Methods for reducing the adverse effects of interferon

Abstract

The present invention relates to methods for reducing the adverse effects of interferon and to novel compositions and methods of treatment.

Description

[Technical field]

[0001] The present invention relates to the field of medicine, and in particular to the use of interferon to treat a disease or disorder. [Background technology]

[0002] Interferons (IFNs) are a type of cytokine released by cells in response to the presence of several pathogens, such as viruses, bacteria and parasites, but also by tumor cells.

[0003] IFN has been developed and marketed as a drug therapy in different forms, e.g., as a wild-type cytokine or a pegylated form. Additionally, variants of IFN and sustained release dosage forms of IFN are under development.

[0004] IFNs are used for treatment in various therapeutic areas. IFNs are used to treat viral infections, especially chronic viral infections, such as HBV (Hepatitis B Virus), HCV (Hepatitis C Virus), herpes viruses and papilloma viruses (HPV). In addition, they are used for the treatment of cancer, especially for hematopoietic cancers, such as multiple myeloma, lymphoma and leukemia, or for solid tumors, such as malignant melanoma, renal cell carcinoma and osteosarcoma. IFNα2a is used to treat viral infections, and IFN-β1a and IFN-β1b are used to treat and manage multiple sclerosis. IFN-γ is used to treat the immune disease chronic granulomatous disease.

[0005] However, it is also well known that treatment with interferons is associated with adverse effects, often referred to as "influenza-like symptoms" or "influenza-like illness," including fever, myalgia, headache, and fatigue. For example, treatment with IFNs (i.e., IFN-α, IFN-β, and IFN-γ) is associated with a very high incidence of these adverse effects, specifically greater than 25% of patients, and even about 50% or more of patients.

[0006] Adverse effects are problematic when long-term treatment with IFN is required. A significant number of patients have been reported to discontinue treatment prematurely due to these adverse effects. Similarly, due to the toxicity of high-dose treatment with IFN, trials have been conducted with lower doses, but the therapeutic effect was lost or significantly reduced. As a result, the adverse effects have prompted researchers to find novel treatments for diseases in which IFN treatment has been demonstrated to be effective. In addition, these adverse effects are a major obstacle to the further development of IFN-based clinical treatments. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] WO 03 / 016288 [Patent Document 2] U.S. Patent No. 6,005,086 [Patent Document 3] U.S. Patent No. 5,382,657 [Patent Document 4] U.S. Patent No. 5,951,974 [Patent Document 5] U.S. Patent No. 5,981,709 [Patent Document 6] WO2013107791 [Patent Document 7] WO2010030671 [Patent Document 8] WO2008124086 [Patent Document 9] WO2015007520 [Patent Document 10] WO2013059885 [Patent Document 11] WO18077893 [Patent Document 12] WO18064574 [Patent Document 13] EP1392714 [Patent Document 14] EP1568706

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Non-licensed literature

[0008] [Non-licensed document 1] Takahashi, JMAJ, 2004, 47, 60-63

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[0009] Therefore, there is a strong need for new therapeutic solutions to reduce the adverse effects associated with IFN treatment, which could allow the consideration of higher doses of IFN therapy, facilitate its development for new therapeutic indications, and make current treatments better tolerated by patients. [Means for solving the problem]

[0010] The present invention arises from the discovery of the surprising ability of FXR agonists to reduce the adverse effects of IFN therapy, particularly influenza-like symptoms, such that FXR agonists enhance a subject's resistance to treatment with IFN.

[0011] Thus, the present invention relates to an FXR agonist for use in reducing adverse effects resulting from treatment with interferon. The present invention also relates to a pharmaceutical composition comprising an FXR agonist for use in reducing adverse effects resulting from treatment with interferon. The present invention further relates to the use of an FXR agonist for the manufacture of a medicament for use in reducing adverse effects resulting from treatment with interferon. The present invention relates to a method for reducing adverse effects of IFN therapy in a subject receiving treatment with IFN, comprising administering to the subject an effective amount of an FXR agonist and administering a therapeutically effective amount of IFN, thereby reducing adverse effects resulting from treatment with IFN.

[0012] In one embodiment, the interferon is selected from the group consisting of IFN-α, IFN-β, IFN-γ, IFN-λ, and pegylated forms thereof, more particularly from the group consisting of IFN-α1a, IFN-α1b, IFN-α2a, IFN-α2b, IFN-β1a, IFN-β1b, IFN-γ1b, IFN-λ1a, and pegylated forms thereof. In a particular embodiment, the interferon is IFN-α2 or a pegylated form thereof, in particular IFN-α2a, IFN-α2b, or a pegylated form thereof. In a particular embodiment, the interferon is IFN-α2a or a pegylated form thereof.

[0013] In one embodiment, the FXR agonist is selected from the group consisting of FXR agonists disclosed in Table 1. In a specific embodiment, the FXR agonist is EYP001. For example, the FXR agonist can be administered once a day. The FXR agonist can also be administered twice a day. More specifically, the FXR agonist is administered as long as the treatment with IFN is performed. Specifically, the FXR agonist is administered in a therapeutic amount effective for reducing the adverse effects of IFN, particularly influenza-like symptoms.

[0014] In one embodiment, the adverse effects are flu-like symptoms, particularly fever, weakness, muscle pain, headache, back or leg pain, bone or muscle aches, myalgia, and fatigue.

[0015] In another aspect, the present invention also relates to a pharmaceutical composition or kit as a combined preparation for simultaneous, separate or sequential use, said pharmaceutical composition or kit comprising IFN and an FXR agonist, wherein IFN is selected from the group consisting of IFN-α1a, IFN-α1b and their pegylated forms; IFN-β, preferably IFN-β1, such as IFN-β1a and IFN-β1b, or their pegylated forms; IFN-γ1, particularly IFN-γ1b, or their pegylated forms; and IFN-λ or IFN-λ or their pegylated forms. The pharmaceutical composition or kit is for use in treating hepatitis B virus infection. The present invention further relates to the use of the pharmaceutical composition or kit for the manufacture of a medicament for treating hepatitis B virus infection. The present invention further relates to a method for treating Hepatitis B virus infection in a subject, comprising administering a therapeutically effective amount of the pharmaceutical composition, or administering a therapeutically effective amount of IFN as defined above and a therapeutically effective amount of an FXR agonist, thereby reducing adverse effects resulting from treatment with IFN. The FXR agonist can be selected from the group consisting of FXR agonists disclosed in Table 1. In a specific embodiment, the FXR agonist is EYP001. For example, the FXR agonist can be administered once a day. The FXR agonist can also be administered twice a day. More specifically, the FXR agonist is administered as long as treatment with IFN is performed. Specifically, the FXR agonist is administered in a therapeutic amount effective for reducing the adverse effects of IFN, particularly influenza-like symptoms. In one embodiment, the FXR agonist is administered in a therapeutic amount effective for reducing the adverse effects of IFN, particularly influenza-like symptoms, and for reducing the replication of Hepatitis B virus infection.

[0016] In another aspect, the present invention also relates to a pharmaceutical composition or kit as a combined preparation for simultaneous, separate or sequential use, the pharmaceutical composition or kit being an antiviral agent for Hepatitis C virus (HCV), Hepatitis D virus (HDV), Herpes simplex virus (HSV), Papillomavirus (HPV) (e.g., condylomata acuminata), acuminate), varicella zoster virus, cytomegalovirus (CMV) and rhinovirus; cancer, in particular a solid cancer or hematopoietic cancer, preferably selected from AIDS-related Kaposi's sarcoma, leukemia, such as hairy cell leukemia, chronic myeloid leukemia and non-Hodgkin's leukemia, lymphoma, such as follicular lymphoma, cutaneous T-cell lymphoma and adult T-cell leukemia-lymphoma, carcinoid tumor, melanoma, multiple myeloma, renal cell carcinoma and neuroendocrine tumor; and other diseases, such as age-related macular degeneration, hemangiomatosis, Behcet's syndrome, thrombocythemia, polycythemia vera, primary myelofibrosis, Churg-Strauss syndrome, inflammatory bowel disease and mycobacterial infection. The present invention further relates to the use of the pharmaceutical composition or kit for the manufacture of a medicament for treating the above-defined diseases. The present invention further relates to a method for treating the above-defined diseases in a subject, comprising administering a therapeutically effective amount of the pharmaceutical composition or comprising administering a therapeutically effective amount of IFN-α and a therapeutically effective amount of an FXR agonist, thereby reducing adverse effects resulting from treatment with IFN. The FXR agonist can be selected from the group consisting of FXR agonists disclosed in Table 1. The IFN-α can be IFN-α1 or IFN-α2 or a pegylated form thereof, preferably selected from the group consisting of IFN-α1a, IFN-α1b, IFN-α2a and IFN-α2b or a pegylated form thereof. In a specific embodiment, the interferon is IFN-α2a or a pegylated form thereof. The FXR agonist can be selected from the group consisting of FXR agonists disclosed in Table 1.In a specific embodiment, the FXR agonist is EYP001. For example, the FXR agonist can be administered once a day. The FXR agonist can also be administered twice a day. More specifically, the FXR agonist is administered as long as the treatment with IFN is performed. Specifically, the FXR agonist is administered in a therapeutic amount effective for reducing the adverse effects of IFN, particularly influenza-like symptoms. In one embodiment, the FXR agonist is administered in a therapeutic amount effective for reducing the adverse effects of IFN, particularly influenza-like symptoms, and for providing a therapeutic effect on one of the diseases defined above.

[0017] In another aspect, the present invention also relates to a pharmaceutical composition or kit as a combined preparation for simultaneous, separate or sequential use, said pharmaceutical composition or kit comprising IFN-β and an FXR agonist for use in treating a disease selected from the group consisting of multiple sclerosis, Guillain-Barre syndrome, rheumatoid arthritis and cancer, in particular solid or hematopoietic cancer. Furthermore, the present invention relates to the use of this pharmaceutical composition or kit for the manufacture of a medicament for treating a disease as defined above. The present invention further relates to a method for treating a disease as defined above in a subject, comprising administering a therapeutically effective amount of this pharmaceutical composition or comprising administering a therapeutically effective amount of IFN-β and a therapeutically effective amount of an FXR agonist, thereby reducing adverse effects resulting from treatment with IFN. IFN-β is preferably IFN-β1 or a pegylated form thereof, more preferably selected from the group consisting of IFN-β1a and IFN-β1b or a pegylated form thereof. The FXR agonist can be selected from the group consisting of FXR agonists disclosed in Table 1. In a specific embodiment, the FXR agonist is EYP001. For example, the FXR agonist can be administered once a day. The FXR agonist can also be administered twice a day. More specifically, the FXR agonist is administered as long as the treatment with IFN is performed. Specifically, the FXR agonist is administered in a therapeutic amount effective for reducing the adverse effects of IFN, particularly influenza-like symptoms. In one embodiment, the FXR agonist is administered in a therapeutic amount effective for reducing the adverse effects of IFN, particularly influenza-like symptoms, and for providing a therapeutic effect on one of the diseases defined above.

[0018] In another embodiment, the present invention also relates to a pharmaceutical composition or kit as a combined preparation for simultaneous, separate or sequential use, said pharmaceutical composition or kit comprising IFN-γ and an FXR agonist for use in treating a disease selected from the group consisting of bacterial infections, in particular mycobacterial infections, fibrosis such as idiopathic fibrosing alveolitis, leishmaniasis, osteoporosis and cancer, in particular solid or hematopoietic cancers. Furthermore, the present invention relates to the use of this pharmaceutical composition or kit for the manufacture of a medicament for treating a disease as defined above. The present invention further relates to a method for treating a disease as defined above in a subject, comprising administering a therapeutically effective amount of this pharmaceutical composition or comprising administering a therapeutically effective amount of IFN-γ and a therapeutically effective amount of an FXR agonist, thereby reducing adverse effects resulting from treatment with IFN. The FXR agonist may be selected from the group consisting of the FXR agonists disclosed in Table 1. In a specific embodiment, the FXR agonist is EYP001. For example, the FXR agonist can be administered once a day. The FXR agonist can also be administered twice a day. More specifically, the FXR agonist is administered as long as the treatment with IFN is performed. Specifically, the FXR agonist is administered in a therapeutic amount effective for reducing the adverse effects of IFN, particularly influenza-like symptoms. In one embodiment, the FXR agonist is administered in a therapeutic amount effective for reducing the adverse effects of IFN, particularly influenza-like symptoms, and for providing a therapeutic effect on one of the diseases defined above.

[0019] In another embodiment, the present invention also relates to a pharmaceutical composition or kit as a combined preparation for simultaneous, separate or sequential use, said pharmaceutical composition or kit comprising an IFN-lambda and an FXR agonist for use in treating a disease selected from the group consisting of fibrosis and hepatitis D virus infection. Furthermore, the present invention relates to the use of this pharmaceutical composition or kit for the manufacture of a medicament for treating a disease as defined above. The present invention further relates to a method for treating a disease as defined above in a subject, comprising administering a therapeutically effective amount of this pharmaceutical composition or comprising administering a therapeutically effective amount of an IFN-lambda and a therapeutically effective amount of an FXR agonist, thereby reducing adverse effects resulting from treatment with IFN. The FXR agonist can be selected from the group consisting of the FXR agonists disclosed in Table 1. In a specific embodiment, the FXR agonist is EYP001. For example, the FXR agonist can be administered once a day. The FXR agonist can also be administered twice a day. More specifically, the FXR agonist is administered as long as the treatment with IFN is performed.Specifically, the FXR agonist is administered in a therapeutic amount effective for reducing the adverse effects of IFN, particularly influenza-like symptoms.In one embodiment, the FXR agonist is administered in a therapeutic amount effective for reducing the adverse effects of IFN, particularly influenza-like symptoms, and for providing a therapeutic effect on one of the diseases defined above. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] The present invention is based on the discovery of the surprising ability of FXR agonists to reduce the adverse effects of IFN therapy, particularly influenza-like syndrome. Experimental evidence has been provided with the FXR agonist EYP001 against the side effects of pegylated IFNα, particularly influenza-like syndrome. First, the disease being treated by interferon does not affect the side effects observed as a result of treatment with interferon. The side effects are independent of the disease being treated. Indeed, influenza-like syndrome has been observed during IFNα treatment of HBV infection, but it has also been observed during IFNα treatment of other diseases. Thus, the present disclosure supports the effect of FXR agonists against the side effects of IFN therapy, whatever the disease being treated. Second, the flu-like syndrome is not specific to IFN-α, but has been observed with other interferons, such as IFN-β (Takahashi, JMAJ, 2004, 47, 60-63; Patti et al., J Neurol, 2020, 267, 1812-1823) and IFN-γ (Vlachoyiannopoulos et al., Ann Rheum Dis, 1996, 55, 761-768; Prescrire Int, 2006, 15, 179-180; Windbichler et al., Br J Cancer, 2000, 82, 1138-1144). Thus, it is quite certain that FXR agonists can reduce the side effects associated with other interferons. Similarly, the flu-like syndrome is not specific to pegylated interferon. Therefore, FXR agonists can reduce the side effects of interferons, whether they are pegylated or not. Thus, this application fully supports the use of EYP001 to reduce the side effects of interferon.Finally, it is believed that the benefits of EYP001 may also be achieved with alternative FXR agonists, particularly selective FXR agonists.

[0021] The present invention relates to an FXR agonist or a pharmaceutical composition comprising the same for use in reducing adverse effects resulting from treatment with interferon. Accordingly, the present invention also relates to an FXR agonist or a pharmaceutical composition comprising the same for use in enhancing the tolerance of a subject to treatment with interferon.

[0022] The present invention further relates to the use of an FXR agonist or a pharmaceutical composition comprising same for the preparation of a medicament for reducing adverse effects resulting from treatment with interferon.

[0023] The present invention further relates to a method for reducing adverse effects resulting from treatment with interferon, comprising administering to a patient a therapeutically effective amount of an FXR agonist, thereby reducing the adverse effects. More specifically, the method comprises administering a therapeutically effective amount of interferon and a therapeutically effective amount of an FXR agonist, the therapeutically effective amount of the FXR agonist being the amount necessary to reduce the adverse effects of interferon.

[0024] The invention finally relates to a kit comprising an interferon and an FXR agonist as a combined preparation for simultaneous, separate or sequential use to reduce the adverse effects of interferon during treatment with interferon.

[0025] More specifically, the adverse effect of interferon is influenza-like symptoms, including fever, weakness, muscle pain, headache, back or leg pain, bone or muscle pain, myalgia, and fatigue. FXR agonists reduce at least one aspect of influenza-like symptoms, such as an aspect selected from among fever, muscle pain, headache, and fatigue. Preferably, FXR agonists reduce several aspects of influenza-like symptoms, such as two or three aspects.

[0026] By reducing an adverse effect, it is intended to reduce the frequency of occurrence of the adverse effect in the treated patient or population of treated patients, and / or to reduce the intensity of the adverse effect, and / or to delay the onset of the adverse effect. Specifically, the reduction is at least a 10, 20, 30, 40 or 50% reduction.

[0027] During the treatment with interferon, FXR agonist should be administered in the amount necessary to reduce the adverse effects of interferon.In the first embodiment, interferon should be used at the recommended dose for the therapeutic indication.Alternatively, FXR agonist can be used so that higher doses of interferon can be used without increasing adverse effects.For example, when used in combination with FXR agonist, it can be considered to increase the dose of interferon by 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100%.

[0028] The interferon may be for use in treating viral infections or cancer. In one aspect, the viral infection is Hepatitis B virus (HBV), Hepatitis C virus (HCV), Hepatitis D virus (HDV), Herpes simplex virus (HSV), Papillomavirus (HPV) (e.g., genital warts), Varicella-Zoster virus, Cytomegalovirus (CMV) or Rhinovirus. In a particular embodiment, the viral infection is not an infection with Hepatitis B virus. In another aspect, the cancer is a solid cancer or hematopoietic cancer, preferably AIDS-related Kaposi's sarcoma, leukemia, such as hairy cell leukemia, chronic myelogenous leukemia and non-Hodgkin's leukemia, lymphoma, such as follicular lymphoma, cutaneous T-cell lymphoma and adult T-cell leukemia lymphoma, carcinoid tumor, melanoma, multiple myeloma, renal cell carcinoma and neuroendocrine tumor. In a further aspect, the interferon is for use to treat other diseases selected from the group consisting of multiple sclerosis, Guillain-Barre syndrome, rheumatoid arthritis, age-related macular degeneration, hemangiomatosis, Behcet's syndrome, thrombocythemia, polycythemia vera, primary myelofibrosis, Churg-Strauss syndrome, inflammatory bowel disease, bacterial infections such as mycobacterial infections, fibrosis, leishmaniasis and osteoporosis.

[0029] definition The term "FXR" refers to the farnesoid X receptor, which is a nuclear receptor that is activated by supraphysiological levels of farnesol (Forman et al., Cell, 1995, 81, 687-693). FXR is also known as NR1H4, retinoid X receptor-interacting protein 14 (RIP14) and bile acid receptor (BAR). FXR, which contains a conserved DNA-binding domain (DBD) and a C-terminal ligand-binding domain (LBD), binds to and is activated by a variety of naturally occurring bile acids (BAs), including the primary bile acid chenodeoxycholic acid (CDCA) and its taurine and glycine conjugates. Upon activation, the FXR-RXR heterodimer binds to the promoter regions of target genes and controls the expression of multiple genes involved in bile acid homeostasis. FXR target genes in the liver are classified into two major groups. The first group acts to reduce hepatic bile acid concentrations by increasing excretion and decreasing their synthesis. The second group of FXR target genes, such as the phospholipid transfer protein PLTP and apolipoproteins, regulate lipoprotein levels in serum and reduce plasma triglyceride concentrations. For a more detailed list of FXR-regulated genes, see, e.g., WO 03 / 016288, pages 22-23. U.S. Patent No. 6,005,086 discloses nucleic acid sequences coding for mammalian FXR proteins. The human polypeptide sequence of FXR is deposited in the Nucleotide and Protein Database under the accession numbers NM_005123, Q96RI1, NP_005114, AAM53551, AAM53550, AAK60271.

[0030] As used herein, the term "FXR agonist" has its general meaning in the art and specifically refers to a compound that functions by targeting and binding to the farnesoid X receptor (FXR) and activates FXR at least 40% above background in the assay described in Maloney et al. (J. Med. Chem. 2000, 43:2971-2974).

[0031] In some embodiments, the FXR agonist of the present invention is a selective FXR agonist. As used herein, the term "selective FXR agonist" refers to an FXR agonist that does not exhibit significant cross-reactivity with one or more, ideally substantially all, of a panel of nuclear receptors consisting of LXRα, LXRβ, PPARα, PPARγ, PPARδ, RXRα, RARγ, VDR, PXR, ERα, ERβ, GR, AR, MR and PR. Methods for measuring significant cross-reactivity are described in J. Med. Chem. 2009, 52, pp. 904-907.

[0032] As used herein, the terms "treatment," "treat," or "treating" refer to any action intended to improve the health status of a patient, such as cure, prevention, prophylaxis, and suppression of a disease. In certain embodiments, such terms refer to the amelioration or eradication of a disease or symptoms associated therewith. In other embodiments, the terms refer to minimizing the spread or worsening of a disease as a result of the administration of one or more therapeutic agents to a subject having such a disease.

[0033] As used herein, the terms "subject," "individual," or "patient" are used interchangeably and refer to humans, including adults, children, newborns, and humans in the prenatal stage. Alternatively, animals, particularly pet animals or farm or zoo animals, may also be considered as "subjects," "individuals," or "patients."

[0034] The terms "quantity," "amount," and "dose" are used interchangeably herein and may refer to the absolute amount of a molecule.

[0035] As used herein, the term "therapeutic effect" means an effect induced by an active ingredient or a pharmaceutical composition according to the present invention that can prevent or delay the appearance or development of a disease or disorder, or that can cure or attenuate the effects of a disease or disorder.

[0036] As used herein, the term "therapeutically effective amount" refers to an amount of active ingredient or pharmaceutical composition that prevents, removes, or reduces the harmful effects of a disease, particularly an infectious disease. It is clear that a person skilled in the art can adapt the amount to be administered depending on the subject to be treated, the nature of the disease, etc. In particular, the dosage and schedule of administration may vary depending on the nature, stage, and severity of the disease to be treated, as well as the weight, age, and general health of the subject to be treated, and the judgment of the physician.

[0037] As used herein, the term "excipient or pharma- ceutically acceptable carrier" refers to any ingredient, other than the active ingredient, present in a pharmaceutical composition. Its addition may be intended to give the final product a particular viscosity or other physical or taste characteristic. An excipient or pharma-ceutically acceptable carrier must be devoid of any interaction, especially chemical interaction, with the active ingredient.

[0038] As used herein, the term "pegylated form" refers to pegylated interferon.

[0039] interferon The interferon can be any IFN.

[0040] In one aspect, the IFN is selected from type I IFN, type II IFN and type III IFN.

[0041] Type I IFNs bind to the IFN-α / β receptor. Type I IFNs include IFN-α (alpha), IFN-β (beta), IFN-κ (kappa), IFN-δ (delta), IFN-ε (epsilon), IFN-τ (tau), IFN-ω (omega) and IFN-ζ (zeta). Preferably, the type I IFN is IFN-α or IFN-β. IFN-α contains 13 subtypes (designated IFN-α1, IFN-α2, IFN-α4, IFN-α5, IFN-α6, IFN-α7, IFN-α8, IFN-α10, IFN-α13, IFN-α14, IFN-α16, IFN-α17, IFN-α21). These subtypes can be divided into various subsubtypes, e.g., IFN-α1a, IFN-α1b, IFN-α2a, IFN-α2b, etc. Similarly, IFN-β contains multiple subtypes, e.g., IFN-β1 and IFN-β3, which are further divided into subsubtypes, e.g., IFN-β1a, IFN-β1b, etc.

[0042] Type II IFN includes IFN-γ. Specifically, IFN-γ can be IFN-γ1, particularly IFN-γ1b.

[0043] Type III IFNs include IFN-λ, which includes, but is not limited to, IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4.

[0044] IFN includes salts, functional derivatives, variants, muteins, fusion proteins, analogs and active fragments thereof, which have the same functional effect as wild-type IFN. Alternatively, IFN can be in a derivative form of IFN, particularly to increase its half-life. Thus, IFN can be derivatized with water-soluble polymers, such as polyethylene glycol (i.e., PEG-IFN). Such PEG-IFN is described in U.S. Patent Nos. 5,382,657, 5,951,974 and 5,981,709, the disclosures of which are incorporated by reference. Variants of IFN are well known in the art. For example, for IFN-α, see WO2013107791, Piehler et al. (2000, J Biol Chem, 275, 40425-33), WO2010030671, WO2008124086, WO2015007520, and WO2013059885, and for IFN-γ, see WO18077893 and WO18064574.

[0045] In one aspect, the IFN is pegylated IFN, more particularly pegylated type I IFN, in particular pegylated IFN-α, such as pegylated IFN-α2, including pegylated IFN-α2a or pegylated IFN-α2b, pegylated IFN-β (e.g., IFN-β1a or IFN-β1b) or pegylated IFN-γ.

[0046] In one aspect, the IFN is a consensus IFN-α (e.g., INFERGEN®, Locteron®), IFN-α1b (e.g., HAPGEN®), IFN-α2a (Roferon-A®, MOR-22, Inter 2A, Inmutag, Inferon), pegylated IFN-α2a (e.g., PEGASYS®, YPEG-IFNα-2a, PEG-INTRON®, Pegaferon), IFN-α2b (e.g., INTRON A®, Alfarona, Bioferon, Inter 2B, citpheron, Zavinex, Ganapar, etc.), pegylated IFN-α2b (e.g., Pegintron®, Albuferon, AOP2014 / P1101, Algeron, Pai Ge Bin), IFN-α2c (e.g., Berofor Alpha), IFN-β1a (e.g., REBIF®, AVONEX®), pegylated IFN-β1a (e.g., Plegridy), IFN-β1b (e.g., Betaseron®), IFN-γ (e.g., Ingaron), pegylated IFN-γ (e.g., Ingaron), and IFN-like proteins (e.g., Novaferon, HSA-IFN-α2a fusion protein, HSA-IFN-α2b fusion protein).

[0047] IFN can be administered daily, once a week, or twice, three times, four times, five times, or six times a week. The duration of treatment is generally long-term, for example from 2 weeks to several months. For example, the duration is from 3-4 months up to 24 months. The dose can vary from 1 million units to 20 million units, for example 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 million units. IFN can be administered by subcutaneous, intramuscular, intravenous, transdermal, or intratumoral administration, preferably by subcutaneous or intramuscular administration.

[0048] In a particular embodiment, the IFN is IFNα2a, IFNα2b or a pegylated form thereof, which is administered subcutaneously once a week at various doses, for example, 1 μg to 500 μg, preferably 10 μg to 500 μg, more preferably 100 μg to 250 μg, such as 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 μg, for 2-4 months up to 24 months. In a very particular embodiment, the treatment continues for 12 to 52 weeks, preferably 45 to 52 weeks, for example 48 weeks. In a more particular embodiment, the IFN is IFNα2a or a pegylated form thereof.

[0049] FXR agonists FXR agonists are well known to those of skill in the art.

[0050] For example, one of skill in the art can readily identify FXR agonists from the following documents, the disclosures of which are incorporated herein by reference: Abenavoli L, et al. Pharmaceuticals (Basel). 2018 Oct 11;11(4). pii: E104. doi: 10.3390 / ph11040104. Review. Adorini L, et al. Drug Discov Today. 2012 Sep;17(17-18):988-97. doi: 10.1016 / j.drudis.2012.05.012. Epub 2012 May 29. Review. Akwabi-Ameyaw A, et al. Bioorg Med Chem Lett. 2009 Aug 15;19(16):4733-9. doi: 10.1016 / j.bmcl.2009.06.062. Epub 2009 Jun 21. Akwabi-Ameyaw A, et al. Bioorg Med Chem Lett. 2008 Aug 1;18(15):4339-43. doi: 10.1016 / j.bmcl.2008.06.073. Epub 2008 Jun 28. Akwabi-Ameyaw A, et al. Bioorg Med Chem Lett. 2011 Oct 15;21(20):6154-60. doi: 10.1016 / j.bmcl.2011.08.034. Epub 2011 Aug 11. Baghdasaryan A, et al. Hepatology. 2011 Oct;54(4):1303-12. doi: 10.1002 / hep.24537. Bass JY, et al. Bioorg Med Chem Lett. 2009 Jun 1;19(11):2969-73. doi: 10.1016 / j.bmcl.2009.04.047. Epub 2009 Apr 18. 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[0051] Typically, FXR agonists include the classes of steroidal and non-steroidal FXR agonists.

[0052] In certain embodiments of the present invention, the FXR agonist is selected from the group consisting of those disclosed in the following publications, the disclosures of which are incorporated herein by reference: EP1392714, EP1568706, JP2005281155, US20030203939, US2005080064, US2006128764, US20070015796, US20080038435, US20100184809, US2 0110105475, US6,984,560, WO2000037077, WO200040965, WO200076523, WO2003015771, WO2003015777, WO2003016280, WO2003016288, WO2003 030612, WO2003016288, WO2003080803, WO2003090745, WO2004007521, WO2004048349, WO2004046162, WO2004048349, WO2005082925, WO20050 92328, WO2005097097, WO2007076260, WO2007092751, WO2007140174, WO2007140183, WO2008002573, WO2008025539, WO2008025540, WO200802 573, WO2008051942, WO2008073825, WO2008157270, WO2009005998, WO2009012125, WO2009027264, WO2009080555, WO2009127321, WO20091497 95, WO2010028981, WO2010034649, WO2010034657, WO2017218330, WO2017218379, WO2017201155, WO2017201152, WO2017201150, WO201718965 2, WO2017189651, WO2017189663, WO2017147137, WO2017147159, WO2017147174, WO2017145031, WO2017145040, WO2017145041, WO2017133521 , WO2017129125, WO2017128896, WO2017118294, WO2017049172, WO2017049176, WO2017049173, WO2017049177, WO2016173397, WO2016173493,WO2016168553, WO2016161003, WO2016149111, WO2016131414, WO2016130809, WO2016097933, WO2016096115, WO2016096116, WO2016086115, WO20160 73767, WO2015138986, WO2018152171, WO2018170165, WO2018170166, WO2018170173, WO2018170182, WO2018170167, WO2017078928, WO2014184271, W The compound is selected from small molecule compounds acting as FXR modulators disclosed in US2013007387, WO2012087519, WO2011020615, WO2010069604, WO2013037482, US2017275256, WO2005080064, WO2018190643, WO2018215070, WO2018215610, WO2018214959, WO2018081285, WO2018067704, WO2019007418, WO2018059314, and WO2017218337.

[0053] In one aspect, the FXR agonist can be any FXR agonist disclosed in the following patent applications: WO2017 / 049172, WO2017 / 049176, WO2017 / 049173, WO2017 / 049177, WO2018 / 170165, WO2018 / 170166, WO2018 / 170173, WO2018 / 170182, and WO2018 / 170167.

[0054] Specific examples of FXR agonists include EYP001, GW4064 (disclosed in PCT Publication No. WO 00 / 37077 or US 2007 / 0015796), 6-ethyl-chenodeoxycholic acid, and in particular 3α,7α-dihydroxycholic acid, also known as INT-747. 7α-dihydroxy-6α-ethyl-5β-cholan-24-oic acid; INT-777; 6-ethyl-ursodeoxycholic acid; INT-1103; UPF-987; WAY-362450; MFA-1; GW9662; T0901317; Fexaramine; 3β-azido-6α-ethyl-7α-hydroxy-5β-cholan-24-oic acid; Tropifixor (LJN452); Fexaramine-3 (Fex-3); BAR502; BAR704; PX20606; PX20350; 3α,7α,11β-trihydroxy-6α-ethyl-5β-cholan-24-oic acid (TC-100); 6-(4-{[5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}pi 3,6-Dimethyl-1-(2-methylphenyl)-4-(4-phenoxyphenyl)-4,8-dihydro-1H-pyrazolo[3,4-e][1,4]thiazepin-7-one; obeticholic acid, cholic acid, deoxycholic acid, glycocholic acid, glycodeoxycholic acid, taurocholic acid, taurodihydrofusidate, taurodeoxycholic acid, cholate, glycocholate, deoxycholate, taurocholate, taurodeoxycholate, chenodeoxycholic acid, ursodeoxycholic acid, tauroursodeoxycholic acid, glycoursodeoxycholic acid, 7-B-methyl cholic Acid, methyl lithocholate, GSK-8062 (CAS number 943549-47-1).In some embodiments, the FXR agonist is selected from naturally occurring bile acids, preferably chenodeoxycholic acid (CDCA) or CDCA conjugated with taurine or glycine (tauro-CDCA or glyco-CDCA), and synthetic derivatives of naturally occurring bile acids, preferably 6-ethyl-CDCA or 6-ethyl-CDCA conjugated with taurine or glycine, natural non-steroidal agonists, preferably diterpenoids such as cafestol and kahweol, or synthetic non-steroidal FXR agonists.

[0055] In some embodiments, the FXR agonist is selected from the group consisting of obeticholic acid (Intercept Pharma), cholic acid (CT-RS); GS-9674 (Cilofexor) (Phenex Pharmaceuticals AG), Tropifezor (LJN452) (Novartis Pharmaceuticals), EYP001, EDP-305, steroidal non-carboxylate FXR agonists (Enanta Pharmaceuticals), tulofexorate isopropyl (Pfizer), INT-767 (Intercept Pharmaceuticals), LY-2562175 (Lilly), AGN-242266 (formerly AKN-083, Allergan), EP-024297 (Enanta Pharmaceuticals), EGFR-1, EGFR-2, EGFR-3, EGFR-4, EGFR-5, EGFR-6, EGFR-7, EGFR-8, EGFR-9, EGFR-11, EGFR-12, EGFR-13, EGFR-14, EGFR-15, EGFR-15-16, EGFR-15-17, EGFR-16-18, EGFR-17-19, EGFR-21-19, EGFR-22-19, EGFR-23-19, EGFR-24-19, EGFR-25-19, EGFR-23-19, EGFR-24-19, EGFR-25-19, EGFR-32-19, EGFR-32-19, EGFR-42-19, EGFR-5-19, EGFR-14-19, EGFR-23-19, EGFR-32-19, EGFR-42-19, EGFR-14-19, EGFR-23-19, EGFR-32-1 In a particular embodiment, the FXR agonist is selected from the group consisting of INT-747, a compound identified by CAS number EDP-305 (Enanta Pharmaceuticals), a steroidal non-carboxylic acid FXR agonist, and a compound identified by CAS number 1192171-69-9 (described in WO 2009127321).

[0056] In certain embodiments, the FXR agonist is selected from the group consisting of LJN452 (Tropifezor), GS-9674 (Cilofexor), LMB763 (Nidufexor), OCA (Ocaliva), EDP-305, TERN-001, and PXL007 (also named EYP001).

[0057] In certain embodiments, the FXR agonist is selected from the group consisting of the compounds disclosed in Table 1 and any pharma- ceutically acceptable salts thereof.

[0058] [Table 1A]

[0059] [Table 1B]

[0060] [Table 1C]

[0061] [Table 1D]

[0062] [Table 1E]

[0063] In a preferred embodiment of the invention, the FXR agonist is EYP001.

[0064] The FXR agonist can be administered with or without food (i.e., under fed or fasted conditions, respectively). The FXR agonist can be administered once, twice or three times a day, preferably once or twice, for example, in the morning (e.g., between 6 and 10 a.m.) or in the evening (e.g., between 6 and 10 p.m.). In one embodiment, the FXR agonist is administered once a day. In another embodiment, the FXR agonist is administered twice a day. The FXR agonist is preferably administered every day. However, administration every 2, 3, 4, 5, 6 or 7 days can also be considered. The daily dosage of the FXR agonist can vary over a wide range, from 0.01 to 1,000 mg per adult per day, in particular from 1 to 1,000 mg per adult per day, preferably from 50 to 800 mg per adult per day, more preferably from 100 to 600 mg per adult per day, even more preferably from 150 to 400 mg per adult per day or from 200 to 400 mg per adult per day. Preferably, the composition contains 5, 10, 15, 25, 50, 75, 100, 150, 200, 300, 400 or 500 mg of the FXR agonist. The medicament typically contains about 0.05 mg to about 500 mg of the FXR agonist, preferably from about 5 mg to about 500 mg of the FXR agonist per day, preferably from 50 mg to about 500 mg of the FXR agonist. FXR agonists can be administered by oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, topical or rectal administration, preferably by oral administration.

[0065] Pharmaceutical Compositions and Kits One aspect of the present disclosure relates to a pharmaceutical composition comprising an IFN and an FXR agonist.

[0066] In particular, the IFN is IFN-α, preferably IFN-α1 or IFN-α2, such as IFN-α1a, IFN-α1b, IFN-α2a and IFN-α2b, or pegylated forms thereof. Alternatively, the IFN is IFN-β, preferably IFN-β1, such as IFN-β1a and IFN-β1b, or pegylated forms thereof. The IFN may also be IFN-γ1, in particular IFN-γ1b, or pegylated forms thereof. The IFN may also be IFN-λ or IFN-λ or pegylated forms thereof.

[0067] The present disclosure relates to a pharmaceutical composition comprising an FXR agonist and an IFN, wherein the IFN is selected from the group consisting of IFN-α1a, IFN-α1b and pegylated forms thereof; IFN-β, preferably IFN-β1, such as IFN-β1a and IFN-β1b, or pegylated forms thereof; IFN-γ1, particularly IFN-γ1b or pegylated forms thereof; and IFN-λ or IFN-λ or pegylated forms thereof. Preferably, the FXR agonist is selected from the group disclosed in Table 1. In one embodiment, the FXR agonist is EYP001.

[0068] In a further aspect, the disclosure relates to a kit comprising an IFN and an FXR agonist as a combined preparation for simultaneous, separate or sequential use, wherein the IFN is selected from the group consisting of IFN-α1a, IFN-α1b and pegylated forms thereof; IFN-β, preferably IFN-β1, such as IFN-β1a and IFN-β1b, or pegylated forms thereof; IFN-γ1, particularly IFN-γ1b or pegylated forms thereof; and IFN-λ or IFN-λ or pegylated forms thereof. Preferably, the FXR agonist is selected from the group disclosed in Table 1. In one embodiment, the FXR agonist is EYP001.

[0069] Specifically, the FXR agonist and IFN are not administered by the same route. For example, the FXR agonist is administered by oral route, while the IFN is administered by subcutaneous or intramuscular route. Alternatively, the FXR agonist and IFN can be considered to be administered by the same route.

[0070] The pharmaceutical composition or kit disclosed above is for use in treating Hepatitis B virus infection, particularly against viral replication, e.g., for treating chronic Hepatitis B. One aspect of the present disclosure is - the use of said pharmaceutical composition or kit as disclosed above for the preparation of a medicament for treating a Hepatitis B virus infection, in particular against viral replication, such as for treating chronic Hepatitis B, - an IFN selected from the group consisting of IFN-α1a, IFN-α1b or pegylated forms thereof; IFN-β, preferably IFN-β1, such as IFN-β1a and IFN-β1b or pegylated forms thereof; IFN-γ1, in particular IFN-γ1b or pegylated forms thereof; and IFN-λ or IFN-λ or pegylated forms thereof, for use in combination with an FXR agonist, preferably selected from the group disclosed in Table 1, in particular EYP001, for treating a Hepatitis B virus infection, in particular against viral replication, for example for treating chronic Hepatitis B, - an FXR agonist, preferably selected from the group disclosed in Table 1, in particular EYP001, for use in treating a Hepatitis B virus infection, in particular against viral replication, for example for treating chronic Hepatitis B, in combination with an IFN selected from the group consisting of IFN-α1a, IFN-α1b or pegylated forms thereof; IFN-β, preferably IFN-β1, such as IFN-β1a and IFN-β1b or pegylated forms thereof; IFN-γ1, in particular IFN-γ1b or pegylated forms thereof; and IFN-λ or IFN-λ or pegylated forms thereof, Regarding.

[0071] The present disclosure relates to a method for treating a subject infected with hepatitis B virus, particularly a method for treating chronic hepatitis B in a patient, comprising administering a therapeutically effective amount of an FXR agonist, preferably an FXR agonist selected from the group disclosed in Table 1, particularly EYP001; and administering a therapeutically effective amount of an IFN selected from the group consisting of IFN-α1a, and IFN-α1b or pegylated forms thereof; IFN-β, preferably IFN-β1, such as IFN-β1a and IFN-β1b, or pegylated forms thereof; IFN-γ1, particularly IFN-γ1b or pegylated forms thereof; and IFN-λ or IFN-λ or pegylated forms thereof, thereby reducing the adverse effects of IFN. Specifically, the FXR agonist is administered in a therapeutic amount effective for reducing the adverse effects of IFN, particularly influenza-like syndrome. Optionally, the FXR agonist may be administered in a therapeutic amount effective for reducing the adverse effects of IFN, particularly influenza-like symptoms, and effective for reducing the replication of Hepatitis B viral infection.

[0072] In a very specific embodiment, the present disclosure provides a method of treating a subject infected with Hepatitis B virus, in particular a method of treating chronic Hepatitis B in a patient, said method comprising administering a therapeutically effective amount of EYP001 and administering a therapeutically effective amount of IFNα2a, IFNα2b or a pegylated form thereof; - EYP001 is administered in a therapeutic amount effective for reducing the adverse effects of IFNα2a, IFNα2b or pegylated forms thereof, in particular influenza-like syndrome, more preferably in a therapeutic amount effective for reducing the adverse effects of IFNα2a, IFNα2b or pegylated forms thereof and for reducing the replication of HBV, more particularly in a daily dose of 50 to 800 mg per adult human per day, preferably 100 to 600, even more preferably 150 to 400 mg per adult human per day or 200 to 400 mg per adult human per day, for example about 300 mg per adult human per day, optionally administered once or twice a day, preferably orally, and - IFNα2a, IFNα2b or pegylated forms thereof are administered once a week by subcutaneous route in various doses, for example from 1 μg to 500 μg, preferably from 10 μg to 500 μg, more preferably from 100 μg to 250 μg, such as 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 μg, Optionally, treatment may continue for 2-4 months up to 24 months, such as between 2 and 24 months or between 2 and 12 months, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 months.

[0073] With respect to reducing HBV replication, it means reducing HBV replication by at least 10-fold or 100-fold compared to HBV replication in the absence of EYP001. HBV replication can be assessed by measuring at least one of the following levels: HBeAg level, HBsAg level, HBcrAg level, pregenomic RNA (HBV pgRNA) level, precore RNA level, relaxed circular DNA (HBV rcDNA) level, HBV cccDNA level, or HBV DNA level. For example, HBV replication can be assessed by measuring HBV DNA level, which is reduced by at least 10-fold or 100-fold compared to HBV replication in the absence of EYP001. Alternatively, HBV cccDNA level is reduced by at least 10, 15, 20, 25, 30, 35, 40, 45, or 50% compared to non-treatment.

[0074] In this embodiment, the disclosure relates to a pharmaceutical composition comprising EYP001 for use in treating a subject infected with Hepatitis B virus, in particular for use in treating chronic Hepatitis B, said pharmaceutical composition being used in combination with IFNα2a, IFNα2b or pegylated forms thereof, where EYP001 is administered in a therapeutic amount effective for reducing the adverse effects of IFNα2a, IFNα2b or pegylated forms thereof. The disclosure also relates to the use of a pharmaceutical composition comprising EYP001 for the manufacture of a medicament for use in treating a subject infected with Hepatitis B virus, in particular for use in treating chronic Hepatitis B, said pharmaceutical composition being used in combination with IFNα2a, IFNα2b or pegylated forms thereof, where EYP001 is administered in a therapeutic amount effective for reducing the adverse effects of IFNα2a, IFNα2b or pegylated forms thereof. Preferably, the therapeutic amount administered is effective for reducing the adverse effects of IFNα2a, IFNα2b or pegylated forms thereof and for reducing the replication of HBV. For example, the daily dose of EYP001 is 50 to 800 mg per adult per day, preferably 100 to 600 mg per adult per day, even more preferably 150 to 400 mg per adult per day or 200 to 400 mg per adult per day, for example about 300 mg per adult per day, which can be administered once or twice a day, preferably orally. Preferably, IFNα2a, IFNα2b or pegylated forms thereof will be administered once a week by subcutaneous route in various doses, e.g. from 1 μg to 500 μg, preferably from 10 μg to 500 μg, more preferably from 100 μg to 250 μg, e.g. 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 μg, etc. Optionally, the treatment may continue for 2-4 months up to 24 months, e.g. between 2 and 24 months or between 2 and 12 months, e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 months.More specifically, EYP001 is administered while treatment with IFNα2a, IFNα2b or pegylated forms thereof is being performed.

[0075] The present disclosure further relates to a method for treating or preventing the development of a cancer, comprising administering to a patient a therapeutically effective amount of the cancer cell, such as a pulmonary artery disease, a pulmonary artery disease, or a pulmonary artery disease, including but not limited to, a pulmonary artery disease, a pulmonary artery disease, a pulmonary artery disease, or a pulmonary pulmonary disease, including but not limited to ... The present disclosure relates to a pharmaceutical composition or kit comprising IFN-α and an FXR agonist for use in treating a disease selected from the group consisting of solid or hematopoietic cancers selected from among carcinoid tumors, melanoma, multiple myeloma, renal cell carcinoma, and neuroendocrine tumors; and other diseases, such as age-related macular degeneration, hemangiomatosis, Behcet's syndrome, thrombocythemia, polycythemia vera, primary myelofibrosis, Churg-Strauss syndrome, inflammatory bowel disease, and mycobacterial infections, as a combined preparation for simultaneous, separate, or sequential use. The present disclosure further relates to the use of IFN-α and an FXR agonist for the preparation of a medicament for treating such diseases, to IFN-α for use in combination with an FXR agonist for treating such diseases, to FXR agonists for use in combination with IFN-α for treating such diseases, and to a method of treating such diseases in a patient, comprising administering a therapeutically effective amount of an FXR agonist and a therapeutically effective amount of IFN-α, thereby reducing adverse effects resulting from treatment with IFN-α. The IFN-α can be selected from the group consisting of IFN-α1a, IFN-α1b, IFN-α2a and IFN-α2b or pegylated forms thereof. The FXR agonist can be selected from the group disclosed in Table 1, in particular EYP001. In a very specific embodiment, the IFN-α is IFN-α2a or a pegylated form thereof and the FXR agonist is EYP001. More specifically, the FXR agonist is administered as long as the treatment with IFN-α is performed. In particular, the FXR agonist is administered in a therapeutic amount effective for reducing the adverse effects of IFN-α, in particular influenza-like symptoms.In one embodiment, the FXR agonist is administered in a therapeutic amount effective for reducing the adverse effects of IFN-α, particularly influenza-like syndrome, and effective for providing a therapeutic effect in one of the above-defined diseases. For example, the daily dose of EYP001 is 50 to 800 mg per adult per day, preferably 100 to 600 mg per adult per day, even more preferably 150 to 400 mg per adult per day or 200 to 400 mg per adult per day, for example about 300 mg per adult per day, which can be administered once or twice a day, preferably orally. Preferably, IFNα2a, IFNα2b or pegylated forms thereof will be administered once a week by subcutaneous route in various doses, e.g. from 1 μg to 500 μg, preferably from 10 μg to 500 μg, more preferably from 100 μg to 250 μg, e.g. 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 μg, etc. Optionally, the treatment may continue for 2-4 months up to 24 months, e.g. between 2 and 24 months or between 2 and 12 months, e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 months.

[0076] The disclosure further relates to a pharmaceutical composition or kit comprising IFN-β and an FXR agonist for use in treating a disease selected from the group consisting of multiple sclerosis, Guillain-Barre syndrome, rheumatoid arthritis and cancer, particularly solid or hematopoietic cancer, as a combined preparation for simultaneous, separate or sequential use. The disclosure further relates to the use of IFN-β and an FXR agonist for the preparation of a medicament for treating such a disease, to IFN-β for use in combination with an FXR agonist for treating such a disease, to FXR agonists for use in combination with IFN-β for treating such a disease, and to a method of treating such a disease in a patient comprising administering a therapeutically effective amount of an FXR agonist and a therapeutically effective amount of IFN-β, thereby reducing adverse effects resulting from treatment with IFN-β. The IFN-β may be IFN-β1, such as IFN-β1a and IFN-β1b, or a pegylated form thereof. The FXR agonist can be selected from the group disclosed in Table 1. In a very specific embodiment, the FXR agonist is EYP001. More specifically, the FXR agonist is administered as long as the treatment with IFN-β is performed. Specifically, the FXR agonist is administered in a therapeutic amount effective for reducing the adverse effects of IFN-β, particularly influenza-like symptoms. In one embodiment, the FXR agonist is administered in a therapeutic amount effective for reducing the adverse effects of IFN-β, particularly influenza-like symptoms, and effective for providing a therapeutic effect on one of the diseases defined above.

[0077] The disclosure further relates to a pharmaceutical composition or kit comprising IFN-γ and an FXR agonist for use in treating a disease selected from the group consisting of bacterial infections, particularly mycobacterial infections, fibrosis such as idiopathic fibrosing alveolitis, leishmaniasis, osteoporosis and cancer, particularly solid or hematopoietic cancers, as a combined preparation for simultaneous, separate or sequential use. The disclosure further relates to the use of IFN-γ and an FXR agonist for the preparation of a medicament for treating such a disease, to IFN-γ for use in combination with an FXR agonist for treating such a disease, to FXR agonists for use in combination with IFN-γ for treating such a disease, and to a method of treating such a disease in a patient comprising administering a therapeutically effective amount of an FXR agonist and a therapeutically effective amount of IFN-γ, thereby reducing adverse effects resulting from treatment with IFN-γ. The IFN-γ may be IFN-γ1, particularly IFN-γ1b or a pegylated form thereof. The FXR agonist may be selected from the group disclosed in Table 1. In a very specific embodiment, the FXR agonist is EYP001. More specifically, the FXR agonist is administered as long as the treatment with IFN-γ is performed. Specifically, the FXR agonist is administered in a therapeutic amount effective for reducing the adverse effects of IFN-γ, in particular influenza-like symptoms. In one embodiment, the FXR agonist is administered in a therapeutic amount effective for reducing the adverse effects of IFN-γ, in particular influenza-like symptoms, and effective for providing a therapeutic effect on one of the diseases defined above.

[0078] The disclosure further relates to a pharmaceutical composition or kit comprising an IFN-λ and an FXR agonist for use in treating a disease selected from the group consisting of fibrosis (WO18115199) and hepatitis D virus infection (WO17143253) as a combined preparation for simultaneous, separate or sequential use. The disclosure further relates to the use of an IFN-λ and an FXR agonist for the preparation of a medicament for treating fibrosis or hepatitis D virus infection, to an IFN-λ for use in combination with an FXR agonist for treating fibrosis or hepatitis D virus infection, to an FXR agonist for use in combination with an IFN-λ for treating fibrosis or hepatitis D virus infection, and to a method of treating fibrosis or hepatitis D virus infection in a patient comprising administering a therapeutically effective amount of an FXR agonist and a therapeutically effective amount of IFN-λ, thereby reducing adverse effects resulting from treatment with IFN-λ. The IFN-λ may be IFN-λ or a pegylated form thereof. The FXR agonist may be selected from the group disclosed in Table 1. In a very specific embodiment, the FXR agonist is EYP001. More specifically, the FXR agonist is administered as long as the treatment with IFN-λ is performed. Specifically, the FXR agonist is administered in a therapeutic amount effective for reducing the adverse effects of IFN-λ, in particular influenza-like symptoms. In one embodiment, the FXR agonist is administered in a therapeutic amount effective for reducing the adverse effects of IFN-λ, in particular influenza-like symptoms, and effective for providing a therapeutic effect on fibrosis or hepatitis D virus infection.

[0079] IFN can be used alone or in combination with other therapeutic agents. The other therapeutic agents can be, for example, antitumor agents, antiviral agents, antibacterial agents, anti-inflammatory agents, immunosuppressive molecules. A non-exhaustive list of therapeutic agents that can be used in combination with IFN includes tamoxifen; megestrol acetate; anthracyclines such as epirubicin, doxorubicin, daunorubicin, idarubicin, nemorubicin, pixantrone, sabarubicin, and valrubicin; lonidamine; antimetabolites such as 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), capecitabine (Xeloda®), cytarabine (Ara-C®), floxuridine, fludarabin, and the like. vinblastine, gemcitabine (Gemzar®), hydroxycarbamide, methotrexate, pemetrexed (Alimta®), vinblastine; cisplatin, carboplatin or dicycloplatin; cytokines / hormones such as IL-2, TNF-α, octreotide; nitrogen mustard alkylating agents such as cyclophosphamide or melphalan; retinoids such as acitretin; antivirals such as ribavirin, taribavirin, simeprevir, sofosbuvir, zidovudine, lopinavir; antibiotics such as minocycline.

[0080] For example, specific combinations of therapeutic agents may be selected from the following list, which is not exhaustive: IFN-γ + TNF-α + nitrogen mustard alkylating agent, such as cyclophosphamide or melphalan; IFN-α + ribavirin; IFN-α + IL-2; IFN-α + zidovudine; IFN-α + vinblastine; IFN-α + octreotide; IFN-α + TNF-α; IFN-β + minocycline; IFN-β + lopinavir + ritonavir; IFN-β + methylprednisolone; etc.

[0081] In a particular embodiment, the FXR agonist, particularly the FXR agonist of Table 1, more particularly EYP001, and IFN-α or its pegylated form can be used in combination with at least one further active ingredient. Preferably, the further active ingredient is an antiviral drug, more particularly an antiviral drug with activity against HBV. In this context, the combination of the FXR agonist and IFN is used to treat HBV infection, particularly chronic HBV. In a preferred embodiment, the at least one further active ingredient is a polymerase inhibitor selected from the group consisting of L-nucleosides, deoxyguanosine analogs and nucleoside phosphonates. In a very particular embodiment, the at least one further active ingredient is selected from the group consisting of lamivudine, telbivudine, emtricitabine, entecavir, adefovir and tenofovir.

[0082] Further aspects and advantages of the present invention will be described in the following examples, which should be considered as illustrative and not limiting. EXAMPLES

[0083] Twenty-five patients chronically infected with HBV received 4 weeks of treatment combining IFN (pegylated IFNα2a, PEG-IFN, once-weekly subcutaneous injections) with daily oral FXR agonist EYP001a or placebo. Overall, 21 patients (84%) developed IFN-associated influenza-like adverse events: fever, weakness, muscle pain, headache, back or leg pain, bone or muscle aches, myalgia, and fatigue. The frequency of influenza-like AEs was unexpectedly reduced by at least one-third, by a significant margin, when IFN treatment was combined with EYP001 (Table 2). Patient characteristics (Tables 3 and 4) did not differ between treatment groups and did not explain the reduction in IFN-associated influenza-like AEs (Table 2). A summary of patient characteristics and parameters of HBV infection are provided in Tables 3 and 4, respectively.

[0084] [Table 2]

[0085] [Table 3]

[0086] [Table 4]

Claims

1. For use in reducing adverse effects in a subject resulting from treatment with interferon-α (IFN-α) or a pegylated form thereof, 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof (EYP001), wherein the adverse effect is influenza-like syndrome.

2. 2. The pharmaceutical composition of claim 1, wherein the IFN-α is selected from the group consisting of IFN-α1a, IFN-α1b, IFN-α2a, IFN-α2b and pegylated forms thereof.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the influenza-like symptoms include fever, weakness, muscle pain, headache, back or leg pain, bone or muscle aches, myalgia, or fatigue.

4. A pharmaceutical composition described in any one of claims 1 to 3, wherein the influenza-like symptoms include fever, muscle pain, headache, or fatigue.

5. 5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the interferon is IFN-α2a or any pegylated form thereof.

6. 5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the interferon is pegylated IFN-α.

7. A pharmaceutical composition according to any one of claims 1 to 6, wherein the interferon is pegylated IFN-α2a.

8. 8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the subject is infected with Hepatitis B virus.

9. A pharmaceutical composition described in any one of claims 1 to 8, wherein the subject is suffering from chronic hepatitis B.

10. A pharmaceutical composition described in any one of claims 1 to 9, wherein the subject is further infected with Hepatitis D virus.

11. 11. The pharmaceutical composition of any one of claims 1 to 10, wherein EYP001 is to be administered once a day.

12. 11. The pharmaceutical composition of any one of claims 1 to 10, wherein EYP001 is to be administered twice daily.

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