mg BID, 75 mg BID, 100 mg BID, 50 mg QD, 75 mg QD, or 100 mg QD, and the ritonavir at a dose of 50 mg BID or 100 mg BID.
  • interferon alpha, lonafarnib, and ritonavir therapy comprises administering to the subject interferon alpha (e.g., pegylated interferon alpha-2a) at a dose of 180 micrograms (mcg) per week, lonafarnib at a dose of 50 mg twice daily (BID), and ritonavir at a dose of 100 mg BID.
  • interferon alpha e.g., pegylated interferon alpha-2a
  • lonafarnib at a dose of 50 mg twice daily (BID)
  • ritonavir at a dose of 100 mg BID.
  • the subject is administered interferon alpha at about 200 mcg to about 100 mcg QD
  • lonafarnib at from about 25 mg to about 50 mg BID
  • ritonavir from about 50 mg to about 150 mg BID.
  • interferon alpha, lonafarnib, and ritonavir therapy comprises administering to the subject interferon alpha at a dose of 120-180 mcg per week, lonafarnib at a dose of 50 mg BID, and ritonavir at a dose of 100 mg BID.
  • the interferon alpha is administered at 120 mcg per week, 110 mcg per week, 100 mcg per week, 90 mcg per week, 80 mcg per week, 120 - 70 mcg per week, 200 - 120 mcg per week, or 170 - 130 mcg per week.
  • interferon alpha is administered at a dose of 180 mcg QW.
  • interferon alpha is administered at a dose of 90 mcg two times per week.
  • interferon alpha is administered at a dose of 90 mcg every 3 - 4 days.
  • interferon alpha is administered at a dose of 80 mcg two times per week. In some embodiments, interferon alpha is administered at a dose of 80 mcg every 3 - 4 days. In some embodiments, interferon alpha is administered at a dose of 100 - 70 mcg two times per week. In some embodiments, interferon alpha is administered at a dose of 100 - 70 mcg every 3 - 4 days. In some embodiments, interferon alpha is administered at a dose of 120 mcg QW. In some embodiments, interferon alpha is administered at a dose of 80 mcg QW.
  • a subject being treated for HDV infection receives an adjustment in the dosing regimen of the interferon alpha and/or lonafarnib components during the course of treatment.
  • the subject receives a dose reduction of interferon alpha and/or lonafarnib, in that one or more later doses is a lower dose than one or more earlier doses.
  • a dose is reduced if the subject exhibits unacceptable side effects.
  • a subject may receive multiple dose reductions during the course of treatment with interferon alpha, lonafarnib, and ritonavir.
  • the dosage administered to the subject is not reduced before 8 weeks of treatment at the first dosage (e.g., at a first dosage of 180 mcg QW), or before 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or 7 weeks of treatment at the first dosage. In some embodiments, the dosage administered to the subject is not reduced before 9 - 12 weeks of treatment at the first dosage (e.g., at a first dosage of 180 mcg QW).
  • the Ion afa rn ib dose may be reduced at the same time (or times) as the interferon alpha dose, and/or the lonafarnib dose may be reduced at different times from the interferon alpha dose. In some embodiments, the dose of interferon alpha is reduced, and the dose of the lonafarnib is not reduced. In some embodiments, the dose of lonafarnib is reduced and the dose of interferon alpha is not reduced.
  • the interferon alpha, lonafarnib, and ritonavir therapy comprises administering to the subject interferon alpha at a first interferon alpha dose (e.g., 180 micrograms per week) and lonafarnib at a first lonafarnib dose (e.g., 50 mg BID) for a first treatment period, followed by administering to the subject interferon alpha at a second interferon alpha dose (e.g., 120 micrograms per week) and lonafarnib at a second lonafarnib dose (e.g., 25 mg BID) for a second treatment period.
  • the length of time for the first treatment period is the same as the length of time for the second treatment period.
  • the ritonavir dose remains the same in both treatment periods.
  • the first treatment period and the second treatment period are different lengths of time. In some embodiments, the first treatment period is longer than the second treatment period. In some embodiments, the second treatment period is longer than the first treatment period.
  • Subjects may receive lonafarnib, ritonavir, and optionally interferon alpha, therapy for a predetermined time, until not tolerated, or until an endpoint is reached.
  • the patient is treated with lonafarnib-ritonavir co-therapy for at least 30 days. In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least 60 days. In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least 90 days. In some embodiments, the patient is treated with lonafarnib-ritonavir co- therapy for at least 180 days. In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least one year.
  • the patient is treated with lonafarnib- ritonavir co-therapy for at least 4 weeks. In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least 8 weeks. In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least 12 weeks. In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least 24 weeks. In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least 48 weeks.
  • the patient is treated with lonafarnib-ritonavir co-therapy for at least 60 weeks. In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least 72 weeks. In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least 84 weeks.
  • the interferon, lonafarnib, and ritonavir therapy is continued for at least 30 days, e.g., at least 60 days, at least 90 days, at least 120 days, at least 150 days, or at least 180 days.
  • the interferon, lonafarnib, and ritonavir treatment is continued for at least 6 months, e.g., at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least one year, at least 15 months, at least 18 months, or at least 2 years.
  • the interferon, lonafarnib, and ritonavir is continued for at least 6 weeks, e.g., at least 12 weeks, at least 18 weeks, at least 24 weeks, at least 30 weeks, at least 36 weeks, at least 42 weeks, at least 48 weeks, at least 60 weeks, at least 72 weeks, at least 84 weeks, or at least 96 weeks.
  • the interferon, lonafarnib, and ritonavir therapy is continued for the remainder of the subject's life or until administration is no longer needed or no longer effective in maintaining the virus at a sufficiently low level to provide meaningful therapeutic benefit.
  • HDV subjects will respond to a therapy, as described herein, by clearing virus to undetectable levels.
  • treatment is suspended unless and until the HDV levels return to detectable levels.
  • Other subjects will experience a reduction in viral load and improvement of symptoms but will not clear the virus to undetectable levels and will remain on therapy for a defined period of time (e.g., for about 1 year, about 2 years, about 3 years, or longer) or so long as the therapy provides therapeutic benefit.
  • treatment with interferon alpha, lonafarnib, and ritonavir therapy results in a reduction of HDV viral load in the subject of at least 1.5 logTM HDV RNA copies/mL serum when measured after 24 weeks of treatment.
  • treatment with interferon alpha, lonafarnib, and ritonavir therapy results in a reduction of HDV viral load in the subject of at least 2.0 logio HDV RNA copies/mL serum when measured after 24 or 48 weeks of treatment.
  • a therapy described herein results in a reduction of HDV viral load in the subject of at least 2.5 logTM HDV RNA copies/mL serum when measured after 24 weeks of treatment.
  • treatment with a therapy described herein results in a sustained reduction of HDV viral load (e.g., a decrease of at least 1.5 logio HDV RNA lU/mL serum, at least 2.0 logio HDV RNA copies/mL serum, or at least 2.5 logio HDV RNA lU/mL serum, or a decrease in HDV RNA to undetectable levels) that is sustained for a period of time (e.g., 1 month, 3 months, 6 months, 1 year or longer) while the course of treatment is still ongoing.
  • a sustained reduction of HDV viral load e.g., a decrease of at least 1.5 logio HDV RNA lU/mL serum, at least 2.0 logio HDV RNA copies/mL serum, or at least 2.5 logio HDV RNA lU/mL serum, or a decrease in HDV RNA to undetectable levels
  • a period of time e.g., 1 month, 3 months, 6 months, 1 year or longer
  • treatment with interferon alpha, lonafarnib, and ritonavir therapy results in a sustained reduction of HDV viral load that is sustained for a period of time (e.g., 1 month, 3 months, 6 months, 1 year or longer) after the course of treatment is finished.
  • the interferon alpha, lonafarnib, and ritonavir therapy results in HDV RNA levels (e.g., serum HDV RNA levels or plasma HDV RNA levels) below 1,000 copies/mL.
  • the HDV RNA levels remain below 1,000 copies/mL for at least one month, e.g., at least three months, at least one year, or longer.
  • the course of treatment results in HDV RNA levels (e.g., serum HDV RNA levels or plasma HDV RNA levels) below 100 copies/mL.
  • the HDV RNA levels remain below 100 copies/mL for at least one month, at least three months, at least one year, or longer.
  • the phrase "remains below” refers to remaining below an initial measured value (e.g., 100 copies/mL or 100 lU/mL) for a period of time, for example, at 1 month (or another specified time) a viral load measurement taken at least 1 month (or at the other specified time) after determination of the initial measured value is no higher than the initial value.
  • the subject does not receive interferon alpha therapy during the specified time.
  • the subject does not receive any anti-HDV treatment during the specified time.
  • therapy as disclosed herein is continued for a period of time until HDV RNA levels are below 3 logic HDV RNA copies/mL (below 1,000 copies/mL), or sometimes until HDV RNA levels are below 2 logic HDV RNA copies/mL (below 100 copies/mL) or below the level of detection.
  • therapy is continued for a period of time (such as 1 to 3 months or longer) after viral load has dropped to acceptably low levels (e.g., undetectable levels).
  • therapy is continued until the HDV viral load is reduced to undetectable levels.
  • a subject treated according to the methods described herein exhibits a reduction in HDV viral load to undetectable levels during the course of treatment, and the subject maintains the reduction in HDV viral load to undetectable levels for at least 12 weeks after the end of treatment. In some embodiments, a subject treated according to the methods described herein exhibits a reduction in HDV viral load to undetectable levels during the course of treatment, and the subject maintains the reduction in HDV viral load to undetectable levels for at least 24 weeks after the end of treatment.
  • the subject's HDV titer rises from baseline prior to dropping below baseline during the course of treatment. In some embodiments, the subject's HDV level rises to more than 150% of baseline, or more than 200% of baseline. In some embodiments, the rise in the titer is from 25 - 50% of baseline, from 25 - 100% of baseline, or from 50 - 200% of baseline. In some embodiments, the rise in the titer occurs within 2 weeks after initiation of therapy. In some embodiments, the subject's elevated HDV titer drops to below baseline within 2 weeks, or within 3 weeks, of initiation of therapy.
  • a subject treated according to the methods described herein exhibits an improvement in one or more liver function parameters.
  • the improved liver function is an 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, alfa2-macroglobulin, apolipoprotein Al, haptoglobin, gamma-glutamyl transpeptidase (GGT).
  • serum markers e.g., one, two, three, four, five, six or more markers
  • serum albumin e.g., one, two, three, four, five, six or more markers
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • prothrombin alfa2-macroglobulin
  • apolipoprotein Al apolipoprotein Al
  • a subject treated according to the methods described herein exhibits an improvement in liver fibrosis (e.g., as assessed by biopsy with histological analysis, transient ultrasound elastography (e.g., FibroScan®), or magnetic resonance elastography).
  • liver fibrosis e.g., as assessed by biopsy with histological analysis, transient ultrasound elastography (e.g., FibroScan®), or magnetic resonance elastography).
  • treatment results in an improvement of at least 5%, e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 70%, at least 75%, at least 80%, or at least 100%, or between 5 - 50%, between 10 - 80%, or between 50 - 100% improvement in one or more liver function parameters (e.g., an improvement in serum marker(s) or an improvement in liver fibrosis) in the subject as compared to prior to the initiation of treatment.
  • treatment results in an improvement in one or more liver function parameters (e.g., an improvement in serum marker(s) or an improvement in liver fibrosis) to the level of a healthy control subject that is not infected with HDV or HBV.
  • the subject exhibits an improvement in serum ALT levels to a level that is within the upper limit of normal.
  • the subject treated according to the methods described herein has an improved histologic response.
  • Histologic response is herein defined as an improvement in Ishak modified histology activity index (HAI) after 48 weeks of treatment.
  • HAI is >2 points relative to baseline.
  • a subject treated according to the methods described herein exhibits a reduction in HBV viral load compared to the baseline level at the initiation of treatment and/or compared to a similarly infected subject not receiving treatment effective to reduce the subject's HDV viral load.
  • treatment results in a reduction of at least 1 logio in HBV viral load.
  • the subject's HDV and/or HBV viral load is measured to determine the baseline viral load.
  • the subject's viral load is reduced compared to baseline.
  • the subject's viral load is substantially reduced compared to baseline, such as to very low levels or to an undetectable level.
  • treatment results in an at least 2 logio reduction of HBV viral load.
  • subjects treated according to the methods described herein exhibit a reduction in HBsAg levels or an improvement in clearance of HBsAg antigen.
  • subjects treated according to the methods described herein Prior to treatment the subject's HBsAg level is measured to determine a baseline. After a period of treatment (e.g., after 12, after 24, or after 48 weeks of treatment), the subject's HBsAg level is reduced compared to baseline. In some embodiments, subjects treated according to the methods described herein exhibits the presence of anti-HBs antibody. [0102] Subjects treated according to the methods described herein according to the present disclosure may also be treated with one or more other antiviral agents such as nucleoside and nucleotide analogs, compounds used to treat HBV infections, and other agents.
  • antiviral agents such as nucleoside and nucleotide analogs, compounds used to treat HBV infections, and other agents.
  • a subject who is treated according to the methods described herein is treated with an antiviral agent that is used for the treatment of HBV.
  • Anti-HBV medications that are currently approved with the exception of interferons, inhibit reverse transcriptase and are nucleoside or nucleotide analogs. These medications, while effective against HBV DNA, are not effective against HDV as they do not clear HBsAg, which HDV needs to replicate.
  • Currently approved anti-HBV nucleoside/nucleotide analogs include lamivudine (Epivir-HBV®, Zeffix®, or Heptodin®), adefovir dipivoxil (Hepsera®), entecavir (Baraclude®), telbivudine (Tyzeka® or Sebivo®), clevudine (Korea/Asia), tenofovir (Viread® or Vemlidy®).
  • a subject who is administered interferon alpha therapy is also administered a nucleoside or nucleotide analogs including, but not limited to, lamuvidine, adefovir, telbivudine, entecavir, tenofovir, or clevudine.
  • the subject is receiving nucleoside or nucleotide analog therapy prior to the onset of interferon alpha therapy.
  • nucleoside or nucleotide analog therapy is initiated at the start of interferon alpha therapy or during the course of interferon alpha therapy with lonafarnib and ritonavir.
  • a subject who is treated according to the methods described herein exhibits improvements in liver histology after the start of the treatment. In some embodiments, a subject who is treated according to the methods described herein exhibits a reduction in one or more of liver inflammation, liver necrosis, or liver fibrosis. In some embodiments, a subject who is treated according to the methods described herein exhibits improvements in liver histology after the start of the treatment and a reduction in one or more of liver inflammation, liver necrosis, or liver fibrosis. In some embodiments, the subject exhibits the above responses within 4, 8, 12, 24, 36, or 48 weeks of treatment. In some embodiments, the improvement of liver histology may be assessed as > 2-point improvement in Ishak HAI and no worsening of fibrosis by Ishak scoring.
  • a subject who is treated according to the methods described herein, after completion of the treatment exhibits one or more of following responses: further decline in HDV RNA levels, further decline in alanine aminotransferase (ALT) levels, further improvement of the liver histology, or further reduction in the one or more of liver inflammation, liver necrosis, or liver fibrosis.
  • ALT alanine aminotransferase
  • the above one or more of the responses are observed in comparison to one or both the start or the completion of the treatment.
  • the above one or more responses are observed at least 24 weeks after the completion of the treatment.
  • the present disclosure provides methods of identifying subjects (patients) suffering from hepatitis delta virus (HDV) infection who are likely or not likely to achieve clinical response to treatment according to the methods of the present disclosure.
  • such methods involve measuring HDV RNA levels in the subject at the start of the treatment and at about 12 weeks (e.g., 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks) after the start of the treatment.
  • a > 2 logio decline in HDV RNA levels is observed in the subject between the start of the treatment and at about 12 weeks (e.g., 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks) after the start of the treatment, then the subject is likely to achieve the clinical response to the treatment. If the > 2 logiodecline in HDV RNA levels between the start of the treatment and at about 12 weeks (e.g., 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks) after the start of the treatment is not observed in the subject, then the subject not likely to achieve the clinical response to the treatment.
  • such methods involve measuring HDV RNA levels in the subject at a first timepoint after start of the treatment and at least two additional successive timepoints of the treatment. If a decline in HDV RNA levels starting at a first timepoint after the start of the treatment and continuing through the further two timepoints of the treatment is observed in the subject, then the subject is likely to achieve the clinical response to the treatment. If continued decline in HDV RNA levels starting at the first timepoint and continuing through the further two timepoints of the treatment is not observed in the subject, then the subject not likely to achieve the clinical response to the treatment, at least two additional successive timepoints can be referred to as "second timepoint" and "third timepoint", respectively.
  • first interval The interval between the start of the treatment and first second timepoint may be referred to as "first interval.”
  • second interval The interval between the first timepoint and the second timepoint may be referred to as "second interval.”
  • third interval The interval between the second timepoint and the third timepoint may be referred to as "third interval.”
  • the durations of the first interval, the second interval, and the third interval may vary.
  • the duration of the first interval may be at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, or at least 20 weeks.
  • the duration of the second interval may be at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks.
  • the duration of the third interval may be at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks.
  • the subject exhibits a decline in HDV RNA levels, in comparison to timepoint at or before the start of the treatment, at the timepoint of 12 weeks after the start of the treatment (first timepoint). The subject then exhibits continued decline in HDV RNA levels at the timepoint of 18 weeks (second timepoint) after the start of the treatment and 22 weeks (third timepoint) after the treatment.
  • the subject exhibits a decline in HDV RNA levels, in comparison to timepoint at or before the start of the treatment, at the timepoint of 16 weeks after the start of the treatment (first timepoint). The subject then exhibits continued decline in HDV RNA levels at the timepoint of 20 weeks (second timepoint) after the start of the treatment and 24 weeks (third timepoint) after the treatment.
  • the clinical response can be measured by one or more treatment endpoints described elsewhere in the present disclosure.
  • any reference to a series of embodiments is to be understood as a reference to each of those embodiments disjunctively (e.g., "Embodiments 1-4" is to be understood as “Embodiments 1, 2, 3, or 4").
  • Embodiment 1 is a method of treating hepatitis delta virus (HDV) infection in a patient who has at least one of HDV levels that do not significantly decline with interferon therapy, intolerance to interferon, or a contraindication to interferon, the method comprising administering a therapeutically effective amount of lonafarnib and a CYP3A4 inhibitor.
  • HDV hepatitis delta virus
  • Embodiment 2 is the embodiment of embodiment 1, wherein the contraindication is at least one of severe depression, advanced liver disease, leukopenia, severe thrombocytopenia, active autoimmune disease, compensated chronic hepatitis, and/or a severe concomitant disease that precludes IFN therapy.
  • the contraindication is at least one of severe depression, advanced liver disease, leukopenia, severe thrombocytopenia, active autoimmune disease, compensated chronic hepatitis, and/or a severe concomitant disease that precludes IFN therapy.
  • Embodiment 3 is the embodiment of embodiments 1 or 2, wherein the CYP3A4 inhibitor is ritonavir.
  • Embodiment 4 is the embodiment of embodiments 1-3, wherein the patient has chronic HDV for at least 6 months in duration before the administration of lonafarnib.
  • Embodiment 5 is the embodiment of embodiments 1-4, wherein lonafarnib is administered at 50 to 200 mg per day.
  • Embodiment 6 is the embodiment of embodiments 1-5, wherein lonafarnib is administered orally at 50 mg BID.
  • Embodiment 7 is the embodiment of embodiments 1-6, wherein ritonavir is administered at a daily dose of 50 to 200 mg.
  • Embodiment 8 is the embodiment of embodiments 1-7, wherein ritonavir is administered orally at 100 mg BID.
  • Embodiment 9 is the embodiment of embodiments 1-8, wherein lonafarnib and ritonavir are administered for at least 12 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks, at least 54 weeks, or from 12 weeks to 96 weeks.
  • Embodiment 10 is the embodiment of embodiments 1-9, wherein lonafarnib and ritonavir are administered for 48 weeks.
  • Embodiment 11 is the embodiment of embodiments 1-10, wherein the patient has both a
  • Embodiment 12 is the embodiment of embodiments 1-10, wherein the patient has both a
  • RNA levels > 2 logio decline in HDV RNA levels and normalized alanine aminotransferase (ALT) levels within 4, 8, 12, 24, 36, or 48 weeks of treatment.
  • ALT normalized alanine aminotransferase
  • Embodiment 13 is the embodiment of embodiments 11 or 12, wherein the > 2 logio decline in HDV RNA levels and the normalized alanine aminotransferase (ALT) levels are sustained post-treatment.
  • Embodiment 14 is the embodiment of embodiments 11 or 12, wherein the > 2 logio decline in HDV RNA levels and the normalized alanine aminotransferase (ALT) levels are sustained for up to 24 weeks post-treatment.
  • ALT normalized alanine aminotransferase
  • Embodiment 15 is the embodiment of embodiments 1-10, wherein the patient has a
  • Embodiment 16 is the embodiment of embodiments 1-10, wherein the patient has a
  • Embodiment 17 is the embodiment of embodiments 15 or 16, wherein the > 2 logio decline in HDV RNA levels are sustained post-treatment.
  • Embodiment 18 is the embodiment of embodiments 15-17, wherein the > 2 logiodecline in HDV RNA levels are sustained for up to 24 weeks post-treatment.
  • Embodiment 19 is the embodiment of embodiments 1-10, wherein the patient has normalized alanine aminotransferase (ALT) levels within 48 weeks of treatment.
  • ALT alanine aminotransferase
  • Embodiment 20 is the embodiment of embodiments 1-10, wherein the patient has normalized alanine aminotransferase (ALT) levels within 4, 8, 12, 24, 36, or 48 weeks of treatment.
  • ALT alanine aminotransferase
  • Embodiment 21 is the embodiment of embodiments 19 or 20, wherein the normalized alanine aminotransferase (ALT) levels are sustained post-treatment.
  • ALT normalized alanine aminotransferase
  • Embodiment 22 is the embodiment of embodiments 19-21, wherein the normalized alanine aminotransferase (ALT) levels are sustained for up to 24 weeks post-treatment.
  • ALT normalized alanine aminotransferase
  • Embodiment 23 is a method of treating hepatitis delta virus (HDV) infection in a patient, comprising administering a therapeutically effective amount of lonafarnib and a CYP3A4 inhibitor at regular intervals as a chronic therapy.
  • HDV hepatitis delta virus
  • Embodiment 24 is the embodiment of embodiment 23, wherein the CYP3A4 inhibitor is ritonavir.
  • Embodiment 25 is the embodiment of embodiments 23 or 24, wherein the regular intervals are every 6 months.
  • Embodiment 26 is the embodiment of embodiments 23-25, wherein the administering a therapeutically effective amount of lonafarnib and a CYP3A4 inhibitor causes a > 2 logiodecline in HDV RNA levels within 8 weeks of treatment.
  • Embodiment 27 is the embodiment of embodiments 23-26, wherein the administering a therapeutically effective amount of lonafarnib and a CYP3A4 inhibitor causes a 30 to 40 U/L decline in ALT levels within 8 weeks of treatment.
  • Embodiment 28 is the embodiment of embodiments 23-27, wherein the lonafarnib and a
  • Embodiment 29 is the embodiment of embodiment 28, wherein the interferon is pegylated interferon.
  • Embodiment 30 is the embodiment of embodiments 28 or 29, wherein the interferon is pegylated interferon-alfa-2a.
  • Embodiment 31 is the embodiment of embodiments 28-30, wherein the interferon is administered at a dose of 120 to 180 mcg per week.
  • Embodiment 32 is the embodiment of embodiments 28-31, wherein interferon is administered by subcutaneous injection at 180 mcg QW.
  • Embodiment 33 is a method of treating hepatitis delta virus (HDV) infection in a patient, the method comprising administering to the patient a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor.
  • HDV hepatitis delta virus
  • Embodiment 34 is the embodiment of embodiment 33, wherein the therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor at regular intervals as a chronic therapy.
  • Embodiment 35 is the embodiment of embodiments 33 or 34, wherein the interferon alpha is pegylated interferon alpha.
  • Embodiment 36 is the embodiment of embodiment 35, wherein the interferon alpha is pegylated interferon-alfa-2a.
  • Embodiment 37 is the embodiment of embodiments 33 to 36, wherein the interferon alpha is administered at a dose of about 120 to 180 mcg per week.
  • Embodiment 38 is the embodiment of embodiments 33 to 37, wherein interferon alpha is administered by subcutaneous injection at about 180 mcg QW.
  • Embodiment 39 is the embodiment of embodiments 33 to 38, wherein the CYP3A4 inhibitor is ritonavir.
  • Embodiment 40 is the embodiment of embodiments 33 to 38, wherein the patient has chronic HDV for at least 6 months in duration before the administration of lonafarnib.
  • Embodiment 41 is the embodiment of embodiments 33 to 40, wherein the patient has chronic HDV for at least 6 months in duration before the administration of lonafarnib.
  • Embodiment 42 is the embodiment of embodiments 33 to 41, wherein lonafarnib is administered at about 50 to about 200 mg per day.
  • Embodiment 43 is the embodiment of embodiments 33 to 42, wherein lonafarnib is administered orally at 50 mg BID.
  • Embodiment 44 is the embodiment of embodiments 33 to 43, wherein ritonavir is administered at a daily dose of about 50 to about 200 mg.
  • Embodiment 45 is the embodiment of embodiments 33 to 44, wherein ritonavir is administered orally at 100 mg BID.
  • Embodiment 46 is the embodiment of embodiments 33 to 45, wherein lonafarnib and ritonavir are administered for at least 12 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks, at least 54 weeks, or from 12 weeks to 96 weeks.
  • Embodiment 47 is the embodiment of embodiments 33 to 46, wherein lonafarnib and ritonavir are administered for 48 weeks.
  • Embodiment 48 is the embodiment of embodiments 33 to 47, wherein the patient has both a > 2 logiodecline in HDV RNA levels and normalized alanine aminotransferase (ALT) levels within 48 weeks of treatment.
  • ALT normalized alanine aminotransferase
  • Embodiment 49 is the embodiment of embodiments 33 to 47, wherein the patient has both a > 2 logw decline in HDV RNA levels and normalized alanine aminotransferase (ALT) levels within 4, 8, 12, 24, 36, or 48 weeks of treatment.
  • ALT normalized alanine aminotransferase
  • Embodiment 50 is the embodiment of embodiments 48 or 49, wherein the > 2 logio decline in HDV RNA levels and normalized alanine aminotransferase (ALT) levels are sustained posttreatment.
  • Embodiment 51 is the embodiment of embodiments 48 or 49, wherein the > 2 logio decline in HDV RNA levels and normalized alanine aminotransferase (ALT) levels are sustained for up to 24 weeks post-treatment.
  • ALT normalized alanine aminotransferase
  • Embodiment 52 is the embodiment of embodiments 33 to 47, wherein the patient has a
  • Embodiment 53 is the embodiment of embodiment 52, wherein the patient has both a
  • Embodiment 54 is the embodiment of embodiment 52, wherein the > 2 logiodecline in HDV RNA levels are sustained post-treatment.
  • Embodiment 55 is the embodiment of embodiments 53-54, wherein the > 2 logiodecline in HDV RNA levels are sustained for up to 24 weeks post-treatment.
  • Embodiment 56 is the embodiment of embodiment 33, wherein the patient has normalized alanine aminotransferase (ALT) levels within 48 weeks of treatment.
  • ALT alanine aminotransferase
  • Embodiment 57 is the embodiment of embodiments 33 to 47, wherein the patient has normalized alanine aminotransferase (ALT) levels within 4, 8, 12, 24, 36, or 48 weeks of treatment.
  • ALT normalized alanine aminotransferase
  • Embodiment 58 is the embodiment of embodiment 58, wherein the normalized alanine aminotransferase (ALT) levels are sustained post-treatment.
  • ALT normalized alanine aminotransferase
  • Embodiment 59 is the embodiment of embodiments 57 or 58, wherein the normalized alanine aminotransferase (ALT) levels are sustained for up to 24 weeks post-treatment.
  • ALT normalized alanine aminotransferase
  • Embodiment 60 is a method of treating hepatitis delta virus (HDV) infection in a patient, comprising administering a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor at regular intervals as a chronic therapy.
  • HDV hepatitis delta virus
  • Embodiment 61 is the embodiment of embodiment 60, wherein the CYP3A4 inhibitor is ritonavir.
  • Embodiment 62 is the embodiment of embodiments 60 or 61, wherein the regular intervals are every 6 months.
  • Embodiment 63 is the embodiment of embodiments 60-62, wherein the administering a therapeutically effective amount of lonafarnib and a CYP3A4 inhibitor causes a > 2 logiodecline in HDV RNA levels within 8 weeks of treatment.
  • Embodiment 64 is the embodiment of embodiments 60-63, wherein the administering a therapeutically effective amount of lonafarnib and a CYP3A4 inhibitor causes a 30 to 40 U/L decline in ALT levels within 8 weeks of treatment.
  • Embodiment 65 is the embodiment of embodiments 60-64, wherein the lonafarnib and a CYP3A4 inhibitor are co-administered with an interferon.
  • Embodiment 66 is the embodiment of embodiments 60-65, wherein the interferon is pegylated interferon.
  • Embodiment 67 is the embodiment of embodiments 60-66, wherein the interferon is pegylated interferon-alfa-2a.
  • Embodiment 68 is the embodiment of embodiments 60-67, wherein the interferon is administered at a dose of 120 to 180 mcg per week.
  • Embodiment 69 is the embodiment of embodiments 60-68, wherein interferon is administered by subcutaneous injection at 180 mcg QW.
  • Embodiment 70 is a method of reducing both the viral load and ALT levels in a patient with hepatitis delta virus (HDV) infection, the method comprising administering to the patient a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor.
  • HDV hepatitis delta virus
  • Embodiment 71 is the embodiment of embodiment 70, wherein the patient has both a
  • Embodiment 72 is the embodiment of embodiments 70 or 71, wherein the patient has both a > 2 logw decline in HDV RNA levels and normalized alanine aminotransferase (ALT) levels within 4, 8, 12, 24, 36, or 48 weeks of treatment.
  • ALT normalized alanine aminotransferase
  • Embodiment 73 is the embodiment of embodiment 71, wherein the > 2 logio decline in HDV RNA levels and normalized alanine aminotransferase (ALT) levels are sustained post-treatment.
  • Embodiment 74 is the embodiment of embodiment 71, wherein the > 2 logTM decline in HDV RNA levels and normalized alanine aminotransferase (ALT) levels are sustained for up to 24 weeks post-treatment.
  • Embodiment 75 is the embodiment of embodiments 1-74, wherein the patient has improvement in liver histology within 48 weeks of treatment.
  • Embodiment 76 is the embodiment of embodiment 75, wherein the improvement of liver histology comprises > 2-point improvement in Ishak HAI and no worsening of fibrosis by Ishak scoring.
  • Embodiment 77 is the embodiment of embodiments 1-74, wherein the patient has reduction in one or more of liver inflammation, liver necrosis, or liver fibrosis within 4, 8, 12, 24, 36, or 48 weeks of treatment.
  • Embodiment 78 is the embodiment of embodiments 1-77, wherein the patient, after completion of the administering to the patient of the therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor, has one or more of following responses: further decline in HDV RNA levels, further decline in alanine aminotransferase (ALT) levels, further improvement of the liver histology, or further reduction in the one or more of liver inflammation, liver necrosis, or liver fibrosis.
  • ALT alanine aminotransferase
  • Embodiment 79 is the embodiment of embodiment 78, wherein the one or more of the responses are observed in comparison to one or both start or the completion of the administering to the patient of the therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor.
  • Embodiment 80 is the embodiment of embodiments 78 or 79, wherein the patient has the one or more response at least 24 weeks after the completion of the administering to the patient of the therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor.
  • Embodiment 81 is the embodiment of embodiments 1-80, wherein the patient has
  • Embodiment 82 is the embodiment of embodiments 1-81, wherein the patient has a decline in HDV RNA levels starting at a first timepoint after the start of the administering to the patient of the therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor and continuing through a second timepoint and a third timepoint during the administering to the patient of the therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor, wherein the second timepoint occurs after the first timepoint, and wherein the third timepoint occurs after the second timepoint.
  • Embodiment 83 is the embodiment of embodiment 82, wherein an interval between the start of the administering to the patient of the therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor and the first timepoint at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, or at least 20 weeks.
  • Embodiment 84 is the embodiment of embodiments 82 or 83, wherein an interval between the first timepoint and the second timepoint is at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks.
  • Embodiment 85 is the embodiment of embodiments 82-84, wherein an interval between the second timepoint and the third timepoint is at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks.
  • Embodiment 86 is a method of identifying a patient suffering from hepatitis delta virus (HDV) infection and likely or not likely to achieve clinical response to a treatment comprising administering a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor, the method comprising the steps of: administering to the patient a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor for at least 12 weeks; and, measuring HDV RNA levels in the patient at start of the treatment and at 12 weeks after the start of the treatment; wherein > 2 logiodecline in HDV RNA levels between the start of the treatment and at 12 weeks after the start of the treatment indicates the patient likely to achieve the clinical response to the treatment, and wherein absence of the > 2 logiodecline in HDV RNA levels between the start of the treatment and at about 12 weeks after the start of the treatment indicates the patient not likely to achieve the clinical response to the treatment.
  • HDV
  • Embodiment 87 is a method of identifying a patient suffering from hepatitis delta virus (HDV) infection and likely or not likely to achieve clinical response to a treatment comprising administering a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor, the method comprising the steps of: administering the treatment to the patient; and, measuring HDV RNA levels in the patient at a first timepoint after start of the treatment, at a second timepoint during the treatment, and at third timepoint during the treatment, wherein the second timepoint occurs after the first timepoint; wherein the third timepoint occurs after the second timepoint, wherein decline in HDV RNA levels starting at the first timepoint continuing through the second timepoint and the third timepoint indicates the patient likely to achieve the clinical response to the treatment, and wherein absence of the decline in HDV RNA levels starting at the first timepoint and continuing through the second timepoint and the third timepoint indicates the patient not likely to achieve the clinical response to the treatment.
  • HDV hepatit
  • Embodiment 88 is the embodiment of embodiment 87, wherein an interval between the start of the treatment and the first timepoint is at least at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, or at least 20 weeks.
  • Embodiment 89 is the embodiment of embodiments 87 or 88, wherein an interval between the first timepoint and the second timepoint is at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks.
  • Embodiment 90 is the embodiment of embodiments 87-89, wherein an interval between the second timepoint and the third timepoint is at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks.
  • Embodiment 91 is the embodiment of embodiments 87-90, wherein the clinical response comprises one or more of: > 2 logiodecline in HDV RNA levels, normalized alanine aminotransferase (ALT) levels, improvement of liver histology, or reduction in the one or more of liver inflammation, liver necrosis, or liver fibrosis.
  • the clinical response comprises one or more of: > 2 logiodecline in HDV RNA levels, normalized alanine aminotransferase (ALT) levels, improvement of liver histology, or reduction in the one or more of liver inflammation, liver necrosis, or liver fibrosis.
  • ALT normalized alanine aminotransferase
  • Embodiment 92 is the embodiment of embodiment 91, wherein the improvement of liver histology comprises > 2-point improvement in Ishak HAI and no worsening of fibrosis by Ishak scoring.
  • Embodiment 93 is the embodiment of embodiments 87-92, wherein the clinical response is observed at about 48 weeks after the start of the treatment.
  • timepoint is at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks.
  • Lonafarnib inhibited purified human FT with a median inhibitory concentration (IC 5 o) of 1.9 nM.
  • Lonafarnib demonstrated a median effective concentration ( EC 50 ) of 35 pM (2.4 ng/mL) against HDV in a virus particle formation assay in cell culture.
  • Lonafarnib does not have intrinsic activity against HBV, and does not interact with tenofovir (TNF), adefovir (ADV), entecavir (ETV), telbivudine, or lamivudine (LMV) in vitro.
  • TNF tenofovir
  • ADV adefovir
  • ETV entecavir
  • telbivudine or lamivudine (LMV) in vitro.
  • Lonafarnib is primarily metabolized by CYP3A, with negligible renal elimination ( ⁇ 1%). Plasma protein binding of LNF was > 99%. Lonafarnib is widely distributed into tissues following oral administration. [0204] In nonclinical toxicity studies, LNF was generally tolerated and had no major end-organ toxicities at repeated doses of 15 mg/kg up to 6 months in rats and 10 mg/kg up to 1 year in monkeys. At higher doses, the key toxicological findings were bone marrow suppression and testicular toxicity in rats and monkeys, lymphoid and kidney changes in rats, and diarrhea and electroretinographic changes in monkeys.
  • LNF resulted in changes in the male and female reproductive tracts and resorptions, and an abortion in 1 rabbit.
  • males there was a reduction in the weight of both the testis and epididymis with a marked reduction in female pregnancy parameters when mated with LNF-treated males.
  • females rats and rabbits
  • pre- and post-implantation loss there were increased pre- and post-implantation loss, resulting in reduced corpora lutea and decreases in fetal weight for those fetuses that successfully implanted.
  • LNF was not mutagenic or clastogenic.
  • This partially double-blind, randomized study has employed a matrix (factorial) design to evaluate the efficacy and safety of 50 mg lonafarnib/100 mg ritonavir BID with and without PEG I FN-alfa-2a 180 mcg QW for 48 weeks compared to no treatment (placebo lonafarnib and placebo RTV) in patients chronically infected with HDV and receiving anti-HBV nucleos(t)ide maintenance therapy.
  • a schematic of the clinical trial is shown in FIG. 1.
  • ETV tenofovir
  • TNF tenofovir disoproxil fumarate
  • TDF tenofovir alafenamide fumarate
  • TAF HBV deoxyribonucleic acid
  • Patients being treated with another anti-HBV nucleos(t)ide therapy changed treatment to entecavir or tenofovir for at least 12 weeks (and up to 6 months) and presented demonstrable suppression of HBV DNA ( ⁇ 20 lU/mL) prior to initiating study therapy.
  • Study visits were conducted during the screening phases; on Day 1 (Baseline); weeks 1, 2, and 4; every 2 weeks through week 12; and every 4 weeks until the end-of-treatment visit at week 48.
  • Hepatitis B e antigen (HBeAg) levels HBeAg
  • Seroconversion to anti-HBeAb HBeAg
  • HBV genotyping were collected during pre-screening when feasible (i.e., prior to anti-HBV nucleos[t]ide administration); for patients with undetectable HBV DNA levels (i.e., post anti-HBV nucleos[t]ide administration), medical history, when available, will be utilized to record the HBV genotype.
  • Ophthalmological examination to include best corrected distance visual acuity, automated threshold perimetry testing, spectral-domain optical coherence tomography (SD-OCT) testing of the central retina, and assessment of normal dilated retina. Patients with clinically meaningful ophthalmological findings during the treatment phase will be assessed during.
  • SD-OCT spectral-domain optical coherence tomography
  • EOT liver biopsy should be scheduled after the week 44 visit and prior to or during the week 48 visit. If the procedure needs to be rescheduled (up to 14 days after the week 48 visit), sufficient study drug will be released to continue treatment until the biopsy is performed (ie, patients should remain on study drug until the biopsy is performed).
  • An Early Termination liver biopsy may occur at any time after 12 weeks of treatment and ideally within 5 days of final study treatment.
  • 12 FT samples may be analyzed for possible future exploratory assessment.
  • sampling window 10% of the samples will be collected. Depending on the number of sites capable of sample collection one or more sampling windows will be assigned to participating patients.
  • All treatment groups must have received background anti-HBV nucleos(t)ide therapy with entecavir or tenofovir starting at least 12 weeks prior to initiating study therapy and present suppression of HBV DNA and continue this treatment for the entire duration of the study.
  • a liver biopsy was performed according to Table 2. The results of the end-of-treatment visit (after week 44 and leading up to/during the week 48 visit) was compared with pre-study data (within 45 days of initiation of study drug therapy) or screening biopsy results to assess changes in necro- inflammatory and fibrosis scores according to the Ishak modified HAI.
  • Clinical laboratory tests include chemistry, hematology, and urinalysis, as listed in Table 3.
  • ALT increases to > 15 x ULN or for cases of ALT > 10 x ULN with associated signs/symptomsor laboratory evidence of reduced hepatic functional capacity (such as decrease of albumin or increases in coagulation times or bilirubin levels), dosing was interrupted (if occurring during treatment), laboratory and clinical assessments were initiated every 2-5 days (more frequently if necessary).
  • signs/symptomsor laboratory evidence of reduced hepatic functional capacity such as decrease of albumin or increases in coagulation times or bilirubin levels
  • Subjects were included if they had chronic HDV infection of at least 6 months in duration documented by a positive HDV antibody (Ab) test and HDV RNA > 500 lU/mL by quantitative polymerase chain reaction (qPCR) prior to initiation of treatment.
  • the demographic and clinical characteristics describing the population of subjects in DLIV-R with HDV is shown in Table 4.
  • the subject is diagnosed with chronic hepatitis as determined by, for example, one or more of: a liver biopsy, a liver function test, an ultrasound, a hepatic venous pressure gradient (HVPG) measurement, an ALT level, one or more other blood tests, or an albumin level.
  • the biopsy is conducted within the 6 months before the initiation of treatment.
  • the biopsy is conducted within the 18 months before the initiation of treatment, according to the methods provided herein. In some embodiments, the biopsy is conducted within the 1 day to 24 months before the initiation of treatment. In some embodiments, the subject has evidence of chronic hepatitis based on a liver biopsy within 6 months before screening. In some embodiments, the subject has a serum alanine aminotransferase (ALT) level that is above the upper limit of normal (ULN) within 24 weeks prior to treatment and/or at the initiation of treatment, within 24 months prior to the initiation of treatment, from 24 months to 1 month prior to the initiation of treatment, or from 12 months to 1 day prior to the initiation of treatment.
  • ALT serum alanine aminotransferase
  • Subjects were 18 years or older and had the presence of anti-HDV in serum; body mass index (BMI) of > 18 kg/m 2 and weight > 45 kg; demonstrable suppression of HBV DNA ( ⁇ 20 lU/mL) following minimum of 12 weeks of anti-HBV nucleos(t)ide treatment with entecavir or tenofovir (TDF or TAF) prior to initiating study therapy; serum ALT > 1.0 x upper limit of the normal range (ULN) and ⁇ lO x ULN; liver biopsy within 45 days of Day 1 demonstrating evidence of chronic hepatitis. If no liver biopsy was available, the patient had to be willing to consent to and have no contraindication to liver biopsy.
  • BMI body mass index
  • TDF tenofovir
  • Subjects having decompensated liver disease defined by Child-Pugh Class B or C) based on documented Child-Pugh score, were not enrolled.
  • Subjects with ALT levels greater than 1000 U/L (>25 times ULN) were not enrolled.
  • a formal Child-Pugh score assessment is conducted and documented at screening. For patients categorized as Child- Pugh A (with a score of 5) with well compensated liver disease, enrollment will be allowed.
  • Co-infected with human immunodeficiency virus (HIV) or hepatitis C virus (HCV) by detectable HIV RNA and HCV RNA, respectively.
  • Subjects with positive results for HIV or HCV Ab at screening were also not enrolled. Patients with a positive HCV Ab at screening were allowed if they have completed a curative antiviral regimen and have documented undetectable HCV RNA for at least 3 months before screening and at screening. Table 4. Baseline demographics and clinical characteristics of the DLIV-R study population.
  • HVPG hepatic venous pressure gradient
  • WBC White blood cell
  • ANC Absolute neutrophil count
  • TSH Abnormal thyroid-stimulating hormone
  • T4 total thyroxine
  • autoimmune liver disease e.g., autoimmune liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson's disease, alcoholic liver disease, nonalcoholic steatohepatitis, hemochromatosis, alpha-l-anti-trypsin deficiency.
  • alcoholic liver disease e.g., nonalcoholic steatohepatitis, hemochromatosis, alpha-l-anti-trypsin deficiency
  • History of hepatocellular carcinoma e.g., autoimmune liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson's disease, alcoholic liver disease, nonalcoholic steatohepatitis, hemochromatosis, alpha-l-anti-trypsin deficiency.
  • Exceptions were malignancies surgically excised with curative intent and/or evidence of being disease free for at least 5 years (e.g., breast ductal carcinoma in situ [DCIS] or squamous/basal cell skin cancer treated with curative intent), or successfully treated in-situ carcinoma of the cervix.
  • FEVl/FVC forced expiratory volume in 1 second/forced vital capacity
  • pancreatitis or colitis patients with pancreatitis or colitis were also excluded, as were patients with severe or uncontrolled psychiatric disorder (e.g., depression, manic condition, psychosis, acute and/or chronic cognitive dysfunction, suicidal behavior, history of suicide attempt, and relapse of substance abuse), bone marrow or solid organ transplantation (although patients who were stable for 1 year posttransplantation and did not require immunosuppressive therapy(ies), following a case review, were considered), or any other significant medical condition that may require intervention during the study or any condition that may impact proper absorption.
  • severe or uncontrolled psychiatric disorder e.g., depression, manic condition, psychosis, acute and/or chronic cognitive dysfunction, suicidal behavior, history of suicide attempt, and relapse of substance abuse
  • bone marrow or solid organ transplantation although patients who were stable for 1 year posttransplantation and did not require immunosuppressive therapy(ies), following a case review, were considered
  • any other significant medical condition that may require intervention during
  • liver disease patients with an absolute neutrophil count ⁇ 1000/dL and platelets ⁇ 75,000/dL were excluded from the study. Subjects were also not enrolled if they had significant systemic or major illnesses other than liver disease, including, but not limited to, congestive heart failure, renal failure (eGFR ⁇ 50 ml/min), organ transplantation, serious psychiatric disease or depression, or active coronary artery disease; systemic immunosuppressive therapy within the previous 2 months before enrollment; evidence of another form of liver disease in addition to viral hepatitis (for example autoimmune liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson disease, alcoholic liver disease, ongoing drug induced liver disease, nonalcoholic steatohepatitis (but not steatosis), hemochromatosis, or alpha- 1-antitrypsin deficiency); active substance abuse, such as alcohol, inhaled or injection drugs within the previous year; evidence of hepatocellular carcinoma.
  • Subjects were not enrolled if they have elevated AFP; evidence of concurrent hepatitis C infection with positive serum HCV RNA; any experimental therapy or pegylated interferon therapy within 6 months prior to enrollment; active, serious autoimmune disease such as systemic lupus erythematosus, ulcerative colitis, Crohn's disease or rheumatoid arthritis.
  • Patients were initiated on therapy, for example, one or two days after the liver biopsy and remained in the clinical center for 72 hours after induction of therapy for observation of side effects, administration of medication, and timed blood draws to facilitate analysis of virologic response kinetics and pharmacokinetic analysis.
  • frequent blood sampling was performed (0, 6, 12, 18, 24, 36, 48 and 72 hours after the first dose) for viral kinetics, pharmacokinetics, and storage.
  • subjects were dose reduced as follows: Interferon alpha dose reduced from 180 mcg to 120 mcg, and lonafarnib dose reduced from 50 mg to 25 mg. Doses were reduced, for example, if a subject's experienced an adverse event that is greater than or equal to a Grade 3 that is one or more of: related to the alfa or lonafarnib, possibly related to the alfa or lonafarnib, possibly related to the alfa or lonafarnib, and not clinically significant. Doses were reduced, for example, if a subject experienced depression, had new ocular symptoms, hematologic abnormalities, or creatinine clearance of less than 50 mL/min.
  • a 2 logio reduction represents 100-fold improvement in viral burden, and this level of viral load reduction after completion of therapy would represent a meaningful change in HDV burden for patients and has been associated with improved survival (Farci et al. (1994) Treatment of Chronic Hepatitis D with Interferon Alfa-2a, NEJM 330:88-94; Farci, P. (2003) Delta hepatitis: an update, J of Hepatology 39:212-219).
  • IFN interferon
  • a substantial proportion of patients may not have access to PEG IFN-alfa-2a or are intolerant to interform therapy, and a substantial proportion of chronic hepatitis patients have contraindications to interferon (I FN) therapy due to severe depression, advanced liver disease, leukopenia, severe thrombocytopenia, active autoimmune diseases, and severe concomitant diseases.
  • I FN interferon
  • only patients with well compensated chronic hepatitis should be considered for IFN therapy because treatment may result in decompensation of liver disease.
  • ALT is a highly useful peripheral surrogate biochemical marker for the extent of inflammation in the liver. Numerous datasets from studies in chronic HBV patients demonstrate the strong association of treatment induced normalization of ALT with improved necro-inflammation based on liver histology using validated central pathology assessments.
  • LNF+RTV enhances the effects of PEG I FN-alfa-2a at suppressing HDV RNA levels over a 48-week course of treatment during the early phase of treatment. It also suggests that patients who are on LNF+RTV (oral) therapy may not sustain low levels of HDV RNA after 48 weeks of treatment.
  • liver histology improvement is of particular importance because analysis of liver histology is the most direct way to assess improvements in liver injury such as necrosis and inflammation, as well as scarring in the form of fibrosis. Liver necrosis and inflammation is measured by the HAI score and liver scarring is measured by the fibrosis score.
  • HAI score liver necrosis and inflammation is measured by the HAI score
  • liver scarring is measured by the fibrosis score.
  • Histologic response is defined as an improvement in Ishak modified histology activity index (HAI) score of > 2 points relative to baseline and no worsening of fibrosis score.
  • HAI histology activity index
  • the net proportion with improved fibrosis score is defined as the proportion of patients with improved fibrosis score relative to baseline minus the proportion of patients with worsened fibrosis score relative to baseline.
  • a disease as aggressive as hepatitis delta virus demonstrating improvement of HAI score and stabilization of fibrosis score may be predictive of improved long-term clinical outcomes such as time to decompensation, hepatocellular carcinoma, liver transplant, and liver related mortality.
  • This relationship of histologic response and long-term outcomes has been demonstrated in the lamivudine, entecavir, and tenofovir programs in HBV and may do so in chronic HDV as well.
  • the fact that the proportion of patients showing histologic improvement exceeded that which achieved the composite virologic and biochemical endpoint is positive. Thus, the full impact of this specific regimen may yet to be seen.
  • Non-invasive tests used for disease staging in other forms of viral hepatitis show suboptimal performance in chronic HDV.
  • TEAEs are treatment emergent adverse effects, defined as adverse effects with onset on or after the first dose date or onset prior to first dose date but with worsened grade on or after first dose date. Adverse effects without a severity rating reported on or after first dose date will be considered treatment-emergent.
  • TEAE's of special interest include the following categories: diarrhea, nausea, vomiting, fatigue, decreased appetite, weight loss, abdominal pain, anorexia, testicular toxicity, and ophthalmologic findings.
  • the post-treatment week 24 data discussed in this Example were obtained both from (1) the patients who stopped treatment before week 48 and were followed for 24 weeks after the treatment was stopped and (2) the patients who completed 48 weeks of treatment and were subsequently followed for 24 weeks to week 72 of the study. There were 338 such patients in total. Week 72 data were obtained from the patients who completed all 72 weeks of the study (312 patients).
  • ALT normalization at post-treatment week 4 was observed in 25.7% treated with the LNF + RTV regimen (p ⁇ 0.0001 vs placebo) and 38.5% of patients treated with the LNF + RTV + Alfa regimen (p ⁇ 0.0001).
  • Disease control (viral load ⁇ LLOQ (TD and TND) at post-treatment week 24) was achieved in 21.2% of patients with LNF + RTV + Alfa (p ⁇ 0.0001 vs placebo).
  • Alfa monotherapy response was 4.9%.
  • Forty-eight weeks of treatment with LNF + RTV + Alfa was associated with an improvement in liver histology; inflammation, necrosis, and fibrosis were reduced with treatment.
  • Ishak HAI and fibrosis scores decreased from baseline among those patients with a histologic response, compared with an increase among patients who did not achieve a response.
  • the study demonstrated significant improvement in histology in the LNF + RTV + Alfa treatment group. This is of particular importance because analysis of liver histology is the most direct way to assess improvements in liver injury such as necrosis and inflammation, as well as scarring in the form of fibrosis.
  • Alfa peginterferon alfa-2a
  • CMH Cochran-Mantal-Haenszel
  • HAI histology activity index
  • LNF lonafarnib
  • RTV ritonavir.
  • the Modified Ishak HAI Score is calculated on an 18-point scale and is the sum of individual scores in the following four domains: (1) periportal or periseptal interface hepatitis; (2) confluent necrosis; (3) focal spotty lytic necrosis, apoptosis and focal inflammation; and (4) portal inflammation.
  • Alfa peginterferon alfa-2a
  • CMH Cochran-Mantel-Haenszel
  • HAI histology activity index
  • LNF lonafarnib
  • RTV ritonavir.
  • Table 14 shows the number of patients in each treatment group who achieved either the composite primary endpoint, the virologic endpoint, or the biochemical endpoint, and also achieved a histologic response (denoted as n), relative to the number of patients achieving the clinical endpoint alone among patients with paired liver biopsies (denoted as N).
  • n histologic response
  • N paired liver biopsies
  • Alfa peginterferon alfa-2a
  • LNF lonafarnib
  • n number of patients achieving both the clinical endpoint and the histologic endpoint
  • N number of patients achieving the clinical endpoint
  • RTV ritonavir
  • Alfa peginterferon alfa-2a
  • HDV hepatitis Delta virus
  • RNA ribonucleic acid
  • LNF lonafarnib
  • n number of patients achieving both the clinical endpoint and the histologic endpoint
  • N number of patients achieving the clinical endpoint
  • RTV ritonavir.
  • the mean change in logic HDV RNA and mean change in Ishak HAI score have a statistically significant positive linear relationship: Pearson's coefficient 0.347, p ⁇ 0.0001.
  • the comparison of the mean change in HAI score in patients with evaluable histology from the LNF + RTV + Alfa treatment group who achieved biochemical response at week 48 (2.53) and those who did not ( .67) is statistically significant (p ⁇ 0.0001).
  • the mean change in the Ishak HAI score was -3.47 compared to -0.34 for patients who did not achieve a virologic response.
  • Biochemical response is defined as normalization of ALT at week 48.
  • Alfa peginterferon alfa-2a
  • ALT alanine aminotransferase
  • LNF lonafarnib
  • RTV ritonavir
  • Alfa peginterferon alfa-2a
  • HAI histology activity index
  • LNF lonafarnib
  • RNA ribonucleic acid
  • RTV ritonavir
  • the composite primary efficacy endpoint is a direct measure of HDV suppression.
  • the proportion of patients who achieved a response to the composite primary efficacy endpoint was greater at post-treatment week 24, compared to week 48, for both LNF-based regimens.
  • the posttreatment week 24 response rates were also highly significantly different compared to placebo:
  • Week 48 and post-treatment week 24 virologic response (> 2 logw decline in HDV RNA) for the 328 patients is shown in FIG. 19 and reflects the extent of treatment-related disease control at POSTTREATMENT WEEK 24.
  • the virologic response rates improved from 17.4% at week 48 to 21.5% posttreatment week 24 for the LNF + RTV group.
  • the estimated difference between LNF + RTV and placebo was 19.1%, (p ⁇ 0.0001) at post-treatment week 24.
  • the response rate was comparable between week 48 and post-treatment week 24.
  • the response rate for the LNF + RTV treatment group of 15.3% (p ⁇ 0.0001 compared to placebo) at POST-TREATMENT WEEK 24 was greater than that observed at week 48 (10.1%).
  • the virologic response rate ( ⁇ 2 logic reduction HDV RNA) at POST-TREATMENT WEEK 24 was 22.9% and 36.6% for the LNF + RTV and LNF + RTV + Alfa regimens, respectively.
  • 23.7% of patients treated with the LNF + RTV + Alfa regimen had a viral load ⁇ LLOQ (TD or TND); 11.8% of patients had viral load ⁇ LLOQ (TD) and 11.8% of patients with viral load ⁇ LLOQ (TND).
  • the virologic response rates 24 weeks post-treatment in conjunction with the proportions of patients who also achieved ALT normalization at the same timepoint are suggestive of disease control, and of potential long-term clinical consequence with respect to risk for liver-related morbidity and mortality.
  • Alfa peginterferon alfa-2a
  • LNF lonafarnib
  • N no response
  • POST-TREATMENT WEEK 24 post-treatment week 24
  • RTV ritonavir
  • Y yes response.
  • Alfa peginterferon alfa-2a
  • LNF lonafarnib
  • N no response
  • POST-TREATMENT WEEK 24 post-treatment week 24
  • RTV ritonavir
  • Y yes response.
  • Alfa peginterferon alfa-2a
  • LNF lonafarnib
  • N no
  • POST-TREATMENT WEEK 24 24- weeks post-treatment
  • Alfa peginterferon alfa-2a
  • LNF lonafarnib
  • N no
  • POST-TREATMENT WEEK 24 24- weeks post-treatment
  • RTV ritonavir
  • Y yes.
  • non-invasive markers of fibrosis (FibroScan) showed continued improvement in those patients who developed a post-treatment virologic response (N/Y).
  • N/Y post-treatment virologic response
  • the virologic response rates for > 2 logic decline in HDV RNA were 22.9% and 36.6% for LNF + RTV and LNF + RTV + Alfa regimens, respectively. These data illustrate the potential clinical benefit obtained when patients are compliant with a finite 48-week period of LNF- based therapy.
  • Example 8 Early on-Treatment Change in Viral Load Can Be Used as the Basis for a Response-Guided Approach to Therapy with LNF-Based Regimens
  • response-guided therapy can identify patients with a very low likelihood of achieving a clinical response as early as possible following the initiation of treatment with one of the LNF-based regimens, thereby minimizing exposure to ineffective therapy. Conversely, patients who continue treatment would have a higher effective response rate as patients with a low likelihood of achieving a response have been removed from the calculation.
  • On-treatment responses to therapy were examined for potential utility as a predictor for clinical responses, with the illustrative cases summarized below.
  • the on-treatment viral load kinetics of LNF-based therapy can distinguish between responders and non-responders at the week 48 end-of- study timepoint.
  • the potential utility of logio HDV RNA, as a predictive on-treatment biomarker for response to LNF-based therapy was explored using threshold analyses. The following thresholds were explored as examples of on-treatment measures of response at each timepoint from week 8 - week 24: a range of 1 logw HDV RNA decrease to a 3 logio HDV RNA decrease; and slope of change in log 10 HDV RNA.
  • PPV for treatment futility is defined as the proportion of patients that fail to achieve the required thresholds at the specified timepoint, and also fail to meet a clinical endpoint of interest at week 48 (null response).
  • the effective response rate is defined as the response rate for patients who remain on treatment and achieve a clinical response.
  • Application of an algorithm for identifying a null response increases the effective response rate compared to the overall study results for both the LNF + RTV and LNF + RTV + Alfa regimens.
  • Algorithm A Failure to achieve a > 2 logic HDV RNA reduction and a negative slope (continued decline) for 3 consecutive visits (timepoints).
  • a decline in HDV RNA starting at a visit 12 weeks after the initiation of treatment and continuing at visits 16 and 20 weeks after the initiation of treatment would be an example of a decline over 3 consecutive visits.
  • Another example might be a decline in HDV RNA starting at a visit 12 weeks after the initiation (start) of treatment and continuing at visits 18 and 22 weeks after initiation (start) of treatment.
  • Another example might be a decline in HDV RNA starting at a visit 16 weeks after the initiation (start) of treatment and continuing at visits 20 and 24 weeks after initiation (start) of treatment.
  • the time interval between visits may vary but is unlikely to be less than 4-weeks per current clinical practice.
  • Algorithm B Failure to achieve a > 2 logic HDV RNA reduction.
  • defining a clinical response based on a > 2 logic HDV RNA reduction and a negative slope (continued decline) for 3 consecutive visits (timepoints) yields higher effective response rates than defining a clinical response based on a > 2 logic HDV RNA reduction alone.
  • ALT alanine aminotransferase
  • HAI histology activity index
  • HDV hepatitis delta virus
  • LLOQ lower limit of quantitation
  • LNF lonafarnib
  • N/A not applicable
  • PPV positive predictive value
  • POST-TREATMENT WEEK 24 24 weeks post-treatment
  • RNA ribonucleic acid
  • RTV ritonavir
  • TD target detected
  • TND target not detected.
  • ALT alanine aminotransferase
  • HAI histology activity index
  • HDV hepatitis delta virus
  • LLOQ lower limit of quantitation
  • LNF lonafarnib
  • N/A not applicable
  • PPV positive predictive value
  • POST-TREATMENT WEEK 24 24 weeks post-treatment
  • RNA ribonucleic acid
  • RTV ritonavir
  • TD target detected
  • TND target not detected.
  • B Illustrative case 2 (Algorithm B)

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Abstract

Methods of treating a hepatitis delta virus (HDV) infection in a human subject are provided. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of lonafarnib and ritonavir with or without pegylated interferon alpha.

Description

METHODS TO TREAT HEPATITIS DELTA VIRAL INFECTIONS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63/386,496, filed December 7, 2022, and to U.S. Provisional Patent Application No. 63/386,661, filed December 8, 2022, the entire contents of each of which are incorporated by reference herein.
FIELD
[0002] The present invention provides methods for treating viral hepatitis resulting from hepatitis delta virus infection, and so relates to the fields of chemistry, medicinal chemistry, medicine, molecular biology, and pharmacology.
BACKGROUND
[0003] Hepatitis delta virus (HDV) infection is a deadly disease affecting more than 12 million people globally. See, Stockdale et al., J. of Hepatology, 2020, 73:523-32. Approximately half of the patients diagnosed with HDV infection have liver cirrhosis at the time of diagnosis. See, Nourredin et al., Curr. GasteroL Rep., 2014, 16:365.
[0004] HDV is a deficient virus that relies on another virus, hepatitis B virus (HBV), to supply envelope proteins for infectivity and propagation. Consequently, HBV is always present when HDV is present. Three HBV-encoded surface proteins (small, medium, and large HBsAgs) are each recruited onto the surface of HDV. A farnesylated form of the intracellular HDV-encoded large delta antigen (large HDAg) mediates interactions between HDV and the three HBV-encoded surface proteins. See, Glenn et al., 1992, Science, 256:1331-33; Otto and Casey, 1996, J. Biol. Chem., 271:4569-4572. Prenylation is required for this function of the large HDAg because studies have shown that specific mutation of the prenylated site on the large delta antigen prevents both prenylation and HDV particle formation. See, Glenn et al., 1998, J. Virol. 72:9303-06; Bordier et aL, 2002, J. Virol. 76:10465-10472.
[0005] Only about 5% of HBV carriers are also infected with HDV. However, HDV is associated with the most severe form of viral hepatitis, with 70% of patients progressing to liver cirrhosis within 5-10 years, compared to 20% of patients infected by HBV alone (within 5 years) and 10-20% of patients infected with HCV (within 20 years). Westbrook et al., J. Hepatology, 2014, 61:S58-S68; Fattovich et al., Seminars in Liver Diseases, 2003, 23:47-58; Nourredin et al., Curr. Gasterol. Rep., 2014, 16:365. HDV can also worsen preexisting HBV-related liver damage, leading to greater risk of developing liver cirrhosis, hepatic decomposition, and hepatocellular carcinoma. See, Negro, Cold Spring Harb. Perspect. Med., 2014, 4:a021550; Honer zu Siederdissen, Vise. Med., 2016, 32:86-94; Lau, Hepatology, 1999, 30:546-549.
[0006] Despite the availability of multiple, direct antiviral agents directed against HBV, such antiviral agents have not proven effective against HDV. Wedemeyer et al, 1999; Yurdaydin et al, 2002, J. of Hepatol. 37:266-71; Lau et al, 1999, Hepatology 30:546-49; Niro et al, 2006, Hepatology 44:713-20. There is currently no approved therapy for HDV infection. Therefore, there remains a significant unmet medical need for new drugs that can directly interfere with the life cycle of HDV.
BRIEF SUMMARY
[0007] In one aspect, provided herein is a method of treating hepatitis delta virus (HDV) infection in a patient, the method comprising administering to the patient a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor.
[0008] In a nother aspect, provided herein is a method of treating hepatitis delta virus (HDV) infection in a patient, comprising administering a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor at regular intervals as a chronic therapy.
[0009] In a nother aspect, provided herein is a method of reducing both the viral load and alanine aminotransferase (ALT) levels in a patient with hepatitis delta virus (HDV) infection, the method comprising administering to the patient a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1 shows a Phase 3 study schematic according to aspects of this disclosure. There were four treatment arms in the study: 1) 50 mg lonafarnib BID + 100 mg ritonavir BID ("oral"), 2) 50 mg lonafarnib BID + 100 mg ritonavir BID + 180 mcg PEG-IFN-alfa-2a QW ("combo"), 3) 180 mcg PEG- IFN-alfa-2a QW monotherapy, and 4) placebo. For each study arm, patients were treated for 48 weeks and further studied during a 24-week post-treatment period. The primary endpoint at 48 weeks was a composite of >2 log decline in HDV RNA and normalization of ALT. One secondary endpoint at week 48 was based on histological data measured as no worsening fibrosis and a >2- point change in Ishak HAI score.
[0011] FIG. 2 shows a flowchart of the baseline characteristics of patients who were screened and treated in the study shown in FIG. 1 according to aspects of this disclosure. [0012] FIG. 3 shows the percentage of patients in each study arm that achieved the primary endpoint of composite >2 log decline in HDV RNA and ALT normalization at week 48 according to aspects of this disclosure.
[0013] FIG. 4 shows the percentage of patients in each study arm that achieved >2 log decline in HDV RNA at week 48 according to aspects of this disclosure.
[0014] FIG. 5 shows the percentage of patients in each study arm that achieved alanine aminotransferase (ALT) normalization at week 48 according to aspects of this disclosure.
[0015] FIG. 6 shows the percentage of patients in each study arm that achieved HDV RNA levels below the lower limit of quantitation (BLQ or below LLOQ.)) at week 48 according to aspects of this disclosure.
[0016] FIG. 7 shows the mean decline in HDV RNA levels during the 48-week treatment period according to aspects of this disclosure.
[0017] FIG. 8 shows the mean decline in ALT normalization during the 48-week treatment period according to aspects of this disclosure.
[0018] FIG. 9 shows the primary endpoint of composite >2 log decline in HDV RNA and ALT normalization at week at the end of the follow-up period (week 72) according to aspects of this disclosure.
[0019] FIG. 10 shows the percentage of patients in each study arm that achieved >2 log decline in HDV RNA levels at the end of the follow-up period (week 72) according to aspects of this disclosure.
[0020] FIG. 11 shows the mean HDV RNA decline in each study arm during the treatment and follow-up period (72 weeks). Data regarding HDV RNA levels from week 48 to week 72 are only available for 211 patients according to aspects of this disclosure.
[0021] FIG. 12 shows the mean decline in ALT normalization in each study during the treatment and follow-up period (72 weeks). Data regarding ALT normalization from week 48 to week 72 are only available for 211 patients according to aspects of this disclosure.
[0022] FIG. 13 shows the percentage of patients in each study arm who achieve ALT normalization at the end of the follow-up period (week 72). Data is only shown for the 211 patients tested at week 72 according to aspects of this disclosure. [0023] FIG. 14 shows proportion of patients achieving composite > 2 logiodecline in HDV RNA plus ALT normalization at week 48. Abbreviations: Alfa = peginterferon alfa-2a; Cl = confidence interval; LNF = lonafarnib; RTV = ritonavir.
[0024] FIG. 15 shows proportion of patients achieving > 2 logiodecline in HDV RNA at week 48. Abbreviations: Alfa = peginterferon alfa-2a; LNF = lonafarnib; RTV = ritonavir.
[0025] FIG. 16 shows proportion of patients achieving ALT normalization at week 48. Abbreviations: Alfa = peginterferon alfa-2a; LNF = lonafarnib; RTV = ritonavir.
[0026] FIG. 17 shows proportion of patients achieving virologic response (both "target detected" and "target not detected") below the lower limit of quantitation (LLOQ) at week 48. Abbreviations: Alfa = peginterferon alfa-2a; LNF = lonafarnib; RTV = ritonavir.
[0027] FIGS. 18A-18B show the composite primary efficacy endpoint response in patients at week 48 and post-treatment week 24. FIG. 18A shows > 2 logiodecline in HDV RNA. FIG. 18B shows BLQ (below limit of quantitation) in HDV RNA. Abbreviations: Alfa = peginterferon alfa-2a;
LNF = lonafarnib; RTV = ritonavir.
[0028] FIG. 19 shows proportion of patients achieving > 2 logiodecline in HDV RNA in patients at week 48 and post-treatment week 24. Abbreviations: Alfa = peginterferon alfa-2a; LNF = lonafarnib; RTV = ritonavir.
[0029] FIG. 20 shows proportion of patients achieving virologic response (both "target detected" and "target not detected") below LLOQ at week 48 and post-treatment week 24. Abbreviations: Alfa = peginterferon alfa-2a; LNF = lonafarnib; RTV = ritonavir.
[0030] FIG. 21 shows proportion of patients achieving virologic response "target detected" below LLOQ at week 48 and post-treatment week 24. Abbreviations: Alfa = peginterferon alfa-2a;
LNF = lonafarnib; RTV = ritonavir.
[0031] FIG. 22 shows proportion of patients achieving ALT normalization at week 48 and posttreatment week 24. Abbreviations: Alfa = peginterferon alfa-2a; LNF = lonafarnib; RTV = ritonavir.
DETAILED DESCRIPTION
I. DEFINITIONS
[0032] The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In this specification and in the claims that follow, reference will be 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 with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not be construed as representing a substantial difference over the definition of the term as generally understood in the art.
[0033] Although any methods and materials 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 now described. All technical and patent publications cited herein are incorporated herein by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
[0034] All numerical designations, e.g., pH, temperature, time, concentration, and molecular weight, including ranges, are approximations which are varied by increments of plus or minus 0.1 or 1.0, as appropriate. It is to be understood, although not always explicitly stated that all numerical designations are preceded by the term "about."
[0035] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes one or more compounds, i.e., a plurality of compounds.
[0036] The term "administration" refers to introducing a compound, a composition, or an agent of the present disclosure into a host, such as a human. In the context of the present disclosure, preferred routes of administration of the agents are oral administration and subcutaneous administration. Other routes of administration include intravenous administration and oral administration.
[0037] The term "baseline," unless otherwise specified or apparent from context, refers to a measurement (of, e.g., viral load, subject condition, ALT level) made prior to the start of a course of therapy.
[0038] The term "comprising" is intended to mean that the compounds, compositions, and methods include the recited elements, but does not exclude others. "Consisting essentially of" when used to define compounds, compositions, and methods, shall mean excluding other elements that would materially affect the basic and novel characteristics of the claimed invention. Embodiments defined by each of these transition terms are within the scope of this invention. [0039] The terms "course of treatment" and "course of therapy" are used interchangeably herein and refer to the medical interventions made after a subject is diagnosed, e.g., as being infected with HDV and in need of medical intervention. Medical interventions include, without limitation, the administration of drugs for a period of time typical for HDV infected subjects, at least one month and typically several or many months or even years.
[0040] 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 amount of a 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 that of a dilution series of a quantified Hepatitis Delta RNA standard, and a copy number of genome copies is calculated. See, e.g., Kodani et al., 2013, J. Virol. Methods, 193:531-35; Karatayli et al., 2014, J. Clin. Virol, 60:11-15. HDV RNA viral load may be reported as RNA copies per mL serum (or plasma) or using International Units (IU) per mL serum (or plasma). See, Chudy et al., 2013, Collaborative Study to establish a World Health Organization International standard for hepatitis D virus RNA for nucleic acid amplification technique (NAT)-based assays." WHO Expert Committee on Biological Standardization WHO/BS/2013.2227. An assay for measuring HDV RNA viral load is commercially available from ARUP Laboratories (Salt Lake City, UT). The limit of detection for the ARUP HDV RNA assay has been reported to be 31 lU/mL. Analytik Jena AG (Germany) offers the RoboGene® HDV RNA Quantification Kit 2.0, which is CE-IVD certified with WHO standard references to assess the response to antiviral treatment. The limit of detection for the RoboGene® assay is reported to be 6 lU/mL. Reference to a "viral load" without specified units (e.g., "a viral load of less than 100") refers to copies of HDV RNA per mL serum, unless otherwise indicated or apparent from context. Unless otherwise specified, reference to "below the level of detection" means below 8 lU/mL.
[0041] HDV levels are generally presented using logio units. HDV RNA levels may be presented in units of "RNA copies per mL" or as "International Units (IU) per mL." See, Chudy et al., 2013, Collaborative Study to establish a World Health Organization International standard for hepatitis D virus RNA for nucleic acid amplification technique (NAT)-based assays." WHO Expert Committee on Biological Standardization WHO/BS/2013.2227. Both units are used in this specification. As used herein, recitation of "HDV RNA copies per mL," should be read, for purposes of written description or basis, as referring to "HDV RNA copies/mL or HDV lU/mL." Where a specific quantity of HDV RNA copies per mL is recited, a multiplier of 1.2 may be applied, for the purposes of written description and support, to convert the quantity of HDV RNA copies/mL to the quantity of lU/mL. For example, "120 HDV RNA copies per mL" should be read as "100 lU/mL or 120 copies/mL." Changes in HDV RNA levels may be represented as a "log reduction" following the normal conventions of virology.
[0042] The term "HDV infection" with respect to a human (host) refers to the fact that the host is suffering from HDV infection. Typically, an HDV infected human host will have a viral load of HDV RNA of at least about 2 logio HDV RNA copies/mL of host serum or plasma or 102 copies of HDV- RNA/mL of host serum or plasma, often at least about 3 log HDV RNA copies/mL of host serum or plasma or 103 copies of HDV-RNA/mL of host serum or plasma, and, often, especially for subjects not on any therapy, at least about 4 logio HDV RNA copies/mL of host serum or plasma or 104 copies of HDV-RNA/mL of host serum or plasma, such as about 4 logio HDV RNA copies/mL of host serum or plasma to 8 logio HDV RNA copies/mL of host serum or plasma or 104to 10s copies of HDV-RNA/mL of host serum or plasma. As used herein, the term "chronic HDV infection" with respect to a human host refers to an HDV infection that has persisted in the human host for at least 6 months, as documented by a positive HDV antibody (Ab) test and/or HDV RNA detectable by qRT-PCR. Diagnosis and pathogenesis of HDV is described, for example, in Wedemeyer et aL, Nat. Rev. Gastroenterol. Hepatol, 2010, 7:31-40.
[0043] "Composite virologic and biochemical response" is defined as a > 2 log10 reduction in HDV ribonucleic acid (RNA) level and alanine aminotransferase (ALT) normalization relative to baseline.
[0044] The term "lower limit of quantification" refers to the lowest concentration of a substance of analyte (e.g., a viral titer) that can be reliably quantified by a particular assay within a stated confidence limit.
[0045] The terms "subject," "host," or "patient," are used interchangeably and refer to a human infected with HDV, including subjects previously infected with HDV in whom virus has cleared.
[0046] A "sustained reduction" or "sustained decrease" of HDV viral load means a reduction of viral load (e.g., a decrease of at least 1.5 logio HDV RNA lU/mL serum, at least 2.0 logio HDV RNA copies/mL serum, or at least 2.5 logio HDV RNA lU/mL serum, or a decrease in HDV RNA to undetectable levels) for a period time (e.g., 1 month, 3 months, 6 months, 1 year or longer). The sustained reduction may be a period of time during which the course of treatment is still ongoing or a period of time after the course of treatment is finished. A "durable virologic response" occurs when HDV RNA below limit of quantification at 24 weeks post-treatment.
[0047] The term "therapeutically effective amount" as used herein refers to that amount of an embodiment of the agent (e.g., a compound, inhibitory agent, or drug) being administered that will treat to some extent a HDV or a disease, disorder, or condition related to HDV, e.g., relieve one or more of the symptoms of HDV or other disease, i.e., infection, being treated, and/or that amount that will prevent, to some extent, one or more of the symptoms of the HDV or the other disease, i.e., infection, that the subject being treated has or is at risk of developing.
[0048] The terms "treatment," "treating," and "treat" are defined as acting upon a disease, disorder, or condition with an agent to reduce or ameliorate the pharmacologic and/or physiologic effects of HDV or the disease, disorder, or condition and/or its symptoms. For example, "treatment" encompasses delivery of an agent, such as those disclosed herein, that provides for enhanced or desirable effects in the subject (e.g., reduction of viral load, reduction of disease symptoms, etc.). "Treatment," as used herein, covers any treatment of a disease in a human subject, and includes: (a) reducing the risk of occurrence of the disease, such as HDV, in a subject determined to be predisposed to the disease but not yet diagnosed as infected with the disease, (b) impeding the development of the disease, such as HDV, and/or (c) relieving the disease, such as HDV, i.e., causing regression of the disease and/or relieving one or more disease symptoms. "Treatment" is also meant to encompass delivery of an inhibiting agent to provide a pharmacologic effect, even in the absence of a disease or condition.
[0049] The terms "undetectable" or "below the level of detection" or "BLD" or "below the lower limit of quantitation" or "BLQ," as used with reference to HDV RNA levels, means that no HDV RNA copies can be detected by the assay methodology employed or that the RNA levels are below the lower limit of quantitation ("LLOQ"). In some embodiments, the assay is quantitative RT-PCR.
[0050] "Histologic response" is defined as an improvement in Ishak modified histology activity index (HAI) score ("fibrosis score") of > 2 points relative to baseline and no worsening of fibrosis score.
[0051] The "net proportion with improved fibrosis score" is defined as the proportion of patients with improved fibrosis score relative to baseline minus the proportion of patients with worsened fibrosis score relative to baseline.
[0052] The term "interferon alpha" as used herein includes naturally occurring interferon alpha (I FN-alpha); synthetic IFN-alpha; derivatized IFN-alpha (e.g., PEGylated I FN-alpha, glycosylated IFN- alpha, and the like); and analogs of naturally occurring or synthetic IFN-alpha. One example of interferon alpha is interferon alfa (INN) or ulFN-alpha-Le, a pharmaceutical drug composed of natural interferon alpha (IFN-a), obtained from the leukocyte fraction of human blood following induction with Sendai virus. In some embodiments, an IFN-alpha is a derivative of IFN-alpha that is derivatized (e.g., chemically modified relative to the naturally occurring peptide) to alter certain properties such as serum half-life. As such, the term "IFN-alpha" includes IFN-alpha derivatized with polyethylene glycol ("pegylated IFN-alpha" or "pegylated interferon alpha"), and the like. PEGylated IFN-alpha, and methods for making same are known. One example of pegylated interferon alpha is peginterferon alfa 2a (PEG IFN-alfa-2a or pegylated I FN-alfa-2a).
[0042] FibroScan® (Echosens, Waltham, Massachusetts) is a non-invasive ultrasound-based test that measures the pressure required to distend the liver (liver elasticity) and can be used to assess the extent of fibrosis. The scores are as follows: Fl: 2-7 KPa (little to no scarring); F2: 7.5-10 KPa (moderate scarring); F3: 10-14 KPa (sever scarring); F4: >14 KPa (cirrhosis).
II. METHODS OF TREATMENT
[0053] The present disclosure provides methods of treating hepatitis delta virus (HDV) infection. In one aspect, the method of treatment is useful for a patient that has a contraindication to interferon. In some embodiments, the methods comprise administering a therapeutically effective amount of lonafarnib and a CYP3A4 inhibitor (e.g., ritonavir or cobicistat). In some embodiments, the contraindication is at least one of severe depression, advanced liver disease, leukopenia, severe thrombocytopenia, active autoimmune disease, compensated chronic hepatitis, and/or a severe concomitant disease that precludes IFN therapy. The present disclosure also provides methods of identifying patients likely or not likely to respond to the methods of treatment provided in the present disclosure.
[0054] Lonafarnib ("LN F") is a small molecule prenyltransferase inhibitor that has been used to inhibit HDV particle assembly by blocking farnesyltransferase from attaching the 15-carbon farnesyl group onto the prenylation motif of the HDV large delta antigen (HDAg). Lonafarnib therapy for the treatment of HDV has been previously describes, for example, in US 2017/0042862, which is incorporated by reference herein. Previous clinical studies, however, have shown that 100 mg lonafarnib administered BID for 28 days did not reduce HDV viral load sufficiently to be developed as a therapeutic. See, WO 2017/079009. Furthermore, higher doses were poorly tolerated due to gastrointestinal-related adverse effects. Id.
[0055] In some embodiments, methods are provided for treating hepatitis delta virus (HDV) infection by administration of lonafarnib in combination with a CYP3A4 inhibitor. CYP3A4 is a member of the cytochrome P450 family of oxidizing enzymes. Cytochrome P450 is involved in the turnover of other molecules, including lonafarnib. In some embodiments, a CYP3A inhibitor, such as ritonavir ("RTV") or cobicistat is also co-administered. In some embodiments, the CYP3A inhibitor is ritonavir. In some embodiments, a CYP3A inhibitor, such as ritonavir, can boost serum levels of lonafarnib by preventing its degradation. Lonafarnib and ritonavir co-therapy has been previously described, for example, in WO 2015/168648 and in WO 2017/079009, which are incorporated by reference herein. [0056] In some embodiments, an interferon for use in a therapeutic method as described herein is a pegylated interferon alpha (e.g., pegylated I FN-a lfa-2a). Immune modulators such as interferons may be useful in treating HDV as both the direct cytotoxic effects of HDV and the host's immune response to HDV are known to contribute to the detrimental effects of HDV infection. Interferons are polypeptides that may inhibit viral replication and cellular proliferation and modulate immune response. Based on the type of receptor through which they signal, human interferons have been classified into three major types (Types I, II, and III). All type I IFNs bind to a specific cell surface receptor complex known as the IFN-alpha receptor (IFNAR) that consists of IFNAR1 and IFNAR2 chains. The type I interferons present in humans are IFN-alpha, IFN-beta, IFN-epsilon, and IFN- omega. To date, clinical studies with interferon alpha monotherapy have reported unsatisfactory anti-HDV effects. See, for example, Wedemeyer et al, Lancet Infectious Diseases, 2019.
A. Patient Population
[0057] In some embodiments, a subject to be treated with a therapy disclosed herein is a subject having an HDV infection, e.g., an acute HDV infection or a chronic HDV infection. In some embodiments, the subject to be treated has a chronic HDV infection of at least 6 months in duration as documented by a positive HDV antibody (Ab) test, and/or detectable HDV RNA by qRT-PCR. In some embodiments, a subject to be treated with a therapeutic method described herein is a subject having an acute HDV infection, e.g., a newly diagnosed HDV infection or a HDV infection otherwise believed not to have existed in the subject for more than six months. Diagnosis and pathogenesis of HDV is described, for example, in Wedemeyer et al., Nat. Rev. Gastroenterol. Hepatol, 2010, 7:31-40. HDV is known to exist in a variety of subtypes; the methods described herein are suitable for treating all HDV subjects, regardless of HDV subtype. In some embodiments, the subject is an adult (18 years or older), and in other embodiments, the subject is pediatric.
[0058] In some embodiments, the HDV viral load of the subject is >2 log™ above the lower limit of quantification (LLOQ.) of the HDV RNA assay. In some embodiments, the viral load is measured at three pre-treatment points with a mean viral load of >2 logi0 above the LLOQ, of the HDV RNA assay.
[0059] There are multiple variants of both HBV and HDV in populations. Genotype 1 is widely distributed around the world, and genotype 3 is associated with more severe liver disease. See, Shirvani-Dastgerdi and Tacke, 2015, 4:36-41. In some embodiments, the patient is infected with a genotype 1 virus.
[0060] In some embodiments, a subject to be treated has a baseline viral load of at least 102 HDV RNA copies per mL serum or plasma or at least 102 HDV RNA lU/mL serum or plasma, e.g., at least 103 HDV RNA copies per mL or at least 103 HDV RNA lU/mL serum or plasma, at least 104 HDV RNA copies per mL or at least 104 HDV RNA lU/mL serum or plasma, at least 105 HDV RNA copies per mL or at least 105 HDV RNA lU/mL serum or plasma, at least 106 HDV RNA copies per mL or at least 106 HDV RNA ID/mL serum or plasma, at least 107 HDV RNA copies per mL or at least 107 HDV RNA lU/mL serum or plasma, or at least 108 HDV RNA copies per mL or at least 108 HDV RNA lU/mL serum or plasma. In some embodiments, HDV viral load is measured using serum samples from the subject. In some embodiments, HDV viral load is measured using plasma samples from the subject. In some embodiments, viral load is measured by quantitative RT-PCR. qRT-PCR assays for quantification of HDV RNA in serum or plasma are known in the art, e.g., as described above. In some embodiments, a subject to be treated has a baseline viral load that is up to about 104 HDV RNA copies per mL serum or plasma or up to about 104 HDV RNA l U/mL serum or plasma. In some embodiments, a subject to be treated has a baseline viral load that is up to about 105 HDV RNA copies per mL serum or plasma and/or up to about 105 HDV RNA lU/mL serum or plasma. In some embodiments, a subject to be treated has a baseline viral load that is up to about 10s HDV RNA copies per mL serum or plasma and/or up to about 10G HDV RNA lU/mL serum or plasma.
[0061] In some embodiments, HDV viral load is measured using serum samples from the subject. In some embodiments, HDV viral load is measured using plasma samples from the subject. In some embodiments, viral load is measured by quantitative RT-PCR. qRT-PCR assays for quantification of HDV RNA in serum or plasma are known in the art, e.g., as described above.
[0062] In some embodiments, a subject to be treated has one or more of: the presence of a nti- HDV in serum; presence of quantifiable HDV RNA in serum at three time pre-treatment points with a mean HDV RNA level greater than 2 logio above the LLOQ. of the HDV RNA assay; the demonstration of chronicity as evidenced by the presence of HDV RNA in serum for at least 6 months; or presence of anti-HDV antibody for at least 6 months.
[0063] In some embodiments, a subject to be treated exhibits one or more symptoms of liver dysfunction. In some embodiments, the subject exhibits one or more liver function parameters that are outside the normal parameters for a healthy control (e.g., a subject that is not infected with HDV and/or HBV). In some embodiments, the liver function parameter is selected from the group consisting of serum albumin, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and prothrombin activity. In some embodiments, the subject has a serum ALT level that is at least two-fold higher than the upper limit of normal (ULN) (e.g., at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 10-fold or higher than the ULN). Liver function parameters are described in the art. See, e.g., Limdi et al., Postgrad Med J, 2003, 79:307-312. Methods of measuring these liver function parameters are known in the art. [0064] In some embodiments, the subject has compensated liver disease (e.g., as classified according to the Child-Turcotte-Pugh Classification System) with or without liver cirrhosis. It will be recognized by a person of ordinary skill in the art that the Child-Turcotte-Pugh Classification System is used to classify the severity of liver disease and is determined by assessing serum albumin levels, bilirubin levels, international normalized ratio of prothrombin time levels, ascites formation, and encephalopathy. In some embodiments, the subject has a Child-Turcotte-Pugh score of 5-6 (class A). In some embodiments, the subject has a Child-Turcotte-Pugh score of 1-6. In some embodiments, the subject has a Child-Turcotte-Pugh score of a sub-range of 1-6, e.g., 1-2, 1-3, 2-4, 3-4, 2-5, 3-5, or 2-6. In some embodiments, the subject has compensated liver disease with liver cirrhosis. In some embodiments, the subject has compensated liver disease without liver cirrhosis.
[0065] In some embodiments, the subject is diagnosed with chronic hepatitis as determined by, for example, one or more of: a liver biopsy, a liver function test, an ultrasound, a hepatic venous pressure gradient (HVPG) measurement, an ALT level, one or more other blood tests, or an albumin level. In some embodiments, the biopsy is conducted within the 6 months before the initiation of treatment. In some embodiments, the biopsy is conducted within the 18 months before the initiation of treatment, according to the methods provided herein. In some embodiments, the biopsy is conducted within the 1 day to 24 months before the initiation of treatment. In some embodiments, the subject has evidence of chronic hepatitis based on a liver biopsy within 6 months before screening. In some embodiments, the subject has a serum alanine aminotransferase (ALT) level that is above the upper limit of normal (ULN) within 24 weeks prior to treatment and/or at the initiation of treatment, within 24 months prior to the initiation of treatment, from 24 months to 1 month prior to the initiation of treatment, or from 12 months to 1 day prior to the initiation of treatment. In various embodiments, the subject meets one or more independently selected criteria in Example 1.
[0066] In some embodiments the subject exhibits > 2 logiodecline in HDV RNA levels at about 12 weeks of treatment according to the methods of the present disclosure. In some embodiments, the subject exhibits a decline in HDV RNA levels starting at a first timepoint after the start of the treatment, the decline continuing through at least two additional successive timepoints of the treatment according to the methods of the present disclosure. The at least two additional successive timepoints can be referred to as "second timepoint" and "third timepoint", respectively. The interval between the start of the treatment and the first timepoint maybe referred to as "first interval." The interval between the first timepoint and the second timepoint may be referred to as "second interval." The interval between the second timepoint and the third timepoint may be referred to as "third interval." The durations of the first interval, the second interval, and the third interval may vary. In some embodiments, the duration of the first interval may be at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, or at least 20 weeks. In some embodiments, the duration of the second interval may be at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks. In some embodiments, the duration of the third interval may be at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks. In an exemplary embodiment, the subject exhibits a decline in HDV RNA levels, in comparison to timepoint at or before the start of the treatment, at the timepoint of 12 weeks after the start of the treatment (first timepoint). The subject then exhibits continued decline in HDV RNA levels at the timepoint of 18 weeks (second timepoint) after the start of the treatment and 22 weeks (third timepoint) after the treatment. In another exemplary embodiment, the subject exhibits a decline in HDV RNA levels, in comparison to timepoint at or before the start of the treatment, at the timepoint of 16 weeks after the start of the treatment (first timepoint). The subject then exhibits continued decline in HDV RNA levels at the timepoint of 20 weeks (second timepoint) after the start of the treatment and 24 weeks (third timepoint) after the treatment.
B. Dosages
[0067] In some embodiments the patient receiving lonafarnib-ritonavir co-therapy receives lonafarnib at a daily dose of 50 mg/day to 150 mg/day, or at a daily dose of 50 mg/day to 100 mg/day, for example, 25 mg/day, 50 mg/day, 75 mg/day, or 100 mg/day, preferably wherein each administration of lonafarnib is no more than 75 mg, e.g., 25 mg or 50 mg; and ritonavir is at a daily dose of 100 mg/day - 200 mg/day, preferably wherein each administration of ritonavir is no more than 100 mg.
[0068] In some embodiments, the patient may receive 75 mg lonafarnib BID and 100 mg ritonavir BID. In some embodiments, the patient may receive 50 mg lonafarnib BID and 100 mg ritonavir BID, or 25 mg lonafarnib BID and 100 mg ritonavir BID, or 75 mg lonafarnib BID and 100 mg ritonavir QD. In some embodiments, the patient receives a daily dose of 100 mg lonafarnib and 200 mg ritonavir. For example, the patient may receive 50 mg lonafarnib BID and 100 mg ritonavir BID. In some embodiments, the patient receives a daily dose of 75 mg lonafarnib and 100 mg ritonavir. For example, the patient may receive 75 mg lonafarnib Q.D and 100 mg ritonavir Q.D. In some embodiments, the patient receives a daily dose of 50 mg lonafarnib and 100 mg ritonavir. For example, the patient may receive 50 mg lonafarnib Q.D and 100 mg ritonavir Q.D. In some embodiments, the patient receives a daily dose of 50 mg lonafarnib and 200 mg ritonavir. For example, the patient may receive 25 mg lonafarnib BID and 100 mg ritonavir BID.
[0069] In some embodiments, the therapeutic approaches disclosed herein comprise administering lonafarnib at a first dose followed by administering lonafarnib at a second dose, wherein the second dose is lower than the first dose. In some embodiments, the therapeutic approaches disclosed herein comprise an escalating dosage regimen comprising administering lonafarnib at a first dose for a first treatment period and then administering lonafarnib at a second dose that is higher than the first dose for a second treatment period. In some embodiments, the patient receives lonafarnib at a first dose of 25 mg BID for the first treatment period followed by lonafarnib at a second dose of 50 mg BID for the second treatment period. In some embodiments, the therapeutic approach comprises administering the lonafarnib at a first dose for a first treatment period and then administering lonafarnib at a second dose that is higher than the first dose for a second treatment period if the patient does not experiences unacceptable gastrointestinal side effects during the first treatment period, or administering the lonafarnib at a first dose for a first treatment period and then administering lonafarnib at a second dose that is lower than the first dose for a second treatment period if the patient experiences unacceptable gastrointestinal side effects during the first treatment period.
[0070] A hepatitis flare is an increase in liver inflammation, sometimes detected as an increase in ALT levels so also called an ALT flare. It typically occurs due to the changes in the immune system's response to hepatitis B infection and precedes a decrease in virus levels. See, e.g., Ghany et al.
(2020) Serum Alanine Aminotransferase Flares in Chronic Hepatitis B: The Good and The Bad, Lancet Gastroenterol. Hepatol., 5:406-17. In another aspect, methods for inducing immune reactivation in a patient infected with HDV and HBV are provided. In some embodiments, the method comprises administering lonafarnib at a total daily dose in the range of 50 mg to 150 mg for at least 12 weeks and/or until a hepatitis flare is observed. In some embodiments, the hepatitis flare is accompanied by a transient increase in the patient's HBV viral load. In some embodiments, the method comprises administering lonafarnib-ritonavir co-therapy in which ritonavir is administered at a total daily dose of 100-200 mg. Following immune reactivation, HDV viral load may be reduced by at least 2 logio, by at least 3 logic, or reduced to an undetectable level.
[0071] In one embodiment, inducing immune reactivation in a patient infected with HDV and HBV involves administering lonafarnib at a first dose followed by administering lonafarnib at a second dose, wherein the second dose is lower than the first dose. For example, in some cases the first dose is administered for at least 8 weeks and the second dose is administered for at least 2 weeks, and optionally at least 4 weeks. In some cases, the first dose of lonafarnib is 50 mg BID and the second dose of lonafarnib is 50 mg QD. In some cases, the first dose of lonafarnib and the second dose of lonafarnib are administered in combination with ritonavir at a dose of 100 mg BID.
[0072] In some embodiments, in the treatment methods described herein, the lonafarnib and the ritonavir are administered together in a single unit dose form, but in other embodiments, they are administered in two separate, single unit dosage forms, i.e., a unit dosage form comprising lonafarnib and a unit dosage form comprising ritonavir. In some embodiments, the unit dose form comprises amorphous lonafarnib. In some embodiments, the unit dose form comprises lonafarnib (e.g., amorphous lonafarnib), ritonavir, and a copolymer. In some embodiments, the co-polymer is povidone.
[0073] In some embodiments, in the treatment methods described herein, the lonafarnib and the ritonavir are administered at about the same time as separate unit dose forms.
[0074] In some embodiments, in the treatment methods described herein, the lonafarnib and the ritonavir are administered together in a liquid formulation containing both lonafarnib and ritonavir.
[0075] In some embodiments, the method comprises treating the patient with lonafarnib, ritonavir, and an interferon (e.g., unpegylated or pegylated interferon alpha or interferon lambda). In some embodiments, the method comprises treating the patient with lonafarnib-ritonavir cotherapy for at least 30 days, wherein the patient has a baseline viral load of at least 105 lU/mL serum before the initiation of treatment, and treatment results in a reduction of viral load to less than 103 lU/mL serum.
[0076] In some embodiments, the lonafarnib component of the therapy is administered at a total daily dose of 50-200 mg per day, e.g., at least 50 mg per day, at least 75 mg per day, at least 100 mg per day, at least 150 mg per day, or at least 200 mg per day. Lonafarnib therapy may be administered once daily (Q.D) or twice daily (BID). In some embodiments, lonafarnib is administered at a dose of 25 mg BID, 50 mg BID, 75 mg BID, 100 mg BID, 50 mg QD, 75 mg QD, or 100 mg QD. In some embodiments, lonafarnib therapy is initiated at the start of interferon alpha therapy or, alternatively, during the course of interferon alpha therapy.
[0077] In some embodiments, the lonafarnib-ritonavir portion of the therapy is at a total daily dose of 50-200 mg of lonafarnib per day (e.g., at least 50 mg per day, at least 75 mg per day, at least 100 mg per day, at least 150 mg per day, or at least 200 mg per day of lonafarnib) and 100-200 mg of ritonavir per day (e.g., at least 100 mg per day, at least 150 mg per day, or at least 200 mg per day of ritonavir). The lonafarnib and ritonavir portion of the therapy may be administered once daily (QD) or twice daily (BID). In some embodiments, the lonafarnib is at a dose of 25 mg BID, 50 mg BID, 75 mg BID, 100 mg BID, 50 mg QD, 75 mg QD, or 100 mg QD, and the ritonavir at a dose of 50 mg BID or 100 mg BID.
[0078] In some embodiments, interferon alpha, lonafarnib, and ritonavir therapy comprises administering to the subject interferon alpha (e.g., pegylated interferon alpha-2a) at a dose of 180 micrograms (mcg) per week, lonafarnib at a dose of 50 mg twice daily (BID), and ritonavir at a dose of 100 mg BID. In one embodiment, the subject is administered interferon alpha at about 200 mcg to about 100 mcg QD, lonafarnib at from about 25 mg to about 50 mg BID, and ritonavir from about 50 mg to about 150 mg BID.
[0079] In some embodiments, interferon alpha, lonafarnib, and ritonavir therapy comprises administering to the subject interferon alpha at a dose of 120-180 mcg per week, lonafarnib at a dose of 50 mg BID, and ritonavir at a dose of 100 mg BID.
[0080] In some embodiments, the interferon alpha is administered at 120 mcg per week, 110 mcg per week, 100 mcg per week, 90 mcg per week, 80 mcg per week, 120 - 70 mcg per week, 200 - 120 mcg per week, or 170 - 130 mcg per week. In some embodiments, interferon alpha is administered at a dose of 180 mcg QW. In some embodiments, interferon alpha is administered at a dose of 90 mcg two times per week. In some embodiments, interferon alpha is administered at a dose of 90 mcg every 3 - 4 days. In some embodiments, interferon alpha is administered at a dose of 80 mcg two times per week. In some embodiments, interferon alpha is administered at a dose of 80 mcg every 3 - 4 days. In some embodiments, interferon alpha is administered at a dose of 100 - 70 mcg two times per week. In some embodiments, interferon alpha is administered at a dose of 100 - 70 mcg every 3 - 4 days. In some embodiments, interferon alpha is administered at a dose of 120 mcg QW. In some embodiments, interferon alpha is administered at a dose of 80 mcg QW.
[0081] In some embodiments, a subject being treated for HDV infection receives an adjustment in the dosing regimen of the interferon alpha and/or lonafarnib components during the course of treatment. In some embodiments, the subject receives a dose reduction of interferon alpha and/or lonafarnib, in that one or more later doses is a lower dose than one or more earlier doses. In some embodiments, a dose is reduced if the subject exhibits unacceptable side effects. In some embodiments, a subject may receive multiple dose reductions during the course of treatment with interferon alpha, lonafarnib, and ritonavir. In some embodiments, the dosage administered to the subject is not reduced before 8 weeks of treatment at the first dosage (e.g., at a first dosage of 180 mcg QW), or before 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or 7 weeks of treatment at the first dosage. In some embodiments, the dosage administered to the subject is not reduced before 9 - 12 weeks of treatment at the first dosage (e.g., at a first dosage of 180 mcg QW). The Ion afa rn ib dose may be reduced at the same time (or times) as the interferon alpha dose, and/or the lonafarnib dose may be reduced at different times from the interferon alpha dose. In some embodiments, the dose of interferon alpha is reduced, and the dose of the lonafarnib is not reduced. In some embodiments, the dose of lonafarnib is reduced and the dose of interferon alpha is not reduced.
[0082] In some embodiments, the interferon alpha, lonafarnib, and ritonavir therapy comprises administering to the subject interferon alpha at a first interferon alpha dose (e.g., 180 micrograms per week) and lonafarnib at a first lonafarnib dose (e.g., 50 mg BID) for a first treatment period, followed by administering to the subject interferon alpha at a second interferon alpha dose (e.g., 120 micrograms per week) and lonafarnib at a second lonafarnib dose (e.g., 25 mg BID) for a second treatment period. In some embodiments, the length of time for the first treatment period is the same as the length of time for the second treatment period. In some embodiments, the ritonavir dose remains the same in both treatment periods.
[0083] In some embodiments, the first treatment period and the second treatment period are different lengths of time. In some embodiments, the first treatment period is longer than the second treatment period. In some embodiments, the second treatment period is longer than the first treatment period.
[0084] The doses proposed in this study were selected based on safety and efficacy data derived from the LNF program to date. Due to the robust reductions observed in HDV RNA, as well as alanine aminotransferase (ALT) normalization through 24 weeks of dosing in Study EIG-300, the LNF 50 mg + RTV 100 mg BID and LNF 50 mg + RTV 100 mg BID + PEG I FN-alfa-2a 180 mcg QW regimens emerged as those of greatest potential utility.
[0085] In Study EIG-300, LNF doses ranging from 25 mg BID to 300 mg BID, with and without RTV (once daily [QD]/BID), with and without 180 mcg QW PEG I FN-alfa-2a, were explored. The most commonly observed safety findings were consistent with the chronic hepatitis indication being studied and with the previously reported Gl effects of LNF, which included nausea, vomiting, and diarrhea. The frequency and severity of these Gl complaints as well as the frequency of dose reductions and discontinuations were dose-related (i.e., most prominent at doses > 75 mg BID) and occurred less frequently with the lower doses of 25 mg and 50 mg BID.
[0086] Efficacy data from this study showed a statistically significant difference in viral load response of the LNF 50 mg BID + RTV 100 mg BID group as compared to the LNF 25 mg BID + RTV 100 mg BID group. The addition of PEG I FN-alfa-2a to either LN F 25 mg BID + RTV 100 mg BID or LNF 50 mg BID + RTV 100 mg BID therapy resulted in a significant difference in virologic response as compared to the corresponding all-oral therapies.
[0087] While the LNF 25 mg + RTV 100 mg BID regimen was less efficacious than the LNF 50 mg + RTV 100 mg BID regimen, notable HDV RNA reduction was observed in this regimen, which supports dose reductions of the LNF 50 mg + RTV 100 mg BID regimen to LNF 25 mg + RTV 100 mg BID regimen.
[0088] Therefore, based on the collective evidence of safety, efficacy/pharmacodynamics (PD), and PK from Study EIG-300, the LNF 50 mg + RTV 100 mg BID and LNF 50 mg + RTV 100 mg BID + PEG IFN-alfa-2a regimens, with the option to dose reduce LNF, were selected for this Phase 3 study.
C. Duration of Treatment and Treatment Endpoints
[0089] Subjects may receive lonafarnib, ritonavir, and optionally interferon alpha, therapy for a predetermined time, until not tolerated, or until an endpoint is reached.
[0090] In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least 30 days. In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least 60 days. In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least 90 days. In some embodiments, the patient is treated with lonafarnib-ritonavir co- therapy for at least 180 days. In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least one year. In some embodiments, the patient is treated with lonafarnib- ritonavir co-therapy for at least 4 weeks. In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least 8 weeks. In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least 12 weeks. In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least 24 weeks. In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least 48 weeks. In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least 60 weeks. In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least 72 weeks. In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least 84 weeks.
[0091] In some embodiments, the interferon, lonafarnib, and ritonavir therapy is continued for at least 30 days, e.g., at least 60 days, at least 90 days, at least 120 days, at least 150 days, or at least 180 days. In some embodiments, the interferon, lonafarnib, and ritonavir treatment is continued for at least 6 months, e.g., at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least one year, at least 15 months, at least 18 months, or at least 2 years. In some embodiments, the interferon, lonafarnib, and ritonavir is continued for at least 6 weeks, e.g., at least 12 weeks, at least 18 weeks, at least 24 weeks, at least 30 weeks, at least 36 weeks, at least 42 weeks, at least 48 weeks, at least 60 weeks, at least 72 weeks, at least 84 weeks, or at least 96 weeks. In other embodiments, the interferon, lonafarnib, and ritonavir therapy is continued for the remainder of the subject's life or until administration is no longer needed or no longer effective in maintaining the virus at a sufficiently low level to provide meaningful therapeutic benefit.
[0092] In accordance with the methods herein, some HDV subjects will respond to a therapy, as described herein, by clearing virus to undetectable levels. In some embodiments, for subjects in which HDV RNA levels are below the level of detection, treatment is suspended unless and until the HDV levels return to detectable levels. Other subjects will experience a reduction in viral load and improvement of symptoms but will not clear the virus to undetectable levels and will remain on therapy for a defined period of time (e.g., for about 1 year, about 2 years, about 3 years, or longer) or so long as the therapy provides therapeutic benefit.
[0093] In some embodiments, treatment with interferon alpha, lonafarnib, and ritonavir therapy results in a reduction of HDV viral load in the subject of at least 1.5 log™ HDV RNA copies/mL serum when measured after 24 weeks of treatment. In some embodiments, treatment with interferon alpha, lonafarnib, and ritonavir therapy results in a reduction of HDV viral load in the subject of at least 2.0 logio HDV RNA copies/mL serum when measured after 24 or 48 weeks of treatment. In some embodiments, a therapy described herein results in a reduction of HDV viral load in the subject of at least 2.5 log™ HDV RNA copies/mL serum when measured after 24 weeks of treatment.
[0094] In some embodiments, treatment with a therapy described herein results in a sustained reduction of HDV viral load (e.g., a decrease of at least 1.5 logio HDV RNA lU/mL serum, at least 2.0 logio HDV RNA copies/mL serum, or at least 2.5 logio HDV RNA lU/mL serum, or a decrease in HDV RNA to undetectable levels) that is sustained for a period of time (e.g., 1 month, 3 months, 6 months, 1 year or longer) while the course of treatment is still ongoing. In some embodiments, treatment with interferon alpha, lonafarnib, and ritonavir therapy results in a sustained reduction of HDV viral load that is sustained for a period of time (e.g., 1 month, 3 months, 6 months, 1 year or longer) after the course of treatment is finished. In some embodiments, the interferon alpha, lonafarnib, and ritonavir therapy results in HDV RNA levels (e.g., serum HDV RNA levels or plasma HDV RNA levels) below 1,000 copies/mL. In some embodiments, the HDV RNA levels remain below 1,000 copies/mL for at least one month, e.g., at least three months, at least one year, or longer. In some embodiments, the course of treatment results in HDV RNA levels (e.g., serum HDV RNA levels or plasma HDV RNA levels) below 100 copies/mL. In some embodiments, the HDV RNA levels remain below 100 copies/mL for at least one month, at least three months, at least one year, or longer. The phrase "remains below" refers to remaining below an initial measured value (e.g., 100 copies/mL or 100 lU/mL) for a period of time, for example, at 1 month (or another specified time) a viral load measurement taken at least 1 month (or at the other specified time) after determination of the initial measured value is no higher than the initial value. In some embodiments, the subject does not receive interferon alpha therapy during the specified time. In some embodiments, the subject does not receive any anti-HDV treatment during the specified time.
[0095] In some embodiments, therapy as disclosed herein is continued for a period of time until HDV RNA levels are below 3 logic HDV RNA copies/mL (below 1,000 copies/mL), or sometimes until HDV RNA levels are below 2 logic HDV RNA copies/mL (below 100 copies/mL) or below the level of detection. In some embodiments, therapy is continued for a period of time (such as 1 to 3 months or longer) after viral load has dropped to acceptably low levels (e.g., undetectable levels). In some embodiments, therapy is continued until the HDV viral load is reduced to undetectable levels.
[0096] In some embodiments, a subject treated according to the methods described herein exhibits a reduction in HDV viral load to undetectable levels during the course of treatment, and the subject maintains the reduction in HDV viral load to undetectable levels for at least 12 weeks after the end of treatment. In some embodiments, a subject treated according to the methods described herein exhibits a reduction in HDV viral load to undetectable levels during the course of treatment, and the subject maintains the reduction in HDV viral load to undetectable levels for at least 24 weeks after the end of treatment.
[0097] In some embodiments, the subject's HDV titer rises from baseline prior to dropping below baseline during the course of treatment. In some embodiments, the subject's HDV level rises to more than 150% of baseline, or more than 200% of baseline. In some embodiments, the rise in the titer is from 25 - 50% of baseline, from 25 - 100% of baseline, or from 50 - 200% of baseline. In some embodiments, the rise in the titer occurs within 2 weeks after initiation of therapy. In some embodiments, the subject's elevated HDV titer drops to below baseline within 2 weeks, or within 3 weeks, of initiation of therapy.
[0098] In some embodiments, a subject treated according to the methods described herein exhibits an improvement in one or more liver function parameters. In some embodiments, the improved liver function is an 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, alfa2-macroglobulin, apolipoprotein Al, haptoglobin, gamma-glutamyl transpeptidase (GGT). In some embodiments, a subject treated according to the methods described herein exhibits an improvement in liver fibrosis (e.g., as assessed by biopsy with histological analysis, transient ultrasound elastography (e.g., FibroScan®), or magnetic resonance elastography). In some embodiments, treatment results in an improvement of at least 5%, e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 70%, at least 75%, at least 80%, or at least 100%, or between 5 - 50%, between 10 - 80%, or between 50 - 100% improvement in one or more liver function parameters (e.g., an improvement in serum marker(s) or an improvement in liver fibrosis) in the subject as compared to prior to the initiation of treatment. In some embodiments, treatment results in an improvement in one or more liver function parameters (e.g., an improvement in serum marker(s) or an improvement in liver fibrosis) to the level of a healthy control subject that is not infected with HDV or HBV. In some embodiments, the subject exhibits an improvement in serum ALT levels to a level that is within the upper limit of normal.
[0099] In some embodiments, the subject treated according to the methods described herein has an improved histologic response. Histologic response is herein defined as an improvement in Ishak modified histology activity index (HAI) after 48 weeks of treatment. In some embodiments, the HAI is >2 points relative to baseline.
[0100] In some embodiments, a subject treated according to the methods described herein exhibits a reduction in HBV viral load compared to the baseline level at the initiation of treatment and/or compared to a similarly infected subject not receiving treatment effective to reduce the subject's HDV viral load. In some embodiments, treatment results in a reduction of at least 1 logio in HBV viral load.
[0101] Prior to treatment, the subject's HDV and/or HBV viral load is measured to determine the baseline viral load. After a period of treatment (e.g., after 12, after 24, or after 48 weeks of treatment), the subject's viral load is reduced compared to baseline. In some embodiments, after a period of treatment (e.g., after 12, after 24, or after 48 weeks of treatment), the subject's viral load is substantially reduced compared to baseline, such as to very low levels or to an undetectable level. In some embodiments, treatment results in an at least 2 logio reduction of HBV viral load. In some embodiments, subjects treated according to the methods described herein exhibit a reduction in HBsAg levels or an improvement in clearance of HBsAg antigen. Prior to treatment the subject's HBsAg level is measured to determine a baseline. After a period of treatment (e.g., after 12, after 24, or after 48 weeks of treatment), the subject's HBsAg level is reduced compared to baseline. In some embodiments, subjects treated according to the methods described herein exhibits the presence of anti-HBs antibody. [0102] Subjects treated according to the methods described herein according to the present disclosure may also be treated with one or more other antiviral agents such as nucleoside and nucleotide analogs, compounds used to treat HBV infections, and other agents.
[0103] In some embodiments, a subject who is treated according to the methods described herein is treated with an antiviral agent that is used for the treatment of HBV. Anti-HBV medications that are currently approved with the exception of interferons, inhibit reverse transcriptase and are nucleoside or nucleotide analogs. These medications, while effective against HBV DNA, are not effective against HDV as they do not clear HBsAg, which HDV needs to replicate. Currently approved anti-HBV nucleoside/nucleotide analogs include lamivudine (Epivir-HBV®, Zeffix®, or Heptodin®), adefovir dipivoxil (Hepsera®), entecavir (Baraclude®), telbivudine (Tyzeka® or Sebivo®), clevudine (Korea/Asia), tenofovir (Viread® or Vemlidy®). In some embodiments, a subject who is administered interferon alpha therapy is also administered a nucleoside or nucleotide analogs including, but not limited to, lamuvidine, adefovir, telbivudine, entecavir, tenofovir, or clevudine. In some embodiments, the subject is receiving nucleoside or nucleotide analog therapy prior to the onset of interferon alpha therapy. In some embodiments, nucleoside or nucleotide analog therapy is initiated at the start of interferon alpha therapy or during the course of interferon alpha therapy with lonafarnib and ritonavir.
[0104] In some embodiments, a subject who is treated according to the methods described herein exhibits improvements in liver histology after the start of the treatment. In some embodiments, a subject who is treated according to the methods described herein exhibits a reduction in one or more of liver inflammation, liver necrosis, or liver fibrosis. In some embodiments, a subject who is treated according to the methods described herein exhibits improvements in liver histology after the start of the treatment and a reduction in one or more of liver inflammation, liver necrosis, or liver fibrosis. In some embodiments, the subject exhibits the above responses within 4, 8, 12, 24, 36, or 48 weeks of treatment. In some embodiments, the improvement of liver histology may be assessed as > 2-point improvement in Ishak HAI and no worsening of fibrosis by Ishak scoring.
[0105] In some embodiments, a subject who is treated according to the methods described herein, after completion of the treatment, exhibits one or more of following responses: further decline in HDV RNA levels, further decline in alanine aminotransferase (ALT) levels, further improvement of the liver histology, or further reduction in the one or more of liver inflammation, liver necrosis, or liver fibrosis. In some embodiments, the above one or more of the responses are observed in comparison to one or both the start or the completion of the treatment. In some embodiments, the above one or more responses are observed at least 24 weeks after the completion of the treatment.
III. METHODS OF IDENTIFYING PATIENTS
[0106] In a nother aspect, the present disclosure provides methods of identifying subjects (patients) suffering from hepatitis delta virus (HDV) infection who are likely or not likely to achieve clinical response to treatment according to the methods of the present disclosure. In some embodiments, such methods involve measuring HDV RNA levels in the subject at the start of the treatment and at about 12 weeks (e.g., 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks) after the start of the treatment. If a > 2 logio decline in HDV RNA levels is observed in the subject between the start of the treatment and at about 12 weeks (e.g., 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks) after the start of the treatment, then the subject is likely to achieve the clinical response to the treatment. If the > 2 logiodecline in HDV RNA levels between the start of the treatment and at about 12 weeks (e.g., 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks) after the start of the treatment is not observed in the subject, then the subject not likely to achieve the clinical response to the treatment. In some embodiments, such methods involve measuring HDV RNA levels in the subject at a first timepoint after start of the treatment and at least two additional successive timepoints of the treatment. If a decline in HDV RNA levels starting at a first timepoint after the start of the treatment and continuing through the further two timepoints of the treatment is observed in the subject, then the subject is likely to achieve the clinical response to the treatment. If continued decline in HDV RNA levels starting at the first timepoint and continuing through the further two timepoints of the treatment is not observed in the subject, then the subject not likely to achieve the clinical response to the treatment, at least two additional successive timepoints can be referred to as "second timepoint" and "third timepoint", respectively. The interval between the start of the treatment and first second timepoint may be referred to as "first interval." The interval between the first timepoint and the second timepoint may be referred to as "second interval." The interval between the second timepoint and the third timepoint may be referred to as "third interval." The durations of the first interval, the second interval, and the third interval may vary. In one example, the duration of the first interval may be at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, or at least 20 weeks. In another example, the duration of the second interval may be at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks. In one more example, the duration of the third interval may be at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks. In an exemplary embodiment, the subject exhibits a decline in HDV RNA levels, in comparison to timepoint at or before the start of the treatment, at the timepoint of 12 weeks after the start of the treatment (first timepoint). The subject then exhibits continued decline in HDV RNA levels at the timepoint of 18 weeks (second timepoint) after the start of the treatment and 22 weeks (third timepoint) after the treatment. In another exemplary embodiment, the subject exhibits a decline in HDV RNA levels, in comparison to timepoint at or before the start of the treatment, at the timepoint of 16 weeks after the start of the treatment (first timepoint). The subject then exhibits continued decline in HDV RNA levels at the timepoint of 20 weeks (second timepoint) after the start of the treatment and 24 weeks (third timepoint) after the treatment. In the above embodiments of the methods of identifying subjects (patients), the clinical response can be measured by one or more treatment endpoints described elsewhere in the present disclosure.
IV. EXEMPLARY EMBODIMENTS
[0107] The following embodiments are contemplated. As used below, any reference to a series of embodiments is to be understood as a reference to each of those embodiments disjunctively (e.g., "Embodiments 1-4" is to be understood as "Embodiments 1, 2, 3, or 4").
The following embodiments are contemplated. As used below, any reference to a series of embodiments is to be understood as a reference to each of those embodiments disjunctively (e.g., "Embodiments 1-4" is to be understood as "Embodiments 1, 2, 3, or 4").
[0108] Embodiment 1 is a method of treating hepatitis delta virus (HDV) infection in a patient who has at least one of HDV levels that do not significantly decline with interferon therapy, intolerance to interferon, or a contraindication to interferon, the method comprising administering a therapeutically effective amount of lonafarnib and a CYP3A4 inhibitor.
[0109] Embodiment 2 is the embodiment of embodiment 1, wherein the contraindication is at least one of severe depression, advanced liver disease, leukopenia, severe thrombocytopenia, active autoimmune disease, compensated chronic hepatitis, and/or a severe concomitant disease that precludes IFN therapy.
[0110] Embodiment 3 is the embodiment of embodiments 1 or 2, wherein the CYP3A4 inhibitor is ritonavir. [0111] Embodiment 4 is the embodiment of embodiments 1-3, wherein the patient has chronic HDV for at least 6 months in duration before the administration of lonafarnib.
[0112] Embodiment 5 is the embodiment of embodiments 1-4, wherein lonafarnib is administered at 50 to 200 mg per day.
[0113] Embodiment 6 is the embodiment of embodiments 1-5, wherein lonafarnib is administered orally at 50 mg BID.
[0114] Embodiment 7 is the embodiment of embodiments 1-6, wherein ritonavir is administered at a daily dose of 50 to 200 mg.
[0115] Embodiment 8 is the embodiment of embodiments 1-7, wherein ritonavir is administered orally at 100 mg BID.
[0116] Embodiment 9 is the embodiment of embodiments 1-8, wherein lonafarnib and ritonavir are administered for at least 12 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks, at least 54 weeks, or from 12 weeks to 96 weeks.
[0117] Embodiment 10 is the embodiment of embodiments 1-9, wherein lonafarnib and ritonavir are administered for 48 weeks.
[0118] Embodiment 11 is the embodiment of embodiments 1-10, wherein the patient has both a
> 2 logiodecline in HDV RNA levels and normalized alanine aminotransferase (ALT) levels within 48 weeks of treatment.
[0119] Embodiment 12 is the embodiment of embodiments 1-10, wherein the patient has both a
> 2 logio decline in HDV RNA levels and normalized alanine aminotransferase (ALT) levels within 4, 8, 12, 24, 36, or 48 weeks of treatment.
[0120] Embodiment 13 is the embodiment of embodiments 11 or 12, wherein the > 2 logio decline in HDV RNA levels and the normalized alanine aminotransferase (ALT) levels are sustained post-treatment.
[0121] Embodiment 14 is the embodiment of embodiments 11 or 12, wherein the > 2 logio decline in HDV RNA levels and the normalized alanine aminotransferase (ALT) levels are sustained for up to 24 weeks post-treatment.
[0122] Embodiment 15 is the embodiment of embodiments 1-10, wherein the patient has a
> 2 logiodecline in HDV RNA levels within 48 weeks of treatment. [0123] Embodiment 16 is the embodiment of embodiments 1-10, wherein the patient has a
> 2 logio decline in HDV RNA levels within 4, 8, 12, 24, 36, or 48 weeks of treatment.
[0124] Embodiment 17 is the embodiment of embodiments 15 or 16, wherein the > 2 logio decline in HDV RNA levels are sustained post-treatment.
[0125] Embodiment 18 is the embodiment of embodiments 15-17, wherein the > 2 logiodecline in HDV RNA levels are sustained for up to 24 weeks post-treatment.
[0126] Embodiment 19 is the embodiment of embodiments 1-10, wherein the patient has normalized alanine aminotransferase (ALT) levels within 48 weeks of treatment.
[0127] Embodiment 20 is the embodiment of embodiments 1-10, wherein the patient has normalized alanine aminotransferase (ALT) levels within 4, 8, 12, 24, 36, or 48 weeks of treatment.
[0128] Embodiment 21 is the embodiment of embodiments 19 or 20, wherein the normalized alanine aminotransferase (ALT) levels are sustained post-treatment.
[0129] Embodiment 22 is the embodiment of embodiments 19-21, wherein the normalized alanine aminotransferase (ALT) levels are sustained for up to 24 weeks post-treatment.
[0130] Embodiment 23 is a method of treating hepatitis delta virus (HDV) infection in a patient, comprising administering a therapeutically effective amount of lonafarnib and a CYP3A4 inhibitor at regular intervals as a chronic therapy.
[0131] Embodiment 24 is the embodiment of embodiment 23, wherein the CYP3A4 inhibitor is ritonavir.
[0132] Embodiment 25 is the embodiment of embodiments 23 or 24, wherein the regular intervals are every 6 months.
[0133] Embodiment 26 is the embodiment of embodiments 23-25, wherein the administering a therapeutically effective amount of lonafarnib and a CYP3A4 inhibitor causes a > 2 logiodecline in HDV RNA levels within 8 weeks of treatment.
[0134] Embodiment 27 is the embodiment of embodiments 23-26, wherein the administering a therapeutically effective amount of lonafarnib and a CYP3A4 inhibitor causes a 30 to 40 U/L decline in ALT levels within 8 weeks of treatment.
[0135] Embodiment 28 is the embodiment of embodiments 23-27, wherein the lonafarnib and a
CYP3A4 inhibitor are co-administered with an interferon. [0136] Embodiment 29 is the embodiment of embodiment 28, wherein the interferon is pegylated interferon.
[0137] Embodiment 30 is the embodiment of embodiments 28 or 29, wherein the interferon is pegylated interferon-alfa-2a.
[0138] Embodiment 31 is the embodiment of embodiments 28-30, wherein the interferon is administered at a dose of 120 to 180 mcg per week.
[0139] Embodiment 32 is the embodiment of embodiments 28-31, wherein interferon is administered by subcutaneous injection at 180 mcg QW.
[0140] Embodiment 33 is a method of treating hepatitis delta virus (HDV) infection in a patient, the method comprising administering to the patient a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor.
[0141] Embodiment 34 is the embodiment of embodiment 33, wherein the therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor at regular intervals as a chronic therapy.
[0142] Embodiment 35 is the embodiment of embodiments 33 or 34, wherein the interferon alpha is pegylated interferon alpha.
[0143] Embodiment 36 is the embodiment of embodiment 35, wherein the interferon alpha is pegylated interferon-alfa-2a.
[0144] Embodiment 37 is the embodiment of embodiments 33 to 36, wherein the interferon alpha is administered at a dose of about 120 to 180 mcg per week.
[0145] Embodiment 38 is the embodiment of embodiments 33 to 37, wherein interferon alpha is administered by subcutaneous injection at about 180 mcg QW.
[0146] Embodiment 39 is the embodiment of embodiments 33 to 38, wherein the CYP3A4 inhibitor is ritonavir.
[0147] Embodiment 40 is the embodiment of embodiments 33 to 38, wherein the patient has chronic HDV for at least 6 months in duration before the administration of lonafarnib.
[0148] Embodiment 41 is the embodiment of embodiments 33 to 40, wherein the patient has chronic HDV for at least 6 months in duration before the administration of lonafarnib. [0149] Embodiment 42 is the embodiment of embodiments 33 to 41, wherein lonafarnib is administered at about 50 to about 200 mg per day.
[0150] Embodiment 43 is the embodiment of embodiments 33 to 42, wherein lonafarnib is administered orally at 50 mg BID.
[0151] Embodiment 44 is the embodiment of embodiments 33 to 43, wherein ritonavir is administered at a daily dose of about 50 to about 200 mg.
[0152] Embodiment 45 is the embodiment of embodiments 33 to 44, wherein ritonavir is administered orally at 100 mg BID.
[0153] Embodiment 46 is the embodiment of embodiments 33 to 45, wherein lonafarnib and ritonavir are administered for at least 12 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks, at least 54 weeks, or from 12 weeks to 96 weeks.
[0154] Embodiment 47 is the embodiment of embodiments 33 to 46, wherein lonafarnib and ritonavir are administered for 48 weeks.
[0155] Embodiment 48 is the embodiment of embodiments 33 to 47, wherein the patient has both a > 2 logiodecline in HDV RNA levels and normalized alanine aminotransferase (ALT) levels within 48 weeks of treatment.
[0156] Embodiment 49 is the embodiment of embodiments 33 to 47, wherein the patient has both a > 2 logw decline in HDV RNA levels and normalized alanine aminotransferase (ALT) levels within 4, 8, 12, 24, 36, or 48 weeks of treatment.
[0157] Embodiment 50 is the embodiment of embodiments 48 or 49, wherein the > 2 logio decline in HDV RNA levels and normalized alanine aminotransferase (ALT) levels are sustained posttreatment.
[0158] Embodiment 51 is the embodiment of embodiments 48 or 49, wherein the > 2 logio decline in HDV RNA levels and normalized alanine aminotransferase (ALT) levels are sustained for up to 24 weeks post-treatment.
[0159] Embodiment 52 is the embodiment of embodiments 33 to 47, wherein the patient has a
> 2 logiodecline in HDV RNA levels within 48 weeks of treatment.
[0160] Embodiment 53 is the embodiment of embodiment 52, wherein the patient has both a
> 2 logio decline in HDV RNA levels within 4, 8, 12, 24, 36, or 48 weeks of treatment. [0161] Embodiment 54 is the embodiment of embodiment 52, wherein the > 2 logiodecline in HDV RNA levels are sustained post-treatment.
[0162] Embodiment 55 is the embodiment of embodiments 53-54, wherein the > 2 logiodecline in HDV RNA levels are sustained for up to 24 weeks post-treatment.
[0163] Embodiment 56 is the embodiment of embodiment 33, wherein the patient has normalized alanine aminotransferase (ALT) levels within 48 weeks of treatment.
[0164] Embodiment 57 is the embodiment of embodiments 33 to 47, wherein the patient has normalized alanine aminotransferase (ALT) levels within 4, 8, 12, 24, 36, or 48 weeks of treatment.
[0165] Embodiment 58 is the embodiment of embodiment 58, wherein the normalized alanine aminotransferase (ALT) levels are sustained post-treatment.
[0166] Embodiment 59 is the embodiment of embodiments 57 or 58, wherein the normalized alanine aminotransferase (ALT) levels are sustained for up to 24 weeks post-treatment.
[0167] Embodiment 60 is a method of treating hepatitis delta virus (HDV) infection in a patient, comprising administering a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor at regular intervals as a chronic therapy.
[0168] Embodiment 61 is the embodiment of embodiment 60, wherein the CYP3A4 inhibitor is ritonavir.
[0169] Embodiment 62 is the embodiment of embodiments 60 or 61, wherein the regular intervals are every 6 months.
[0170] Embodiment 63 is the embodiment of embodiments 60-62, wherein the administering a therapeutically effective amount of lonafarnib and a CYP3A4 inhibitor causes a > 2 logiodecline in HDV RNA levels within 8 weeks of treatment.
[0171] Embodiment 64 is the embodiment of embodiments 60-63, wherein the administering a therapeutically effective amount of lonafarnib and a CYP3A4 inhibitor causes a 30 to 40 U/L decline in ALT levels within 8 weeks of treatment.
[0172] Embodiment 65 is the embodiment of embodiments 60-64, wherein the lonafarnib and a CYP3A4 inhibitor are co-administered with an interferon.
[0173] Embodiment 66 is the embodiment of embodiments 60-65, wherein the interferon is pegylated interferon. [0174] Embodiment 67 is the embodiment of embodiments 60-66, wherein the interferon is pegylated interferon-alfa-2a.
[0175] Embodiment 68 is the embodiment of embodiments 60-67, wherein the interferon is administered at a dose of 120 to 180 mcg per week.
[0176] Embodiment 69 is the embodiment of embodiments 60-68, wherein interferon is administered by subcutaneous injection at 180 mcg QW.
[0177] Embodiment 70 is a method of reducing both the viral load and ALT levels in a patient with hepatitis delta virus (HDV) infection, the method comprising administering to the patient a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor.
[0178] Embodiment 71 is the embodiment of embodiment 70, wherein the patient has both a
> 2 logiodecline in HDV RNA levels and normalized alanine aminotransferase (ALT) levels within 48 weeks of treatment.
[0179] Embodiment 72 is the embodiment of embodiments 70 or 71, wherein the patient has both a > 2 logw decline in HDV RNA levels and normalized alanine aminotransferase (ALT) levels within 4, 8, 12, 24, 36, or 48 weeks of treatment.
[0180] Embodiment 73 is the embodiment of embodiment 71, wherein the > 2 logio decline in HDV RNA levels and normalized alanine aminotransferase (ALT) levels are sustained post-treatment.
[0181] Embodiment 74 is the embodiment of embodiment 71, wherein the > 2 log™ decline in HDV RNA levels and normalized alanine aminotransferase (ALT) levels are sustained for up to 24 weeks post-treatment.
[0182] Embodiment 75 is the embodiment of embodiments 1-74, wherein the patient has improvement in liver histology within 48 weeks of treatment.
[0183] Embodiment 76 is the embodiment of embodiment 75, wherein the improvement of liver histology comprises > 2-point improvement in Ishak HAI and no worsening of fibrosis by Ishak scoring.
[0184] Embodiment 77 is the embodiment of embodiments 1-74, wherein the patient has reduction in one or more of liver inflammation, liver necrosis, or liver fibrosis within 4, 8, 12, 24, 36, or 48 weeks of treatment.
[0185] Embodiment 78 is the embodiment of embodiments 1-77, wherein the patient, after completion of the administering to the patient of the therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor, has one or more of following responses: further decline in HDV RNA levels, further decline in alanine aminotransferase (ALT) levels, further improvement of the liver histology, or further reduction in the one or more of liver inflammation, liver necrosis, or liver fibrosis.
[0186] Embodiment 79 is the embodiment of embodiment 78, wherein the one or more of the responses are observed in comparison to one or both start or the completion of the administering to the patient of the therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor.
[0187] Embodiment 80 is the embodiment of embodiments 78 or 79, wherein the patient has the one or more response at least 24 weeks after the completion of the administering to the patient of the therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor.
[0188] Embodiment 81 is the embodiment of embodiments 1-80, wherein the patient has
> 2 logiodecline in HDV RNA levels at 12 weeks of the administering to the patient of the therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor.
[0189] Embodiment 82 is the embodiment of embodiments 1-81, wherein the patient has a decline in HDV RNA levels starting at a first timepoint after the start of the administering to the patient of the therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor and continuing through a second timepoint and a third timepoint during the administering to the patient of the therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor, wherein the second timepoint occurs after the first timepoint, and wherein the third timepoint occurs after the second timepoint.
[0190] Embodiment 83 is the embodiment of embodiment 82, wherein an interval between the start of the administering to the patient of the therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor and the first timepoint at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, or at least 20 weeks.
[0191] Embodiment 84 is the embodiment of embodiments 82 or 83, wherein an interval between the first timepoint and the second timepoint is at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks. [0192] Embodiment 85 is the embodiment of embodiments 82-84, wherein an interval between the second timepoint and the third timepoint is at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks.
[0193] Embodiment 86 is a method of identifying a patient suffering from hepatitis delta virus (HDV) infection and likely or not likely to achieve clinical response to a treatment comprising administering a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor, the method comprising the steps of: administering to the patient a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor for at least 12 weeks; and, measuring HDV RNA levels in the patient at start of the treatment and at 12 weeks after the start of the treatment; wherein > 2 logiodecline in HDV RNA levels between the start of the treatment and at 12 weeks after the start of the treatment indicates the patient likely to achieve the clinical response to the treatment, and wherein absence of the > 2 logiodecline in HDV RNA levels between the start of the treatment and at about 12 weeks after the start of the treatment indicates the patient not likely to achieve the clinical response to the treatment.
[0194] Embodiment 87 is a method of identifying a patient suffering from hepatitis delta virus (HDV) infection and likely or not likely to achieve clinical response to a treatment comprising administering a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor, the method comprising the steps of: administering the treatment to the patient; and, measuring HDV RNA levels in the patient at a first timepoint after start of the treatment, at a second timepoint during the treatment, and at third timepoint during the treatment, wherein the second timepoint occurs after the first timepoint; wherein the third timepoint occurs after the second timepoint, wherein decline in HDV RNA levels starting at the first timepoint continuing through the second timepoint and the third timepoint indicates the patient likely to achieve the clinical response to the treatment, and wherein absence of the decline in HDV RNA levels starting at the first timepoint and continuing through the second timepoint and the third timepoint indicates the patient not likely to achieve the clinical response to the treatment.
[0195] Embodiment 88 is the embodiment of embodiment 87, wherein an interval between the start of the treatment and the first timepoint is at least at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, or at least 20 weeks. [0196] Embodiment 89 is the embodiment of embodiments 87 or 88, wherein an interval between the first timepoint and the second timepoint is at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks.
[0197] Embodiment 90 is the embodiment of embodiments 87-89, wherein an interval between the second timepoint and the third timepoint is at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks.
[0198] Embodiment 91 is the embodiment of embodiments 87-90, wherein the clinical response comprises one or more of: > 2 logiodecline in HDV RNA levels, normalized alanine aminotransferase (ALT) levels, improvement of liver histology, or reduction in the one or more of liver inflammation, liver necrosis, or liver fibrosis.
[0199] Embodiment 92 is the embodiment of embodiment 91, wherein the improvement of liver histology comprises > 2-point improvement in Ishak HAI and no worsening of fibrosis by Ishak scoring.
[0200] Embodiment 93 is the embodiment of embodiments 87-92, wherein the clinical response is observed at about 48 weeks after the start of the treatment. timepoint is at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks.
EXAMPLES
[0201] The following examples are provided to illustrate, but not to limit, the claimed invention.
Example 1. Nonclinical Data
[0202] Lonafarnib inhibited purified human FT with a median inhibitory concentration ( IC5o) of 1.9 nM. Lonafarnib demonstrated a median effective concentration ( EC50) of 35 pM (2.4 ng/mL) against HDV in a virus particle formation assay in cell culture. Lonafarnib does not have intrinsic activity against HBV, and does not interact with tenofovir (TNF), adefovir (ADV), entecavir (ETV), telbivudine, or lamivudine (LMV) in vitro.
[0203] Lonafarnib is primarily metabolized by CYP3A, with negligible renal elimination (< 1%). Plasma protein binding of LNF was > 99%. Lonafarnib is widely distributed into tissues following oral administration. [0204] In nonclinical toxicity studies, LNF was generally tolerated and had no major end-organ toxicities at repeated doses of 15 mg/kg up to 6 months in rats and 10 mg/kg up to 1 year in monkeys. At higher doses, the key toxicological findings were bone marrow suppression and testicular toxicity in rats and monkeys, lymphoid and kidney changes in rats, and diarrhea and electroretinographic changes in monkeys. In both rat and rabbit reproductive toxicity studies, LNF resulted in changes in the male and female reproductive tracts and resorptions, and an abortion in 1 rabbit. In males, there was a reduction in the weight of both the testis and epididymis with a marked reduction in female pregnancy parameters when mated with LNF-treated males. For females (rats and rabbits), there were increased pre- and post-implantation loss, resulting in reduced corpora lutea and decreases in fetal weight for those fetuses that successfully implanted. In genotoxicity studies, LNF was not mutagenic or clastogenic.
Example 2. Clinical Study Protocol for Treating HDV with Lonafarnib and Ritonavir with or without Pegylated Interferon alpha
[0205] Provided herein is a Phase 3 partially double-blind, randomized study of the efficacy and safety of lonafarnib and ritonavir with and without PEG IFN-alfa-2a for 48 weeks compared with PEG IFN-alfa-2a monotherapy and placebo treatment in patients chronically infected with HDV being maintained on anti-HBV nucleos(t)ide. This partially double-blind, randomized study has employed a matrix (factorial) design to evaluate the efficacy and safety of 50 mg lonafarnib/100 mg ritonavir BID with and without PEG I FN-alfa-2a 180 mcg QW for 48 weeks compared to no treatment (placebo lonafarnib and placebo RTV) in patients chronically infected with HDV and receiving anti-HBV nucleos(t)ide maintenance therapy. A schematic of the clinical trial is shown in FIG. 1.
[0206] Approximately 400 patients from more than 100 clinical sites located in Asia, Europe, North America, Israel, and New Zealand were randomized with an allocation ratio of 7:5:2:2 to the following treatment arms:
Group 1 LNF 50 mg BID + RTV 100 mg BID (175 patients)
Group 2 LNF 50 mg BID + RTV 100 mg BID + PEG I FN-alfa-2a 180 mcg QW (125 patients)
Group 3 placebo LNF + placebo RTV + PEG IFN-alfa-2a 180 mcg QW (50 patients)
Group 4 placebo LNF + placebo RTV (50 patients)
[0207] All patients received/maintained background anti-HBV nucleos(t)idetherapy with entecavir
(ETV) or tenofovir (TNF; tenofovir disoproxil fumarate [TDF] or tenofovir alafenamide fumarate
[TAF]) for at Ieastl2 weeks prior to initiating study therapy and present demonstratable suppression of HBV deoxyribonucleic acid (DNA) (< 20 lU/mL) and continued this treatment for the duration of the study (tenofovir or entecavir). Patients being treated with another anti-HBV nucleos(t)ide therapy changed treatment to entecavir or tenofovir for at least 12 weeks (and up to 6 months) and presented demonstrable suppression of HBV DNA (< 20 lU/mL) prior to initiating study therapy. Study visits were conducted during the screening phases; on Day 1 (Baseline); weeks 1, 2, and 4; every 2 weeks through week 12; and every 4 weeks until the end-of-treatment visit at week 48.
[0208] All patients who completed 48 weeks of treatment had a liver biopsy for histology assessment at end-of-treatment (prior to treatment discontinuation) and were followed for an additional 24 weeks off-study treatment (post-treatment weeks 4, 8, 12, 16, 20, and 24) to monitor safety and efficacy parameters.
Table 1. Protocol synopsis
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Study Assessments
A. HDV Analyses - RNA Viral Load, Mutational Analysis, and Sequencing
[0209] Samples were collected for HDV RNA viral load determination and possible mutational analyses throughout the study as noted in Tables 2 and 3. Hepatitis D virus RNA viral load samples will be analyzed using a validated and sensitive reverse transcription-polymerase chain reaction (RT- PCR) assay. Detailed assay information will be presented in a separate laboratory manual.
[0210] Blood samples for possible future exploratory analyses of HDV RNA sequencing will be collected. These samples will be retained for a maximum of 5 years after the last patient last visit, or for a shorter period of time based on local regulations or ethics committee (ECs) dictate and will be stored at a facility selected by the Sponsor. Any samples remaining after the 5-year period of retention will be destroyed. For resistance surveillance, genotypic analysis of the full HDV genome will be conducted if a patient experiences virologic failure (an increase in serum HDV RNA of at least 1 logio from the nadir value or detectable HDV RNA after prior undetectability with outcome confirmed on 2 consecutive visits).
B. HBV Analyses - DNA Viral Load, Serology, and Genotyping
[0211] Blood samples for determination of HBV DNA viral load and the following HBV serology markers were collected:
Hepatitis B surface antigen (HBsAg) levels;
Seroconversion to anti-HBsAb;
Hepatitis B e antigen (HBeAg) levels; and Seroconversion to anti-HBeAb.
[0212] Additionally, blood samples for HBV genotyping were collected during pre-screening when feasible (i.e., prior to anti-HBV nucleos[t]ide administration); for patients with undetectable HBV DNA levels (i.e., post anti-HBV nucleos[t]ide administration), medical history, when available, will be utilized to record the HBV genotype.
Table 2. Schedule of events: treatment phase
Figure imgf000041_0001
Figure imgf000042_0001
Table 2 footnotes:
Abbreviations: BL = baseline; D = Day; DNA = deoxyribonucleic acid; EOT = end-of-treatment; ET = early termination; FT = farnesyl transferase; HBV = hepatitis B virus; HCV = hepatitis C virus; HDV = hepatitis D virus; HIV = human immunodeficiency virus; IWRS = interactive web response system; RNA = ribonucleic acid; W = week; PK-pharmacokinetic.
1 Subject to study withdrawal procedures, including subsequent study visits and collection of data.
2 For weeks 1, 2, 4, 6, 8, 10, and 12, a ±3-day window for the visits applies. For the remainder of the study visits, a+ 4-day window applies.
3TO be conducted at the discretion of the Investigator based on adverse event or symptomology.
4 Ophthalmological examination to include best corrected distance visual acuity, automated threshold perimetry testing, spectral-domain optical coherence tomography (SD-OCT) testing of the central retina, and assessment of normal dilated retina. Patients with clinically meaningful ophthalmological findings during the treatment phase will be assessed during.
5 Only for patients being treated with tenofovir (TDF or TAF) and with a history of pathologic fracture or evidence or other risk factors for osteoporosis or bone loss. sThe EOT liver biopsy should be scheduled after the week 44 visit and prior to or during the week 48 visit. If the procedure needs to be rescheduled (up to 14 days after the week 48 visit), sufficient study drug will be released to continue treatment until the biopsy is performed (ie, patients should remain on study drug until the biopsy is performed).
7 An Early Termination liver biopsy may occur at any time after 12 weeks of treatment and ideally within 5 days of final study treatment.
8 If a FibroScan cannot be conducted at the site due to equipment limitations, only a Fibro Test will be conducted.
9 AS applicable. Supplemental clinical laboratory samples will also be collected to evaluate serum concentrations of testosterone, follicle stimulating hormone (FSH), luteinizing hormone (LH), and inhibin B.
10 Patients in a PEG I FN-alfa-2a treatment arm with well-controlled depression will be monitored for worsening depression.
11 HDV RNA samples may be analyzed for mutation analysis and possible future exploratory assessment .
12 FT samples may be analyzed for possible future exploratory assessment.
13 Sparse PK samples for population PK modeling will be collected at a minimum of 2 visits after week 4.
14 For elimination phase random sparse sampling, at each sampling window, 10% of the samples will be collected. Depending on the number of sites capable of sample collection one or more sampling windows will be assigned to participating patients.
15 All treatment groups must have received background anti-HBV nucleos(t)ide therapy with entecavir or tenofovir starting at least 12 weeks prior to initiating study therapy and present suppression of HBV DNA and continue this treatment for the entire duration of the study.
16 As necessary, based on the timing of the final liver biopsy. C. Liver Biopsy
[0213] A liver biopsy was performed according to Table 2. The results of the end-of-treatment visit (after week 44 and leading up to/during the week 48 visit) was compared with pre-study data (within 45 days of initiation of study drug therapy) or screening biopsy results to assess changes in necro- inflammatory and fibrosis scores according to the Ishak modified HAI.
[0214] After the end-of-treatment samples were collected and prepared, slides from the screening and end-of-treatment visit were read by a central reader, Zachary D. Goodman, MD, PhD, who remained blinded to the sampling timepoint (i.e., Screening vs end-of-treatment). For samples collected prior to the initiation of treatment (and still within the required < 45-day window), the material (e.g., slide[s]) were shipped to the central reader for evaluation.
D. Clinical Laboratory Tests
[0215] Clinical laboratory tests include chemistry, hematology, and urinalysis, as listed in Table 3.
[0216] For the monitoring of on-treatment and post-treatment ALT flares, blood samples were collected for HDV RNA and HBV DNA assessment, and the frequency of ALT monitoring and other liver related tests (albumin, fractionated bilirubin, international normalized ratio [INR], alkaline phosphatase, and gamma-glutamyl transferase [GGT]) to every2-5 days for patients with ALT increases to > 10 x ULN was increased until the ALT level has stabilized. For ALT increases to > 15 x ULN or for cases of ALT > 10 x ULN with associated signs/symptomsor laboratory evidence of reduced hepatic functional capacity (such as decrease of albumin or increases in coagulation times or bilirubin levels), dosing was interrupted (if occurring during treatment), laboratory and clinical assessments were initiated every 2-5 days (more frequently if necessary).
[0217] Patients with elevated ALT (> 10 x ULN) beyond a 2-week period without evidence of associated decline in HDV RNA typically discontinued study drug treatment.
Subject Population
[0218] Subjects were included if they had chronic HDV infection of at least 6 months in duration documented by a positive HDV antibody (Ab) test and HDV RNA > 500 lU/mL by quantitative polymerase chain reaction (qPCR) prior to initiation of treatment. The demographic and clinical characteristics describing the population of subjects in DLIV-R with HDV is shown in Table 4. In some embodiments, the subject is diagnosed with chronic hepatitis as determined by, for example, one or more of: a liver biopsy, a liver function test, an ultrasound, a hepatic venous pressure gradient (HVPG) measurement, an ALT level, one or more other blood tests, or an albumin level. In some embodiments, the biopsy is conducted within the 6 months before the initiation of treatment. In some embodiments, the biopsy is conducted within the 18 months before the initiation of treatment, according to the methods provided herein. In some embodiments, the biopsy is conducted within the 1 day to 24 months before the initiation of treatment. In some embodiments, the subject has evidence of chronic hepatitis based on a liver biopsy within 6 months before screening. In some embodiments, the subject has a serum alanine aminotransferase (ALT) level that is above the upper limit of normal (ULN) within 24 weeks prior to treatment and/or at the initiation of treatment, within 24 months prior to the initiation of treatment, from 24 months to 1 month prior to the initiation of treatment, or from 12 months to 1 day prior to the initiation of treatment.
Table 3. Clinical laboratory tests
Figure imgf000045_0001
[0219] As shown in FIG. 2, of the 908 patients initially screened, 501 patients failed the screening criteria of HDV RNA > 500 lU/mL, HBV DNA < 20 lU/mL, and ALT > ULN. Of the 407 patients that were enrolled, 405 patients were dosed in one of the study arms. Patients were randomized across the four arms in a ratio of 7 to 5 to 2 to 2 - with 178 randomized to the all-oral arm, 125 to the combination arm, 52 to the peg alfa comparator arm, and 52 to the placebo arm. Discontinuation rates were similar across all the arms - around 18-19%. The baseline characteristics of the 407 dosed patients are shown in Table 3. In terms of the baseline characteristics of patients enrolled in the study; the mean age was in the early to mid 40's, participants were predominantly male, with 73% white, 23% Asian, and 2% Black. Geographically, 74% of enrolled patients were in Europe, 15% in Asia, 6% in North America, and the remaining 5% were in Israel or New Zealand. The mean HDV RNA level was around 5 logs across the arms and baseline ALT was comparable across the arms as well. As expected, the predominant HDV genotype was type 1. Cirrhosis was found to be present at baseline in approximately 27% of patients, as determined by investigator assessment during screening. Cirrhotic patients were required to be well- compensated, defined as Child-Pugh class A, to be eligible for the study.
[0220] Subjects were 18 years or older and had the presence of anti-HDV in serum; body mass index (BMI) of > 18 kg/m2 and weight > 45 kg; demonstrable suppression of HBV DNA (< 20 lU/mL) following minimum of 12 weeks of anti-HBV nucleos(t)ide treatment with entecavir or tenofovir (TDF or TAF) prior to initiating study therapy; serum ALT > 1.0 x upper limit of the normal range (ULN) and < lO x ULN; liver biopsy within 45 days of Day 1 demonstrating evidence of chronic hepatitis. If no liver biopsy was available, the patient had to be willing to consent to and have no contraindication to liver biopsy.
[0221] Subjects having decompensated liver disease, defined by Child-Pugh Class B or C) based on documented Child-Pugh score, were not enrolled. Subjects with ALT levels greater than 1000 U/L (>25 times ULN) were not enrolled. A formal Child-Pugh score assessment is conducted and documented at screening. For patients categorized as Child- Pugh A (with a score of 5) with well compensated liver disease, enrollment will be allowed. Co-infected with human immunodeficiency virus (HIV) or hepatitis C virus (HCV) by detectable HIV RNA and HCV RNA, respectively.
[0222] Subjects with positive results for HIV or HCV Ab at screening were also not enrolled. Patients with a positive HCV Ab at screening were allowed if they have completed a curative antiviral regimen and have documented undetectable HCV RNA for at least 3 months before screening and at screening. Table 4. Baseline demographics and clinical characteristics of the DLIV-R study population.
Figure imgf000047_0001
[0223] Patients with a history or current evidence of significant portal hypertension such as hepatic venous pressure gradient (HVPG) > 10 mmHg; current presence or history of esophageal or abdominal varices, variceal bleeding, or splenomegaly > 12 cm length on imaging were also excluded. In a case when the spleen measures larger than 12 cm and the Principal Investigator believes the subject meets all other non-cirrhotic criteria, a discussion with the Medical Monitor was warranted for patient inclusion.
[0224] Current evidence or history of ascites requiring diuretics or paracentesis, or hepatic encephalopathy were also criteria for exclusion, as were any of the following abnormal laboratory test results at screening:
Platelet count < 90,000 cells/mm3;
White blood cell (WBC) count < 3,000 cells/mm3;
Absolute neutrophil count (ANC) < 1,500 cells/mm3;
Hemoglobin < 11 g/dL for women or < 12 g/dL for men;
Confirmed creatinine clearance (< 30 mL/min by Cockcroft -Gault);
Alfa-fetoprotein > 100 ng/mL;
Abnormal thyroid-stimulating hormone (TSH) or total thyroxine (T4) levels. Patients with well- controlled thyroid function may have been enrolled following discussion with the Medical Monitor.;
Bilirubin > 2 mg/dL, regardless of cirrhosis status. Following discussion with the Medical Monitor and case review, patients may have been appropriate to enroll.;
Evidence of another form of viral hepatitis or another form of liver disease (e.g., autoimmune liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson's disease, alcoholic liver disease, nonalcoholic steatohepatitis, hemochromatosis, alpha-l-anti-trypsin deficiency).; History of hepatocellular carcinoma.
[0225] Patients with any of the following were also excluded: current eating disorder (as defined by Diagnostic and Statistical Manual of Mental Disorders [DSM]-5); evidence of alcohol substance use disorder, as defined by DSM-5, or excessive intake, defined as > 20 g/day for females (1.5 standard alcohol drinks) or > 30 g/day for males (2.0 standard alcohol drinks) where a standard drink contains 14 g of alcohol: 355 mL/12 oz of beer, 148 mL/5 oz of wine, or 44 mL/1.5 oz of spirits; blood alcohol concentration > 0.08%; or drug abuse within the previous 6 months before screening with the exception of cannabinoids and their derivatives. [0226] Also excluded were patients with a prior history or current evidence of immunologically mediated disease (e.g., rheumatoid arthritis, inflammatory bowel disease, severe psoriasis, systemic lupus erythematosus) that requires more than intermittent nonsteroidal anti-inflammatory medications for management or that requires chronic use of systemic corticosteroids in the 6 months before screening (periodic use of oral steroid taper and inhaled asthma medications are allowed), Retinal disorder or clinically relevant ophthalmic disorder. Also excluded were patients with any malignancy within 5 years before screening. Exceptions were malignancies surgically excised with curative intent and/or evidence of being disease free for at least 5 years (e.g., breast ductal carcinoma in situ [DCIS] or squamous/basal cell skin cancer treated with curative intent), or successfully treated in-situ carcinoma of the cervix. Patients with cardiomyopathy or significant ischemic cardiac or cerebrovascular disease (including history of angina, myocardial infarction, or interventional procedure for coronary artery disease), chronic pulmonary disease (e.g., chronic obstructive pulmonary disease) associated with functional impairment, as defined by a forced expiratory volume in 1 second/forced vital capacity ( FEVl/FVC) ratio < 0.7. Patients with pancreatitis or colitis were also excluded, as were patients with severe or uncontrolled psychiatric disorder (e.g., depression, manic condition, psychosis, acute and/or chronic cognitive dysfunction, suicidal behavior, history of suicide attempt, and relapse of substance abuse), bone marrow or solid organ transplantation (although patients who were stable for 1 year posttransplantation and did not require immunosuppressive therapy(ies), following a case review, were considered), or any other significant medical condition that may require intervention during the study or any condition that may impact proper absorption.
[0227] Patients with an absolute neutrophil count <1000/dL and platelets <75,000/dL were excluded from the study. Subjects were also not enrolled if they had significant systemic or major illnesses other than liver disease, including, but not limited to, congestive heart failure, renal failure (eGFR <50 ml/min), organ transplantation, serious psychiatric disease or depression, or active coronary artery disease; systemic immunosuppressive therapy within the previous 2 months before enrollment; evidence of another form of liver disease in addition to viral hepatitis (for example autoimmune liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson disease, alcoholic liver disease, ongoing drug induced liver disease, nonalcoholic steatohepatitis (but not steatosis), hemochromatosis, or alpha- 1-antitrypsin deficiency); active substance abuse, such as alcohol, inhaled or injection drugs within the previous year; evidence of hepatocellular carcinoma. Subjects were not enrolled if they have elevated AFP; evidence of concurrent hepatitis C infection with positive serum HCV RNA; any experimental therapy or pegylated interferon therapy within 6 months prior to enrollment; active, serious autoimmune disease such as systemic lupus erythematosus, ulcerative colitis, Crohn's disease or rheumatoid arthritis.
[0228] To prevent the possibility of a hepatitis B flare during the study, all patients were treated with nucleos(t)ide analogues while on the study (24 weeks of entecavir or tenofovir + lonafarnib/ritonavir/alfa and 24 weeks of entecavir or tenofovir during the post-therapy monitoring phase). Patients who were not on nucleos(t)ide analogues prior to starting lonafarnib/ritonavir/alfa were started on either entecavir or tenofovir (which are first line nucleos(t)ide analogues recommended by the AASLD and EASL for the treatment of HBV) prior to instituting HDV therapy (to reduce the risk of a hepatitis B flare). HBV viral loads were monitored after starting nucleoside analogue therapy at each outpatient visit during the entire course of study participation. Adequate HBV suppression (serum HBV DNA level <2000 lU/mL) on nucleoside analogue therapy was required prior to starting HDV therapy to allow for improved determination of response to experimental HDV therapy.
[0229] Patients were initiated on therapy, for example, one or two days after the liver biopsy and remained in the clinical center for 72 hours after induction of therapy for observation of side effects, administration of medication, and timed blood draws to facilitate analysis of virologic response kinetics and pharmacokinetic analysis. During the admission, frequent blood sampling was performed (0, 6, 12, 18, 24, 36, 48 and 72 hours after the first dose) for viral kinetics, pharmacokinetics, and storage.
[0230] Under certain conditions, subjects were dose reduced as follows: Interferon alpha dose reduced from 180 mcg to 120 mcg, and lonafarnib dose reduced from 50 mg to 25 mg. Doses were reduced, for example, if a subject's experienced an adverse event that is greater than or equal to a Grade 3 that is one or more of: related to the alfa or lonafarnib, possibly related to the alfa or lonafarnib, possibly related to the alfa or lonafarnib, and not clinically significant. Doses were reduced, for example, if a subject experienced depression, had new ocular symptoms, hematologic abnormalities, or creatinine clearance of less than 50 mL/min.
Example 3. Trial Results
[0231] This Phase 3 study (D-LIVR) was designed to demonstrate the clinical benefits of LNF + RTV and LNF + RTV + PEG IFN-alfa-2a in patients with chronic HDV infection by impacting the two critical dimensions of the pathophysiology of chronic HDV hepatitis: (1) HDV viral production and necro- inflammatory injury of the liver as reflected by ALT elevations in the peripheral blood. Because virologic response reduction of > 2 logic and ALT normalization after 48 weeks of treatment (end-of-treatment) each represents a highly meaningful benefit to HDV patients, these endpoints were used in a composite primary endpoint where patients achieving both (1) virologic response and (2) ALT normalization relative to baseline will be counted as a composite responder.
A. Primary Endpoint: Composite > 2 logw Reduction + ALT Normalization at Week 48
[0232] Two regimens were compared to no treatment control (placebo LNF + placebo RTV): (1) LNF 50 mg BID + RTV 100 mg BID (oral arm) and (2) LNF 50 mg BID + RTV 100 mg BID + PEG IFN-alfa-2a 180 mcg once weekly (QW, combo arm). The PEG IFN-alfa-2a study arm is included only to show the contribution of PEG IFN-alfa-2a to the effect.
[0233] As shown in FIG. 3, the primary endpoint of a composite response, or composite virologic and biochemical response, was achieved with statistical significance in both lonafarnib arms. The composite response rate in the oral arm was 10.1% (p=0.0044), whereas the composite response rate in the combination arm was 19.2% (p<0.0001). By comparison, there was only 1 responder in the placebo study arm, accounting for the 1.9% response rate. The composite response rate in the oral arm was comparable to the PEG IFN-alfa-2a study arm (10.1% versus 9.6%). The composite response rate in the combination arm was two times that in the PEG I FN-alfa-2a arm (19.2% versus 9.6%). Thus, the study results highlight two key findings. First , a small subset of patients with chronic HDV infection may achieve virologic and biochemical improvements with an oral lonafarnib regimen after 48 weeks of treatment. Second, combining lonafarnib and ritonavir with peginterferon alfa demonstrated the potential to nearly double the response rate.
B. Virologic Response Endpoint: > 2 logw Reduction at Week 48
[0234] A 2 logio reduction represents 100-fold improvement in viral burden, and this level of viral load reduction after completion of therapy would represent a meaningful change in HDV burden for patients and has been associated with improved survival (Farci et al. (1994) Treatment of Chronic Hepatitis D with Interferon Alfa-2a, NEJM 330:88-94; Farci, P. (2003) Delta hepatitis: an update, J of Hepatology 39:212-219). In the study EIG-300, LOWR-2, we previously observed a 2 logw improvement in HDV RNA reduction when adding LNF 50 mg BID/ RTV 100 mg BID to PEG I FN-alfa-2a in a 24-week regimen, which predicts that even higher rates of HDV RNA suppression to a 2 logwthreshold may be achieved by combining LNF/RTV with the immune modulatory effects PEG IFN-alfa-2a.
[0235] However, a substantial proportion of patients may not have access to PEG IFN-alfa-2a or are intolerant to interform therapy, and a substantial proportion of chronic hepatitis patients have contraindications to interferon (I FN) therapy due to severe depression, advanced liver disease, leukopenia, severe thrombocytopenia, active autoimmune diseases, and severe concomitant diseases. Furthermore, only patients with well compensated chronic hepatitis should be considered for IFN therapy because treatment may result in decompensation of liver disease. See, e.g., Section 5.9 of Pegasys product label available at www.accessdate.fda.gov ("Chronic hepatitis C patients (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons.") Therefore, development of LNF/RTV oral therapy is necessary to adequately serve the HDV patient population.
[0236] In the present study, we observed that the secondary endpoint of virologic response, separately, is also statistically significant in both lonafarnib treatment study arms. For example, as shown in FIG. 4, 14.6% (p=0.0026) of patients in the oral arm achieved >2 log decline in HDV RNA, as did 32% (p<0.0001) of patients in the combo arm, compared to 3.8% of patients receiving placebo.
C. Biochemical Response Endpoint: ALT Normalization at Week 48
[0237] In our previous EIG-300, LOWR-2 study, the majority of HDV patients with ALT > upper limit of normal (ULN) who were treated with LNF 25 or 50 mg BID/RTV 100 mg BID and LNF 25 or 50 mg BID/RTV 100 mg BID/PEG IFN-alfa-2a 180 mcg/QW normalized their ALT after only 24 weeks of treatment (Study EIG-300). Spontaneous normalization of ALT is rare in untreated HDV patients, with < 10% of the untreated HDV patients from the HIDIT-1 study achieving ALT normalization with 48 weeks of treatment (Wedemeyer et al. (2011) Peginterferon plus Adefovir versus Either Drug Alone for Hepatitis Delta, NEJM 364:322-331). ALT is a highly useful peripheral surrogate biochemical marker for the extent of inflammation in the liver. Numerous datasets from studies in chronic HBV patients demonstrate the strong association of treatment induced normalization of ALT with improved necro-inflammation based on liver histology using validated central pathology assessments. Data from 7 independent studies from the HBV registrational programs for entecavir, adefovir, and tenofovir, which included lamivudine and placebo as controls, demonstrate this strong association of normalized ALT with improved liver histology (defined as > 2-point improvement in necro-inflammatory score and no worsening of fibrosis) in patients treated for 48 weeks (Chang et al. (2006) A Comparison of Entecavir and Lamivudine for HBeAg-Positive Chronic Hepatitis B, NEJM, 354:1001-1010; Lai et al (2006) Entecavir Adis Drug Evaluations 66:1623-24.; Sherman et al. (2006) Optimizing Management Strategies in Special Patient Populations Am J of Gastroenterology 101:S26-S31; Marcellin et al. (2008) Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B NEJM 359:2442-2455; Hadziyannis et al. (2003) Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B NEJM 348:800-807; Peters et al. (2004) Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B Gastroenterology 126:91-101; Marcellin et al. (2003) Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B NEJM 348:808-816).
[0238] Here, we compared the proportion of patients with ALT normalization relative to baseline at end-of-treatment (week 48) in patients who receive LNF 50 mg/RTV 100 mg BID (oral arm) vs placebo. We also compared the proportion of patients with ALT normalization relative to baseline at end-of- treatment (week 48) in patients who receive LNF 50 mg/RTV 100 mg BID with PEG IFN-alfa-2a 180 mcg QW (combo arm) vs patients who receive placebo. We further compared the proportion of patients with ALT normalization relative to baseline at end-of-treatment (week 48) in patients who receive LNF 50 mg/RTV 100 mg BID with PEG I FN-alfa-2a 180 mcg QW (combo arm) vs patients who receive PEG IFN- alfa-2a 180 mcg QW.
[0239] As shown in FIG. 5, 24.7% (p=0.003) of patients in the oral arm achieved ALT normalization, whereas 34.4% (p<0.0001) of patients in the combo arm achieved ALT normalization. By comparison, 11.5% of patients in the PEG IFN-alfa-2a arm achieved ALT normalization. These are in comparison to ALT normalization achieved in 7.7% of those patients receiving placebo.
D. Lower Limit of Quantitation (LLOQ) Virologic Response
[0240] We compared the proportion of patients with HDV RNA < LLOQ (target detected and not detected) at end-of-treatment (week 48) in patients who received LNF 50 mg/RTV 100 mg BID (oral arm) vs patients who receive placebo. We also compared the proportion of patients with HDV RNA < LLOQ (target detected and not detected) at end-of-treatment (week 48) in patients who received LNF 50 mg/RTV 100 mg BID with PEG I FN-alfa-2a 180 mcg QW (combo arm) vs patients who receive placebo. We further measured the proportion of patients with HDV RNA < LLOQ (target detected and not detected) at end-of-treatment (week 48) in patients who received PEG IFN-alfa-2a 180 mcg QW monotherapy.
[0241] As shown in FIG. 6, 8.4% of patients in the oral arm had HDV RNA levels below the LLOQ, whereas 20.8% of patients in the combo arm had HDV levels below the LLOQ. By comparison, 26.9% of patients treated with PEG IFN-alfa-2a monotherapy had below LLOQ levels of HDV RNA. These results are compared to 3.8% of the patients receiving placebo. E. Mean HVD and ALT Decline during the 48-week treatment
[0242] As shown in FIG. 7, the mean HDV RNA levels followed distinct trajectories for each of the four study arms. The placebo control showed a minimal 0 to -0.5 decrease in mean log lU/mL HDV RNA levels at all timepoints. PEG IFN-alfa-2a monotherapy showed a steady decline from 0 to about -2 log lU/mL HDV RNA levels during the 48 weeks of treatment. LNF+RTV (oral) and LNF+RTV+PEG I FN-alfa-2a (combo) both showed a greater initial decrease in mean log lU/mL HDV RNA levels than with the PEG IFN-alfa-2a monotherapy, but in each case HDV RNA levels partially recovered during the course of treatment. This suggests that LNF+RTV enhances the effects of PEG I FN-alfa-2a at suppressing HDV RNA levels over a 48-week course of treatment during the early phase of treatment. It also suggests that patients who are on LNF+RTV (oral) therapy may not sustain low levels of HDV RNA after 48 weeks of treatment.
[0243] The changes in ALT levels over the course of the 48-week treatment further suggest that LNF+RTV can enhance the effectiveness of treatment with PEG IFN-alfa-2a alone. As shown in FIG. 8, patients treated with PEG IFN-alfa-2a showed a mean change in ALT decline (U/L) similar to patients given only placebo. In contrast, both study arms where patients were given LNF+RTV (oral and combo) show a significant decline in ALT during the course of the 48-week treatment, from a mean value of 0 to -35 U/L. As with the HDV levels, though, it seems that the ALT decline caused by LNF+RTV is substantially gone by the end of the 48-week treatment period.
[0244] For both HDV RNA and ALT over 48 weeks, we observe the most rapid first phase of decline and most durable improvement in the combination arm, which likely explains why it delivered the best composite and histologic results in the D-LIVR study. In contrast, in the oral arm we observe a gradual loss of virologic and ALT response beginning at approximately week 16 of the study. This likely explains the difference between the phase 2 results which were based on week 24 and those observed in these 48-week data from D-LIVR.
F. Histologic Response
[0245] Histologic improvement is of particular importance because analysis of liver histology is the most direct way to assess improvements in liver injury such as necrosis and inflammation, as well as scarring in the form of fibrosis. Liver necrosis and inflammation is measured by the HAI score and liver scarring is measured by the fibrosis score. [0246] We compared the histologic response rate at end-of-treatment (week 48) in patients who receive LNF 50 mg/RTV 100 mg BID vs patients who receive placebo. We also compared the histologic response rate at end-of-treatment (week 48) in patients who receive LNF 50 mg/RTV 100 mg BID with PEG IFN-alfa-2a 180 mcg QW vs patients who receive placebo. We further compared the histologic response rate at end-of-treatment (week 48) in patients who receive LNF 50 mg/RTV 100 mg BID with PEG IFN-alfa-2a 180 mcg QW vs patients who receive PEG IFN-alfa-2a 180 mcg QW.
[0247] Histologic response is defined as an improvement in Ishak modified histology activity index (HAI) score of > 2 points relative to baseline and no worsening of fibrosis score. We compared the net proportion of patients with improved fibrosis score at end-of-treatment (week 48) relative to baseline in patients who receive LNF 50 mg/RTV 100 mg BID vs patients who receive placebo. To compare the net proportion of patients with improved fibrosis score at end-of-treatment (week 48) relative to baseline in patients who receive LNF 50 mg/RTV 100 mg BID with PEG IFN-alfa-2a 180 mcg QW vs patients who receive placebo. We also compared the net proportion of patients with improved fibrosis score at end- of-treatment (week 48) relative to baseline in patients who receive LNF 50 mg/RTV 100 mg BID with PEG IFN-alfa-2a 180 mcg QW vs patients who receive PEG IFN-alfa-2a 180 mcg QW.
[0248] The net proportion with improved fibrosis score is defined as the proportion of patients with improved fibrosis score relative to baseline minus the proportion of patients with worsened fibrosis score relative to baseline. We also evaluated the proportion of patients with % improvement, (b) % unchanged, and (c) % worsening of Ishak modified HAI score. We further evaluated the change from baseline in Ishak modified HAI score at end-of-treatment (week 48).
[0249] Histologic analysis of paired liver biopsies collected at baseline and week 48 was conducted blinded by a single expert pathologist. The data for the histology response rate at week 48 is shown in Tables 5A - 5D below. The data is based on analysis of patients with evaluable paired biopsies (n=229).
Table 5A
Figure imgf000055_0001
Table 5B
Figure imgf000056_0001
1 Ishak HAI score based on 18-point scoring system
2 Ishak fibrosis score based on a 6-point scoring system
Table 5C
Figure imgf000056_0002
Table 5D
Figure imgf000056_0003
[0250] In the combination (combo) arm, histologic improvement of a 2-point improvement in HAI and no worsening of fibrosis by Ishak fibrosis scoring was demonstrated in 53% of the patients (35 out of 66 patients) with a statistically significant p-value of 0.0139 versus 27% of those patients receiving placebo (8 out of 30 patients). This statistical analysis was multiplicity controlled and met the same stringent p-value requirement as the primary efficacy endpoint. Response in the oral arm versus placebo 33% (35 of 107 patients) with a p-value of 0.61, and in the peginterferon alfa comparator arm was 38% (10 of 26 patients) with a p-value of 0.46.
[0251] To our knowledge, the histologic response in the combination arm of D-LIVR is the first time a statistically significant improvement in liver biopsy has been demonstrated in a chronic HDV study. This is the third key finding from this study and represents an important milestone in the development of therapeutic agents to treat this aggressive form of chronic viral hepatitis. Of note, statistical significance in liver histology compared to placebo was not observed with peg alpha, the current mainstay of HDV therapy. To provide some historical perspective, in the lamivudine HBV pivotal studies, the treatment effect for lamivudine versus placebo is similar to what we have observed in this study for the combination arm, with lamivudine rates in the mid 50% range and placebo rates in the mid 20% range. These data supported the approval of lamivudine for chronic HBV.
[0252] In a disease as aggressive as hepatitis delta virus, demonstrating improvement of HAI score and stabilization of fibrosis score may be predictive of improved long-term clinical outcomes such as time to decompensation, hepatocellular carcinoma, liver transplant, and liver related mortality. This relationship of histologic response and long-term outcomes has been demonstrated in the lamivudine, entecavir, and tenofovir programs in HBV and may do so in chronic HDV as well. The fact that the proportion of patients showing histologic improvement exceeded that which achieved the composite virologic and biochemical endpoint is positive. Thus, the full impact of this specific regimen may yet to be seen. Non-invasive tests used for disease staging in other forms of viral hepatitis show suboptimal performance in chronic HDV.
G. Overall Safety / Adverse Effects
Table 6. Overall safety through week 48
Figure imgf000058_0001
deemed unrelated to treatment
2Deemed related to treatment
[0253] TEAEs are treatment emergent adverse effects, defined as adverse effects with onset on or after the first dose date or onset prior to first dose date but with worsened grade on or after first dose date. Adverse effects without a severity rating reported on or after first dose date will be considered treatment-emergent. TEAE's of special interest include the following categories: diarrhea, nausea, vomiting, fatigue, decreased appetite, weight loss, abdominal pain, anorexia, testicular toxicity, and ophthalmologic findings.
[0254] As shown in Table 6, at week 48, both the oral and combo lonafarnib treatment regimens were well-tolerated, showing comparable discontinuation rates across all arms and comparable TEAEs across the active treatment arms, ranging from 94-96% in each of the active treatment groups and 71% in the placebo group. Mild to moderate gastrointestinal issues were the main adverse effects reported in the study. In general, both lonafarnib-based treatment regimens were well-tolerated: Discontinuation due to treatment emergent adverse events occurred in 9% patients treated with the oral regimen and 8% from the combination therapy arm. This compares to 2% of patients in each of the peginterferon alfa and placebo groups.
[0255] The majority of treatment emergent adverse events across all treatment groups were reported as mild or moderate in severity. As expected, the most frequent treatment emergent adverse events associated with lonafarnib treatment were gastrointestinal-related. Serious treatment emergent adverse events were reported in 8% of patients treated with the oral regimen. The proportion of patients reporting serious treatment emergent adverse events treated with combination therapy was 14%. These compare with 10% in patients treated with peg alpha alone and 4% of the patients in the placebo group. There were two deaths reported during the course of the study: one patient treated with peginterferon alfa died due to decompensated cirrhosis that was attributed to drug therapy. The other death was an apparent cardiac-related death in the lonafarnib/ritonavir arm which was deemed unrelated to study drug by the local investigator.
H. Dose Modifications
[0256] As shown in Table 7 , overall, treatment compliance throughout the 48 weeks of the study was very good at more than 80% in each of the four treatment groups. Physicians were permitted to modify treatment for their patients during the course of this study. By week 48, 33% of patients across the three active arms had a dose reduction, and 50% of those who reduced subsequently dose increased (i.e. the dose reduction was temporary).
Table 7. Incidences of dose modifications during the course of treatment.
Figure imgf000059_0001
Example 4. Preliminary End of Study Week 72 or Post-Treatment Week 24Results
A. Composite endpoint at week 72 or post-treatment week 24
[0257] At the time the preliminary data discussed in this Example were obtained, 211 patients have completed the follow-up phase to week 72. Patients that discontinued treatment at week 48 are not included in this group, so the composite endpoint response rate at week 72 shown in FIG. 9 is higher than for the week 48 data shown in FIG. 3. See data summarized in Tables 8, 9A, and 9B.
Table 8. Composite endpoint response through end of follow-up
Figure imgf000060_0001
Table 9A. Data recap - virologic/biochemical endpoints
Figure imgf000060_0002
Table 9B. Data recap - histological endpoint
Figure imgf000060_0003
*>2-point improvement in HAI Score and No Worsening in Ishak Fibrosis Score B. >2 log decline in HDV RNA levels and ALT normalization at week 72
[0258] As shown in FIG. 10, we observed significant declines in HDV RNA levels at week 72 for both study arms of patients treated with LNF + RTV. 25% of patients treated with LNF + RTV (oral) showed >2 log decline in HDV RNA levels. 37.3% of patients treated with LNF + RTV+PEG IFN-alfa-2a showed a >2 log decline in HDV RNA levels. In comparison, none of the patients treated with placebo showed a >2 log decline in HDV RNA levels at the 72-week timepoint. Therefore, the response to treatment we observed at week 48, as shown in FIG. 4, was sustained.
[0259] As shown in FIG. 11, we also observed significant ALT normalization at week 72 for the study arms of patients treated with LNF + RTV (oral) or with LNF + RTV + PEG IFN-alfa-2a (combo) compared to patients treated with placebo. 25% of patients treated with LNF + RTV showed ALT normalization at 72 weeks, whereas 37.3% of patients treated with LNF + RTV + PEG IFN-alfa-2a showed ALT normalization at 72 weeks and only 4.2% of patients treated with placebo showed ALT normalization at 72 weeks.
C. Mean HDV RNA levels and ALT decline during 48-week treatment and 24-week post-treatment timepoints
[0260] As shown in FIG. 12, the overall change in HDV levels observed during treatment and posttreatment (72 weeks) varied by study arm. Interestingly, the initial rapid decrease in HDV levels and then increase in HDV levels observed at week 48 for LNF + RTV (oral) and LNF + RTV + PEG IFN-alfa-2a (combo) shown in FIG. 7 was followed by a transient increase in HDV RNA levels during the posttreatment period. As shown in FIG. 13, this transient increase in HDV RNA levels coincides in time with a transient increase in ALT levels (U/L) for patients that had been treated with LNF+RTV (oral) or LNF + RTV + PEG IFN-alfa-2a (combo).
Example 5. Week 48, Post-Treatment Week 24, and Week 72 Study Results
[0261] The post-treatment week 24 data discussed in this Example were obtained both from (1) the patients who stopped treatment before week 48 and were followed for 24 weeks after the treatment was stopped and (2) the patients who completed 48 weeks of treatment and were subsequently followed for 24 weeks to week 72 of the study. There were 338 such patients in total. Week 72 data were obtained from the patients who completed all 72 weeks of the study (312 patients).
[0262] The primary composite endpoint at week 48, defined as a > 2 logic reduction in HDV RNA level and ALT normalization relative to baseline, was met with evidence of statistical significance for both LNF-based regimens (Table 8). Key secondary endpoints were also met for both LNF-based regimens. The significance level for LNF + RTV vs. placebo was 0.03, and that for LNF + RTV + Alfa vs. placebo was 0.02. Histologic composite endpoint was > 2-point improvement in HAI score and no worsening in Ishak fibrosis score. The results summarized in Table 10 show response rate for 229 participants with evaluable biopsy: LNF + RTV (n = 107), LNF + RTV + Alfa (n = 66), Alfa (n = 26), and Placebo (n = 30).
Table 10. Summary of week 48 and post-treatment week 24 study results
Figure imgf000062_0001
[0263] The study data summarized above provided a compelling body of evidence for the effectiveness of LNF-based therapy. It also provided a sound clinical rationale for using LNF-therapy as a finite treatment of chronic HDV infection. HDV suppression (response to the composite efficacy endpoint at post-treatment week 24) occurred in 13.9% (p < 0.0001 vs placebo) of patients treated with LNF + RTV and 26.0% (p < 0.0001 vs placebo) of patients treated with LNF + RTV + Alfa. The proportion of patients with a response of both viral load < LLOQ ("target detected" (TD) and "target not detected" (TND) and ALT normalization at post-treatment week 24 was 6.3% (p = 0.0015 vs placebo) for patients treated with LNF + RTV and 17.3% (p < 0.0001 vs placebo) for patients treated with LNF + RTV + Alfa. The < LLOQ (TD) response rate for the LNF + RTV + Alfa regimen was 10.6% (p = 0.04 vs placebo) at post-treatment week 24. ALT normalization at post-treatment week 4 was observed in 25.7% treated with the LNF + RTV regimen (p < 0.0001 vs placebo) and 38.5% of patients treated with the LNF + RTV + Alfa regimen (p < 0.0001). Disease control (viral load < LLOQ (TD and TND) at post-treatment week 24) was achieved in 21.2% of patients with LNF + RTV + Alfa (p < 0.0001 vs placebo). Viral load < LLOQ (TD) at post-treatment week 24 was achieved in 10.6% patients treated with LNF + RTV +Alfa (p = 0.04 vs placebo). Viral load < LLOQ (TND) at post-treatment week 24 was also achieved in 10.6% patients treated with LNF + RTV +Alfa (p = 0.0003 vs placebo). For reference, Alfa monotherapy response was 4.9%. Importantly, treatment with LNF-based regimens resulted in significant evidence of disease modifying activity as demonstrated histologically by improvement or no change in the fibrosis score and reduction of inflammation and necrosis at week 48; 53% histologic response rate with LNF + RTV +Alfa (p = 0.014 vs placebo).
A. Efficacy at week 48
1. Composite response
[0264] The primary endpoint of a > 2 logw reduction in HDV RNA level and ALT normalization relative to baseline was achieved with significance in both LNF-based treatment arms, LNF + RTV and LNF + RTV + Alfa (FIG. 14). Study participants receiving LNF + RTV and LNF + RTV + Alfa showed a week 48 composite response of 10.1% (p = 0.0044) and 19.2% (p < 0.0001), respectively, compared to those receiving placebo (1.9%). The composite response rate in the Alfa monotherapy comparator arm, included in the study to show contribution of effect, was 9.6%. The composite response rate in the LNF + RTV + Alfa arm was twice that of the Alfa monotherapy arm (19.2% vs 9.6%).
2. Virologic and biochemical responses
[0265] The secondary endpoints of virologic response (> 2 logio decline in HDV RNA) and biochemical response (ALT normalization) at week 48 were achieved with significance in both LNF-based treatment arms (FIG. 15 and FIG. 16). Study entry required HDV RNA > 500 lU/mL by qPCR assay prior to initiation of study treatment. Significance level for the virologic response (0.03 for LNF + RTV vs placebo and 0.02 for LNF + RTV + Alfa vs placebo) had to be met to test the biochemical response. Study participants receiving LNF + RTV and LNF + RTV + Alfa showed a virologic response of 14.6% (p = 0.0026) and 32% (p < 0.0001), respectively, compared to those receiving placebo (3.8%). Viral loads over time are shown in the next subsection. The biochemical response rates were 24.7% (p = 0.003) and 34.4% (p < 0.0001) for the LNF + RTV and LNF + RTV + Alfa arms, respectively, compared to 7.7% for those receiving placebo. By end of treatment, week 48, 20.8% of participants receiving LNF + RTV + Alfa were below the LLOQ (TD or TND); FIG. 17). 3. Histologic response
[0266] Histologic response at week 48 was defined as > 2-point improvement in Ishak HAI and no worsening of fibrosis by Ishak scoring. A total of 229 evaluable paired biopsies at baseline and week 48 were collected. The statistical analysis was multiplicity controlled using a fixed-sequence method and the stringent p-value requirement (alpha = 0.03 for LNF + RTV, alpha = 0.02 for LNF + RTV+ Alfa) Histologic response was seen in 33% of patients treated with the LNF + RTV regimen (N/S) and 53% of patients treated with LNF + RTV + Alfa (p = 0.0135; Table 11). The histologic composite endpoint was met in 35 out of 66 (53%) patients treated with LNF + RTV + Alfa, significantly more than in the placebo arm (6 of 30, p = 0.0135) (Table 11 and Table 12). Forty-eight weeks of treatment with LNF + RTV + Alfa was associated with an improvement in liver histology; inflammation, necrosis, and fibrosis were reduced with treatment. Ishak HAI and fibrosis scores decreased from baseline among those patients with a histologic response, compared with an increase among patients who did not achieve a response. The study demonstrated significant improvement in histology in the LNF + RTV + Alfa treatment group. This is of particular importance because analysis of liver histology is the most direct way to assess improvements in liver injury such as necrosis and inflammation, as well as scarring in the form of fibrosis.
Table 11. Histology composite endpoint response rates at week 48 (histologic composite endpoint)
Figure imgf000064_0001
Table 12. Mean change in Ishak HAI and fibrosis scores at week 48 - histology evaluable participants
Figure imgf000065_0001
* Difference versus placebo p = 0.6247 (CMH test)
** Difference versus placebo p = 0.0135 (CMH test)
# Difference versus placebo p = 0.46 (CMH test)
1 Ishak HAI score based on an 18-point scoring system
2 Ishak fibrosis score based on a 6-point scoring system
Abbreviations: Alfa = peginterferon alfa-2a; CMH = Cochran-Mantal-Haenszel; HAI = histology activity index; LNF = lonafarnib; RTV = ritonavir.
[0267] In general, histologic response was associated with either an improvement or no change in the Ishak fibrosis score (Table 13). A similar number of patients who achieved a histologic response had either no change or improvement in the fibrosis score in the LNF + RTV and Alfa monotherapy groups. In contrast, two-thirds (62.9%) of patients treated with LNF + RTV + Alfa demonstrated no change in the fibrosis score, and 37.1% demonstrated an improvement. Among the patients who did not achieve a histologic response, the fibrosis score worsened in 44% of those treated with Alfa monotherapy compared with 22.2% and 32.3% of those treated with the LNF + RTV and LNF + RTV + Alfa regimens, respectively. Table 13. Ishak fibrosis score at week 48 - histology evaluable participants
Figure imgf000066_0001
* Difference versus placebo, p = 0.6247 (CMH test)
" Difference versus placebo, p = 0.0135 (CMH test)
# Difference versus placebo, p = 0.46 (CMH test)
1 The Modified Ishak HAI Score is calculated on an 18-point scale and is the sum of individual scores in the following four domains: (1) periportal or periseptal interface hepatitis; (2) confluent necrosis; (3) focal spotty lytic necrosis, apoptosis and focal inflammation; and (4) portal inflammation.
Abbreviations: Alfa = peginterferon alfa-2a; CMH = Cochran-Mantel-Haenszel; HAI = histology activity index; LNF = lonafarnib; RTV = ritonavir.
[0268] Responders to the histologic endpoint treated with the LNF + RTV regimen had an end-of- treatment mean HDV RNA of 1.7 logic lU/mL compared with 5.0 logic lU/mL among non-responders. The end-of-treatment mean logic change from baseline in HDV RNA was -1.5 logic lU/mL amongst histologic responders compared with an increase of 0.1 logic lU/mL amongst the histologic non-responders.
Similar results were observed amongst patients treated with LNF + RTV + Alfa. Responders to the histologic endpoint had an end-of-treatment mean log HDV RNA of 1.6 lU/mL compared with
4.4 logw lU/mL amongst the patients who did not meet the histologic endpoint. The end-of-treatment mean logic change from baseline in HDV RNA was -2.2 logio lU/mL amongst histologic responders compared with compared with -1.5 logw lU/mL amongst the histologic non-responders. The above data demonstrated that patients who had a histological response to treatment with LNF-based regimens at week 48 generally achieve the specified viral decline threshold sooner after the initiation of treatment, and had a significantly longer duration of viral suppression, compared with non-responders.
[0269] Although patients who achieved a histology response treated with the LNF + RTV regimen had a longer median duration of viral suppression compared to non-responders, the difference was not significant: 14.5 weeks and 8.7 weeks, respectively, HR 0.68. For patients treated with LNF + RTV + Alfa, however, the median duration of viral suppression (3 2 logic reduction from baseline in HDV RNA) was significantly longer for week 48 histology responders compared to non-responders. With viral suppression thresholds of 2.5 and 2.0 logic, the median was reached at 31.7 and 24.1 weeks, respectively, significantly longer than the non-responders (p = 0.0179 [HR = 0.44] and 0.0053 [HR = 0.34]), respectively. The above data demonstrated that the viral suppression is both more pronounced and more durable.
B. Relationship between clinical efficacy response and histologic response at week 48
[0270] Table 14 shows the number of patients in each treatment group who achieved either the composite primary endpoint, the virologic endpoint, or the biochemical endpoint, and also achieved a histologic response (denoted as n), relative to the number of patients achieving the clinical endpoint alone among patients with paired liver biopsies (denoted as N). In general, when treatment with LNF- based therapy results in a patient achieving one of the clinical endpoints, there is a high probability the patient will also achieve a histologic response. Overall, a greater proportion of patients treated with LNF-based therapy achieved both a clinical and histologic response compared to patients treated with Alfa alone: Specifically, 57.1%-64.5% of patients treated with one of the LNF-based regimens achieved both a clinical and histologic endpoint, compared with only 33% or fewer patients treated with Alfa alone. A comparison of the two LNF-based regimens shows a slightly greater proportion of patients treated with LNF + RTV achieved a composite and histologic response compared to those treated with LNF + RTV + Alfa. Conversely, the proportion of patients who achieved either a virologic or biochemical response as well as a histologic response was greater among those treated with the LNF + RTV +Alfa regimen, with response rates more than double those observed for patients treated with Alfa alone. Table 14.
Number and proportion of patients achieving both a clinical and histologic endpoint at week 48
Figure imgf000068_0001
Abbreviations: Alfa = peginterferon alfa-2a; LNF = lonafarnib; n = number of patients achieving both the clinical endpoint and the histologic endpoint, N = number of patients achieving the clinical endpoint; RTV = ritonavir.
1. Relationship between histologic response and virologic response at week 48
[0271] In general, patients receiving active treatment and those achieving a histologic response had a meaningful decline in viral load from baseline (range -4.6 to -3.1 logic lU/mL) compared to those patients who did not achieve the endpoint (-3.7 to -3.3 logic IU/mL). The data are summarized in Table 15.
Table 15. Mean change in logic HDV RNA among patients who achieved a histologic and virologic response at week 48
Figure imgf000068_0002
Abbreviations: Alfa = peginterferon alfa-2a; HDV = hepatitis Delta virus; RNA = ribonucleic acid; LNF = lonafarnib; n = number of patients achieving both the clinical endpoint and the histologic endpoint, N = number of patients achieving the clinical endpoint; RTV = ritonavir.
[0272] The mean change in logic HDV RNA and mean change in Ishak HAI score have a statistically significant positive linear relationship: Pearson's coefficient 0.347, p < 0.0001. The comparison of the mean change in HAI score in patients with evaluable histology from the LNF + RTV + Alfa treatment group who achieved biochemical response at week 48 (2.53) and those who did not ( .67) is statistically significant (p < 0.0001). The mean change in the Ishak HAI score was -3.47 compared to -0.34 for patients who did not achieve a virologic response. Similar findings were observed for patients with evaluable histology and treated with LNF + RTV + Alfa: for patients achieving a virologic response at week 48, the mean change in HAI score was -2.77 compared to -1.48 for patients who did not achieve the virologic response. There was no difference in the change in Ishak HAI for patients treated with Alfa who achieved a virologic response (-1.00) and those who did not (-1.15).
2. Relationship between histologic response and biochemical response at week 48
[0273] Among patients with a histologic response, a total of 29.9% of patients treated with LNF + RTV and 39.3% of patients treated with LNF + RTV + Alfa also achieved a biochemical response at week 48 (Table 16). The greatest mean decrease in ALT from baseline was associated with treatment with LNF + RTV + Alfa (-91.0 I U/L). The mean decrease among patients who achieved the histologic endpoint was approximately 1.5-fold greater among patients treated with LNF-based regimens compared to those treated with Alfa.
Table 16.
Mean change in ALT among patients who achieved a histologic and biochemical response at week 48
Figure imgf000069_0001
Note: Biochemical response is defined as normalization of ALT at week 48.
Abbreviations: Alfa = peginterferon alfa-2a; ALT = alanine aminotransferase; LNF = lonafarnib; RTV = ritonavir.
[0274] There is a statistically significant correlation between the mean change in Ishak HAI score and mean change in ALT levels in the LNF + RTV + Alfa treatment group (Pearson's correlation coefficient: 0.142, p = 0.0313). The comparison of the mean change in HAI score in patients with evaluable histology from the LNF + RTV + Alfa treatment group who achieved biochemical response at week 48 (-2.24) and those who did not (-0.72) is statistically significant (p = 0.0004). For patients with evaluable histology treated with LNF + RTV and achieving a biochemical response at week 48, the mean change in the Ishak HAI score was -2.06 compared to -0.40 for patients who did not achieve a biochemical response (Table 17). The same findings were observed for patients with evaluable histology treated with LNF + RTV + Alfa: for patients achieving a biochemical response at week 48, the mean change in HAI score was -1.~n compared to -1.48 for patients who did not achieve the biochemical response. In contrast, patients treated with Alfa monotherapy and not achieving a biochemical response had a greater decrease in the Ishak HAI score than those who did achieve a biochemical response: -1.30 vs -0.33, respectively.
Table 17. Mean change in Ishak HAI score according to biochemical response at week 48
Figure imgf000070_0001
Abbreviations: Alfa = peginterferon alfa-2a; HAI = histology activity index; LNF = lonafarnib; RNA = ribonucleic acid; RTV = ritonavir.
C. Efficacy 24 weeks after cessation of treatment
[0275] A total of 361/407 randomized patients entered the 24-week off-treatment follow-up period. Per protocol, patients who discontinued treatment early, prior to week 48, were required to be followed for 24 weeks post-treatment. Therefore, the 24-week follow-up period included patients who discontinued treatment prior to week 48 as well as patients who completed 48 weeks of study treatment). A total of 328 patients had completed the 24-week follow-up period and were evaluated for secondary endpoints at post-treatment week 24.
[0276] Two analyses were performed for the data collected at post-treatment week 24: an "all randomized" patient analysis (n = 328), including patients who completed 24 weeks of post-treatment follow-up, regardless of whether they discontinued treatment early; and a "completers" patient analysis (n = 301) of patients who completed 48 weeks of treatment and 24 weeks of follow-up. In general, the response rate associated with LNF-based treatment was greater at post-treatment week 24, compared to week 48 for each of the clinical efficacy endpoints. These results may have important clinical consequences, particularly for patients with viral loads < LLOQ. (TD or TND), < LLOQ (TD) and < LLOQ (TND) at post-treatment week 24. The study data showed the potential for LNF-based treatments as finite therapies, since lower viral loads are generally associated with favorable long-term clinical outcomes in other viral hepatitides. 1. Composite response
[0277] The composite primary efficacy endpoint is a direct measure of HDV suppression. The response rate for all randomized patients at week 48 and post-treatment week 24 (n = 328) is shown in FIGS. 18A- 18B. The proportion of patients who achieved a response to the composite primary efficacy endpoint was greater at post-treatment week 24, compared to week 48, for both LNF-based regimens. The posttreatment week 24 response rates were also highly significantly different compared to placebo:
LNF + RTV vs placebo (13.9% vs 0%) (p < 0.0001); and LNF + RTV + Alfa vs placebo (26.0% vs 0%) (p < 0.0001).
2. Virologic response
[0278] Week 48 and post-treatment week 24 virologic response (> 2 logw decline in HDV RNA) for the 328 patients is shown in FIG. 19 and reflects the extent of treatment-related disease control at POSTTREATMENT WEEK 24. The virologic response rates improved from 17.4% at week 48 to 21.5% posttreatment week 24 for the LNF + RTV group. The estimated difference between LNF + RTV and placebo was 19.1%, (p < 0.0001) at post-treatment week 24. For the LNF + RTV + Alfa group, the response rate was comparable between week 48 and post-treatment week 24. There was an estimated difference of 31.1% between LNF + RTV + Alfa compared to placebo at post-treatment week 24 (p < 0.0001).
[0279] Further examination of the data demonstrated that 4.2% of patients treated with LNF + RTV and 10.6% of patients treated with LNF + RTV + Alfa achieved viral loads < LLOQ (TD) (N/S and p = 0.04, respectively, compared to placebo) at post-treatment week 24 (FIG. 21). Finally, 2.1% of patients treated with LNF + RTV and 10.6% of patients treated with LNF + RTV + Alfa achieved viral loads < LLOQ (TND) (N/S and p = 0.0003, respectively, compared to placebo) at post-treatment week 24.
3. Biochemical response
[0280] The proportion of patients achieving ALT normalization at week 48 was greater with LNF + RTV (24.7%) and LNF + RTV + Alfa (34.4%) than with Alfa monotherapy (11.5%). The proportion of patients achieving ALT normalization at post-treatment week 24 is shown in FIG. 22. Treatment with LNF + RTV + Alfa was associated with the largest proportion of patients (38.5%) achieving ALT normalization at posttreatment week 24. The post-treatment week 24 ALT data in concert with the virologic response are potentially clinically important. Sustained suppression of viral load along with ALT normalization has been shown to reduce the risk for long-term adverse clinical outcomes in other forms of viral hepatitides [0281] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
Example 6. Post-Treatment Week 24 Sensitivity Analyses
A. Completers' analysis
[0282] A sensitivity analysis was conducted on the 301 patients who completed all 72 weeks of the study, including the week 48 visit. Response to the composite primary efficacy endpoint persisted through the 24-week follow-up period (Table 18). In general, the response rates for the LNF + RTV + Alfa regimen were greater than those for Alfa monotherapy. Among completers treated with LNF + RTV + Alfa, the response rate at POST-TREATMENT WEEK 24 (29.0%) for the composite primary efficacy endpoint was greater than at week 48 (19.2%; FIG. 14), and highly significantly different compared to placebo (p < 0.0001). Similarly, the response rate for the LNF + RTV treatment group of 15.3% (p < 0.0001 compared to placebo) at POST-TREATMENT WEEK 24 was greater than that observed at week 48 (10.1%). The virologic response rate (< 2 logic reduction HDV RNA) at POST-TREATMENT WEEK 24 was 22.9% and 36.6% for the LNF + RTV and LNF + RTV + Alfa regimens, respectively. Importantly, 23.7% of patients treated with the LNF + RTV + Alfa regimen had a viral load < LLOQ (TD or TND); 11.8% of patients had viral load < LLOQ (TD) and 11.8% of patients with viral load < LLOQ (TND). The virologic response rates 24 weeks post-treatment in conjunction with the proportions of patients who also achieved ALT normalization at the same timepoint are suggestive of disease control, and of potential long-term clinical consequence with respect to risk for liver-related morbidity and mortality.
Table 18. Response rates in patients who completed all 72 weeks of the study (n = 301)
Figure imgf000073_0001
[0283] The impact of cessation of therapy on clinical outcomes was further examined using the data from the 301 patients who completed 24 weeks of off treatment follow-up. As shown in Table 13 and Table 14, four subgroups of response patterns to the composite primary endpoint at week 48 and POSTTREATMENT WEEK 24 were identified:
I. Response at both timepoints (Y/Y);
II. Response at week 48 but non-response at post-treatment week 24 (Y/N);
III. Non-response at week 48 but response at post-treatment week 24 (N/Y);
IV. Non-response at both timepoints (N/N).
Collectively, the response rates at week 72, after 48 weeks of treatment and 24 weeks of follow-up, illustrated the full potential clinical benefit of the LNF-based regimens for use in the clinical setting.
[0284] Response to the composite endpoint at post -treatment week 24 was greatest following treatment with LNF + RTV + Alfa (29.0%, Table 19). The overall post-treatment week 24 response rate for LNF + RTV was not different to that for treatment with Alfa (15.3% and 15.4% respectively), driven primarily by off-treatment effects observed in patients who did not achieve the composite endpoint response at week 48 but did at post-treatment week 24 (14 patients, 10.7%). Similar results were observed for LNF + RTV + Alfa: a total of 19 (20.4%) patients reached the composite endpoint during the 24-week follow-up period. This contrasts with only 3 new (7.7%) patients treated with Alfa who reached the composite endpoint at post-treatment week 24.
Table 19.
Identification of composite endpoint response patterns between weeks 48 and post-treatment week 24
Figure imgf000074_0001
Abbreviations: Alfa = peginterferon alfa-2a; LNF = lonafarnib; N = no response; POST-TREATMENT WEEK 24 = post-treatment week 24; RTV = ritonavir; Y = yes response.
Table 20.
Identification of virologic endpoint response patterns between weeks 48 and post-treatment week 24
Figure imgf000074_0002
Abbreviations: Alfa = peginterferon alfa-2a; LNF = lonafarnib; N = no response; POST-TREATMENT WEEK 24 = post-treatment week 24; RTV = ritonavir; Y = yes response.
[0285] Treatment with LNF + RTV + Alfa was associated with the largest overall virologic response (36.6% Table 20). A total of 18 (13.7%) and 14 (15.1%) of patients treated with LNF + RTV or LNF + RTV + Alfa, respectively, developed an off-treatment virologic response. This contrasts with only 1 patient (2.6%) treated with Alfa who developed a virologic response during the follow-up period. It was concluded that post -treatment virologic responses were generally due to "beneficial" flares, likely resulting from reconstitution of the immune system.
B. Post-treatment changes in fibrosis score in patients achieving a virologic response 24 weeks after cessation of treatment
[0286] The mean FibroScan result (KPa) and change in FibroScan result for patients who developed a virologic response after Week 48 (N/Y) and for those who maintained a virologic response between Week 48 and post-treatment week 24 (Y/Y) are shown in Table 21 and Table 22, respectively.
Table 21. FibroScan results (mean KPa) at week 48 and post-treatment week 24 according to virologic response at week 48
Figure imgf000075_0001
Abbreviations: Alfa = peginterferon alfa-2a; LNF = lonafarnib; N = no; POST-TREATMENT WEEK 24 = 24- weeks post-treatment; RTV - ritonavir; Y = yes.
Table 22. FibroScan results (mean change from baseline KPa) at week 48 and post-treatment week 24 according to virologic response at week 48
Figure imgf000075_0002
Abbreviations: Alfa = peginterferon alfa-2a; LNF = lonafarnib; N = no; POST-TREATMENT WEEK 24 = 24- weeks post-treatment; RTV = ritonavir; Y = yes. [0287] In general, non-invasive markers of fibrosis (FibroScan) showed continued improvement in those patients who developed a post-treatment virologic response (N/Y). For patients treated with LNF + RTV the mean change from baseline was -0.17 KPa at week 48 and -1.41 KPa at POST-TREATMENT WEEK 24. The corresponding results for patients treated with LNF + RTV + Alfa were -0.51 KPa and -0.26 KPa at week 48 and post-treatment week 24, respectively. Similarly, the improvement in liver elasticity was maintained in those patients who achieved a virologic response at both Week 48 and POST-TREATMENT WEEK 24 (Y/Y). For patients treated with LNF + RTV the mean change from baseline was not meaningfully different at Week 48 and post-treatment week 24: -3.3 KPa and -2.98 KPa, respectively. For patients treated with LNF + RTV + Alfa the mean change from baseline was -1.16 KPa at Week 48 and - 2.60 KPa at POST-TREATMENT WEEK 24. Similar findings were observed based on FibroTest results.
C. Virologic response between week 48 and post-treatment week 24
[0288] Importantly, 19 (13.2%) patients treated with the LNF + RTV regimen who were nonresponders to the virologic endpoint at Week 48 achieved a virologic response at POST-TREATMENT WEEK 24. Among patients treated with the LNF + RTV + Alfa regimen, 15 (14.4%) who were nonresponders at Week 48 achieved a virologic response at post-treatment week 24.
Example 7. Efficacy Results
[0289] The response rates 24 weeks after cessation of treatment, which are discussed in the previous Example, are of potentially great clinical importance in the context of a 48-week finite therapy. In an analysis of the 328 patients completing 24 weeks of off-treatment follow-up, the composite endpoint was achieved at post-treatment week 24 by 13.9% and 26.0% of patients treated with the LNF + RTV and LNF + RTV + Alfa regimen, respectively, indicating suppression of HDV infection in these patients. In the same analysis of 328 patients, the virologic endpoint at post-treatment week 24 was achieved by 21.5% of patients treated with the LNF + RTV regimen and 33.7% of patients treated with the LNF + RTV + Alfa regimen. The proportion of patients with a virologic response < LLOQ (TD or TND) was 6.3% and 21.2% for the LNF + RTV and LNF + RTV + Alfa regimens, respectively, demonstrating control of the HDV infection in these patients. Viral loads < LLOQ (TD) were achieved by 4.2% of patients treated with LNF + RTV and 10.6% of patients treated with LNF + RTV + Alfa. The respective response rates for < LLOQ (TND) are 2.1% and 10.6%. [0290] Among the 301 patients who completed 72 weeks of study (48 weeks treatment and 24 weeks of follow-up), the composite endpoint response rates with the LNF + RTV and LNF + RTV + Alfa regimens were 15.3% and 29.0%, respectively. The virologic response rates for > 2 logic decline in HDV RNA were 22.9% and 36.6% for LNF + RTV and LNF + RTV + Alfa regimens, respectively. These data illustrate the potential clinical benefit obtained when patients are compliant with a finite 48-week period of LNF- based therapy.
[0291] Overall, the study results, in conjunction with evidence of disease modification from liver biopsies and continued improvement in liver elasticity (FibroScan), provide compelling support for the effectiveness of LNF-based therapy in the treatment of chronic HDV infection. These results may have consequences for the risk of long-term liver-related morbidity and mortality, demonstrating the clinical benefit that may be derived from the treatment of chronic HDV with LNF-based therapy.
Example 8. Early on-Treatment Change in Viral Load Can Be Used as the Basis for a Response-Guided Approach to Therapy with LNF-Based Regimens
[0292] The study uncovered the potential for response-guided LNF-based therapy. Response-guided therapy can identify patients with a very low likelihood of achieving a clinical response as early as possible following the initiation of treatment with one of the LNF-based regimens, thereby minimizing exposure to ineffective therapy. Conversely, patients who continue treatment would have a higher effective response rate as patients with a low likelihood of achieving a response have been removed from the calculation.
[0293] On-treatment responses to therapy were examined for potential utility as a predictor for clinical responses, with the illustrative cases summarized below. The on-treatment viral load kinetics of LNF-based therapy can distinguish between responders and non-responders at the week 48 end-of- study timepoint. The potential utility of logio HDV RNA, as a predictive on-treatment biomarker for response to LNF-based therapy was explored using threshold analyses. The following thresholds were explored as examples of on-treatment measures of response at each timepoint from week 8 - week 24: a range of 1 logw HDV RNA decrease to a 3 logio HDV RNA decrease; and slope of change in log10 HDV RNA.
[0294] The findings were characterized by a Positive Predictive Value (PPV) for treatment futility. A
PPV for treatment futility is defined as the proportion of patients that fail to achieve the required thresholds at the specified timepoint, and also fail to meet a clinical endpoint of interest at week 48 (null response). The effective response rate is defined as the response rate for patients who remain on treatment and achieve a clinical response. Application of an algorithm for identifying a null response increases the effective response rate compared to the overall study results for both the LNF + RTV and LNF + RTV + Alfa regimens.
[0295] Illustrative cases below are provided for two potential algorithms for identifying a null response.
Algorithm A: Failure to achieve a > 2 logic HDV RNA reduction and a negative slope (continued decline) for 3 consecutive visits (timepoints). A decline in HDV RNA starting at a visit 12 weeks after the initiation of treatment and continuing at visits 16 and 20 weeks after the initiation of treatment would be an example of a decline over 3 consecutive visits. Another example might be a decline in HDV RNA starting at a visit 12 weeks after the initiation (start) of treatment and continuing at visits 18 and 22 weeks after initiation (start) of treatment. Another example might be a decline in HDV RNA starting at a visit 16 weeks after the initiation (start) of treatment and continuing at visits 20 and 24 weeks after initiation (start) of treatment. The time interval between visits may vary but is unlikely to be less than 4-weeks per current clinical practice.
Algorithm B: Failure to achieve a > 2 logic HDV RNA reduction.
In general, defining a clinical response based on a > 2 logic HDV RNA reduction and a negative slope (continued decline) for 3 consecutive visits (timepoints) yields higher effective response rates than defining a clinical response based on a > 2 logic HDV RNA reduction alone.
A. Illustrative case 1 (Algorithm A)
[0296] The effective response rates at week 48 and post-treatment week 24 achieved by application of Algorithm A at week 12 to patients treated with LNF + RTV or LNF + RTV + Alfa are shown in Table 23. Not only are the effective response rates increased, but the "predictive value" for null response (PPV) is extremely strong. Table 23. Effective response rates based on Algorithm A: > 2 LoglO HDV RNA reduction at week 12 and a negative slope for 3 consecutive visits (timepoits)
Figure imgf000079_0001
Abbreviations: ALT = alanine aminotransferase, HAI = histology activity index, HDV = hepatitis delta virus; LLOQ = lower limit of quantitation; LNF = lonafarnib; N/A = not applicable; PPV = positive predictive value; POST-TREATMENT WEEK 24 = 24 weeks post-treatment; RNA = ribonucleic acid; RTV = ritonavir; TD = target detected; TND = target not detected.
Table 24. Effective response rates based on Algorithm B: > 2 LoglO HDV RNA reduction at week 12
Figure imgf000079_0002
Abbreviations: ALT = alanine aminotransferase, HAI = histology activity index, HDV = hepatitis delta virus; LLOQ = lower limit of quantitation; LNF = lonafarnib; N/A = not applicable; PPV = positive predictive value; POST-TREATMENT WEEK 24 = 24 weeks post-treatment; RNA = ribonucleic acid; RTV = ritonavir; TD = target detected; TND = target not detected. B. Illustrative case 2 (Algorithm B)
[0297] The effective response rates achieved by application of Algorithm B at week 12 to patients treated with LNF + RTV and LNF + RTV + Alfa are shown in Table 24. The effective response rates are increased.
[0298] Initial analyses indicate an algorithm predictive for a null response can identify those patients with a high probability of not achieving a clinical endpoint at week 48; thereby allowing early cessation of treatment for likely futility and minimizing exposure to side effects of treatment. Importantly, the algorithm is also able to identify those patients treated with either LNF-based regimen with a high probability of non-response at post-treatment week 24, after cessation of treatment.
[0299] It should be understood that, although the present invention has been specifically disclosed by certain aspects, embodiments, and optional features, modification, improvement and variation of such aspects, embodiments, and optional features can be resorted to by those skilled in the art, and that such modifications, improvements, and variations are considered to be within the scope of this disclosure.
[0300] The inventions have 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. In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group.
[0301] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

Claims

WHAT IS CLAIMED IS:
1. A method of treating hepatitis delta virus (HDV) infection in a patient, the method comprising administering to the patient a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor.
2. The method of claim 1, wherein the interferon alpha is pegylated interferon alpha.
3. The method of claim 1 or 2, wherein the interferon alpha is pegylated interferon-alfa-2a.
4. The method of any one of claims 1 to 3, wherein the interferon alpha is administered at a dose of about 120 to 180 mcg per week.
5. The method of any one of claims 1 to 4, wherein interferon alpha is administered by subcutaneous injection at about 180 mcg QW.
6. The method any one of claims 1 to 5, wherein the CYP3A4 inhibitor is ritonavir.
7. The method any one of claims 1 to 6, wherein the patient has chronic HDV for at least 6 months in duration before the administration of lonafarnib.
8. The method of any one of claims 1 to 6, wherein lonafarnib is administered at about 50 to about 200 mg per day.
9. The method of any one of claims 1 to 8, wherein lonafarnib is administered orally at 50 mg BID.
10. The method of any one of claims 1 to 9, wherein ritonavir is administered at a daily dose of about 50 to about 200 mg.
11. The method of any one of claims 1 to 10, wherein ritonavir is administered orally at 100 mg BID.
12. The method of any one of claims 1 to 11, wherein lonafarnib and ritonavir are administered for at least 12 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks, at least 54 weeks, or from 12 weeks to 96 weeks.
13. The method of any one of claims 1 to 12, wherein lonafarnib and ritonavir are administered for 48 weeks.
14. The method of any one of claims 1 to 13, wherein the patient has both a > 2 logiodecline in HDV RNA levels and normalized alanine aminotransferase (ALT) levels within 48 weeks of treatment.
15. The method of any one of claims 1 to 13, wherein the patient has both a > 2 logic decline in HDV RNA levels and normalized alanine aminotransferase (ALT) levels within 4, 8, 12, 24, 36, or 48 weeks of treatment.
16. The method of claim 14 or 15, wherein the > 2 logic decline in HDV RNA levels and the normalized alanine aminotransferase (ALT) levels are sustained post-treatment.
17. The method of any one of claims 14 to 16, wherein the > 2 logic decline in HDV RNA levels and the normalized alanine aminotransferase (ALT) levels are sustained for up to 24 weeks post-treatment.
18. The method of any one of claims 14 to 17, wherein the patient has the > 2 logiodecline in HDV RNA levels within 48 weeks of treatment.
19. The method of any one of claims 1 to 13, wherein the patient has a > 2 logic decline in HDV RNA levels within 4, 8, 12, 24, 36, or 48 weeks of treatment.
20. The method of claim 19, wherein the > 2 logiodecline in HDV RNA levels is sustained posttreatment.
21. The method of claim 19, wherein the > 2 logiodecline in HDV RNA levels is sustained for up to 24 weeks post-treatment.
22. The method of claim 19, wherein the patient has normalized alanine aminotransferase (ALT) levels within 48 weeks of treatment.
23. The method of claim 19, wherein the patient has normalized alanine aminotransferase (ALT) levels within 4, 8, 12, 24, 36, or 48 weeks of treatment.
24. The method of claim 23, wherein the normalized alanine aminotransferase (ALT) levels are sustained post-treatment.
25. The method of claim 23, wherein the normalized alanine aminotransferase (ALT) levels are sustained for up to 24 weeks post-treatment.
26. A method of treating hepatitis delta virus (HDV) infection in a patient, comprising administering a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor at regular intervals as a chronic therapy.
27. The method of claim 26, wherein the CYP3A4 inhibitor is ritonavir.
28. The method of claim 26 or 1 , wherein the regular intervals are every 6 months.
29. The method of any one of claims 26 to 28, wherein the administering a therapeutically effective amount of lonafarnib and a CYP3A4 inhibitor causes a > 2 logic decline in HDV RNA levels within 8 weeks of treatment.
30. The method of any one of claims 26 to 29, wherein the administering a therapeutically effective amount of lonafarnib and a CYP3A4 inhibitor causes a 30 to 40 U/L decline in ALT levels within 8 weeks of treatment.
31. The method of any one of claims 26 to 30, wherein the lonafarnib and a CYP3A4 inhibitor are coadministered with an interferon.
32. The method of claim 31, wherein the interferon is pegylated interferon.
33. The method of claim 32, wherein the interferon is pegylated interferon-alfa-2a.
34. The method of any one of claims 31 to 33, wherein the interferon is administered at a dose of
120 to 180 mcg per week.
35. The method of any one of claims 31 to 34, wherein the interferon is administered by subcutaneous injection at 180 mcg QW.
36. A method of reducing both the viral load and ALT levels in a patient with hepatitis delta virus (HDV) infection, the method comprising administering to the patient a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor.
37. The method of claim 36, wherein the patient has both a > 2 logiodecline in HDV RNA levels and normalized alanine aminotransferase (ALT) levels within 48 weeks of treatment.
38. The method of claim 36, wherein the patient has both a > 2 logic decline in HDV RNA levels and normalized alanine aminotransferase (ALT) levels within 4, 8, 12, 24, 36, or 48 weeks of treatment.
39. The method of any one of claims 36 to 38, wherein the > 2 logic decline in HDV RNA levels and the normalized alanine aminotransferase (ALT) levels are sustained post-treatment.
40. The method of any one of claims 36 to 39, wherein the > 2 logic decline in HDV RNA levels and the normalized alanine aminotransferase (ALT) levels are sustained for up to 24 weeks post-treatment.
41. The method of any one of claims 1 to 40, wherein the patient has improvement in liver histology within 48 weeks of treatment.
42. The method of claim 41, wherein the improvement of liver histology comprises > 2-point improvement in Ishak HAI and no worsening of fibrosis by Ishak scoring.
43. The method of any one of claims 1 to 41, wherein the patient has reduction in one or more of liver inflammation, liver necrosis, or liver fibrosis within 4, 8, 12, 24, 36, or 48 weeks of treatment.
44. The method of any one of claims 1 to 43, wherein the patient, after completion of the administering to the patient of the therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor, has one or more of following responses: further decline in HDV RNA levels, further decline in alanine aminotransferase (ALT) levels, further improvement of the liver histology, or further reduction in the one or more of liver inflammation, liver necrosis, or liver fibrosis.
45. The method of claim 44, wherein the one or more of the responses are observed in comparison to one or both start or the completion of the administering to the patient of the therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor.
46. The method of claim 44 or 45, wherein the patient has the one or more response at least 24 weeks after the completion of the administering to the patient of the therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor.
47. The method of any one of claims 1-46, wherein the patient has > 2 logw decline in HDV RNA levels at about 12 weeks of the administering to the patient of the therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor.
48. The method of any one of claims 1-47, wherein the patient has a decline in HDV RNA levels starting at a first timepoint after the start of the administering to the patient of the therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor and continuing through a second timepoint and a third timepoint during the administering to the patient of the therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor, wherein the second timepoint occurs after the first timepoint, and wherein the third timepoint occurs after the second timepoint.
49. The method of claim 48, wherein an interval between the start of the administering to the patient of the therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor and the first timepoint is at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, or at least 20 weeks.
50. The method of claim 48 or 49, wherein an interval between the first timepoint and the second timepoint is at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks.
51. The method of any one of claims 48 to 50, wherein an interval between the second timepoint and the third timepoint is at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks.
52. A method of identifying a patient suffering from hepatitis delta virus (HDV) infection and likely or not likely to achieve clinical response to a treatment comprising administering a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor, comprising: administering to the patient a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor for at least 12 weeks; and, measuring HDV RNA levels in the patient at start of the treatment and at 12 weeks after the start of the treatment; wherein > 2 logw decline in HDV RNA levels between the start of the treatment and at 12 weeks after the start of the treatment indicates the patient likely to achieve the clinical response to the treatment, and wherein absence of the > 2 logio decline in HDV RNA levels between the start of the treatment and at about 12 weeks after the start of the treatment indicates the patient not likely to achieve the clinical response to the treatment.
53. A method of identifying a patient suffering from hepatitis delta virus (HDV) infection and likely or not likely to achieve clinical response to a treatment comprising administering a therapeutically effective amount of interferon alpha, lonafarnib and a CYP3A4 inhibitor, comprising: administering the treatment to the patient; and, measuring HDV RNA levels in the patient at a first timepoint after start of the treatment, at a second timepoint during the treatment, and at third timepoint during the treatment, wherein the second timepoint occurs after the first timepoint, wherein the third timepoint occurs after the second timepoint, wherein decline in HDV RNA levels starting at the first timepoint continuing through the second timepoint and the third timepoint indicates the patient likely to achieve the clinical response to the treatment, and wherein absence of the decline in HDV RNA levels starting at the first timepoint and continuing through the second timepoint and the third timepoint indicates the patient not likely to achieve the clinical response to the treatment.
54. The method of claim 53, wherein an interval between the start of the treatment and the first timepoint is at least at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, or at least 20 weeks.
55. The method of claim 53 or 54, wherein an interval between the first timepoint and the second timepoint is at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks.
56. The method of any one of claims 53 to 55, wherein an interval between the second timepoint and the third timepoint is at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks.
57. The method of any one of claims 52 to 56, wherein the clinical response comprises one or more of: > 2 logiodecline in HDV RNA levels, normalized alanine aminotransferase (ALT) levels, improvement of liver histology, or reduction in the one or more of liver inflammation, liver necrosis, or liver fibrosis.
58. The method of claim 57, wherein the improvement of liver histology comprises > 2-point improvement in Ishak HAI and no worsening of fibrosis by Ishak scoring.
59. The method of any one of claims 52 to 54, wherein the clinical response is observed at about 48 weeks after the start of the treatment.
PCT/US2023/082638 2022-12-07 2023-12-06 Methods to treat hepatitis delta viral infections WO2024123860A1 (en)

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