Methods for treating primary membranous nephropathy

Abstract

Provided herein is a method of treating primary membranous nephropathy in a patient in need thereof, comprising administering to the patient a BTK inhibitor, for example, (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof.

Description

[Technical Field]

[0001] Provided herein are methods and materials involved in the diagnosis and / or treatment of mammals with primary membranous nephropathy (e.g., primary membranous nephropathy associated with elevated levels of PLA2R and / or THSD7A in the glomerular basement membrane (GBM)). For example, provided herein are methods and materials for administering a Bruton's tyrosine kinase (BTK) inhibitor to treat a mammal (e.g., a human) with primary membranous nephropathy. [Background technology]

[0002] Membranous nephropathy is one of the most common causes of nephrotic syndrome. It is classified as primary membranous nephropathy or secondary membranous nephropathy. Primary membranous nephropathy accounts for 70-75% of cases, while secondary membranous nephropathy accounts for 25-30% of cases. Membranous nephropathy results from an autoimmune response to target antigen accumulation in the GBM, an integral part of the glomerular capillaries that form the filtration unit of the kidney. In approximately 70% of primary cases, membranous nephropathy has been reported to result from accumulation of target antigens for the phospholipase A2 receptor (PLA2R) in the GBM, followed by the formation of antigen-antibody complexes (Beck et al., N. Engl. J. Med., 361:11-21 (2009)). Thrombospondin type-1 domain-containing 7A (THSD7A) has also been reported to be an antigen responsible for approximately 5% of primary membranous nephropathy cases (Tomas et al., N. Engl. J. Med., 24:2277-2287 (2014)). Secondary membranous nephropathy is often associated with autoimmune diseases such as lupus, mixed connective tissue disorder, and Sjögren's syndrome. The target antigen in the remaining 25% of primary membranous nephropathy cases is currently under investigation.

[0003] Although many recent advances have been made in the treatment of primary membranous nephropathy, more effective and / or enhanced therapies remain needed. Citation or identification of any reference in this section shall not be construed as an admission that the reference is prior art to the present application. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Beck et al.,N.Engl.J.Med.,361:11-21(2009) [Non-patent document 2] Tomas et al.,N.Engl.J.Med.,24:2277-2287(2014) Summary of the Invention [Means for solving the problem]

[0005] Provided herein is a method for treating a patient with primary membranous nephropathy, the method comprising administering a Bruton's tyrosine kinase inhibitor to the patient. In some embodiments, the Bruton's tyrosine kinase inhibitor is Compound A, named (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide, or having the following structure: [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate or prodrug thereof.

[0006] In some embodiments, the patient is identified as having (i) elevated levels of autoantibodies specific to an antigen, or (ii) renal tissue comprising elevated levels of an antigen. In one embodiment, the antigen is expressed by human podocytes, such as PLA2R or THSD7A. In some embodiments, the antigen is PLA2R. In some embodiments, the level of the autoantibody specific to PLA2R is greater than about 20 RU / mL, about 40 RU / mL, about 50 RU / mL, about 60 RU / mL, or about 80 RU / mL in serum before the administering step. In some embodiments, the antigen is THSD7A. In some embodiments, the level of the autoantibody present in the patient is reduced by at least about 5%, about 25%, or about 50% after the administering step.

[0007] In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof, is administered once, twice, or three times daily. In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof, is administered twice daily. In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof, is administered once daily.

[0008] In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof, is administered at about 40 mg to about 320 mg per day. In some embodiments, Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof is administered at about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, or about 320 mg per day. In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof, is administered at about 40 mg, about 80 mg, about 160 mg, or about 320 mg per day. In one embodiment, the method provides for a patient to achieve an AUC of Compound A in plasma of about 1,607 ng*h / ml to about 2,984 ng*h / ml. 0-24h In one embodiment, the method provides an AUC of Compound A in plasma of about 1,836 ng*h / ml to about 2,754 ng*h / ml in the patient. 0-24h In one embodiment, the method provides an AUC of Compound A in plasma of about 2,066 ng*h / ml to about 2,525 ng*h / ml in the patient. 0-24h In one embodiment, the method provides an AUC of Compound A in plasma of about 2295 ng*h / ml in the patient. 0-24h In one embodiment, the method provides an AUC of Compound A in plasma of about 2180 ng*h / ml in the patient. 0-24h to provide.

[0009] In some embodiments, the patient achieves a partial or complete remission. [Brief explanation of the drawings]

[0010] [Figure 1]The research schema is shown. [Figure 2] Part 2: Demonstrate multiple testing strategies DETAILED DESCRIPTION OF THE INVENTION

[0011] definition As used herein, "Compound A" refers to a compound named (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide, or having the structure of formula (I): (I), or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof. Compound A, along with its pharmaceutically acceptable salts and solvates, is disclosed and claimed in WO 2014 / 173289 and WO 2018 / 033853, the entire disclosures of which are incorporated herein by reference, as being useful as inhibitors of BTK activity. Compound A is compound 27b in WO 2014 / 173289 and compound 1 in WO 2018 / 033853. Compound A can be prepared as described in WO 2014 / 173289 and WO 2018 / 033853. Unless otherwise specified, "Compound A," as used herein, refers to Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof. Compound A disclosed herein may contain one or more asymmetric atoms or may be capable of existing as enantiomers. Thus, the compounds of the present invention include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures. All tautomers and mixtures of tautomers are also understood to be included within the scope of Compound A. As used herein, all amounts specified for Compound A are given as the amount of the free or salt-free compound.

[0012] In one embodiment, a solid form of Compound A is used for the treatments provided herein. In one embodiment, a crystalline form of Compound A is used for the treatments provided herein. In one embodiment, an amorphous form of Compound A is used for the treatments provided herein. In one embodiment, the free base of Compound A is used for the treatments provided herein. In one embodiment, Form A of Compound 1 of WO2833853 is used for the treatments provided herein. In some embodiments, Form A has an X-ray powder diffraction pattern comprising diffraction peaks having 2θ angle values ​​independently selected from about 14.8±0.2°, about 16.4±0.2°, and about 21.4±0.2°. In some embodiments, Form A has an X-ray powder diffraction pattern comprising diffraction peaks having 2θ angle values ​​independently selected from about 14.8±0.2°, about 15.6±0.2°, about 16.4±0.2°, and about 21.4±0.2°. In some embodiments, Form A has an X-ray powder diffraction pattern comprising diffraction peaks having 2θ angle values ​​independently selected from about 12.2±0.2°, about 12.9±0.2°, about 14.8±0.2°, about 15.6±0.2°, about 16.4±0.2°, and about 21.4±0.2°. In some embodiments, Form A has an X-ray powder diffraction pattern comprising diffraction peaks having 2θ angle values ​​independently selected from about 12.2±0.2°, about 12.9±0.2°, about 14.8±0.2°, about 15.6±0.2°, about 16.4±0.2°, about 17.7±0.2°, about 18.5±0.2°, about 20.7±0.2°, and about 21.4±0.2°.

[0013] The term "BTK inhibitor," as used herein, refers to a compound that has inhibitory activity against Bruton's tyrosine kinase (BTK). Exemplary BTK inhibitors include the aforementioned ibrutinib, acalabrutinib, evobrutinib, fenebrutinib, posertinib, becabrutinib, tirabrutinib, spebrutinib, and zanubrutinib.

[0014] The term "autoantibody," as used herein, refers to its general meaning in the art and refers to an antibody produced by a subject's (or patient's) immune system and directed against the subject's (or patient's) own antigen (e.g., PLA2R or THSD7A). Immune complexes containing autoantibodies and their specific antigens can attack the body's own cells, tissues, and / or organs, causing inflammation and cellular damage. The terms "autoantibody recognizing PLA2R" and "autoantibody specific for PLA2R" can be used interchangeably with "anti-PLA2R autoantibody." The terms "autoantibody recognizing THSD7A" and "autoantibody specific for THSD7A" can be used interchangeably with "anti-THSD7A autoantibody."

[0015] As used herein, the term "PLA2R" refers to its common meaning in the art (secretory phospholipase A2 receptor, also known as PLA2R1), and herein refers to the M-type phospholipase A2 receptor, particularly the receptor encoded by the PLA2R1 gene in humans, which is known as a major antigen in idiopathic membranous nephropathy. An exemplary human native PLA2R1 amino acid sequence is provided in NP_001007268 (GenPept database), and an exemplary human native PLA2R1 mRNA sequence is provided in NM_001007267 (GenBank database). Note that all references to databases, such as codes or accession numbers disclosed herein, refer to the versions available online as of October 10, 2022.

[0016] The term "THSD7A," as used herein, refers to its general meaning in the art (e.g., thrombospondin type I domain-containing 7A) and refers to a 1,657-amino acid protein that is highly expressed on podocytes and is involved in endothelial cell migration and filopodia formation during angiogenesis via a FAK-dependent mechanism. This term may include naturally occurring THSD7A as well as its mutants and modified forms. THSD7A may be from any source but is typically mammalian (e.g., human and non-human primates or other mammalian species) THSD7A, particularly human THSD7A. The amino acid sequence of an exemplary human native THSD7A is provided in Q9UPZ6 (UniProt database) and NP_056019 (GenPept database, precursor sequence), and the mRNA sequence of an exemplary human native THSD7A is provided in NM_015204 (GenBank database, precursor sequence). Please note that all references to databases, such as codes or accession numbers, disclosed herein refer to the versions available online on October 10, 2022.

[0017] The term "antigen" or "Ag," as used herein, is defined as a molecule capable of eliciting an immune response. This immune response may involve either antibody production or activation of specific immunocompetent cells, or both. Those skilled in the art will understand that any macromolecule, including virtually any protein or peptide, can function as an antigen. Furthermore, antigens can be derived from recombinant or genomic DNA. Those skilled in the art will understand that any DNA containing a nucleotide sequence or partial nucleotide sequence encoding a protein that elicits an immune response, therefore, encodes an "antigen" as the term is used herein. Furthermore, those skilled in the art will understand that an antigen need not be encoded solely by the full-length nucleotide sequence of a gene. It will be readily apparent that the present invention includes, but is not limited to, the use of partial nucleotide sequences of one or more genes, and that these nucleotide sequences can be arranged in various combinations to encode a polypeptide that elicits a desired immune response. Furthermore, those skilled in the art will understand that an antigen need not be encoded by a "gene" at all. It will be readily apparent that an antigen can be synthetic, derived from a biological sample, or a macromolecule other than a polypeptide. Such biological samples may include, but are not limited to, tissue samples, tumor samples, cells, or fluids containing other biological components.

[0018] As used herein, the term "treating" and its derivatives refer to therapeutic therapy. With respect to a particular condition, treating means: (1) ameliorating the condition or one or more of the biological manifestations of the condition, (2) inhibiting (a) one or more points in the biological cascade leading to or causing the condition, or (b) one or more of the biological manifestations of the condition, (3) alleviating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more of the biological symptoms of the condition.

[0019] As used herein, the term "effective amount" refers to an amount of a drug or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal, or human that is desired, for example, by a researcher or clinician. Furthermore, a "therapeutically effective amount" refers to an amount that results in improved treatment, cure, prevention, or amelioration of a disease, disorder, or side effects, or a reduction in the rate of progression of a disease or disorder, compared to a corresponding subject not administered such amount. The term also encompasses within its scope an amount effective to enhance normal physiological function.

[0020] As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or its salt and a solvent). It is understood that Compound A can be presented as a solvate, separately, or both. For the purposes of the present invention, such a solvent may be one that does not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, dimethyl sulfide, ethanol, and acetic acid. In one embodiment, the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, but are not limited to, water, ethanol, and acetic acid. In another embodiment, the solvent used is water (i.e., a hydrate).

[0021] Compound A may have the ability to crystallize in more than one form, a property known as polymorphism, and such polymorphic forms ("polymorphs") are understood to be within the scope of Compound A. Polymorphs generally can occur as a response to changes in temperature or pressure, or both, and can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical properties known in the art, such as X-ray diffraction patterns, solubility, and melting point.

[0022] As used in this specification and the appended claims, the indefinite articles "a" and "an," and the definite article "the," include plural as well as singular references, unless the context clearly indicates otherwise.

[0023] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in connection with a dose, amount, or weight percent of a component of a composition or dosage form, mean a dose, amount, or weight percent that is recognized by one of ordinary skill in the art as providing an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percent. In certain embodiments, the terms "about" and "approximately," when used in this context, contemplate a dose, amount, or weight percent that is within 30%, within 20%, within 15%, within 10%, or within 5% of the specified dose, amount, or weight percent.

[0024] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in connection with a numerical value or value provided to characterize a particular solid form, such as a particular temperature or temperature range (e.g., those describing melting, dehydration, desolvation, or glass transition temperature); mass change (e.g., mass change as a function of temperature or humidity); solvent or water content (e.g., in terms of mass or percentage); or peak position (e.g., such as in analysis by IR or Raman spectroscopy or XRPD), indicate that the value or range of values ​​can deviate to an extent that would be considered reasonable by one of ordinary skill in the art and still describe the solid form. Techniques for characterizing crystalline forms and amorphous solids include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X-ray diffraction, vibrational spectroscopy such as infrared (IR) and Raman spectroscopy, solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies. In certain embodiments, the terms "about" and "approximately," when used in this context, indicate that a numerical value or range of values ​​may vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value or range of values. For example, in some embodiments, XRPD peak position values ​​can vary by up to ±0.2° 2θ (or ±0.2 degrees 2θ) while describing a particular XRPD peak.

[0025] As used herein, the term "pharmaceutically acceptable salt(s)" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and inorganic bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts of the compounds provided herein include, but are not limited to, those well known in the art, see, for example, Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th eds., Mack Publishing, Easton PA (1995).

[0026] As used herein, and unless otherwise indicated, the terms "stereoisomer" or "stereoisomerically pure" refer to one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center is substantially free of the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers is substantially free of other diastereomers of that compound. A typical stereoisomerically pure compound is greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. The compounds may contain chiral centers and may exist as racemates, individual enantiomers or diastereomers, and mixtures thereof, and all such isomers, including mixtures thereof, are included in the embodiments disclosed herein.

[0027] The use of stereomerically pure forms of such compounds, as well as mixtures of those forms, are encompassed within the embodiments disclosed herein. For example, mixtures containing equal or unequal amounts of enantiomers of a particular compound may be used in the methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques, such as chiral columns or chiral resolving agents. See, for example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN, 1972).

[0028] It should also be noted that the compounds may include E and Z isomers, or mixtures thereof, as well as cis and trans isomers, or mixtures thereof. In certain embodiments, the compounds are isolated as either the E or Z isomer. In other embodiments, the compounds are mixtures of E and Z isomers.

[0029] "Tautomers" are isomers of a compound that exist in equilibrium with one another. The concentration of isomers may vary depending on the environment in which the compound is found, for example, whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole may exhibit the following isomeric forms, which are referred to as tautomers of each other: [ka]

[0030] As will be readily understood by one of ordinary skill in the art, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds provided herein are within the scope of the invention.

[0031] The term "subject" includes animals, including animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs, and in one embodiment includes mammals, and in another embodiment includes humans, but is not limited to these.

[0032] When used in therapy, Compound A may be administered as a drug substance, although the active ingredient can also be presented as a pharmaceutical composition. The present invention further provides pharmaceutical compositions comprising Compound A and one or more pharmaceutically acceptable carriers, diluents, or excipients. Compound A is as described above. The carrier(s), diluent(s), or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation, pharmaceutically formulateable, and not toxic to the recipient thereof. In accordance with another aspect of the present invention, there is also provided a process for preparing a pharmaceutical composition comprising admixing Compound A with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0033] Pharmaceutical compositions can be presented in unit dosage form, containing a predetermined amount of active ingredient per unit dosage.As is well known to those skilled in the art, the amount of active ingredient per dosage depends on the condition to be treated, the route of administration, and the age, weight and condition of the patient.Preferred unit dosage compositions are those that comprise a daily dose or sub-dose of active ingredient, or an appropriate fraction thereof.In addition, such pharmaceutical compositions can be prepared by any method well known in the pharmaceutical technology.

[0034] Compound A may be administered by any suitable route, including oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural).

[0035] Pharmaceutical compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foams; or oil-in-water or water-in-oil liquid emulsions.

[0036] Unless otherwise defined, in all administration protocols described herein, the regimen of administered compounds does not necessarily begin with the initiation of treatment and end with the end of treatment, but only requires that the number of consecutive days on which both compounds are administered, and any consecutive days on which only one of the constituent compounds is administered, or the indicated administration protocol (including the amount of compound administered) occur at some point during the course of treatment.

[0037] Unless otherwise defined, in all administration protocols described herein, the regimen of administered compounds does not necessarily begin with the initiation of treatment and end with the end of treatment, but only requires that the number of consecutive days on which both compounds are administered, and any consecutive days on which only one of the constituent compounds is administered, or the indicated administration protocol (including the amount of compound administered) occur at some point during the course of treatment.

[0038] As used herein, the term "kit" or "kit of parts" refers to a pharmaceutical composition or compositions used to administer Compound A in accordance with the present disclosure. In one embodiment, the kit can include Compound A in a single pharmaceutical composition, such as a tablet, or in separate pharmaceutical compositions. In one aspect, a kit is provided in which Compound A includes components associated with a pharmaceutically acceptable excipient, diluent, or carrier. The kit can also be provided with instructions, such as dosage and administration instructions. Such dosage and administration instructions can be of the type provided to a physician, for example, on a pharmaceutical label, or can be of the type provided by a physician as instructions to a patient.

[0039] The term "dose" as used herein is understood to mean a dose intended to slowly raise the plasma or blood concentration level of a compound to a therapeutically effective level or to maintain such a therapeutically effective level.

[0040] The term "elevated level" as used herein with respect to polypeptide, antigen, or antibody levels refers to a level of a polypeptide, antigen, or antibody that is higher (e.g., at least 10, 25, 35, 45, 50, 55, 65, 75, 80, 90, or 100% higher) than the median amount of polypeptide, antigen, or antibody present in normal tissue or serum of a mammal not suffering from primary membranous nephropathy.

[0041] kit Provided herein are kits that include a compound provided herein and a means for monitoring a patient's response to administration of the compound provided herein.

[0042] In other embodiments, kits are provided that include a compound provided herein and a means for measuring the amount of inhibition of BTK in a patient. In certain embodiments, the kits include a means for measuring the inhibition of BTK in the patient's circulating plasma, serum, blood, or tumor cells and / or skin biopsy, or kidney biopsy / aspirate. In certain embodiments, kits are provided that include a compound provided herein and a means for measuring the amount of inhibition of BTK before, during, and / or after administration of a compound provided herein.

[0043] In certain embodiments, the kits provided herein further comprise instructions for administering a compound provided herein and / or for monitoring a patient's response to administration of the compound.

[0044] treatment Provided herein is a method of treating a patient with primary membranous nephropathy, the method comprising administering a Bruton's tyrosine kinase inhibitor to the patient. Provided herein is a Bruton's tyrosine kinase inhibitor for use in treating or preventing primary membranous nephropathy. Provided herein is the use of a Bruton's tyrosine kinase inhibitor in the manufacture of a medicament for treating or preventing primary membranous nephropathy.

[0045] In some embodiments, the patient is a human.

[0046] In some embodiments, the Bruton's tyrosine kinase inhibitor is Compound A, which has the name (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide, or has the following structure: [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof.

[0047] In some embodiments, the patient is identified as having renal tissue comprising (i) elevated levels of an antigen-specific autoantibody, or (ii) elevated levels of an antigen. In one embodiment, the antigen is expressed by human podocytes. In one embodiment, the antigen is expressed by human podocytes, such as PLA2R or THSD7A. In some embodiments, the antigen is PLA2R or THSD7A. In some embodiments, the antigen is PLA2R. In some embodiments, the antigen is THSD7A. In one embodiment, the patient is identified as having biopsy-confirmed primary membranous nephropathy and persistent nephrotic syndrome after a run-in period. In one embodiment, the patient is a PLA2R-mediated patient with primary membranous nephropathy. In one embodiment, the patient is a THSD7A-mediated patient with primary membranous nephropathy.

[0048] In some embodiments, the patient is identified as having elevated levels of autoantibodies. In some embodiments, the level of autoantibodies present in the patient is reduced by at least about 5 percent, at least about 25 percent, or at least about 50 percent after the administering step. In some embodiments, the level of autoantibodies present in the patient's serum is reduced by at least about 5 percent, at least about 25 percent, or at least about 50 percent after the administering step. In some embodiments, the level of autoantibodies present in the subject (e.g., in serum) is reduced by at least about 5 percent after the administering step. In some embodiments, the level of autoantibodies present in the subject (e.g., in serum) is reduced by at least about 25 percent after the administering step. In some embodiments, the level of autoantibodies present in the subject (e.g., in serum) is reduced by at least about 50 percent after the administering step.

[0049] In some embodiments, the patient is identified as having an elevated level of antigen-specific autoantibodies in serum. In some embodiments, the antigen is PLA2R. In some embodiments, the antigen is THSD7A. In some embodiments, the level of PLA2R-specific autoantibodies is greater than about 20 RU / mL, about 40 RU / mL, about 50 RU / mL, about 60 RU / mL, or about 80 RU / mL in the serum before the administering step. In some embodiments, the level of PLA2R-specific autoantibodies is greater than about 20 RU / mL in the serum before the administering step. In some embodiments, the level of PLA2R-specific autoantibodies is greater than about 40 RU / mL in the serum before the administering step. In some embodiments, the level of PLA2R-specific autoantibodies is greater than about 50 RU / mL in the serum before the administering step. In some embodiments, the level of PLA2R-specific autoantibodies is greater than about 60 RU / mL in the serum before the administering step. In some embodiments, the level of autoantibodies specific for PLA2R is greater than about 80 RU / mL in the serum before the administering step.

[0050] In some embodiments, the patient is identified as having kidney tissue containing an elevated level of the antigen. In some embodiments, the level of the antigen present in the patient's kidney tissue is reduced by at least about 5 percent, at least about 25 percent, or at least about 50 percent after the administering step. In some embodiments, the level of the antigen present in the patient's kidney tissue is reduced by at least about 5 percent after the administering step. In some embodiments, the level of the antigen present in the patient's kidney tissue is reduced by at least about 25 percent after the administering step. In some embodiments, the level of the antigen present in the patient's kidney tissue is reduced by at least about 50 percent after the administering step.

[0051] In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof, is administered one to three times daily. In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof, is administered once daily. In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof, is administered twice daily. In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof, is administered three times daily.

[0052] In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof, is administered at about 40 mg to about 320 mg per day.

[0053] In some embodiments, Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof is administered at about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, or about 320 mg per day.

[0054] In some embodiments, Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof is administered at about 40 mg, about 80 mg, about 160 mg, or about 320 mg per day. In some embodiments, Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof is administered at about 160 mg or about 320 mg per day.

[0055] In some embodiments, the methods comprise administering to the patient Compound A twice daily (BID) at a dose of about 160 mg, or once daily (QD) at a dose of about 160 mg.

[0056] In some embodiments, the methods involve orally administering to the patient Compound A twice daily (BID) at a dose of about 160 mg, or once daily (QD) at a dose of about 160 mg.

[0057] In some embodiments, the methods comprise orally administering to the patient Compound A at a dose of about 160 mg twice daily (BID).

[0058] In some embodiments, the methods comprise orally administering to the patient Compound A once daily (QD) at a dose of about 160 mg.

[0059] In some embodiments, the patient achieves a partial or complete response.

[0060] In some embodiments, the patient achieves a partial response.

[0061] In some embodiments, the patient achieves a complete remission.

[0062] In some cases, the progress of treatment and / or the severity of one or more symptoms associated with membranous nephropathy can be monitored. Any suitable method can be used to determine whether membranous nephropathy has been treated. For example, immunological techniques (e.g., ELISA) can be performed to determine whether the level of autoantibodies (e.g., anti-PLA2R autoantibodies or anti-THSD7A autoantibodies) present in a mammal treated as described herein decreases after administration of one or more BTK inhibitors. Disease remission and recurrence can be monitored by testing for one or more markers of membranous nephropathy. In some cases, remission can be confirmed by detecting the disappearance or decrease of autoantibodies specific to THSD7A and PLA2R in serum. In some cases, recurrence of membranous nephropathy can be confirmed by the reappearance or increase of autoantibodies against THSD7A and PLA2R in serum.

[0063] In some cases, remission can be predicted by detecting the disappearance or decrease of serum THSD7A- or PLA2R-specific autoantibodies.In some cases, recurrence of membranous nephropathy can be predicted by the reappearance or increase of serum THSD7A- or PLA2R-specific autoantibodies.

[0064] In one embodiment, Compound A is administered 1 to 3 times daily. In one embodiment, Compound A is administered 3 times daily. In one embodiment, Compound A is administered 2 times daily. In one embodiment, Compound A is administered once daily.

[0065] In one embodiment, the method provides a method for administering to a patient an AUC of Compound A in plasma of about 1,607 ng*h / ml to about 2,984 ng*h / ml. 0-24h In one embodiment, the method provides an AUC of Compound A in plasma of about 1,836 ng*h / ml to about 2,754 ng*h / ml in the patient. 0-24h In one embodiment, the method provides an AUC of Compound A in plasma of about 2,066 ng*h / ml to about 2,525 ng*h / ml in the patient. 0-24h In one embodiment, the method provides an AUC of Compound A in plasma of about 2295 ng*h / ml in the patient. 0-24h In one embodiment, the method provides an AUC of Compound A in plasma of about 2180 ng*h / ml in the patient. 0-24h to provide.

[0066] In one embodiment, the method provides a method for administering to a patient an AUC of Compound A in plasma of about 1,622 ng*h / ml to about 3,786 ng*h / ml. 0-∞ In one embodiment, the method provides an AUC of Compound A in plasma of about 2,163 ng*h / ml to about 3,245 ng*h / ml in a patient. 0-∞ In one embodiment, the method provides an AUC of Compound A in plasma of about 2,424 ng*h / ml to about 2,974 ng*h / ml in the patient. 0-∞ In one embodiment, the method provides an AUC of Compound A in plasma of about 2704 ng*h / ml in the patient. 0-∞ to provide.

[0067] In one embodiment, the method provides a method for administering to a patient an AUC of Compound A in plasma of about 1,087 ng*h / ml to about 2,535 ng*h / ml. 0-∞ In one embodiment, the method provides an AUC of Compound A in plasma of about 1,449 ng*h / ml to about 2,173 ng*h / ml in the patient. 0-∞ In one embodiment, the method provides an AUC of Compound A in plasma of about 1,630 ng*h / ml to about 1,992 ng*h / ml in the patient. 0-∞ In one embodiment, the method provides an AUC of Compound A in plasma of about 1,811 ng*h / ml in the patient.0-∞ to provide.

[0068] In one embodiment, the method provides a method for administering to a patient an AUC of Compound A in plasma of about 843 ng*h / ml to about 1,967 ng*h / ml. 0-∞ In one embodiment, the method provides an AUC of Compound A in plasma of about 1,124 ng*h / ml to about 1,686 ng*h / ml in a patient. 0-∞ In one embodiment, the method provides an AUC of Compound A in plasma of about 1,265 ng*h / ml to about 1,546 ng*h / ml in the patient. 0-∞ In one embodiment, the method provides an AUC of Compound A in plasma of about 1,405 ng*h / ml in the patient. 0-∞ to provide.

[0069] In one embodiment, the method provides a method for administering to a patient an AUC of Compound A in plasma of about 843 ng*h / ml to about 3,786 ng*h / ml. 0-∞ to provide.

[0070] In some embodiments, the AUC 0-24h and AUC 0-∞ is measured in the plasma of the subject. In some embodiments, AUC 0-24h and AUC 0-∞ is measured in the subject's blood.

[0071] In one embodiment, the subject achieves partial or complete remission. In one embodiment, the subject achieves partial remission. In one embodiment, the subject achieves complete remission. In one embodiment, the subject achieves partial or complete remission for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months. In one embodiment, the subject achieves partial or complete remission for 1 year, 2 years, 3 years, or 4 years.

[0072] The present embodiments can be more fully understood by reference to the detailed description and examples that are intended to exemplify non-limiting embodiments.

[0073] Example The following examples are purely illustrative and should not be construed as limiting in any way. Unless otherwise specified, the experimental methods in the examples described below are conventional. [Example]

[0074] Example 1 [Table 1] 1. Research purpose 1.1 Research purpose The objective was to evaluate the efficacy and safety of zanubrutinib in patients with primary membranous nephropathy receiving optimal supportive care. Main purpose: Part 1 To evaluate the efficacy of zanubrutinib as measured by reduction in proteinuria in patients with primary membranous nephropathy receiving optimal supportive care Part 2 To evaluate the efficacy of zanubrutinib compared with tacrolimus, as measured by complete remission rate, in patients with primary membranous nephropathy receiving optimal supportive care Secondary purpose: Part 1 To evaluate the efficacy of zanubrutinib in patients with primary membranous nephropathy receiving optimal supportive care by: Treatment failure -immunological response - Overall remission Complete remission -recurrence To evaluate the safety and tolerability of zanubrutinib in patients with primary membranous nephropathy Part 2 To assess the efficacy of zanubrutinib compared to tacrolimus in patients with primary membranous nephropathy receiving optimal supportive care in: - Overall remission Treatment failure Time to first remission -recurrence - Health-related quality of life (HRQoL) -Prevention of progressive loss of kidney function To evaluate the safety and tolerability of zanubrutinib in patients with primary membranous nephropathy Exploratory: Part 1 Evaluate the pharmacokinetics (PK) of zanubrutinib -Evaluate the relationship between biomarkers and efficacy of zanubrutinib Part 2 Evaluate the pharmacokinetics (PK) of zanubrutinib To assess the immunological response in patients with anti-PLA2R antibodies at baseline -Evaluate the relationship between biomarkers and efficacy of zanubrutinib Patient-reported symptom severity 1.2 Definition of the first-order estimate The main scientific question of interest in Part 2 is: "Does zanubrutinib increase the rate of complete remission compared with tacrolimus in patients with primary membranous nephropathy receiving optimal supportive care?" The primary estimate is described by the following attributes: 1.Treatment of interest: The experimental treatment in this study is zanubrutinib. The comparative study control treatment is tacrolimus. 2. Group All adult patients with primary membranous nephropathy as defined by inclusion / exclusion criteria. 3. Variables The primary variable was complete remission status (Yes / No) at 104 weeks. 4. Handling of Concomitant Events Early discontinuation of study drug before week 65: If a patient discontinues study drug early for any reason (except in the tacrolimus group for patients who completed tapering before week 65 per protocol), the patient will be considered a non-responder in complete remission at week 104 (combined strategy). Treatment failure: If a patient experiences treatment failure, they are considered a non-responder in complete remission at week 104 (combined strategy). 5. Population-level summaries Difference in complete response rate between the zanubrutinib and tacrolimus groups at 104 weeks. 2.Research design 2.1 Research design overview This is a two-part, phase 2 / 3, multicenter, open-label study evaluating the efficacy and safety of zanubrutinib in patients with primary membranous nephropathy for up to 132 weeks. To be enrolled, patients must have a diagnosis of primary membranous nephropathy confirmed by renal biopsy. Additionally, patients must have a urinary protein level of >3.5g / 24 hours at the initial screening and confirmatory assessments. 2.1.1 Part 1 Part 1 is an open-label, single-arm exploratory evaluation of the efficacy and safety of zanubrutinib in patients with primary membranous nephropathy. Thirty eligible patients with anti-PLA2R antibodies >50RU / mL and UPCR (mg / mg or g / g based on a 24-hour urine collection) >3.5 will receive zanubrutinib 160mg twice daily for 64 weeks, after a 12-week run-in with best supportive care. Part 1 has four periods: an initial screening period, a run-in period, a treatment period, and a follow-up period. Initial Screening Period: The initial screening assessment will occur within 4 weeks prior to the start of the 12-week run-in period. Patients who agree to participate will sign an Informed Consent Form (ICF) prior to the study-specific assessments at screening. Screening procedures are outlined in the Assessment Schedule (Table 2). Repeat screening procedures or tests are permitted if the patient did not previously meet the eligibility criteria or if documented results are required within the protocol-specified screening period. Only one rescreening is permitted per patient. Run-in period: All patients will receive optimal supportive care according to local guidelines during a 12-week run-in period. The maximum tolerated or tolerated dose of ACEI or ARB will be administered during the run-in period (ACEI or ARB will not be discontinued if a slow and stable increase (≤30%) in blood creatinine is observed. Concomitant use of ACEI with ARB or renin inhibitors is prohibited). If there is a record of administration of the maximum tolerated or tolerated dose of ACEI or ARB before starting study drug administration, that administration period will be counted toward the run-in period. A confirmatory assessment will be conducted during the last 2 weeks of the run-in period. Treatment duration: The treatment period will be 64 weeks. After the run-in period, 30 eligible patients will receive zanubrutinib 160 mg twice daily for 64 weeks. Continued Observation Period: After the treatment period, there will be a 40-week follow-up period. Patients will be re-examined as shown in Table 2. Patients who discontinue the study drug early will still participate in the study and will return to their originally scheduled visits. Table 2 shows the assessment schedule illustrating the review procedures for Part 1. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] 2.1.2 Part 2 Once Part 1 registration is complete, Part 2 registration will begin. Part 2 is a randomized, open-label, active-controlled study comparing the efficacy of zanubritinib with tacrolimus and evaluating its safety in patients with primary membranous nephropathy receiving optimal supportive care. At randomization, eligible patients will be stratified by baseline (moderate risk vs. high risk) and regional (China vs. rest of the world) risk classification for progressive renal function loss. Approximately 252 eligible patients will be randomly assigned in a 1:1:1 ratio to receive zanubritinib 160 mg twice daily, 160 mg once daily, or tacrolimus for 64 weeks. Tacrolimus oral capsules will be administered at an initial dose of 0.05 mg / kg / day in two divided doses every 12 hours for 52 weeks (the dose will be adjusted to maintain a target trough blood concentration of 3-8 ng / mL), then tapered starting at week 53 and ultimately discontinued by week 64. Patients are required to receive optimal supportive care throughout the study. Patients who discontinue study drug early during the treatment period will remain in the study and will continue to visit as originally scheduled. After the treatment period, there will be a 40-week follow-up period. Part 2 has four periods: an initial screening period, a run-in period, a treatment period, and a follow-up period. Initial Screening Period: The initial screening assessment will occur within 4 weeks prior to the start of the 24-week run-in period unless otherwise noted. Patients who agree to participate will sign an Informed Consent Form (ICF) prior to the study-specific assessments at screening. Screening procedures are outlined in the Assessment Schedule (Table 3). Repeat screening procedures or tests are permitted if the patient did not previously meet the eligibility criteria or if documented results are required within the protocol-specified screening period. Only one rescreening is permitted per patient. Run-in period: All patients will receive optimal supportive care according to local guidelines during the 24-week run-in period unless otherwise specified. The maximum tolerated or tolerated dose of ACEI or ARB will be administered during the run-in period (ACEI or ARB will not be discontinued if there is a slow and stable increase (≤30%) in blood creatinine. Combinations of ACEI or ARB or concomitant use with renin inhibitors are prohibited). If there is a record of administration of the maximum tolerated or tolerated dose of ACEI or ARB before randomization, this administration will be counted towards the run-in period. A confirmatory assessment will be conducted during the last 2 weeks of the run-in period. Patients who meet any of the following conditions will not require a run-in period and may be immediately entered into the study and randomized: Set 1 conditions: i. At least 24 weeks of treatment with the maximum tolerated or maximum tolerated dose of an ACEI or ARB with documented adequate blood pressure control (blood pressure <130 / 80 mmHg on at least two measurements within the month prior to randomization); and ii. Urinary protein creatinine ratio (UPCR) (based on a 24-hour urine collection) >3.5 at initial screening with a documented reduction of less than 50% after 24 weeks of ACEI or ARB treatment. Set 2 conditions: i. Adequate blood pressure control (blood pressure <130 / 80 mmHg on at least two occasions within the month prior to randomization), and ii. eGFR < 60 mL / min / 1.73 m at initial screening 2 and / or UPCR (based on a 24-hour urine collection) >8. Randomization and Treatment Duration: Treatment duration is 64 weeks. At randomization, eligible patients will be stratified by two factors: Baseline risk stratification of progressive kidney function loss: moderate risk vs. high risk Region: China vs. the rest of the world Baseline risk stratification for progressive kidney function loss: Medium risk is defined as: eGFR ≥ 60 mL / min / 1.73 m 2, and a UPCR (based on a 24-hour urine collection) >3.5 with a documented reduction of less than 50% after 24 weeks of ACEI or ARB treatment, and ·Does not meet high-risk criteria. High risk is defined as follows: eGFR <60 mL / min / 1.73 m 2 , and / or UPCR (based on a 24-hour urine collection) >8, or eGFR ≥ 60 mL / min / 1.73 m 2 , and UPCR (based on a 24-hour urine collection) >3.5 with a documented decrease of less than 50% after 24 weeks of ACEI or ARB treatment; and at least one of the following: a) serum albumin <25g / L; b) serum anti-PLA2R Abs >50RU / mL These stratification factors were selected to take into account potential regional differences in efficacy (due to differences in access to standard treatment and ethnicity) and risk stratification for progressive renal decline. After the run-in period, approximately 252 eligible patients will be randomly assigned in a 1:1:1 ratio to receive zanubrutinib 160 mg twice daily, 160 mg once daily, or tacrolimus for 64 weeks. Group A: zanubrutinib 160 mg twice daily Group B: zanubrutinib 160 mg once daily Group C: Tacrolimus oral capsules will be administered at an initial dose of 0.05 mg / kg / day in two divided doses for 52 weeks, tapered from the 53rd week, and finally discontinued by the 64th week. Continued observation period: After the treatment period, there will be a 40-week follow-up period. Patients will be re-examined as shown in Table 3. Patients who discontinue the study drug early will still participate in the study and will continue to visit as originally scheduled. Study Assessments: Efficacy assessments include UPCR (based on a 24-hour urine collection) and blood creatinine. Patient-reported outcomes (PROs) will be collected at the visits specified in Table 3 using the Kidney Disease and Quality of Life Instrument™-36 (KDQoL-36), the European Quality of Life 5-Dimension 5-Level Health Questionnaire (EQ-5D-5L), and the Patient Global Impression of Symptom Severity (PGI-S). Safety assessments will include adverse events, serious adverse events, laboratory values, vital signs, physical examination, and ECG. Adverse events will be classified as mild, moderate, or severe. Safety data will be monitored periodically by the Data Monitoring Committee (DMC). Blood and urine samples will be collected to assess PK and / or biomarkers as shown in Table 3. Table 3 is the assessment schedule showing the review procedures for Part 2. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] 2.1.3 Rescue treatment Salvage treatment is permitted in both Part 1 and Part 2 but is not required if any of the following conditions are met and secondary causes have been excluded: At week 24, a reduction in urinary protein creatinine ratio (UPCR) (based on a 24-hour urine sample) of <25% compared to baseline (confirmed by repeat measurement within 2 weeks), a UPCR (based on a 24-hour urine sample) of >3.5, and, for patients with positive anti-PLA2R antibodies at baseline, antibody levels of >50RU / mL. At week 52, there is a <50% decrease in UPCR (24-hour urine sample) compared to baseline (confirmed by repeat measurement within 2 weeks), and no immunological response is achieved in patients with a UPCR (24-hour urine sample) >3.5 and positive anti-PLA2R antibodies at baseline. From week 65, in patients who experienced a relapse, from week 1, in patients who relapsed. Salvage therapies include: Rituximab: Rituximab administered intravenously at a dose of 1 g every 2 weeks, or Cyclophosphamide + glucocorticoids Note: The dosage and duration of salvage therapy may refer to institutional treatment guidelines. Patients should discontinue study medication if receiving rescue therapy. 2.2 Research Schema The research schema is shown in Figure 1. 2.3 Research period The total duration of the study is expected to be approximately 5.5 years. 2.4 Discussion of study design, including choice of control group This study is designed to determine whether treatment with zanubrutinib is effective and well tolerated in patients with primary membranous nephropathy receiving optimal supportive care. Two-part research design Part 1 is an open-label, single-arm pilot study of the efficacy and safety of zanubrutinib in patients with primary membranous nephropathy receiving optimal supportive care. The primary endpoint of this part is the change in proteinuria at week 24 compared to baseline. Safety assessments and several primary efficacy endpoints, such as the proportion of patients with treatment failure and immunological response at week 24, will be analyzed descriptively. Part 2 is a phase 3, randomized, multicenter, active-controlled, open-label evaluation of the efficacy and safety of zanubrutinib in patients with primary membranous nephropathy. Patients enrolled must have received at least 24 weeks of optimal supportive care, unless otherwise noted. Additionally, patients must have a UPCR (based on a 24-hour urine collection) >3.5 at initial screening and confirmatory assessments. Two different regimens of zanubrutinib will be compared with an active control. The primary endpoint of Part 2 is complete remission status (Yes / No) at 104 weeks. Based on efficacy and safety results at 24 weeks in Part 1 (including the proportion of patients with treatment failure and immunological response), the study may be discontinued if efficacy and / or safety results are not satisfactory. Endpoint Selection The primary endpoint of clinical studies of chronic kidney disease treatments should ideally be the delay of renal function decline to ESKD. However, patients with primary membranous nephropathy are likely to experience progressive renal function decline over many years before reaching ESKD, making this timeframe unsuitable for clinical research. Using remission of proteinuria as a surrogate endpoint facilitates clinical research in patients with chronic kidney disease. Complete remission of proteinuria has been evaluated and shown to be associated with excellent long-term renal survival. In a cohort study of patients with primary membranous nephropathy from the Toronto Glomerulonephritis Registry, none of the patients who achieved complete remission progressed to ESKD during a median follow-up period of 87 months (range, 14 months to 400 months). Results showed that the mean slope of decline in creatinine clearance was -0.12 ± 0.4 mL / min / month. A large Spanish cohort study of 328 patients with primary membranous nephropathy demonstrated that complete remission improves long-term prognosis, with a mean follow-up of 104 months for patients in complete remission. Several analyses of clinical study data suggest that the treatment effect on complete remission at 1 and 2 years may predict long-term renal survival. Another cohort study reported that the cumulative probability of patients in complete remission achieving the primary outcome (defined as a 50% decline in ESKD or eGFR) was significantly lower than that of either partial remission or relapse cohorts at landmarks ranging from 3 to 24 months, supporting the possibility that complete remission may be an acceptable endpoint in clinical studies. Rationale for dose selection This study evaluates the efficacy and safety of two different zanubrutinib regimens in patients with primary membranous nephropathy. The dosing regimen of 320 mg daily (160 mg twice daily), selected as the high dose in this study, is consistent with the clinical dose approved for hematological indications and has shown efficacy and tolerability in patients with B-cell malignancies. Studies of BTK inhibitors in patients with autoimmune diseases have shown that an effective dose must maintain BTK occupancy of >90% in PBMCs and >70% in the spleen. A total daily dose of 160 mg 11 times daily achieved BTK occupancy of >75% in all PBMCs, with median BTK occupancy approaching 100% at each post-dose time point. More importantly, once-daily dosing offers advantages over twice-daily dosing in terms of adherence in patients with chronic diseases, and therefore includes the lower dose of 160 mg once daily. In summary, this study examines the efficacy and safety of zanubrutinib 160 mg twice daily and 160 mg once daily. Selection of control group Considering the possibility of spontaneous remission of membranous nephropathy and the side effects of immunosuppressive therapy, the updated KDIGO 2021 guidelines recommend conservative treatment for patients at low or moderate risk of progressive renal decline. The effects of optimal ACEI or ARB treatment are usually observed within two months of starting medication, with a gradual reduction in proteinuria of 40–50%. However, patients with already severe proteinuria or high anti-PLA2R antibody levels are unlikely to achieve the goal of complete remission with conservative treatment alone, even when using the highest doses of these drugs. In clinical studies with long-term treatment durations, selecting conservative treatment as a control for patients requiring immunosuppressive therapy is ethically questionable. Despite strong evidence that alkylating agents, such as cyclophosphamide combined with glucocorticoids, promote remission and prevent renal decline, they are toxic drugs with serious short- and long-term side effects. Therefore, cyclophosphamide-based immunosuppressive therapy is limited to patients at very high risk for rapid deterioration of renal function and those with life-threatening nephrotic syndrome. This study is intended to target a patient population who meets the criteria for moderate to high risk of progressive renal decline as defined by the KDIGO 2021 guidelines and who are unlikely to have a favorable clinical course after conservative treatment, i.e., patients with nephrotic proteinuria and a 24-hour urinary protein reduction of <50% after run-in. Tacrolimus monotherapy has been shown to be effective in inducing complete and partial remission in RCTs and cohort studies, and its favorable side effect profile is more advantageous than cyclophosphamide as initial treatment for patients with primary membranous nephropathy at moderate to high risk of progressive renal decline. The choice of tacrolimus as the comparator in this study is justified. The high relapse rate after treatment with calcineurin inhibitors is a cause for concern, but for the benefit of enrolled patients, the study provides a salvage treatment for the condition. 3. Selection of study population Specific eligibility criteria for patient selection are described in Sections 3.1 and 3.2. The sponsor will not grant any waivers of eligibility. All clinical laboratory evaluations will be performed by qualified local laboratories unless otherwise specified. 3.1 Inclusion criteria 3.1.1 Part 1 and Part 2 To be eligible to participate in Part 1 and Part 2, patients must meet all of the following criteria: 1. Aged 18 to 75 (inclusive) as of the date of signing the ICF. 2. Able to provide written informed consent (by the patient or the patient's legally authorized representative) and understand and agree to comply with the requirements and assessment schedule of this study. 3. Biopsy-confirmed primary membranous nephropathy. 4. UPCR (based on 24-hour urine collection) >3.5 at initial screening and confirmatory evaluation. 5. Female patients of childbearing potential must use highly effective contraception (section 4.3) for 4 weeks prior to the first dose of study drug, throughout the study, and for at least 30 days after the last dose of study drug. Male patients are eligible if they agree to abstinence (defined as abstaining from heterosexual intercourse from the day before the first dose of study drug, throughout the study, and for at least 30 days after the last dose of study drug, for the entire period of study drug-related exposure), vasectomy, or use of barrier contraception in combination with other methods described in Section 4.3 during study treatment and for at least 30 days after the last dose of study drug. 3.1.2 Part 1 only Each patient eligible for Part 1 must meet all of the criteria in Section 3.1.1 and below: 1. Patients have been receiving treatment with an ACEI or ARB at the maximum tolerated or tolerated dose for at least 12 weeks prior to the first dose of zanubrutinib, and have adequately controlled blood pressure (blood pressure <130 / 80mmHg, measured at least twice within 1 month prior to study treatment assignment). 2. Anti-PLA2R antibodies >50RU / mL at the time of confirmatory evaluation. 3.1.3 Part 2 only Each patient eligible for Part 2 must meet all of the criteria in Section 3.1.1 and below: 1. Patients have been receiving treatment with an ACEI or ARB at the maximum tolerated or tolerated dose for at least 24 weeks prior to randomization, and have adequate blood pressure control (blood pressure <130 / 80 mmHg, measured at least twice within the month prior to randomization). This criterion can be waived for patients with the following Set 2 conditions. Patients with either of the following two conditions will be randomized without a run-in period: Set 1 Conditions i. At least 24 weeks of treatment with the maximum tolerated or maximum tolerated dose of an ACEI or ARB with documented adequate blood pressure control (blood pressure <130 / 80 mmHg on at least two measurements within the month prior to randomization); and ii. Urinary protein creatinine ratio (UPCR) (based on a 24-hour urine collection) >3.5 at initial screening with a documented decrease of less than 50% after ≥24 weeks of ACEI or ARB treatment. Set 2 Conditions i. Adequate blood pressure control (blood pressure <130 / 80 mmHg on at least two occasions within the month prior to randomization), and ii. eGFR <60mL / min / 1.73m at initial screening 2 , and / or UPCR (based on a 24-hour urine collection) >8. 3.2 Exclusion criteria 3.2.1 Part 1 and Part 2 Patients eligible for Part 1 and Part 2 must not meet any of the following exclusion criteria: 1. Female patients who are breastfeeding or pregnant. 2. Patients with secondary causes of membranous nephropathy (e.g., diabetic nephropathy, lupus nephritis) or other primary glomerular diseases such as immunoglobulin A (IgA) nephropathy. 3. Type 1 or type 2 diabetes with hemoglobin A1c (HbA1c) ≥ 7% at screening. 4. eGFR <40 mL / min / 1.73 m 2 (according to the CKD-EPI formula), or initiation of dialysis. 5. Currently undergoing treatment with a strong CYP3A inhibitor or inducer (see table). 6. History of exposure to BTK inhibitors. 7. Received any prohibited substance within the specified time period (see Tables and Tables). 8. Patients with a history of primary immunodeficiency, or underlying diseases such as human immunodeficiency virus (HIV) infection or splenectomy, which make them susceptible to infections. 9. TB positive at screening: a. History of latent or active tuberculosis prior to study drug administration. An exception is made for patients with a history of latent tuberculosis who have documentation that they have completed appropriate treatment for latent tuberculosis prior to the first dose of study drug. It is the investigator's responsibility to verify that previous anti-tuberculosis treatment was appropriate and to provide appropriate documentation. Note: TB preventive treatment options include daily isoniazid for 6 months, weekly rifapentine plus daily isoniazid for 3 months, or daily isoniazid plus daily rifampin for 3 months. A 1-month regimen of once-daily rifapentine and isoniazid or a 4-month regimen of once-daily rifampin may also be considered. b. The medical history and / or physical examination during screening reveals signs or symptoms suggestive of active tuberculosis. c. If you have had or have had recent close contact with a person with active tuberculosis, be referred to a physician specializing in tuberculosis for further evaluation and, if necessary, appropriate treatment. Note: Appropriate treatment is the same as the preventive treatment options defined in the note to Criterion A. d. Positive interferon-gamma release assay screening test result (T-SPOT.TB [Oxford Immunotec] or quantiFERON-TB Gold test will be used in this study). Patients with an equivocal initial interferon-gamma release assay test result should undergo a repeat test, provided they meet other TB inclusion criteria. If other risk factors for TB are present, the test should not be repeated. If the test result is again equivocal, the patient will be excluded. If the interferon-gamma release assay test result is positive due to previous latent TB, patients are eligible if they have adequate documentation of having completed anti-TB treatment before randomization. e. A chest radiograph or computed tomography scan interpreted by a qualified radiologist and having a diagnostic evaluation consistent with evidence of currently active or old, inactive tuberculosis has been obtained within 12 weeks prior to study treatment assignment. 10. Active granulomatous infection prior to study treatment assignment, nontuberculous mycobacterial infection or opportunistic infection requiring hospitalization or parenteral antibiotic treatment within 1 year prior to study treatment assignment. 11. Infection requiring hospitalization or treatment with intravenous anti-infective medication not completed more than 4 weeks prior to study treatment assignment. 12. Severe liver failure (Child-Pugh C). 13. Current alcohol, drug, or chemical abuse or a history of such abuse within 1 year prior to the start of study treatment. 14. History of cancer (treated with curative therapy ≥ 2 years prior to study treatment assignment) except for cervical intraepithelial carcinoma, basal cell skin cancer, or squamous cell carcinoma. 15. History of intracranial hemorrhage. 16. Clinically significant cardio-cerebrovascular disease, including: Unstable angina, or myocardial infarction or cerebral infarction within 9 months prior to study treatment assignment b. New York Heart Association Class III or IV congestive heart failure as shown in the table below: [Table 10] c. History of clinically significant arrhythmias (e.g., sustained ventricular tachycardia, ventricular fibrillation, or torsades de pointes). d. QTcF by Fredericia's formula >480 milliseconds. e. History of Mobitz II second- or third-degree heart block without a permanent pacemaker. f. Hypertension as evidenced by systolic blood pressure >130 mmHg and diastolic blood pressure >80 mmHg on two or more consecutive blood pressure measurements within the last month prior to study treatment assignment. 17. History of severe bleeding disorders such as blood product A, blood product B, and von Willebrand disease, or a history of spontaneous bleeding requiring a blood transfusion or other medical intervention. 18. Inability to swallow capsules or any condition that significantly affects gastrointestinal function, such as malabsorption syndrome, gastric or small intestinal resection, bariatric surgery, symptomatic inflammatory bowel disease, or partial or complete intestinal obstruction. 19. Known infection with serological status reflecting active or chronic HBV or the following Hepatitis C Virus (HCV) antibodies: aPresence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with HBcAb but no HBsAg are eligible if they have undetectable HBV DNA (<20 IU / mL) and are willing to undergo monitoring for HBV reactivation. b. Presence of HCV antibodies. 20. Have undergone major surgery within 4 weeks prior to starting study treatment. 21. Vaccination with a live vaccine within 4 weeks prior to administration of the study drug. Note: COVID-19 vaccines are permitted except for live vaccines that may be developed. Seasonal influenza vaccines are generally inactivated and permitted. Nasal vaccines are live and not permitted. 22. Concurrent participation in another therapeutic clinical study. 23. Positive laboratory test result for COVID-19 as determined by antigen testing or polymerase chain reaction (PCR) testing by approved methods within 4 weeks prior to study treatment assignment. 24. Unwilling or unable to participate in all required study evaluations and procedures. 25. Unwilling or unable to follow dietary instructions given by the investigator. 26. Unable to understand the purpose and risks of the study and unable to provide a signed and dated ICF and authorization for use of protected health information (in accordance with national and local patient privacy regulations) unless surrogate consent and authorization has been obtained in accordance with national and local laws and regulations. For clarity, surrogate consent and authorization may include, but is not limited to, a state-appointed guardian, health care power of attorney, durable power of attorney, or family member / next of kin. 27. Any disease, determined by the investigator to occur alone or in combination: a. Making administration of the study drug unsafe. b. Interfering with the evaluation of the investigational product. c. Interfere with patient safety or the interpretation of study results. 28. Alanine aminotransferase and / or aspartate aminotransferase ≥ 3 × upper limit of normal (ULN) and total bilirubin ≥ 2 × ULN; and in the absence of colony-stimulating factors or blood transfusions, meet all of the following within 14 days prior to study treatment assignment: Hemoglobin level ≦80g / L (8.0g / dL) Platelet count ≤ 50 x 10 9 / L(50,000 cells / mm3) ·White blood cell count ≦2.0×10 9 / L(2,000 pieces / mm3) ·Neutrophil ≦1.5×10 9 / L(1500 cells / mm3) ·CD4+ T cell count ≦0.4×10 9 / L(400 cells / mm3) Note: If a screening test is abnormal, the test may be repeated once with another sample before the screen is deemed a failure. 3.2.2 Part 1 only Each patient eligible for Part 1 must not meet any of the exclusion criteria in Section 3.2.1 or the following: 1. Hypersensitivity to zanubrutinib or its formulation excipients 2. Evidence of a 50% or greater reduction in 24-hour urinary protein within 12 weeks prior to zanubrutinib administration. 3.2.3 Part 2 only Each patient eligible for Part 2 must not meet any of the exclusion criteria in section 3.2.1 or the following: 1. Evidence of a 50% or greater reduction in 24-hour urinary protein within 24 weeks prior to randomization 2. History of resistance or intolerance to tacrolimus 3. Hypersensitivity to zanubrutinib, tacrolimus, or their formulation excipients. 4. Enrollment and Study Procedures Study enrollment and procedures are summarized in the following subsections. The timing of all study procedures is provided in the assessment schedule (Tables 2 and 3). 4.1 Period of visit Study visits are scheduled for several specific study weeks (Tables 2 and 3). Procedures for a given visit may be spread out over the period to allow for drug resupply and completion of study procedures. 4.2 Informed consent At the screening visit, research site personnel must explain all aspects of the study to the potential participant, including all scheduled visits and activities. Patients must be given a copy of the ICF to read and be allowed sufficient time to fully understand the study and ask questions. Research site personnel must obtain signed informed consent before administering any study-specific treatment, except when it is part of best supportive care, and the informed consent process must be documented in the patient's clinical record. Informed consent will be obtained before the screening period. Consent must be obtained using the most recent version of a form approved by the Independent Ethics Committee / Institutional Review Board (IEC / IRB). Repeat screening procedures or tests are permitted if the patient did not previously meet the eligibility criteria or if documented results are required within the protocol-specified screening period. Only one rescreening is permitted per patient. For patients who provide informed consent and subsequently fail the eligibility criteria or who withdraw consent before randomization, study site personnel must document the screening failure in the patient's source documentation, which must include demographic and medical history, reasons for the screening failure, eligibility criteria considered, and treatments administered. 4.3 Women of childbearing potential and contraception Women are considered to be of childbearing potential (i.e., capable of becoming pregnant) after menarche and until postmenopause, unless they are permanently infertile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Contraceptive methods include: Combined (estrogen and progestogen-containing) hormonal contraceptive methods (oral, intravaginal, or transdermal) with ovulation suppression Progestogen-only hormonal contraception with ovulation suppression (oral, injectable, or implantable) Intrauterine contraceptive devices Intrauterine hormone-releasing system Bilateral tubal occlusion The partner of a vasectomized woman, provided that the vasectomized partner is the only sexual partner of the female study participant of childbearing potential and the vasectomized partner has been medically evaluated for the success of the procedure. Sexual abstinence. This is defined as abstinence from heterosexual intercourse from the day before the first dose of study drug through the duration of the study, and for at least 30 days after the last dose of zanubrutinib or tacrolimus, throughout the entire risk period associated with study treatment. Complete sexual abstinence should only be used as a contraceptive method if it is consistent with the patient's usual and preferred lifestyle. Periodic abstinence (e.g., calendar methods, ovulation methods, symptomatic methods, postovulation methods), declared abstinence during study drug treatment, and drug holidays are not acceptable methods of contraception. Of note, barrier contraception (including male and female condoms, with or without spermicide) is not considered a highly effective method of contraception and, if used, should be used in conjunction with another acceptable method as listed above. Patients using hormonal contraceptives (e.g., birth control pills or devices) must also use a barrier method of contraception (e.g., condoms). Postmenopausal status is defined as the absence of menstruation for 12 months without an alternative medical cause. In women not using hormonal contraception or hormone replacement therapy, a high follicle-stimulating hormone level in the postmenopausal range may confirm menopause. However, if there has not been amenorrhea for 12 months, a single follicle-stimulating hormone measurement is insufficient. 4.4 Enrollment and Randomization Initial screening assessments must be performed within 4 weeks prior to the run-in period unless otherwise noted. Confirmatory assessments will occur during the final 2 weeks of the run-in period. The investigator is responsible for maintaining records of all patients screened and enrolled in the study. Screening procedures are outlined in the assessment schedule (Tables 2 and 3). 4.4.1 Patient Number After obtaining informed consent, research site personnel will access the Interactive Response Technology (IRT) system and assign each potential participant a unique patient number. Patient numbers will be assigned in chronological order, starting with the lowest number. Once assigned to a patient, a patient number cannot be reassigned to another patient. 4.4.2 Break-in period Unless otherwise specified, all patients will receive optimal supportive care during the run-in period. They will receive the maximum tolerated or maximum tolerated dose of an ACEI or ARB during the run-in period. Blood pressure will be monitored during the run-in period and must be confirmed as <130 / 80 mmHg on at least two measurements during the final month of the run-in period prior to study treatment assignment. If there is a record of administration of an ACEI or ARB at the maximum tolerated or maximum allowed dose before the first dose of study drug, the administration period will be counted as a run-in period. In Part 2, patients who meet any of the following criteria may be immediately entered into the study and randomized without the need for a run-in period: Set 1 conditions: i. At least 24 weeks of treatment with the maximum tolerated or maximum tolerated dose of an ACEI or ARB with documented adequate blood pressure control (blood pressure <130 / 80 mmHg on at least two measurements within the month prior to randomization); and ii. UPCR (based on a 24-hour urine collection) >3.5 at initial screening with a documented <50% reduction after 24 weeks or more of ACEI or ARB treatment. Set 2 conditions: i. Adequate blood pressure control (blood pressure <130 / 80 mmHg on at least two occasions within the month prior to randomization), and ii. eGFR < 60 mL / min / 1.73 m at initial screening 2 and / or UPCR (based on a 24-hour urine collection) >8. 4.4.3 Medical history Screening begins with a medical history review at any time after obtaining informed consent. Clinically significant medical history (i.e., previous diagnoses, illnesses, or surgeries) that begin before signing informed consent and that are not related to the study indication but are considered relevant to the patient's study eligibility will be collected and documented in the electronic case report form (eCRF). "Clinically significant" is defined as the presence of an event requiring treatment or follow-up, a diagnosis, laboratory value, or a sign or symptom requiring medical intervention. Concurrent clinically significant medical signs and symptoms during the screening period must be recorded to establish baseline severity. Past medication history / significant non-pharmacological treatment history and demographic data will also be collected. Patient demographic data include date of birth (if necessary and permitted) or year of birth, age, sex, race or predominant ethnicity (if permitted), smoking history, and relevant medical history or current medical conditions (up to the date of signed informed consent), all of which will be recorded on the eCRF. Patient racial or ethnic data will be collected and analyzed to identify differences in the safety and / or efficacy profile of treatments according to these characteristics. Additionally, these data are necessary to assess the diversity of study populations as required by health authorities. Information regarding pregnancy potential will also be collected, as well as any other assessments performed for the purpose of assessing eligibility for inclusion in the study (e.g., physical examination, vital signs, hematology and blood chemistry, urinalysis, pregnancy test, and ECG). See Section 3 for details on eligibility assessment. 4.4.4 Eligibility Verification Prior to enrollment, the investigator is responsible for assessing and confirming that each patient meets all inclusion eligibility criteria for the study and none of the exclusion criteria. All screening results and relevant medical history must be obtained and reviewed by the investigator before eligibility can be determined. Waivers of eligibility will not be permitted. Sponsor verification of patient eligibility will be managed using the International Conference on Harmonisation (ICH) E6 compliant source data verification methodology. The sponsor's medical monitor will support the investigator and / or site staff and answer any inquiries or questions regarding the protocol's eligibility criteria. 4.4.5 Enrollment / Randomization Patients will be enrolled in Part 1 once investigator confirmation of eligibility has been confirmed, and will be assigned study medication by the IRT. Enrollment for Part 2 will begin once all 30 patients have been enrolled in the study. In Part 2, site personnel access the IRT system to randomly assign patients to treatment groups and allocate study medication, which must be initiated within 1 day of randomization. At randomization, patients are stratified by baseline risk classification of progressive kidney function decline (intermediate risk vs. high risk) and region (China vs. Rest of the World [ROW]). 4.5 Study Drug Distribution The study medication (zanubrutinib or tacrolimus) will be dispensed to patients at scheduled visits by study site personnel to ensure an adequate supply for administration throughout the treatment period, as detailed in the Pharmacy Manual. Instructions will be provided for administration, storage, and return of all packs (used and unused) at the next visit. 4.6 Pharmacokinetics Blood samples will be collected to characterize the PK of zanubrutinib in patients with primary membranous nephropathy. PK samples will be collected as specified in Table 9. On days when PK samples are collected, the study drug must be administered under the supervision of the investigator (or his / her designee) after the pre-dose PK samples are collected. The actual time at which each sample is collected will be recorded to the nearest minute on the eCRF. The time of study drug administration for Weeks 1, 4, and the day before Week 4 must be recorded on the eCRF. Additional blood samples may be collected if toxicity or adverse events with suspected drug-drug interactions and mechanisms of toxicity are elicited, and such events, if they occur, must be recorded on the eCRF. Blood samples (2 mL) for PK analysis will be collected in ethylenediaminetetraacetic acid blood collection tubes. Details regarding the handling of PK plasma samples, including labeling and shipping instructions, will be provided in the study's test manual. Samples will be sent to a designated bioanalytical laboratory for determination of plasma zanubrutinib concentrations using a validated method. 4.7 Safety Assessment 4.7.1 Physical Examination and Vital Signs A complete physical examination will be performed at screening. A comprehensive physical examination, as well as vital signs (sitting blood pressure, heart rate, and temperature), and weight measurements will be performed at each study visit. Height (cm) will be measured at screening only. A complete physical examination will include evaluation of various body systems according to the standard of care at the study site and as clinically indicated by symptoms. 4.7.2 Electrocardiogram Electrocardiograms will be obtained according to local practice and interpreted on-site to confirm eligibility. 12-lead ECGs will be performed three times: at screening, at the confirmatory assessment, at week 52, at end of treatment (EOT), and as clinically indicated (e.g., investigator-indicated abnormal and clinically significant). ECG recordings should be performed after the patient has been at rest for at least 10 minutes. If blood is drawn at the same time, an ECG evaluation must be performed before the blood is drawn. The patient must be at rest in a semi-recumbent or supine position for at least 10 minutes before the ECG is drawn. 4.7.3 Concomitant medications Record any new medications, changes in ongoing medications or treatments, and medications discontinued within 30 days prior to the run-in period and since the last study visit. Concomitant medications must be collected at screening, and during the run-in, treatment, and extension periods. 4.7.4 Adverse Events The severity of adverse events will be assessed and recorded throughout the study. Characterization of adverse events includes severity, duration, and time to onset. All adverse events, including serious adverse events, will be collected. 4.8 Effectiveness Evaluation 4.8.1 Complete remission Complete remission is defined as follows: UPCR (based on a 24-hour urine collection) ≤ 0.3, and Stable eGFR (no change or less than a 15% decrease compared to baseline) 4.8.2 Partial remission Partial response is defined as follows: UPCR (based on a 24-hour urine collection) >0.3 and ≤3.5 with a 50% decrease compared to baseline, and Stable eGFR (no change or less than a 15% decrease compared to baseline) 4.8.3 Overall remission Patients in overall remission were those who achieved either a complete or partial remission. 4.8.4 Definition 4.8.4.1 Recurrence Relapse is defined as a return of UPCR (based on a 24-hour urine collection) to >3.5 after complete or partial remission. NOTE: If there is an underlying cause for recurrent proteinuria, repeat the 24-hour urine protein test within 2 weeks or after the underlying cause has resolved. 4.8.4.2 Treatment failure Treatment failure is defined as any of the following: At week 24, a reduction in UPCR (24-hour urine sample) of <25% compared to baseline (confirmed by repeat measurement within 2 weeks), UPCR (24-hour urine sample) >3.5, and for patients with anti-PLA2R antibody positivity at baseline, antibody levels >50RU / mL At week 52 of treatment, patients who have a <50% decrease in UPCR (24-hour urine sample) compared to baseline (confirmed by repeat measurement within 2 weeks), a UPCR (24-hour urine sample) >3.5, and who were anti-PLA2R antibody positive at baseline will not achieve an immunological response. Initiation of immunosuppressive medications other than the study drug (including rescue therapy) Diagnosis of ESKD or initiation of dialysis Relapse by week 104 - Not achieving complete or partial remission by week 104 Death attributable to the study treatment or underlying disease If treatment failure occurs, the patient will be withdrawn from study drug and the patient's treatment will be adjusted according to clinical guidelines and local practice. 4.8.4.3 Immunological response Immunological response is defined as a decrease in anti-PLA2R antibody levels from baseline to less than 14 RU / ml. NOTE: To quantify anti-PLA2R Ab levels in patients, a commercially available quantitative ELISA assay (EUROIMMUN AG) for the IgG-specific isotype of anti-PLA2R was performed according to the manufacturer's instructions. 4.8.4.4 Baseline Baseline is defined as the last measurement before the first dose of study medication. 4.9 Patient-reported outcomes PRO assessments will continue regardless of discontinuation of study treatment until withdrawal of consent, death, loss to follow-up, or discontinuation of study treatment, whichever occurs first. Patients must complete the KDQoL-36, EQ-5D-5L, and PGI-S according to the assessment schedule (Table 3) at the designated visits for the three groups in Part 2, before receiving study medication and any other treatment. The KDQOL-36 is a validated PRO scale that includes the 12-item Short Form Questionnaire (SF-12) as a general core scale (physical function: 2 items, role-physical: 2 items, pain: 1 item, general health: 1 item, emotional health: 2 items, role-emotional: 2 items, social functioning: 1 item, and energy / fatigue: 1 item) plus three additional kidney disease-related scales: the Kidney Disease Burden Scale (4 items), the Kidney Disease Symptoms / Problems Scale (12 items), and the Kidney Disease Impact Scale (8 items). This scale is the most frequently used PRO scale in clinical settings and research to measure health-related quality of life in patients with kidney disease and has been linguistically validated in 50 languages. Higher scores indicate better HRQoL. The EQ-5D-5L is one of the most frequently used PRO scales in clinical practice and clinical research to measure general HRQoL and is available in over 100 linguistically validated languages. It consists of five domains (mobility, self-care, daily living, pain / discomfort, and anxiety / depression) and a visual analog scale (VAS). Higher scores indicate better HRQoL. 4.10 Inspection Evaluation Samples for UPCR (based on a 24-hour urine collection), urinary creatinine and protein excretion, anti-PLA2R antibodies, and CD4+ T-cell count will be evaluated at a central laboratory. Other samples, such as hematology, chemistry, and coagulation profiles as specified in the protocol, will be evaluated at local laboratories unless otherwise specified. Procedures for collecting, handling, storing, and shipping laboratory samples, as well as details of all materials such as study tubes and labels, will be described in the laboratory manual. Laboratory tests, including but not limited to serum chemistry, hematology, coagulation, serum immunoglobulins, and urinalysis, will be performed at the times specified in the test schedule (Tables 2 and 3) and may also be performed as medically indicated. Certain elements of the laboratory evaluation will be collected. 4.10.1 Urinalysis, urinary protein creatinine ratio, 24-hour urine collection Urinalysis and UPCR (based on a 24-hour urine collection) are required to be performed at scheduled visits as specified in the assessment schedule (Tables 2 and 3), but specimen collection is not performed during the menstrual period for female patients. Unscheduled urine specimen collection must be made up within 7 days of menstruation and should not be considered a protocol deviation. 24-hour urine collection instructions are provided to patients and must be followed to ensure urine collection is complete. 4.10.2 Hematology Required hematological tests will be performed at the routine visits specified in the assessment schedule (Tables 2 and 3). Hematological tests will include hemoglobin, hematocrit, platelet count, red blood cell count, and white blood cell count (with differential). 4.10.3 Chemistry Required serum chemistry tests will be performed at the routine visits specified in the assessment schedule (Tables 2 and 3). Serum chemistry tests include sodium, potassium, chloride, glucose, blood urea nitrogen (or urea), creatinine, total calcium, phosphate / phosphorus, magnesium, total bilirubin, total protein, albumin, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase, and creatine kinase. Estimated glomerular filtration rate is calculated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. 4.10.4 HbA1c Hemoglobin A1c (HbA1c) testing will be performed at the scheduled visit specified in the assessment schedule (Tables 2 and 3). 4.10.5 Tacrolimus Trough Concentration In Part 2, tacrolimus trough concentrations will be monitored at scheduled visits specified in the assessment schedule (Table 3). 4.10.6 Serum immunoglobulins Quantitative serum immunoglobulins (IgG, IgM, and IgA) will be measured at the time points specified in the assessment schedule (Tables 2 and 3). 4.10.7 Coagulation The coagulation profile will include prothrombin time, international normalized ratio, and activated partial thromboplastin time. The coagulation profile will be performed at designated visits (Tables 2 and 3). 4.10.8 Lipid Panel The lipid panel will include total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides. Required serum lipid testing will be performed at the scheduled visits specified in the assessment schedule (Tables 2 and 3). 4.10.9 Hepatitis B and C testing Hepatitis B and C seromarkers and / or viral load should be tested at screening. Hepatitis B testing can be performed in local laboratories if they have the required sensitivity (<20 IU / mL for HBV DNA); otherwise, results must be confirmed at a central laboratory. Hepatitis B testing includes HBsAg, HBcAb, hepatitis B surface antibody (HBsAb), and HBV DNA by PCR (with or without HBsAb) if the patient is HBsAg negative and HBcAb positive. HCV antibodies should be tested. Patients with HBsAg positivity and / or detectable levels of HBV DNA, or HCV antibody positivity are ineligible. HBcAb-positive (HBsAg-negative) and HBV DNA-negative patients should undergo HBV DNA monitoring by PCR. These patients should receive prophylactic antiviral therapy in consultation with a local HBV specialist. If patients are receiving prophylactic antiviral therapy, HBV DNA screening by PCR should be performed at least every 90 days. Table 4 describes how HBV and HCV test results at screening relate to study eligibility. [Table 4] 4.10.10 Pregnancy Test For women of childbearing potential, a laboratory-based, highly sensitive serum pregnancy test must be performed at screening and documented as negative. Pregnant female patients are ineligible for the study. A urine pregnancy test will be performed before study drug administration at all other visits (except screening) specified in the assessment schedule (Tables 2 and 3). For patients who prematurely discontinue study drug, a pregnancy test must be performed at the safety follow-up visit. A positive urine pregnancy test must be confirmed with a serum pregnancy test. Patients with a positive pregnancy test at any time after study drug administration will immediately discontinue participation in the study. 4.10.11 Renal biopsy Renal biopsy results should be used to determine patient eligibility. These results should include light, immunofluorescence, and electron microscopy images, and should demonstrate subepithelial deposits by electron microscopy. If no previous renal biopsy results are available, a renal biopsy should be performed prior to treatment assignment. 4.10.12 COVID-19 Testing COVID-19 testing will be administered to confirm eligibility in accordance with local practice. 4.11 Biomarkers Peripheral blood and urine samples will be collected from patients at different time points as specified in the assessment schedule (Table 9) to examine the association of biomarkers with glomerular disease status, disease activity, and response to zanubrutinib. Such assessments may include protein biomarkers (e.g., autoantibodies, cytokines, and proteomic signatures), gene expression signatures, primary membranous nephropathy-associated gene polymorphisms, and / or other pharmacodynamic (PD) biomarkers such as BTK occupancy and BTK-associated immune cell activity. Collection of blood samples for measurement of serum anti-PLA2R Ab levels by enzyme-linked immunosorbent assay by a central laboratory will be mandatory for all patients during screening and for all patients who test positive for anti-PLA2R Ab at the end of the run-in period and at specific time points during treatment. Patients who initially screen negative for anti-PLA2R Ab will have blood drawn for serum anti-THSD7A Ab levels measured by enzyme-linked immunosorbent assay in a central laboratory. Anti-THSD7A Ab blood will be drawn at the confirmatory evaluation and at subsequent visits if positive at baseline. Blood samples for BTK occupancy will be collected from 10-15 randomized patients in Part 1 and from 10-15 randomized patients each from Groups A and B in Part 2. Blood samples for BTK-related immune cell activity analysis, cytokine analysis, protein signature analysis, gene expression signature analysis, primary membranous nephropathy-related gene polymorphism analysis, and urine samples will be collected from all randomized patients at different time points during treatment to examine the association of specific biomarkers with disease status and patients' clinical response to zanubrutinib. Shipping, storage, and handling of blood and urine samples for biomarker evaluation will be managed by a central laboratory. Samples will be processed and stored separately as described in the test manual. The stored and coded samples may be used for additional medical and / or scientific research projects and regulatory purposes outside of the current study objectives and goals (but always in compliance with applicable law). These research projects may be related to the disease(s) targeted by this study, validation of new technologies / assays, and / or related potential pharmaceuticals. This may include research to help develop methods to detect, monitor, or treat the disease(s) targeted by this study. For samples collected in mainland China, only the biomarkers specified above will be tested. For samples collected outside mainland China, biomarkers may include, but are not limited to, the tests specified above. 4.12 Unscheduled visits Unscheduled visits may be performed whenever clinically indicated and may include clinically indicated vital signs / focused physical examination, review of adverse events, review of concomitant medications and treatments, and hematology and chemistry evaluations. The date and reason for unscheduled visits must be recorded in source documentation. If an unscheduled visit is necessary to assess toxicity, diagnostic testing may be performed as appropriate based on the investigator's assessment, and test results should be recorded on the unscheduled visit page of the eCRF. 4.13 Missed Visit(s) During COVID-19 If a patient is unable to attend the clinic due to COVID-19, evaluations required at that visit may be conducted at an external local hospital rather than at the investigator's facility and will be recorded in the electronic data capture (EDC) system. The investigator must ensure that, at a minimum, the key safety assessments outlined in the protocol (see Section 4.7) are performed. The investigator's telephone or video evaluation should include a discussion of any new or ongoing adverse events, as well as any changes in concomitant medications. The investigator should also discuss the patient's current investigational medication and identify any questions the patient may have regarding the investigational medication. The results of the telephone / video discussion should be recorded in the patient's medical record, as appropriate. Regarding the visit(s) specifically missed due to COVID-19: Do not miss the first day of the first week Unscheduled visits should occur within 4 weeks and should include collection of samples for safety assessment, laboratory evaluation, pharmacokinetics, and biomarkers (unscheduled visits may be omitted if the next visit is within 4 weeks). For patients whose study drug administration has been interrupted due to COVID-19, PK sampling should be omitted at that visit. 4.14 Duration of Treatment The treatment period begins on the date of study treatment assignment and continues until the last dose of study medication, which must occur within one day of treatment assignment. Patients may discontinue study medication for any of the following reasons: Adverse event(s) Patient withdrawal of consent Investigator's decision Unable to track Treatment failure Other reasons (including a positive pregnancy test) Patients may voluntarily withdraw consent to receive treatment at any time. 4.15 Safety Follow-Up Patients who discontinue study drug early and do not intend to seek follow-up care will return to the safety follow-up visit approximately 30 days after the last dose of study drug to collect treatment-emergent adverse events, including any treatment-emergent adverse events (see Section 7.4.2 for definitions) that may have occurred or continued after the patient discontinued study drug. Laboratory assessments are only required if the patient continues to have laboratory abnormalities that the investigator deemed related to the study drug at their previous visit. If the patient is unable to return to the clinic and a laboratory assessment is not required, the investigator or their designee will contact the patient or guardian to collect information. See the assessment schedule (Tables 2 and 3) for assessments performed during safety follow-up. 4.16 Early Discontinuation of Study Drug Discontinuation of study medication does not necessarily mean loss to follow-up or termination of study participation. Patients who discontinue study medication should complete an EOT visit (within 1 week of last dose) as soon as possible to support final efficacy and safety analyses. Reasons for early discontinuation of study medication will be recorded in source documents and the eCRF. Cooperating patients who discontinue study drug are encouraged to return for all scheduled visits until the scheduled Week 104 visit. At a minimum, the following procedures and assessments must be completed at each visit after study drug discontinuation: Vital signs 24-hour urine collection at EOT visit eGFR Adverse events reported within 30 days of the last dose If the patient is not willing to attend all scheduled clinic visits, they must attend the EOT visit, the safety follow-up visit 30 days after the last dose of study drug, and the scheduled visits at Week 52, Week 76, and Week 104. If the patient is not willing to return for the study, at a minimum, UPCR (based on a 24-hour urine collection) and blood creatinine should be assessed at the EOT visit. 4.17 End of research Patients who complete the 104-week visit will cease participation in the study. For patients who discontinue study drug early, attempts should be made to follow up until the planned visit at week 104. Study participation will end after the safety follow-up or the planned visit at week 104, whichever occurs later. Complete withdrawal from the study (including treatment and all follow-up) will occur under the following circumstances: Patient withdrawal of consent Termination of the study by the sponsor Unable to track Other circumstances at the investigator's discretion ·death ·others Patients may voluntarily withdraw consent to participate in a study at any time. Patients who withdraw consent must be informed by the investigator that withdrawing consent for follow-up will jeopardize the public health value of the study. Investigators should explicitly ask patients who withdraw consent how potential adverse events contributed to their decision to withdraw consent, and any adverse event information elicited should be documented. Preferably, patients should withdraw consent in writing; if the patient or their representative refuses to withdraw consent or is physically unable to do so, the institution should document and sign the patient's reasons for not withdrawing consent. 4.18 Lost to follow-up For patients who are believed to be lost to follow-up during the study, every reasonable effort should be made to complete study-related assessments, record any outstanding data, and retrieve study medication. More specifically, attempts should be made to contact the patient by telephone, but if telephone contact is unsuccessful, the patient or alternative contacts (e.g., primary care physician, referring physician, and next of kin) may be contacted by mail. Such efforts should be documented in the patient's source documentation. If all efforts fail to contact the patient, the patient will be recorded as lost to follow-up. 5 Research treatments 5.1 Preparation and Distribution of Study Treatment 5.1.1 Packaging and Labeling Zanubrutinib capsules are supplied in child-resistant high-density polyethylene (HDPE) bottles with an induction seal and bottle label. Please refer to your pharmacy manual for packaging and labeling information. Tacrolimus oral capsules are available commercially. Labeling may include additional local clinical requirements, as appropriate. Refer to the pharmacy manual for packaging and labeling information. Label content complies with all applicable local regulatory requirements. 5.2 Dosage and Administration 5.2.1 Zanubrutinib Zanubrutinib will be dispensed to patients by research center personnel at regular study visits to ensure an adequate supply of medication for home administration throughout the treatment period, as detailed in the pharmacy manual. The investigator will instruct patients to take the study medication as prescribed at the same time each day. Patients will be asked to bring any unused medication and empty bottle packs to each visit. All doses prescribed and dispensed to patients, as well as any dose changes during the study, including the reason for the dose change, must be recorded on the appropriate eCRF. In Part 1 and Part 2 Arm A, zanubrutinib will be administered orally as two 80 mg capsules twice daily (160 mg twice daily) with or without food. In Part 2 and Part 2 Arm B, zanubrutinib will be administered orally as two 80 mg capsules once daily (160 mg once daily) with or without food. Patients will take zanubrutinib capsules with water at approximately the same time each day, with at least 8 hours between consecutive doses. Zanubrutinib capsules should not be opened, broken, or chewed at any time. Patients should be instructed that if they miss a dose of study medication at the scheduled time, they should skip the dose and resume their regular dosing regimen if the next dose is due within 8 hours. If a patient vomits after taking a zanubrutinib capsule, that dose should not be repeated. On PK blood collection days, patients will receive study drug at the investigational site after the pre-dose blood collection under the supervision of the investigator or his / her designee. The investigator or his / her designee must instruct patients not to self-administer study drug before their appointment on that day. 5.2.2 Tacrolimus Patients in Group C will be administered tacrolimus capsules. The initial dose of tacrolimus capsules will be 0.05 mg / kg / day, divided into two doses, every 12 hours. The dose will be adjusted to maintain a target trough blood concentration of 3-8 ng / mL for 52 weeks, tapered from Week 53, and finally discontinued by Week 64. Tacrolimus administration must be consistent with or without food. If patients consistently take tacrolimus with food, they must follow any dietary advice provided by the investigator. Predose tacrolimus blood concentrations (trough concentrations) should be monitored every 2 weeks for the first 2 months of treatment and thereafter as specified in the assessment schedule (Table 3). If target blood concentrations are not achieved, arrange for an unscheduled visit by Week 53, after dose adjustment (see Section 5.5.3). 5.3 Overdose The tacrolimus dose will be adjusted according to blood drug concentrations and tolerability. A zanubrutinib dose exceeding the amount specified in this protocol will be considered an overdose. Adverse events related to study drug overdose or misadministration will be recorded on the Adverse Events eCRF. Serious adverse events related to overdose or misadministration are required to be reported within 24 hours of recognition through the serious adverse event reporting process. There are no specific antidotes for zanubrutinib or tacrolimus. If an overdose occurs, the patient's condition should be closely monitored and appropriate supportive care should be administered. 5.4 Notes Group C should not consume grapefruit or grapefruit juice, and groups A and B should consume it with caution. For complete warnings and precautions regarding tacrolimus, please refer to the Prescribing Information and Summary of Product Characteristics. 5.4.1 Surgery and procedures Bleeding sensitivity has been observed with BTK inhibitors. Study treatment with zanubrutinib should be withheld for 3 to 7 days before and after surgery, depending on the type of surgery and risk of bleeding. 5.5 Dose Modifications 5.5.1 Zanubrutinib Dose Modifications for Hematologic Toxicity Every effort should be made to administer zanubrutinib according to the planned dose and schedule. Dosing will be withheld for individual patients based on investigator assessment under any of the following conditions: Neutrophil count <1.0 x 10 9 / L(<1000 / mm 3 ) was reduced to; Platelet count <25.0 × 10 9 / L(<25,000 / mm 3 ) was reduced to; Platelet count <50.0 × 10 9 / L(<50,000 / mm 3 ) and is accompanied by significant bleeding. If hematologic toxicity occurs for the first time, treatment may be restarted once toxicity is mild or has returned to baseline. If the same event recurs, each dose should be halved until toxicity is mild or has returned to baseline. If the same event recurs a third time, zanubrutinib should be discontinued. Thrombocytopenia (platelet count decrease <50.0 × 10) with significant bleeding requiring medical intervention 9 / L[<50,000 / mm 3 ]), discuss dosage with your medical monitor. 5.5.2 Zanubrutinib Dose Modifications for Hematologic Toxicity Zanubrutinib should be held for any serious bleeding and permanently discontinued for any zanubrutinib-related severe bleeding unless the underlying condition is fully treatable (e.g., gastrointestinal bleeding due to gastric ulcer) and the risk of rebleeding is acceptable. Zanubrutinib should be permanently discontinued for any grade of intracranial hemorrhage (Table). For serious non-hematologic toxicities suspected to be related to zanubrutinib, zanubrutinib will be held until mild or has resolved to baseline, and then resumed at the original dose level, except for hypertension or asymptomatic laboratory events adequately controlled with oral medications (laboratory events indicating hepatic or renal dysfunction are not considered asymptomatic laboratory events). If a severe event recurs, zanubrutinib will be held until mild or has resolved to baseline, and then resumed at half the dose. If a severe event recurs, zanubrutinib will be permanently discontinued. For patients with symptomatic and / or incompletely controlled atrial fibrillation, zanubrutinib may be resumed at the original or half-dose dose, at the investigator's discretion, after atrial fibrillation is adequately controlled (Table). See section 4.10.9 for information regarding discontinuation of zanubrutinib based on hepatitis B or hepatitis C testing. For any active infection or significant exposure to any infection, the investigator must consider whether to interrupt zanubrutinib. Similarly, zanubrutinib should be interrupted in patients with signs or symptoms suggestive of a serious opportunistic infection. [Table 5] 5.5.3 Tacrolimus Administration Interruptions and Changes The daily dose of tacrolimus may need to be adjusted in the following cases: - Tacrolimus blood trough concentration is outside the target range (3-8 ng / mL). · ≥ 30% increase in serum creatinine during the first 24 weeks of tacrolimus treatment. - The occurrence of adverse events that were manageable under tacrolimus administration, as determined by the investigator. In patients who experience a ≥30% increase in serum creatinine during the first 24 weeks of tacrolimus therapy, the tacrolimus dose should be tapered by ≥30% once potential underlying conditions such as excessive diuretic therapy or non-renal volume depletion have been excluded. If azotemia does not improve within 2 weeks of a dose change, tacrolimus should be discontinued, and patients may be treated according to clinical guidelines and local practice. Patients requiring such a change are considered treatment failures. Protocol-specified visits should be performed whenever possible after treatment failure. If a serious adverse event occurs, tacrolimus must be discontinued at the discretion of the investigator, and may be resumed once adverse events other than intolerable nephrotoxicity have resolved. 5.5.4 Discontinuation of Study Treatment Due to Dose Interruption For patients who discontinue study medication (zanubrutinib or tacrolimus) for 8 weeks or more, the decision on whether to discontinue study medication should be discussed with the medical monitor. 6. Prior and concomitant treatment 6.1 Pre-emptive treatment Prior use of any of the following treatments is prohibited: Prior exposure to BTK inhibitors - Intake of all prohibited substances as defined in the table and in the table before assignment of study treatment Any of the following vaccinations: Any live vaccine within 4 weeks prior to study treatment assignment b. Bacillus Calmette-Guerin (BCG) vaccine within 1 year prior to study treatment assignment c. Any prohibited substances listed in the section on if the washout period is not met Previous hematopoietic stem cell transplant Plasmapheresis or leukapheresis within 12 weeks prior to study treatment assignment [Table 6] [Table 7] 6.2 Combination therapy All concomitant medications taken during the study will be recorded on the eCRF along with the indication and date of administration. Bacterial, fungal, or infectious prophylaxis must be initiated prior to or concurrently with study treatment, according to institutional standards. For special infections such as latent tuberculosis or HBV reactivation, see: Patients with latent TB or recent close contacts of patients with active TB must have completed appropriate treatment (see section 3.2) before randomization. Patients with HBsAg-negative, HBcAb-positive, and undetectable HBV DNA (<20 IU / mL) must begin prophylactic antiviral therapy (entecavir or tenofovir alafenamide fumarate) prior to or concurrently with study treatment. HBsAg, alanine aminotransferase, and HBV DNA must be monitored throughout the study. 6.2.1 Optimal supportive care for primary membranous nephropathy Unless contraindicated or otherwise noted, all patients will receive optimal supportive care during the run-in and study periods. The maximum tolerated or maximum tolerated dose of ACEI or ARB should be administered during the run-in period. ACEI or ARB will not be discontinued if a slow and stable increase (≤30%) in blood creatinine is observed. Concomitant use of ACEI or ARB or use with renin inhibitors is prohibited. ACEI or ARB dosage must remain stable throughout the study (stable treatment defined as a dosage increase of less than 25%). For patients who skipped the run-in period (with adequate blood pressure control [blood pressure <130 / 80 mmHg measured on at least two occasions within the month before randomization], eGFR <60 mL / min / 1.73 m2 and / or urine protein >8 g / 24 h at initial screening), an ACEI or ARB was initiated within 12 weeks after randomization and maintained stable after achieving maximum tolerated or tolerated dose during the study. Blood pressure must be well controlled at the end of the run-in period, with blood pressure <130 / 80 mmHg measured at least twice within the month prior to randomization. If blood pressure control goals cannot be achieved with an ACEI or ARB, it is recommended to add antihypertensive medications in the following order: loop diuretics, cardioselective beta-blockers, nondihydropyridine calcium channel blockers, and clonidine. At the start of the run-in period, statins will be initiated as first-line treatment for patients with nephrotic syndrome and hyperlipidemia. Treatment of hyperlipidemia in patients with nephrotic syndrome can follow guidelines applicable to the general population. Antihyperlipidemic treatment will begin at least 2 weeks before study treatment assignment. 6.2.2 Permitted Medications Anticoagulation Therapy: Patients with thromboembolic events, such as venous thrombosis, arterial thrombosis, pulmonary embolism, and nonvalvular atrial fibrillation, require full-dose anticoagulation therapy for 6 to 12 months during the course of nephrotic syndrome. Serum albumin <20 g / L, urine protein >10 g / 24 hours, and obesity >35 kg / m 2 Prophylactic anticoagulation is recommended when either thoracotomy or prolonged immobilization is involved. The use and dosing regimen of anticoagulants should be determined according to clinical guidelines, the investigator's clinical judgment, and the patient's specific clinical characteristics, and should take into account the risk of thromboembolic and serious bleeding events associated with anticoagulation. Nonsteroidal anti-inflammatory drugs should be avoided unless intended for the prevention of cardiovascular, cerebrovascular, or thrombotic events. Class C CYP3A inhibitors: Concomitant use of CYP3A inhibitors, such as diltiazem or schisandra, which may require a dose reduction of tacrolimus, is permitted at the investigator's discretion. Tacrolimus trough concentrations must be monitored and maintained within the target range. 6.2.3 Prohibited Substances The following medications are prohibited while patients are receiving the study drug. If any of these medications are being used, study drug administration will be discontinued: Any other investigational drug (small molecule or biologic) Any other BTK inhibitor Any systemic use of immunosuppressants (including glucocorticoids, see table) except for salvage therapy Combination of ACEI and ARB, or combination of ACEI / ARB and renin inhibitor Any live vaccine during the study or within 3 months of the last dose of study drug ·Strong CYP3A4 inhibitors or inducers for patients in Part 1 and for Groups A and B in Part 2 (see table). Drugs prohibited for use with tacrolimus in Group C of Part 2, such as grapefruit or grapefruit juice, and cyclosporine. [Table 8] 6.3 Potential interactions between the study drug and concomitant medications 6.3.1 Cytochrome P450 Inhibitors / Inducers and Zanubrutinib Strong CYP3A inhibitors or inducers are prohibited. Concomitant use of zanubrutinib with moderate CYP3A inhibitors or inducers (see the table for a list of these agents), as well as grapefruit juice or Seville oranges, should be done with caution due to the potential for affecting the metabolism of zanubrutinib. It is recommended that moderate CYP3A inhibitors and inducers be avoided, if possible, and that an alternative medication be considered. In such cases, a medical monitor should be consulted. For a more complete list, see http: / / medicine.iupui.edu / clinpharm / ddis / main-table / . A clinical drug-drug interaction study (BGB-3111-108 study) showed that zanubrutinib is a mild inducer of CYP3A4 and CYP2C19. Drugs with narrow therapeutic indices that are metabolized by CYP3A4 (alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, and sirolimus) and CYP2C19 (e.g., S-mephenytoin) should be used with caution because zanubrutinib may decrease the plasma exposure of these drugs. 6.3.2 Drugs that may interact with tacrolimus For potential interactions with tacrolimus, refer to the relevant prescribing information. 7 Statistical methods and sample size determination The statistical analysis will be performed by the sponsor or a designee after the study is completed, the database is locked, and the data is released. Details of the statistical analysis will be described in a separate "Statistical Analysis Plan." 7.1 Study Endpoints 7.1.1 Primary Endpoint Part 1: The primary endpoint was the reduction from baseline in UPCR at 24 weeks. Part 2: The primary endpoint was complete remission status (Yes / No) at week 104 (see section 4.8.1 for definition of complete remission). 7.1.2 Secondary Endpoints Part 1: Secondary endpoints were: Treatment failure status up to 24 weeks (Yes / No) Immunological response status at 24 weeks (Yes / No) Complete remission status at weeks 24, 52, 76, and 104 (Yes / No) Overall remission status at weeks 24, 52, 76, and 104 (Yes / No) Recurrence status up to 104 weeks (Yes / No) The incidence and severity of treatment-related adverse events Part 2: The key secondary endpoint was overall remission status (Yes / No) at Week 104 (see Section 4.8.3 for definition of overall remission). Secondary endpoints also include: Complete remission status at 24, 52, and 76 weeks (Yes / No) Overall remission status at weeks 24, 52, and 76 (Yes / No) Treatment failure status at 24, 52, 76, and 104 weeks (Yes / No) Time to first complete response: time from randomization to first complete response Time to first overall remission: time from date of randomization to first overall remission Recurrence status up to 104 weeks (Yes / No) Time to first relapse: the time from the date of first complete or partial remission to the date of first relapse HRQoL measured using KDQoL-36 and EQ-5D-5L Decrease in eGFR of ≥ 30% from baseline by week 52 and week 104 (Yes / No) The incidence and severity of treatment-related adverse events 7.1.3 Exploratory Endpoints Part 1: Exploratory endpoints are: Pharmacokinetics of zanubrutinib in patients with primary membranous nephropathy Biomarkers potentially associated with the efficacy of zanubrutinib in peripheral blood and / or urine samples, including, but not limited to, autoantibodies, cytokines, gene expression signatures, primary membranous nephropathy-associated gene polymorphisms, and / or other PD biomarkers such as BTK occupancy or BTK-associated immune cell activity Part 2: Exploratory endpoints are: Pharmacokinetics of zanubrutinib in patients with primary membranous nephropathy Immunological response status (Yes / No) at weeks 12, 24, 52, and 104 in patients with positive anti-PLA2R antibodies at baseline Change in serum anti-PLA2R antibody titers from baseline to week 104 Time to immunological response: time from date of randomization to date of immunological response Complete remission status at week 104 based on baseline anti-PLA2R antibody status (Yes / No) Overall remission status at week 104 based on baseline anti-PLA2R antibody status (Yes / No) Biomarkers potentially associated with the efficacy of zanubrutinib in peripheral blood and / or urine samples, including, but not limited to, autoantibodies, cytokines, gene expression signatures, primary membranous nephropathy-associated gene polymorphisms, and / or other PD biomarkers such as BTK occupancy or BTK-associated immune cell activity Patient-reported symptom severity measured by PGI-S 7.2 Statistical analysis 7.2.1 Randomization Method As described in Section 4.4.5, patients in Part 2 will be randomized using permuted block stratified randomization using the study's IRT system. 7.2.2 Analysis Sets The full analysis set includes all randomized patients. Following the intention-to-treat principle, patients are analyzed according to the treatment assigned at randomization. This will be the primary analysis set for the efficacy analysis in Part 2. The safety analysis set includes all patients who received at least one dose of study drug. Patients will be analyzed according to the treatment they actually received. In Part 1, the safety analysis set will be used for all efficacy and safety analyses, and in Part 2, the safety analysis set will be used for all safety analyses. The PK analysis set includes all patients who received at least one dose of study drug per protocol and for whom post-dose PK data were available. 7.2.3 Patient breakdown The number of treated patients, patients who discontinued the study drug and / or study, and patients with important protocol deviations will be counted in both Part 1 and Part 2. The number of randomized patients will also be counted in Part 2. The primary reasons for discontinuation of the study drug and / or study will be summarized according to the categories in the eCRF. Important protocol deviations are summarized and listed by category. 7.2.4 Demographic and other baseline characteristics Demographic and other baseline characteristics will be summarized using descriptive statistics in both Part 1 and Part 2. Continuous variables include age, serum anti-PLA2R Ab titer, blood creatinine, body mass index, eGFR, serum albumin, serum cholesterol, systolic and diastolic blood pressure, time since initial membranous nephropathy diagnosis, weight, and UPCR (based on a 24-hour urine collection). Categorical variables include country, sex, region, and race. Categorical variables, including serum anti-PLA2R Ab positivity and stratification factors, will also be summarized in Part 2. 7.2.5 Prior and Concomitant Therapies Concomitant medications will be coded using World Health Organization (WHO) drug dictionary drug codes. Concomitant medications will be further coded to the appropriate Anatomical Therapeutic Chemical (ATC) code indicating the therapeutic classification. Precursor and concomitant medications will be summarized and listed by drug and drug class. A precursor medication is defined as a medication that was discontinued before the first dose of study drug. A concomitant medication is defined as 1) a medication that was started before the first dose of study drug and was continued at the time of the first dose of study drug, or 2) a medication that was started after the date of first dose of study drug but up to 30 days after the patient's last dose. 7.3 Efficacy Analysis 7.3.1 Primary Efficacy Analysis of Part 1 The mean percent decrease from baseline in UPCR at week 24 will be summarized in the safety analysis set. 7.3.2 Primary Efficacy Analysis of Part 2 7.3.2.1 First-order estimates The first-order estimate is defined in Section 1.2. 7.3.2.2 Primary analysis of primary estimates The statistical null hypotheses to be tested for the primary endpoint are: H 0-1 : The zanubrutinib 160 mg twice-daily group (Group A) was not superior to the tacrolimus group (Group C) in terms of complete remission rate at 104 weeks. H 0-2 : The zanubrutinib 160 mg once-daily group (Group B) was not superior to Group C in terms of complete remission rate at week 104. The complete response rate at week 104 for the entire analysis set will be analyzed using a logistic regression model with treatment group and actual stratification factors as covariates. For comparisons of Arm A vs. Arm C and Arm B vs. Arm C, logistic regression models will be used to calculate odds ratios with 95% confidence intervals and p-values. 7.3.2.3 Handling Missing Data Unrelated to Coincidence If a patient does not have the data necessary to calculate complete response at week 104, the missing data will be entered as the value collected at week 90. ​​If the entered value is still missing, the patient will be considered a non-responder for complete response at week 104. 7.3.2.4 Sensitivity analysis of primary endpoint / estimate Sensitivity analyses will be defined in the statistical analysis plan, if necessary. 7.3.2.5 Supplementary analysis Supplementary analyses will be defined in the statistical analysis plan, as appropriate. 7.3.3 Secondary Efficacy Analyses for Part 1 Treatment failure status up to 24 weeks (Yes / No) Immunological response status at 24 weeks (Yes / No) Complete remission status at weeks 24, 52, 76, and 104 (Yes / No) Overall remission status (Yes / No) at weeks 24, 52, 76, and 104 Recurrence status up to 104 weeks (Yes / No) For the secondary endpoints listed above, the analysis will be similar to the primary analysis. 7.3.4 Secondary Efficacy Analyses in Part 2 Overall remission status at 104 weeks (Yes / No) Complete remission status at 24, 52, and 76 weeks (Yes / No) Overall remission status (Yes / No) at weeks 24, 52, and 76 For the secondary endpoints listed above, the analysis will be similar to the primary analysis. Treatment failure status (Yes / No) at 24, 52, 76, and 104 weeks The number (proportion) of patients who experienced treatment failure by weeks 24, 52, 76, and 104 will be summarized by treatment group. Time to first complete remission: Time from date of randomization to first complete remission Time to first complete remission will be analyzed using the Kaplan-Meier method. Kaplan-Meier survival probabilities will be plotted over time for each treatment group. Hazard ratios with 95% confidence intervals will be calculated for comparisons of groups A vs. C, and B vs. C, using Cox proportional hazards models adjusted for stratification factors. Time to first overall remission: time from date of randomization to first overall remission This analysis was similar to the analysis of time to first complete response. Recurrence status up to 104 weeks (Yes / No) The number (proportion) of patients who relapsed by week 104 will be summarized by treatment group. Time to first relapse: the time from the date of first complete or partial remission to the date of first relapse This analysis was similar to the analysis of time to first complete response. HRQoL measured using KDQoL-36 and EQ-5D-5L Descriptive statistics for all PRs and their measures will be presented for all visits by treatment group. Compliance rates will also be summarized for each visit by treatment group. Mixed model repeated measures (MMRM) analysis will be used to compare the mean change in kidney disease burden and impact from baseline to weeks 24 and 52 as measured by the KDQoL-36. The model includes treatment group, actual stratification factors, and visit as fixed effects, baseline score as a continuous covariate, interaction terms for treatment group by visit and baseline score by visit, and patient as a random effect. Differences between groups A vs. C and B vs. C are shown with 95% confidence intervals and p-values. Decrease in eGFR of ≥30% from baseline by week 52 and week 104 (Yes / No) Analyses of the proportion of patients with a ≥30% decline in eGFR from baseline to weeks 52 and 104 were similar to the primary analysis. 7.3.5 Part 2 Exploratory Efficacy Analyses Immunological response status (Yes / No) at weeks 12, 24, 52, and 104 in patients with positive anti-PLA2R antibodies at baseline The number (percentage) of patients who achieved immunological response at 12, 24, 52, and 104 weeks in patients who were anti-PLA2R antibody positive at baseline will be summarized by treatment group. Change in serum anti-PLA2R antibody titers from baseline to week 104 The mean change in serum anti-PLA2R antibody titers from baseline to week 104 will be summarized by treatment group. Time to immunological response: time from date of randomization to date of immunological response Time to immunological response will be analyzed using the Kaplan-Meier method. Kaplan-Meier survival probabilities for each treatment group will be plotted over time. Complete remission status at week 104 based on baseline anti-PLA2R antibody status (Yes / No) The number (proportion) of patients achieving complete remission at week 104 will be summarized by treatment group and baseline anti-PLA2R antibody status. Overall remission status at week 104 based on baseline anti-PLA2R antibody status (Yes / No) The number (proportion) of patients achieving overall remission at week 104 will be summarized by treatment group and baseline anti-PLA2R antibody status. Patient-reported symptom severity measured by PGI-S Descriptive statistics for PGI-S scores will be presented for all visits by treatment group. Compliance rates will also be summarized for each visit by treatment group. 7.4 Safety analysis Safety will be assessed by monitoring and recording all adverse events. Clinical laboratory values ​​(chemistry, hematology, coagulation, or urinalysis), vital signs, physical examination, and ECG findings will also be used to assess safety. Descriptive statistics will be used to analyze all safety data by actual treatment group in the Part 1 and Part 2 safety analysis sets. 7.4.1 Exposure level The extent of study drug exposure will be summarized descriptively as duration of exposure (days), cumulative total dose per patient (mg), dose intensity (mg / day), and relative dose intensity (%). The number (and percentage) of patients who underwent dose modifications will be summarized for each treatment group, along with the reasons for each. The frequency of dose modifications will be summarized by category. A patient data listing is provided for all administration records and summary statistics are calculated. 7.4.2 Adverse Events Verbatim descriptions of adverse events (recorded by the investigator on the eCRF) will be classified into standardized medical terms using the Medical Dictionary for Reproductive Health (MedDRA). Adverse events will be coded in MedDRA by lowest level term, preferred term, and major system organ class. Treatment-emergent adverse events are defined as adverse events that occur or worsen in severity from baseline (pre-treatment) during or after the first dose of study drug and up to 30 days after discontinuation of study drug. Only treatment-emergent adverse events will be included in summary tables. All adverse events, whether treatment-emergent or not, will be documented in the patient data listing. The incidence of treatment-emergent adverse events is reported as the number (proportion) of patients who experienced a treatment-emergent adverse event by system organ class and preferred term. Patients who experienced multiple treatment-emergent adverse events within an system organ class and preferred term are counted only once, at the most severe level within that system organ class and preferred term. The number (proportion) of patients who experienced treatment-related adverse events is summarized by relationship to study drug. Treatment-related treatment-emergent adverse events include events that the investigator considered to be related to the study drug or events for which causality assessment was missing. Serious adverse events, deaths, treatment-related treatment-emergent adverse events, and treatment-emergent adverse events leading to treatment discontinuation or dose modification are summarized. 7.4.3 Laboratory Analysis Laboratory values ​​(chemistry, hematology, coagulation, or urinalysis) are assessed by treatment group and for each laboratory parameter, as appropriate. Laboratory abnormalities are flagged and identified as values ​​outside (higher or lower than) the normal range. Reference (normal) ranges for laboratory parameters are provided. Descriptive summary statistics (e.g., n, mean, standard deviation, median, minimum, maximum for continuous variables; n [%] for categorical variables) for laboratory parameters and their changes from baseline are calculated. Laboratory values ​​are summarized by visit. Some parameters (e.g., serum anti-PLA2R Ab titer, eGFR, serum albumin, and UPCR [based on a 24-hour urine collection]) are plotted over time. Laboratory parameters graded as mild, moderate, or severe are summarized by severity. In summarizing laboratory parameters by severity, items with both high and low severity are summarized separately. 7.4.4 Vital signs Descriptive statistics for vital sign parameters (temperature, heart rate, systolic and diastolic blood pressure, and weight) and change from baseline will be presented by visit and treatment group. Vital signs will be described by patient and visit. 7.5 Pharmacokinetic Analysis PK samples will be collected to measure zanubrutinib concentrations at the time points specified in Table 9. Plasma concentrations at specific time points for each treatment group and their statistics (e.g., sample size, mean, standard deviation, coefficient of variation, median, minimum, maximum, and geometric mean) may be described in the clinical study report. PK data may be used for additional analyses, such as population PK analyses, and the results of such analyses may be reported separately from the clinical study report. Table 9 is an assessment schedule specifying the various time points at which designated PK samples, peripheral blood and urine samples, will be collected from patients to examine the association of biomarkers with glomerular disease status, disease activity, and response to zanubrutinib. [Table 9] 7.6 Other Exploratory Analyses Exploratory biomarker analysis may be performed to understand the association of these markers with study drug response. 7.7 Multiple Testing Strategies In Part 2, a graphical approach with Bonferroni mixtures of weighted Simes tests is used for multiplicity adjustment, as shown in Figure 2. A one-sided alpha of 0.0125 is initially assigned to each primary null hypothesis. The primary null hypotheses are tested first. The secondary null hypotheses H 0-3 is the corresponding first-order null hypothesis H 0-1 is tested only if H is rejected. 0-4 is H 0-2 is rejected. The arrows in the diagram show how the alpha allocated to a successfully rejected null hypothesis is reallocated to test other hypotheses. The weight of each test path indicates the proportion of saved alpha that is shifted along that path to the accepted hypothesis when the hypothesis at the end of the path is successfully rejected. 7.8 Sample Size Considerations Part 1: Approximately 30 patients will be recruited for Part 1. For data from 30 patients to analyze the decrease in UPCR from baseline to week 24, assuming a standard deviation of 2, if the mean decrease from baseline to week 24 is less than 1.2, the posterior probability of a mean decrease of 1.5 or greater is less than 20%, and discontinuation of the study may be considered along with a comprehensive review of data on other efficacy and safety endpoints. Part 2: Sample size calculations are based on the following assumptions: 1. Complete remission rate at 104 weeks: 5% in group C and 22% in groups A and B 2. Overall remission rate at 104 weeks: 25% in group C and 50% in groups A or B 3. One-sided alpha value 0.025 4. Randomization ratio 1:1:1 With these assumptions, a total of 252 randomized patients are required to achieve approximately 90% power for the target treatment effect of complete remission rate under assumption 1 and 82% power for the target treatment effect of overall remission rate under assumption 2. Simulations were performed using R software, version 3.6.1, to determine the sample size.

[0075] Example 2 1. Research purpose.

[0076] Relevant animal models will be used to study the efficacy and mechanism of zanubrutinib in treating primary membranous nephropathy.

[0077] 2. Overall study design

[0078] In this study, we used two animal models of passive Heymann nephritis and genetically modified mice to investigate whether zanubrutinib can alleviate the nephritic state in animals and explore the possible mechanism of zanubrutinib in the treatment of membranous nephropathy (MN). The experimental research plan included establishing nephritic disease models, using zanubrutinib and control drugs to treat the disease models, and collecting and testing blood, urine, tissue, and other samples in the disease models.

[0079] 3. Animal Experiment Procedures

[0080] 3.1 Passive Heymann nephritis rat model

[0081] 3.1.1 Establishment of a passive Heymann nephritis (HN) rat model

[0082] Five-week-old male Sprague-Dawley rats (Viton Lever Laboratory Animal Technology Co, Ltd.) weighing approximately 130-180 g were injected with 0.8 ml / 100 g of sheep anti-Fx1A antibody serum (Potobetex, USA) via a single tail vein to establish the MN mouse model.

[0083] 3.1.2 Experimental design of intervention therapy

[0084] Forty-eight rats were divided into six groups, eight rats per group. Five groups were used as nephritis model rats, and the sixth group served as a negative control group, injected with the same volume of sterile saline. Simultaneously with disease induction, rats received different treatments orally from day 0 until sacrifice on day 42. The disease control group (Group 1) received normal saline; the low-dose zanubrutinib group (Group 2) received 0.3 mg / kg / d twice daily (BID); the medium-dose group (Group 3) received 3 mg / kg / d twice daily (BID); the medium and high-dose groups (Group 4) received 30 mg / kg / d twice daily (BID); and the drug control group (Group 5) received Cromos once daily. The zanubrutinib treatment groups (Groups 2–4) received treatments twice daily, separated by at least 8 hours. The disease control group (Group 1) and drug control group (Group 5) will receive a single injection of saline or tacrolimus once daily.

[0085] For each treatment group (Groups 2-4), 80 μL of whole blood was collected from each rat (24 rats in total) at seven time points: Day 0 and Day 7, before each zanubrutinib administration (recorded as Time 0), and 0.5, 1, 2, 4, 8, and 24 hours after administration. At least 30 μL of plasma was placed in a refrigerated storage vial marked with the group number and time point and stored at -80°C. The pharmacokinetics of zanubrutinib was measured by liquid chromatography-mass spectrometry.

[0086] 3.1.3 Intervention effect of zanubrutinib

[0087] 3.1.3.1 Rat urine and blood samples will be collected weekly, and their body weights will be recorded. 24-hour proteinuria, serum creatinine, blood urea nitrogen, albumin, cholesterol or triglycerides, liver enzymes (AST, ALT), cardiac enzymes (CK / CK-MB, LDH), circulating specific anti-sheep IgG, and total IgG levels will be detected to assess the severity of the disease in the rats.

[0088] 3.1.3.2 After the experiment, fresh lymph nodes and spleens of the rats will be collected, lymphocytes will be extracted, and T cell and B cell subsets will be detected by flow cytometry to evaluate autoimmune activation.

[0089] 3.1.3.3 After the experiment, the kidney tissues of the rats are separated and some kidney tissues are collected to detect the ultrastructural lesions of the renal podocytes and basement membrane, and the staining of renal immunoglobulins and complement molecules is detected by electron microscopy, immunofluorescence, immunohistochemistry, etc. to evaluate kidney damage.

[0090] 3.1.3.4 According to the actual therapeutic effects and the experimental results of the above sections, consider whether it is necessary to extract proteins and RNA from some fresh kidney tissues for proteomics, RNA-seq detection of renal cortical cytokines, and changes in pathway proteins.

[0091] 3.2 PLA2R transgenic mouse model

[0092] 3.2.1 Construction of PLA2R transgenic MN mouse model

[0093] A single tail vein injection of rabbit anti-human PLA2R antibody serum was administered to 5-week-old PLA2R transgenic mice to establish the MN mouse model.

[0094] 3.2.2 Experimental design for each group

[0095] Four groups (groups 1 to 3 each with six rats) were set up to construct the MN model. The disease control group (group 1) received saline, the drug control group (group 2) received tacrolimus by oral gavage starting on day 0, and the zanubritinib group (group 3) received zanubritinib by intragastric administration starting on day 0. zanubritinib (at the dose tested in the Heymann nephritis rat model) was administered continuously daily from day 0. In the negative control group (group 4), four rats were administered the same volume of sterile saline and observed until sacrificed. A total of 22 rats were used.

[0096] 3.2.3 Intervention effect of zanubrutinib

[0097] 3.2.3.1 Collect urine and blood samples from mice weekly to assess the severity of the disease by detecting 24-hour proteinuria, serum creatinine, blood urea nitrogen, albumin, cholesterol or triglycerides, liver enzymes, and myocardial enzymes.

[0098] 3.2.3.2 Mice will be sacrificed and kidney tissue will be collected. Ultrastructural lesions of the renal podocytes and basement membrane will be detected by electron microscopy, immunofluorescence, and immunohistochemistry, and renal damage will be assessed using staining for immunoglobulins and complement molecules.

[0099] 3.2.3.3 Fresh lymph nodes and spleens will be harvested, lymphocytes extracted, and flow cytometry of T and B cell subsets will be performed to assess autoimmune activation.

[0100] 3.2.3.4 Using fresh spleens, explore the mechanism of zanubrutinib's treatment of MN through proteomics and RNA-seq experiments in terms of its inhibition of B cell development and maturation, reduction of specific antibody production, inhibition of immune response, and reduction of complement-level response activation.

[0101] Example 3 As used herein, the solid form of Compound A is Form A of Compound 1 of WO2018 / 033853.

[0102] A number of references have been cited, the disclosures of which are incorporated herein by reference in their entireties.

Claims

1. 1. A method for treating primary membranous nephropathy (pMN), comprising administering to a patient having primary membranous nephropathy a therapeutically effective amount of a Bruton's tyrosine kinase (BTK) inhibitor.

2. The Bruton's tyrosine kinase inhibitor has the name (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or Compound A having the following structure: 【Chemistry 4】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof.

3. 3. The method of claim 2, wherein the patient is identified as having renal tissue comprising (i) elevated levels of autoantibodies specific to an antigen, or (ii) elevated levels of an antigen, wherein the antigen is PLA2R, or THSD7A.

4. The method of any one of claims 1 to 3, wherein the patient is identified with primary membranous nephropathy on biopsy and with persistent nephrotic syndrome after a run-in period.

5. The method of any one of claims 1 to 4, wherein the patient is identified as having elevated levels of the autoantibody.

6. 6. The method of any one of claims 1 to 5, wherein the level of autoantibodies present in the patient is reduced by at least about 5%, at least about 25%, or at least about 50% after the administering step.

7. The method of any one of claims 3 to 6, wherein the antigen is PLA2R.

8. 8. The method of claim 7, wherein the patient is a PLA2R-mediated patient with primary membranous nephropathy.

9. 8. The method of claim 7, wherein the level of autoantibodies specific to PLA2R is greater than or equal to about 20 RU / mL, about 40 RU / mL, about 50 RU / mL, about 60 RU / mL, or about 80 RU / mL in serum before the administration step.

10. The method according to any one of claims 3 to 6, wherein the antigen is THSD7A.

11. 11. The method of claim 10, wherein the patient is a THSD7A-mediated patient with primary membranous nephropathy.

12. The method of any one of claims 1 to 3, wherein the patient is identified as having kidney tissue containing elevated levels of the antigen.

13. 13. The method of claim 12, wherein the level of antigen present in kidney tissue is reduced by at least about 5%, at least about 25%, or at least about 50% after the administering step.

14. The method of any one of claims 1 to 3 and 11 to 13, wherein the antigen is PLA2R.

15. The method according to any one of claims 1 to 3 and 11 to 13, wherein the antigen is THSD7A.

16. 16. The method of any one of claims 2 to 15, wherein Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof, is administered once, twice, or three times daily.

17. 17. The method of any one of claims 2 to 16, wherein Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof, is administered at about 40 mg to about 320 mg per day.

18. 18. The method of claim 17, wherein Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof is administered at about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, or about 320 mg per day.

19. 19. The method of claim 18, wherein Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof, is administered at about 40 mg, about 80 mg, about 160 mg, or about 320 mg per day.

20. 20. The method of claim 19, wherein the method comprises administering to the patient Compound A twice daily (BID) at a dose of about 160 mg, or once daily (QD) at a dose of about 160 mg.

21. 20. The method of claim 19, wherein the method comprises orally administering to the patient Compound A twice daily (BID) at a dose of about 160 mg, or once daily (QD) at a dose of about 160 mg.

22. 20. The method of claim 19, wherein the method comprises orally administering to the patient Compound A at a dose of about 160 mg twice daily (BID).

23. 20. The method of claim 19, wherein the method comprises orally administering to the patient Compound A at a dose of about 160 mg once daily (QD).

24. The method of any one of claims 1 to 20, wherein the patient achieves a partial or complete response.

25. 25. The method of claim 24, wherein the patient achieves a partial response.

26. 25. The method of claim 24, wherein the patient achieves a complete remission.

27. the method comprising administering to the subject an AUC of Compound A in plasma of about 1,607 ng*h / ml to about 2,984 ng*h / ml. ０－２４ｈ The method of any one of claims 1 to 20, wherein

28. the method comprising administering to the subject an AUC of Compound A in plasma of about 843 ng*h / ml to about 3,786 ng*h / ml. ０－∞ The method of any one of claims 1 to 20, wherein

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