Use of the BTK inhibitor 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile for the treatment of membranous nephropathy, IgG4-related disease, and antiphospholipid syndrome

Abstract

The present disclosure provides, for example, a method of treating a disease selected from membranous nephropathy (MN), IgG4-related disease, and antiphospholipid syndrome (APS) in a mammal using a therapeutically effective amount of the BTK inhibitor 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile or a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 957,724, filed on January 6, 2020, and U.S. Provisional Application No. 63 / 039,200, filed on June 15, 2020, the contents of each of which are incorporated herein by reference in their entirety.

[0002] This disclosure relates to the use of a therapeutically effective amount of a compound having the structure:

Chemical Formula

Chemical Formula

Background Art

[0003] Compound (I) is disclosed in Example 31 of Patent Document 1 (filed on September 6, 2013). The disclosed synthesis requires purification by column chromatography and provides Compound (I) which forms a foam upon removal of the solvent and can be crushed to obtain a powder.

[0004] Compound (I) is also known as PRN1008 and rilzabrutinib. Compound (I) and its pharmaceutically acceptable salts are potent Bruton's tyrosine kinase (BTK) inhibitors. The enzyme BTK is a member of the Tec family of non-receptor tyrosine kinases. BTK is expressed in most hematopoietic cells including B cells, mast cells, and macrophages. BTK plays a role in B cell development and activation. BTK activity has been implicated in the pathology of several disorders and conditions such as B cell-related blood cancers (e.g., non-Hodgkin lymphoma and B cell chronic lymphocytic leukemia) and immune-mediated diseases (e.g., rheumatoid arthritis, graft-versus-host disease, Sjögren's syndrome, pemphigus, IBD, lupus, and asthma).

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Summary of the Invention

Means for Solving the Problems

[0006] In some embodiments of the present disclosure, at least about 80% mass / mass, at least about 85% mass / mass, at least about 90% mass / mass, at least about 95% mass / mass, at least about 96% mass / mass, at least about 97% mass / mass, or at least about 99% mass / mass of compound (I) or its pharmaceutically acceptable salt is the (E) isomer. The ratio of the (E) isomer to the (Z) isomer can be calculated by methods well known in the art. One such method is the HPLC total area normalization method.

[0007] In some embodiments, the mammal being treated with compound (I) or a pharmaceutically acceptable salt thereof is untreated with respect to immunosuppressive therapy. In some embodiments, the mammal being treated with compound (I) or a pharmaceutically acceptable salt thereof is untreated with respect to any immunosuppressive therapy. In some embodiments, the mammal is a human.

[0008] In some embodiments, the mammal has been previously treated with immunosuppressive therapy. In some embodiments, the mammal is a human.

[0009] In some embodiments, the present disclosure provides a method of using compound (I) or a pharmaceutically acceptable salt thereof as an adjunctive therapy to immunosuppressive therapy for a disease selected from membranous nephropathy (MN), IgG4-related disease, and antiphospholipid syndrome (APS). In some embodiments, the present disclosure provides a method of using compound (I) or a pharmaceutically acceptable salt thereof as an adjunctive therapy for a disease selected from diseases selected from membranous nephropathy (MN), IgG4-related disease, and antiphospholipid syndrome (APS), where the immunosuppressive agent is used as a first-line or second-line treatment for the disease. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is used in place of immunosuppressive therapy. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is used in combination with immunosuppressive therapy. In some embodiments, the present disclosure provides a method of using compound (I) or a pharmaceutically acceptable salt thereof as an adjunctive therapy for a disease selected from membranous nephropathy (MN), IgG4-related disease, and antiphospholipid syndrome (APS), where the immunosuppressive agent is used as a first-line maintenance or second-line maintenance treatment for the disease. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is used in place of the immunosuppressive agent. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is used in combination with the immunosuppressive agent.

[0010] In some embodiments, the present disclosure provides a method of eliminating or reducing a therapeutic dose of an immunosuppressive therapy used in chronic maintenance therapy in the treatment of a disease selected from membranous nephropathy (MN), IgG4-related disease, and antiphospholipid syndrome (APS) in a mammal in need of treatment, wherein the immunosuppressive therapy is used as a first-line treatment or a second-line treatment, and the method comprises administering to the mammal in need of treatment a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is used in place of the immunosuppressive therapy. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is used in combination with the immunosuppressive therapy.

[0011] In some embodiments, the present disclosure provides a method of using compound (I) or a pharmaceutically acceptable salt thereof as an adjunctive therapy for corticosteroid therapy for a disease selected from membranous nephropathy (MN), IgG4-related disease, and antiphospholipid syndrome (APS). In some embodiments, the present disclosure provides a method of using compound (I) or a pharmaceutically acceptable salt thereof as an adjunctive therapy for a disease selected from membranous nephropathy (MN), IgG4-related disease, and antiphospholipid syndrome (APS), wherein the corticosteroid is used as a first-line or second-line treatment for the disease. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is used in place of the corticosteroid. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is used in combination with the corticosteroid. In some embodiments, the present disclosure provides a method of using compound (I) or a pharmaceutically acceptable salt thereof as an adjunctive therapy for a disease selected from membranous nephropathy (MN), IgG4-related disease, and antiphospholipid syndrome (APS), wherein the corticosteroid is used as a first-line maintenance or second-line maintenance therapy for the disease. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is used in place of the corticosteroid. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is used in combination with the corticosteroid. In some embodiments, the corticosteroid is a glucocorticoid.

[0012] In some embodiments, the present disclosure provides a method of eliminating or reducing the therapeutic dose of corticosteroid therapy in chronic maintenance therapy for the treatment of a disease selected from membranous nephropathy (MN), IgG4-related disease, and antiphospholipid syndrome (APS) in a mammal in need of treatment, wherein the corticosteroid therapy is used as a first-line treatment or second-line treatment, and the method comprises administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof to the mammal in need of such treatment. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is used in place of corticosteroid therapy. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is used in combination with corticosteroid therapy. In some embodiments, the corticosteroid therapy is a glucocorticoid.

[0013] In some embodiments of the present disclosure, compound (I) or a pharmaceutically acceptable salt thereof is administered in combination with a non-corticosteroid immunosuppressant and / or anti-inflammatory agent.

[0014] In some embodiments of the present disclosure, the compound (I) or a pharmaceutically acceptable salt thereof is interferon alpha, interferon gamma, cyclophosphamide, tacrolimus, mycophenolate mofetil, methotrexate, dapsone, sulfasalazine, azathioprine, anti-CD20 agent (e.g., rituximab, dupilumab, ofatumumab, obinutuzumab, or belimumab, or any biosimilar version of the foregoing), anti-TNF alpha agent (e.g., etanercept, infliximab, golimumab, adalimumab, or certolizumab pegol, or any biosimilar version of the foregoing), anti-IL-4 agent against a ligand or its receptor (e.g., dupilumab or any biosimilar version thereof), anti-IL-6 agent against a ligand or its receptor (e.g., tocilizumab, sarilumab, olokizumab, elsililumab, or siltuximab, or any biosimilar version of the foregoing), anti-IL-17 agent against a ligand or its receptor (e.g., secukinumab, ustekinumab, brodalumab, or ixekizumab, or any biosimilar version of the foregoing), anti-IL-23 agent against a ligand or its receptor (e.g., guselkumab or risankizumab, or any biosimilar version), anti-IL-12 / 23 agent against a ligand or its receptor (e.g., ustekinumab or any biosimilar version thereof), anti-IL-12 agent against a ligand or its receptor, anti-IL-1 agent against a ligand or its receptor (e.g., rilonacept, canakinumab, or anakinra, or any biosimilar version of the foregoing), anti-IL-2 agent against a ligand or its receptor (e.g., basiliximab or daclizumab, or any biosimilar version), anti-CD2 agent (e.g., alefacept or any biosimilar version thereof), anti-CD3 agent (e.g., muromonab-cd3 or any biosimilar version thereof), anti-CD80 / 86 agent (e.g., abatacept or belatacept, or any biosimilar version), anti-sphingosine-1-phosphate receptor agent (e.g., fingolimod or any biosimilar version thereof), anti-C5 agent (e.g., eculizumab or any biosimilar version thereof),Administered in combination with an active pharmaceutical ingredient selected from anti-integrin alpha4 agents (e.g., natalizumab or a biosimilar version thereof), anti-α4β7 agents (e.g., vedolizumab or a biosimilar version thereof), anti-mTOR agents (e.g., sirolimus or everolimus), anti-calcineurin agents (e.g., tacrolimus), anti-BAFF / BlyS agents (e.g., belimumab, VAY736, or blisibimod, or a biosimilar version of any of the foregoing), leflunomide, and teriflunomide.,

[0015] Embodiments: Non-limiting embodiments of the present disclosure include the following: 1. A method of treating a disease selected from membranous nephropathy (MN), IgG4-related disease (IgG4-RD), and antiphospholipid syndrome (APS) in a mammal, the (E) isomer, (Z) isomer, and mixture of (E) and (Z) isomers of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile; and / or any pharmaceutically acceptable salt of the foregoing compounds a compound selected from; and a pharmaceutically acceptable carrier or excipient comprising administering to the mammal a pharmaceutical composition comprising the above method.

[0016] 2. The method according to embodiment 1, wherein the disease is acute.

[0017] 3. The method according to embodiment 1 or 2, wherein the disease is an IgG4-RD disease relapse.

[0018] 4. The method according to any one of embodiments 1 to 3, wherein the pharmaceutical composition is administered orally.

[0019] 5. The pharmaceutical composition is administered daily, by the method according to any one of Embodiments 1 to 4.

[0020] 6. The pharmaceutical composition is administered orally daily, by the method according to any one of Embodiments 1 to 5.

[0021] 7. The pharmaceutical composition is administered in place of immunosuppressive therapy, by the method according to any one of Embodiments 1 to 6.

[0022] 8. The pharmaceutical composition is administered in place of corticosteroid therapy, by the method according to any one of Embodiments 1 to 7.

[0023] 9. The pharmaceutical composition is administered in combination with immunosuppressive therapy, by the method according to any one of Embodiments 1 to 6.

[0024] 10. The pharmaceutical composition is administered in combination with corticosteroid therapy, by the method according to any one of Embodiments 1 to 6.

[0025] 11. The pharmaceutical composition is administered in combination with a non-corticosteroid immunosuppressant and / or an anti-inflammatory agent, by the method according to any one of Embodiments 1 to 6 or 8 to 10.

[0026] 12. The pharmaceutical composition is administered in place of immunosuppressive maintenance therapy, by the method according to any one of Embodiments 1 or 4 to 6.

[0027] 13. The pharmaceutical composition is administered in place of corticosteroid maintenance therapy, by the method according to any one of Embodiments 1 or 4 to 6.

[0028] 14. The pharmaceutical composition is administered in combination with immunosuppressive maintenance therapy, by the method according to any one of Embodiments 1, 2, or 4 to 6.

[0029] 15. The pharmaceutical composition is administered in combination with corticosteroid maintenance therapy, by the method according to any one of Embodiments 1, 2, or 4 to 6.

[0030] 16. The pharmaceutical composition is administered in combination with a non-corticosteroid immunosuppressant and / or an anti-inflammatory agent, according to the method of any one of Embodiments 13 to 15.

[0031] 17. The pharmaceutical composition is a compound that is a substantially pure (E) or (Z) isomer of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile, and / or a pharmaceutically acceptable salt of the compound; and a pharmaceutically acceptable carrier or excipient comprising, according to the method of any one of Embodiments 1 to 16.

[0032] 18. At least about 85% mass / mass of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile or at least about 85% mass / mass of a pharmaceutically acceptable salt of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile is the (E) isomer, according to the method of any one of Embodiments 1 to 17.

[0033] 19. The mammal is a human, according to the method of any one of Embodiments 1 to 18.

[0034] 20. The IgG4-related disease is characterized by an IgG4-RD Responder Index (RI) greater than or equal to 2 in at least one organ system, according to the method of any one of Embodiments 1 to 19.

[0035] 21. The method according to any one of Embodiments 1 to 20, wherein the IgG4-related disease is characterized by a serum IgG4 concentration higher than 1.5 times the upper limit of normal.

[0036] 22. The method according to any one of Embodiments 1 to 21, wherein the IgG4-related disease is selected from IgG4-related sialadenitis, IgG4-related ophthalmic disease (IgG4-ROD), IgG4-related pharyngitis, IgG4-related thyroid disease, IgG4-related hypophysitis, IgG4-related pachymeningitis, IgG4-related leptomeningitis, IgG4-related pancreatitis, IgG4-related lung disease, IgG4-related pleurisy, IgG4-related hepatopathy, IgG4-related sclerosing cholangitis, IgG4-related cholecystitis, IgG4-related aortitis, IgG4-related periaortitis, IgG4-related periarteritis, IgG4-related pericarditis, IgG4-related mediastinitis, IgG4-related retroperitoneal fibrosis, IgG4-related mesenteritis, IgG4-related mastitis, IgG4-related kidney disease (IgG4-RKD), IgG4-related prostatitis, IgG4-related perivascular fibrosis, IgG4-related para-testicular pseudotumor, IgG4-related epididymo-orchitis, IgG4-related lymphadenopathy, IgG4-related skin disease, and IgG4-related perineural disease, or a relapse of any of the above IgG4-related diseases.

[0037] 23. The method according to Embodiment 1, wherein the pharmaceutical composition is administered in combination with an active pharmaceutical ingredient selected from interferon alpha, interferon gamma, cyclophosphamide, tacrolimus, mycophenolate mofetil, methotrexate, dapsone, sulfasalazine, azathioprine, anti-CD20 agent, anti-TNF alpha agent, anti-IL-6 agent against a ligand or its receptor, anti-IL-17 agent against a ligand or its receptor, anti-IL-1 agent against a ligand or its receptor, anti-IL-2 agent against a ligand or its receptor, anti-CD2 agent, anti-CD3 agent, anti-CD80 / 86 agent, anti-sphingosine-1-phosphate receptor agent, anti-C5 agent, anti-mTOR agent, anti-calcineurin agent, anti-BAFF / BlyS agent, leflunomide, and teriflunomide.

[0038] 24. The method according to embodiment 1, wherein the pharmaceutical composition is administered in combination with rituximab, ofatumumab, obinutuzumab, or belzutifan, or any biosimilar version of the foregoing.

[0039] 25. The method according to any one of embodiments 1-6, 9-11, or 14-24, wherein the mammal is untreated with respect to immunosuppressive therapy.

[0040] 26. The method according to any one of embodiments 1-6, 9-11, or 14-24, wherein the mammal is untreated with respect to any immunosuppressive therapy.

[0041] 27. The method according to any one of embodiments 1-24, wherein the mammal has been previously treated with immunosuppressive therapy.

Brief Description of the Drawings

[0042]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Mode for Carrying Out the Invention

[0043] Definition: As used herein, an "a" or "an" entity refers to one or more of that entity; for example, "a compound" refers to one or more compounds, or at least one compound, if not otherwise stated. Thus, the terms "a" (or "an"), "one or more", and "at least one" are used interchangeably herein.

[0044] As used herein, the term "about" means approximately, within the range of, generally, or roughly. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries around the recited numerical values. In general, the term "about" is used herein to modify a numerical value by changing the value by up to 10% around the value so recited.

[0045] As used herein, "Compound (I)" has the following structure:

Chemical formula

Chemical formula

[0046] All polymorphic forms and hydrates of Compound (I) are within the scope of this disclosure and the claims appended hereto.

[0047] It will be understood by those skilled in the art that when a compound is designated as the (R) isomer, the compound may contain the corresponding (S) stereoisomer as an impurity, i.e., less than about 1% by weight of the (S) stereoisomer, and vice versa.

[0048] As used herein, "substantially pure" in relation to a geometric or isomeric form refers to a compound such as compound (I) in which more than 70% by mass of that compound is present as a given isomeric form. For example, the phrase "The solid form of compound (I) is a substantially pure (E) isomer of compound (I)" means that the solid form of compound (I) has a solid form of compound (I) that is at least 70% by mass of the (E) isomeric form, and the phrase "The solid form of compound (I) is a substantially pure (Z) isomer of compound (I)" means that the solid form of compound (I) has a solid form of compound (I) that is at least 70% by mass of the (Z) isomeric form. In some embodiments, at least 80% by mass of the solid form of compound (I) is in the (E) form, or at least 80% by mass of the solid form of compound (I) is in the (Z) form. In some embodiments, at least 85% by mass of the solid form of compound (I) is in the (E) form, or at least 85% by mass of the solid form of compound (I) is in the (Z) form. In some embodiments, at least 90% by mass of the solid form of compound (I) is in the (E) form, or at least 90% by mass of the solid form of compound (I) is in the (Z) form. In some embodiments, at least 95% by mass of the solid form of compound (I) is in the (E) form, or at least 95% by mass of the solid form of compound (I) is in the (Z) form. In some embodiments, at least 97% or 98% by mass of the solid form of compound (I) is in the (E) form, or at least 97% or 98% by mass of the solid form of compound (I) is in the (Z) form. In some embodiments, at least 99% by mass of the solid form of compound (I) is in the (E) form, or at least 99% by mass of the solid form of compound (I) is in the (Z) form. The relative amounts of the (E) and (Z) isomers in the solid mixture can be determined according to standard methods and techniques known in the art.

[0049] As used herein, "acute" means a disease (e.g., disease relapse) having a rapid onset and / or a short course.

[0050] As used herein, a "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such salts include, but are not limited to: formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, mucic acid, etc.; or salts formed when any of the acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth ions, or aluminum ions; or coordination with ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc. are included. It is understood that pharmaceutically acceptable salts are non-toxic.

[0051] Further information on suitable pharmaceutically acceptable salts can be found in Remington’s Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, PA, 1985, and the section on suitable pharmaceutically acceptable salts is incorporated herein by reference. See also Berge et al., Pharmaceutical Salts, Journal of Pharmaceutical Sciences, 1, Vol. 66, No. 1, January 1997.

[0052] Treatment decisions often follow formal or informal algorithmic guidelines. Treatment options can often be ranked into a series of treatments or prioritized: first-choice treatment, second-choice treatment, third-choice treatment, etc. The first-choice treatment is the first treatment to be tried. Its priority over other options is usually formally recommended based on clinical trial evidence for the best available combination of its effectiveness, safety, and tolerability, or is selected based on the physician's clinical experience. If the problem cannot be solved by the first-choice treatment or if unacceptable side effects occur, an additional (second-choice) treatment may be used instead or in addition to the treatment plan, followed by third-choice treatment, etc. Thus, as used herein, "first-choice" treatment generally means the treatment that is performed when someone is diagnosed with a particular diagnosis or condition and can be classified as standard treatment.

[0053] As used herein, "maintenance treatment" means a treatment, treatment plan, or series of treatments that are performed after the initial course of treatment of a patient with a disease. Maintenance treatment can be used to halt, slow, or even reverse the progression of the disease, maintain the health improvement achieved by the initial treatment, and / or enhance the gains achieved by the initial treatment.

[0054] "Pharmaceutically acceptable carrier or excipient" means a carrier or excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in the manufacture of pharmaceutical compositions, and includes carriers or excipients that are acceptable for human pharmaceutical use as well as veterinary use. As used herein, "pharmaceutically acceptable carrier or excipient" means one or more pharmaceutically acceptable carriers or excipients.

[0055] As used herein, "treating", "treat", or "treatment" of a disease means: (1) Suppressing a disease, i.e., stopping or reducing the occurrence of the disease or its clinical symptoms; or (2) Alleviating a disease, i.e., causing regression of the disease or its clinical symptoms is included.

[0056] As used herein, "therapeutically effective amount" means an amount of a compound of the present disclosure that is sufficient to achieve such treatment for a disease when administered to a mammal, e.g., a human, for treating the disease. The "therapeutically effective amount" varies depending on the compound, the disease and its severity, and the age, weight, etc. of the mammal to be treated.

[0057] As used herein, "QD" means once a day.

[0058] As used herein, "BID" means twice a day.

[0059] "Mammal" means an animal such as a dog, a cat, and a human as used herein.

[0060] "Membranous nephropathy (MN)" is a kidney disease that affects the filters (glomeruli) of the kidneys and can cause urinary protein, as well as kidney function decline and swelling. This is also known as membranous glomerulopathy and glomerulonephritis. Without wishing to be bound by theory, the treatment of MN is thought to be mediated by depletion of autoantibodies and inhibition of platelet aggregation. Thus, a BTK inhibitor such as compound (I) may be useful in the treatment of MN.

[0061] "IgG4-related disease (IgG4-RD)" is a fibro-inflammatory condition that can affect almost any organ system. Left untreated, IgG4-RD can lead to severe morbidity and death, including organ damage and organ failure. IgG4-RD is characterized by infiltration of tissues with lymphocytes and IgG4-secreting plasma cells, varying degrees of fibrosis (scarring), and a usually rapid response to oral steroid medications. Common symptoms include severe salivary and lacrimal gland swelling, orbital disease, autoimmune pancreatitis, retroperitoneal fibrosis, and tubulointerstitial nephritis. In some embodiments, IgG4-RD is characterized by an IgG4-RD responder index (RI) greater than or equal to 2 in at least one organ system. In some embodiments, IgG4-RD is characterized by a serum IgG4 concentration greater than 1.5 times the upper limit of normal. In some embodiments, IgG4-RD is characterized by an IgG4-RD responder index (RI) greater than or equal to 2 in at least one organ system and a serum IgG4 concentration greater than 1.5 times the upper limit of normal.

[0062] There are no approved drugs for the treatment of IgG4-RD. Treatment is typically corticosteroids (CS); however, patients often relapse after tapering CS, thus requiring chronic CS dosing, which results in serious and debilitating side effects. Rituximab has been shown to have an effective clinical response; however, patients also frequently relapse after treatment. Without wishing to be bound by theory, it is thought that a number of mechanisms of action may potentially result in positive outcomes in IgG4-RD by affecting many of the features that drive the disease, including inflammation, allergic components (IgE and eosinophils), monocytes and macrophages (involved in fibrosis), and B cells involved in disease initiation and maintenance. Accordingly, BTK inhibitors such as compound (I) may be useful in the treatment of IgG4-RD.

[0063] When the organ involved is the salivary gland, the IgG4-related disease is called IgG4-related sialadenitis. Non-limiting examples of IgG4-related sialadenitis include IgG4-related submandibular gland disease and IgG4-related parotitis.

[0064] When the organ involved is the orbit, the IgG4-related disease is called IgG4-related ophthalmic disease (IgG4-ROD). Non-limiting examples of IgG4-ROD include IgG4-related dacryoadenitis (lacrimal gland), IgG4-related orbital inflammation (or IgG4-related orbital inflammatory pseudotumor), IgG4-related orbital myositis (extraocular muscles), and IgG4-related pan-orbital inflammation.

[0065] When the organ involved is the paranasal sinuses, non-limiting examples of IgG4-related diseases include chronic rhinosinusitis and eosinophilic granulomatosis with polyangiitis (upper airway and orbit).

[0066] When the organ involved is the pharynx, a non-limiting example of the IgG4-related disease is IgG4-related pharyngitis.

[0067] When the organ involved is the thyroid gland, a non-limiting example of the IgG4-related disease is IgG4-related thyroid disease.

[0068] When the organ involved is the soft tissue of the head and neck, non-limiting examples of IgG4-related diseases include idiopathic cervical fibrosis, sclerosing tracheitis, and cervical fibrosclerosis.

[0069] When the organ involved is the pituitary gland, the IgG4-related disease is called IgG4-related hypophysitis. Non-limiting examples include IgG4-related panhypophysitis (all of the pituitary gland), IgG4-related adenohypophysitis (anterior pituitary), and IgG4-related infundibuloneurohypophysitis (posterior pituitary and pituitary stalk).

[0070] When the involved organ is the meninges, non-limiting examples of IgG4-related diseases include idiopathic hypertrophic pachymeningitis.

[0071] When the involved organ is the pancreas, non-limiting examples of IgG4-related diseases include type 1 autoimmune pancreatitis, lymphoplasmacytic sclerosing pancreatitis, and chronic pancreatitis with scattered and irregular narrowing of the main pancreatic duct.

[0072] When the involved organ is the lung, non-limiting examples of IgG4-related diseases include pulmonary inflammatory pseudotumor.

[0073] When the involved organ is the pleura, non-limiting examples of IgG4-related diseases include pleurisy.

[0074] When the involved organ is the liver, non-limiting examples of IgG4-related diseases include IgG4-related hepatopathy and IgG4-related cholecystitis.

[0075] When the involved organ is the bile duct, non-limiting examples of IgG4-related diseases include IgG4-related sclerosing cholangitis.

[0076] When the involved organ is the gallbladder, non-limiting examples of IgG4-related diseases include IgG4-related cholecystitis.

[0077] When the involved organ is the aorta, non-limiting examples of IgG4-related diseases include IgG4-related aortitis and IgG4-related periaortitis.

[0078] When the involved organ is a branch of the aorta (including the coronary artery, renal artery, or iliac artery), non-limiting examples of IgG4-related diseases include IgG4-related periaortitis.

[0079] When the organ involved is the breast, non-limiting examples of IgG4-related diseases include IgG4-related mastitis.

[0080] When the organ involved is the kidney, the IgG4-related disease is called IgG4-related kidney disease (IgG4-RKD). Non-limiting examples of IgG4-KD include IgG4-related tubulointerstitial nephritis (IgG4-TIN), membranous glomerulonephritis secondary to IgG4-related disease, and IgG4-related pyelonephritis (renal pelvis).

[0081] When the organ involved is the prostate, non-limiting examples of IgG4-related diseases include IgG4-related prostatitis.

[0082] When the organ involved is the vas deferens, non-limiting examples of IgG4-related diseases include IgG4-related perivasal fibrosis.

[0083] When the organ involved is the scrotum, non-limiting examples of IgG4-related diseases include IgG4-related paratesticular pseudotumor and IgG4-related epididymo-orchitis.

[0084] When the organ involved is the lymph node, non-limiting examples of IgG4-related diseases include IgG4-related lymph node swelling.

[0085] When the organ involved is the skin, non-limiting examples of IgG4-related diseases include IgG4-related skin diseases, such as eosinophilic angiolymphoid hyperplasia and cutaneous pseudolymphoma.

[0086] When the organ involved is the nerve, non-limiting examples of IgG4-related diseases include IgG4-related perineural diseases.

[0087] In some embodiments of the present disclosure, the IgG4-related disease is acute (e.g., IgG4-related disease relapse).

[0088] "Antiphospholipid syndrome (APS)", also sometimes known as Hughes syndrome, is an immune system disorder that causes an increased risk of blood clots. Therefore, people with APS have a higher risk of developing deep vein thrombosis (DVT) (blood clots that usually occur in the lower limbs), arterial thrombosis (blood clots in the arteries) that can cause stroke or heart attack, and conditions such as blood clots in the brain that can cause problems with movement, speech, vision, and memory. Although not wishing to be bound by theory, autoantibodies produced by plasma cells are thought to be important in the pathology of APS. Thrombotic events and pregnancy morbidity are also mediated by immune infiltration. Therefore, BTK inhibitors such as compound (I) may be useful in the treatment of APS.

[0089] Formulation and Administration: In general, the compounds of the present disclosure will be administered in a therapeutically effective amount by any of the acceptable modes of administration (e.g., oral administration) for agents that serve a similar utility. The therapeutically effective amount of the compounds of the present disclosure can range from about 0.01 to about 500 mg per kg of patient body weight per day and can be administered in a single dose or in multiple doses. Appropriate dosage levels can be about 0.1 to about 250 mg / kg per day, for example about 0.5 to about 100 mg / kg per day.

[0090] An appropriate dosage level can also be from about 0.01 to about 250 mg / kg per day, such as from about 0.05 to about 100 mg / kg per day, and still further such as from about 0.1 to about 50 mg / kg per day. Within this range, the dosage can be from about 0.05 to about 0.5, such as from about 0.5 to about 5, and still further such as from about 5 to about 50 mg / kg per day. For oral administration, the composition can be provided in the form of tablets containing from about 1 to about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. The actual amount of the compound of the present disclosure, i.e., the active ingredient, to be administered depends on a number of factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound utilized, the route and form of administration, and other factors.

[0091] Generally, the compounds of the present disclosure are administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., by transdermal, intranasal, or suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. In some embodiments, the pharmaceutical composition is administered orally using a convenient daily dosing schedule, which can be adjusted according to the degree of pain. The composition can take the form of tablets, pills, capsules, semi-solids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition.

[0092] The selection of the formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules including enteric-coated or sustained-release tablets, pills or capsules), and the bioavailability of the drug substance. In recent years, pharmaceutical formulations have been particularly developed for drugs showing insufficient bioavailability based on the principle that bioavailability can be increased by an increase in surface area, i.e., by a decrease in particle size. For example, U.S. Patent No. 4,107,288 describes a pharmaceutical formulation having particles in the range of 10 to 1,000 nm in size, where the active substance is supported on a cross-linked matrix of a polymer. U.S. Patent No. 5,145,684 describes the manufacture of a pharmaceutical formulation in which the drug substance is micronized to nanoparticles (average particle size 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to obtain a pharmaceutical formulation showing significantly high bioavailability. The disclosures of these two patents are incorporated by reference in their parts relating to pharmaceutical formulations.

[0093] The composition generally comprises a compound of the present disclosure in combination with a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient is non-toxic and an auxiliary administration, and does not have an adverse effect on the therapeutic benefit of the compound of the present disclosure. Such excipients can be any solid, liquid, semi-solid, or in the case of an aerosol composition, a gaseous excipient generally available to those skilled in the art.

[0094] Examples of solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, agar, rice, wheat flour, kaolin, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, etc. Liquid and semi-solid excipients can be selected from glycerol, propylene glycol, water, ethanol and various oils including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. For example, liquid carriers for injectable solutions include water, saline, aqueous dextrose solution, and glycols.

[0095] Compressed gas can be used to formulate the compounds of the present disclosure in aerosol form. Suitable inert gases for this purpose are nitrogen, carbon dioxide, and the like.

[0096] Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E.W. Martin (Mack Publishing Company, 20th edition, 2000), which is incorporated herein by reference with respect to the sections related to pharmaceutical excipients and their formulations.

[0097] The level of the compound in the formulation can vary within a sufficient range used by those skilled in the art. Typically, the formulation contains the compound of the present disclosure in a balance of suitable pharmaceutical excipients and is about 0.01 to 99.99% by mass (% by weight) based on the total formulation. For example, the compound is present at about 1 to 80% by mass. With respect to the numerical range 0.01 to 99.99, “about” indicates less than 0.01%. With respect to the numerical range 1 to 80, “about” indicates 0.05 with respect to 1 and 10 with respect to 80, thus covering the range of 0.05 to 90% by mass.

[0098] The compounds of the present disclosure can be used in combination with one or more other drugs in the treatment of diseases or conditions for which the compounds of the present disclosure or other drugs may have utility. Thus, such other drugs can be administered simultaneously with the compounds of the present disclosure, for example, in a fixed-dose combination, or sequentially, by generally used routes and amounts. When the compounds of the present disclosure are used simultaneously with one or more other drugs, a unit dosage form containing such other drugs and the compounds of the present disclosure, i.e., a pharmaceutical composition of a fixed-dose compound, is preferred. However, combination therapy can also include therapies in which the compounds of the present disclosure and one or more other drugs are administered in different overlapping schedules or non-overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present disclosure and the other active ingredients may be used at lower doses than when each is used alone.

[0099] All publications and patents mentioned in this specification are hereby incorporated by reference in their entirety as if each individual publication or patent were specifically and individually indicated to be incorporated by reference.

[0100] A claim or description that includes "or" or "and / or" between at least one member of a group is considered satisfied if one, more than one, or all of the members of the group are present in, used in, or otherwise related to a given product or method, unless the contrary is indicated or is otherwise clear from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, used in, or otherwise related to a given product or method. The present disclosure includes embodiments in which more than one, or all, of the members of the group are present in, used in, or otherwise related to a given product or method.

[0101] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which at least one limitation, element, clause, and descriptive term from at least one of the recited claims is introduced into another claim. For example, any claim that depends on another claim can be modified to include at least one limitation found in any other claim that depends on the same base claim. When elements are presented as a list, for example, in a Markush group format, each subgroup of those elements is also disclosed, and any element can be excluded from the group. Of course, generally, when a disclosure, an aspect of the disclosure is referred to as including a particular element and / or feature, embodiments of that disclosure or aspect of the disclosure consist of or consist essentially of such elements and / or features. For the purpose of brevity, these embodiments are not specifically recited herein in these words. When a range is indicated, the endpoints are included. Further, unless otherwise indicated or apparent from the context and the understanding of one of ordinary skill in the art, values expressed as a range can take any specific value or sub-range within the range described in various embodiments of the present disclosure down to one-tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0102] One of ordinary skill in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments of the disclosure described herein. Such equivalents are intended to be encompassed by the following claims.

Examples

[0103] The following examples are intended to be illustrative and in no way meant to limit the scope of the present disclosure.

[0104] Example 1: Mouse anti-GBM glomerulonephritis model The efficacy of compound (I) (also referred to as PRN1008) compared to the adrenal corticosteroid dexamethasone (Dex) was tested in a murine anti-GBM glomerulonephritis model according to the design shown in Figure 1. Briefly, to induce glomerulonephritis, mice were pre-sensitized with sheep IgG / FCA (test day -5). Five days later (test day 0), anti-GBM sheep IgG was administered to the mice. Treatment with vehicle, compound (I) or Dex using various dosing regimens (compound (I): 10 mg / kg, 20 mg / kg, or 40 mg / kg QD or 20 mg / kg BID; Dex: 1 mg / kg QD; vehicle: QD or BID) was initiated on test day -1, one day prior to injection with anti-GBM sheep IgG. Treatment was continued until test day 10 for a total of 11 days of treatment. Urine protein analysis was performed on test days -6, -4, -1, 1, 3, 6, 8, and 10. After test day 10, mouse serum BUN levels were analyzed as a measure of renal function and kidney tissue diagnosis was performed. In the murine anti-GBM glomerulonephritis model, dose-dependent inhibition of serum BUN levels (Figure 2), severe proteinuria (Figure 3), and increased kidney weight (a surrogate for kidney inflammation) (Figure 5) were observed. Furthermore, treatment with compound (I) resulted in a decrease in proteinuria during the test (Figure 4), and compound (I) reduced kidney pathology (Figure 6), yielding favorable results compared to Dex.

[0105] Example 2 : An open-label, two-group comparative study to evaluate the safety and efficacy of compound (I) in patients with IgG4-RD resistant to rituximab To evaluate the safety and efficacy of daily oral administration of compound (I) in IgG4-RD patients resistant to rituximab, patients were enrolled in an open-label two-group comparative study. Patients having an IgG4-RD responder index (RI) greater than or equal to 2 at screening (i.e., up to 4 days prior to the start of treatment) in at least one organ system and optionally further having a serum IgG4 concentration higher than 1.5 times the upper limit of normal are treated with compound (I) for 12 to 52 weeks. After 12 weeks, the safety of daily oral administration of compound (I) and the ability / efficacy to induce corticosteroid-free disease remission in IgG4-RD are evaluated. Complete remission is defined as an IgG4-RD RI score of 0 at week 12 and no use of corticosteroids or other immunosuppressive drug therapies between weeks 4 and 12. After extended treatment up to 52 weeks, the effect of compound (I) against IgG4-RD disease relapse and corticosteroid sparing are evaluated together with the effect of compound (I) over time on changes in serum concentrations of IgG4, IgE, IgG, IgM, C3, C4, and other serological parameters.

[0106] Example 3 : Assay method for inhibition of B cell antibody production by compound (I) B cells were enriched from the leukocyte concentrate of TrimaAccel® LRS chambers collected after platelet apheresis procedures using Straight from the Miltenyi Biotech LRSC CD19 MicroBead Kit, from healthy volunteers (Stanford Blood Center, Palo Alto, CA). B cells were treated with 3-fold serial dilution of rilzabrutinib in 10 concentrations of DMSO for 1 hour at 37 °C, 5% CO2. Next, compound (I) (rilzabrutinib)-treated B cells and DMSO controls were stimulated with lipopolysaccharide-conjugated trinitrophenyl (TNP-LPS (Santa Cruz Biotechnology)), 5'-cytosine-phosphate-guanine-3' (CpG (ODN2006, Invivogen)), or anti-CD40 (BD Biosciences) + IL21 (R&D Systems) for 7 days at 37 °C, 5% CO2. Inhibition of antibody production by compound (I) was determined by measurement of IgG and IgM in cell culture lysates using the Human IgG and IgM AlphaLISA kits (Perkin Elmer). IC 50 50 was calculated without constraints using non-linear regression in GraphPad Prism using the "log (inhibitor) vs. response - variable slope (four parameters)" analysis.

[0107] Example 4 : Blockade of B cell activation, IgM and IgG antibody production using compound (I) treatment Compound (I) can inhibit B cell activation, BCR-dependent B cell proliferation, and de novo antibody production. To determine the functional activation of compound (I), the ability of the compound to inhibit B cell activation was determined by evaluating anti-IgM-induced CD69 expression in CD20+ B cells in human whole blood (Figure 7). The potency of compound (I) (rilzabrutinib) in the B cell activation assay was found to be well correlated with BTK target occupancy. IC 50The determinations were 126 ± 32 nM and 233 ± 75 nM for inhibition of CD69 B cell expression and BTK target occupancy, respectively. As a further measurement of the effect of compound (I) on B cell function, the ability of compound (I) to inhibit B cell receptor (BCR)-induced human B cell proliferation was determined. The IC 50 for inhibition of human B cell proliferation for compound (I) was 5 ± 2.4 nM. Compound (I) did not block antibody-dependent cell-mediated cytotoxicity (ADCC) when combined with an anti-CD20 antibody, indicating the potential for combination therapy. (Pirunsarn, A., P. Kijrattanakul, S. Chamnanchanunt, C. Polprasert, and P. Rojnuckarin. 2018. A randomized multicenter trial comparing low-dose prednisolone versus observation for prevention of recurrences in adult immune thrombocytopenia. Clin Appl Thromb Hemost 24: 867-873).

[0108] Compound (I) significantly inhibited IgM and IgG antibody production when stimulated in vitro. Compound (I) inhibited IgG antibody production with an IC 50 of 20 ± 20 nM and IgM antibody production with an IC 50 of 800 ± 1000 nM when stimulated via the T cell-dependent pathway using anti-CD40 in combination with IL-21 (Figure 8). Compound (I) also inhibited IgG and IgM antibody production with an IgG IC 50 of 50 ± 90 nM and an IgM IC 50 of 1 ± 1 nM when stimulated via the T cell-independent pathway using the TLR-9 agonist CpG, and further inhibited TNP-LPS-stimulated antibody production with an IgG IC 50 of 300 ± 600 nM and an IgM IC 50 of 200 ± 600 nM (Table 1).

[0109]

Table 1

Claims

1. Use of a compound selected from the (E) isomer, (Z) isomer, and a mixture of the (E) isomer and (Z) isomer of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile, or a pharmaceutically acceptable salt of any of the aforementioned compounds, in the manufacture of a medicament for treating a disease selected from membranous nephropathy (MN) and IgG4-related disease (IgG4-RD).

2. The use according to claim 1, wherein the medicament is for treating an acute disease.

3. The use according to claim 1, wherein the medicament is for treating relapse of IgG4-RD disease.

4. The use according to claim 1, wherein the medicament is administered orally.

5. The use according to any one of claims 1 to 4, wherein the medicament is administered in combination with immunosuppressive therapy or corticosteroid therapy.

6. The use according to any one of claims 1 to 4, wherein the medicament is administered in combination with a non-corticosteroid immunosuppressant and / or an anti-inflammatory agent.

7. The use according to any one of claims 1, 2 or 4, wherein the medicament is administered in combination with immunosuppressive maintenance therapy or corticosteroid maintenance therapy.

8. The use according to any one of claims 1 to 4, wherein the medicament comprises a compound which is the (E) or (Z) isomer of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile, and / or a pharmaceutically acceptable salt of the compound; and optionally, a pharmaceutically acceptable carrier or excipient The use according to any one of claims 1 to 4, wherein the medicament comprises a compound which is the (E) or (Z) isomer of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile, and / or a pharmaceutically acceptable salt of the compound; and optionally, a pharmaceutically acceptable carrier or excipient

9. The agent is at least 85% mass / mass of the (E) isomer of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile or a pharmaceutically acceptable salt of at least 85% mass / mass of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile, for use according to any one of claims 1 to 4.

10. The use according to any one of claims 1 to 4, wherein the agent is administered to a human.

11. The use according to any one of claims 1 to 4, wherein the agent is for treating an IgG4-related disease characterized by an IgG4-RD responder index (RI) greater than or equal to 2 in at least one organ system.

12. The use according to any one of claims 1 to 4, wherein the agent is for treating an IgG4-related disease characterized by a serum IgG4 concentration higher than 1.5 times the normal upper limit.

13. The agent is for treating IgG4-related sialadenitis, IgG4-related ophthalmic disease (IgG4-ROD), IgG4-related pharyngitis, IgG4-related thyroid disease, IgG4-related hypophysitis, IgG4-related dural sclerosis, IgG4-related leptomeningitis, IgG4-related pancreatitis, IgG4-related lung disease, IgG4-related pleurisy, IgG4-related hepatopathy, IgG4-related sclerosing cholangitis, IgG4-related cholecystitis, IgG4-related aortitis, IgG4-related periaortitis, IgG4-related perivasculitis, IgG4-related pericarditis, IgG4-related mediastinitis, IgG4-related retroperitoneal fibrosis, IgG4-related mesenteritis, IgG4-related mastitis, IgG4-related kidney disease (IgG4-RKD), IgG4-related prostatitis, IgG4-related perivascular fibrosis, IgG4-related para-testicular pseudotumor, IgG4-related epididymo-orchitis, IgG4-related lymph node swelling, IgG4-related skin disease, and IgG4-related perineural disease, or a disease selected from a relapse of any of the IgG4-related diseases, for use according to any one of claims 1 to 4.

14. The use according to claim 1, wherein the agent is administered in combination with an active pharmaceutical ingredient selected from interferon alpha, interferon gamma, cyclophosphamide, tacrolimus, mycophenolate mofetil, methotrexate, dapsone, sulfasalazine, azathioprine, anti-CD20 agent, anti-TNF alpha agent, anti-IL-4 agent against a ligand or its receptor, anti-IL-6 agent against a ligand or its receptor, anti-IL-12 agent against a ligand or its receptor, anti-IL-17 agent against a ligand or its receptor, anti-IL-1 agent against a ligand or its receptor, anti-IL-2 agent against a ligand or its receptor, anti-IL-23 agent against a ligand or its receptor, anti-IL-12 / 23 agent against a ligand or receptor, anti-CD2 agent, anti-CD3 agent, anti-CD80 / 86 agent, anti-sphingosine-1-phosphate receptor agent, anti-C5 agent, anti-mTOR agent, anti-calcineurin agent, anti-BAFF / BlyS agent, leflunomide, and teriflunomide.

15. The use according to claim 1, wherein the agent is administered in combination with rituximab, dupilumab, ofatumumab, obinutuzumab, or belzutifan.

16. The use according to any one of claims 1 to 4, wherein the agent is administered to a mammal untreated with respect to immunosuppressive therapy.

17. The use according to any one of claims 1 to 4, wherein the agent is administered to a mammal that has been previously treated with immunosuppressive therapy.

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