Combination of endothelin receptor antagonist and glucocorticoid for treating IgA nephropathy

Abstract

Methods for treating IgA nephropathy and pharmaceutical compositions comprising an endothelin receptor antagonist and a glucocorticoid.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition of an endothelin receptor antagonist and a glucocorticoid for IgA nephropathy and the use of said endothelin receptor antagonist and glucocorticoid in preparing a pharmaceutical composition or kit for treating IgA nephropathy. [Background technology]

[0002] IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and a leading cause of chronic kidney disease and end-stage renal disease (ESRD). While 15%–20% of patients with IgA nephropathy develop end-stage kidney disease (ESKD) within 10 years of disease onset, 30%–40% of patients will develop ESKD within 20 years of disease onset. The incidence of IgAN is particularly high in China. Pathologically, IgAN is characterized by the deposition of circulating immune complexes composed of galactose-deficient IgA1 antibodies and glycan-specific IgG antibodies, which induce mesangial cell activation and inflammatory responses in the renal glomeruli, leading to renal tissue cell damage. IgG-Gd-IgA1 deposits in the mesangial region of renal glomeruli, triggering an inflammatory cascade including local secretion of chemokines, cytokines, and reactive oxygen species, as well as complement activation. This leads to glomerular mesangial cell proliferation, inflammatory cell recruitment, and crescent formation, which can further damage proximal renal tubular epithelial cells and result in tubulointerstitial fibrosis. Patients present with a variety of symptoms, often including microscopic or gross hematuria and proteinuria. Patients may also develop hypertension due to ongoing renal damage. A significant number of patients will develop end-stage renal disease (ESRD) within 10 to 20 years of IgAN diagnosis. During this period, in addition to declining renal function, patients experience a variety of symptoms that significantly reduce their quality of life.

[0003] As described in WO 2021126977A1, atrasentan is a selective endothelin A receptor (ETA) small molecule antagonist, and its use in the treatment of immunoglobulin A nephropathy (IgAN) is currently being studied by Chinook Therapeutics.

[0004] The use of surrogate clinical endpoints has significantly accelerated the development of innovative drugs, but selecting a research endpoint for kidney disease is challenging. Because it takes an average of 20 years for IgAN to develop uremia, observing drug efficacy requires a large sample size and 20 years of follow-up. While this is clearly unrealistic, the emergence of surrogate endpoints can address this issue to some extent. The KDIGO guidelines recommend that a reduction in proteinuria to <1 g / day is a surrogate marker of improved renal prognosis in IgAN and that a reduction to <1 g / day is a reasonable treatment goal. Proteinuria levels are often used as surrogate endpoints in clinical studies and are already widely incorporated into research designs for new drugs for the treatment of IgA nephropathy. In December 2021, the FDA approved Calliditas Therapeutics' new drug TARPEYO® (budesonide) for the treatment of IgA nephropathy, marking the first approval based on a surrogate clinical endpoint: a reduction in proteinuria. Summary of the Invention

[0005] It is an object of the present invention to overcome the limitations of drug treatments by providing more effective combination therapies and corresponding pharmaceutical compositions and kits for treating IgA nephropathy.

[0006] In order to solve the technical problems of the present invention, the present invention is implemented by the following technical solutions:

[0007] A method for treating IgA nephropathy in a subject in need thereof, comprising administering to the subject effective amounts of an endothelin receptor antagonist and a glucocorticoid, wherein the endothelin receptor antagonist and the glucocorticoid may be administered separately in a single dosage form or sequentially.

[0008] In a preferred technical solution of the present invention, the endothelin receptor antagonist is selected from any one of tezosentan, sparsentan, bosentan, macitentan, ambrisentan, sitaxsentan, aprocitentan and atrasentan or their pharmaceutically acceptable salts, or any combination thereof.

[0009] In a preferred technical solution of the present invention, the endothelin receptor antagonist is selected from atrasentan or a pharmaceutically acceptable salt thereof.

[0010] In a preferred technical solution of the present invention, the glucocorticoid is selected from any one of dexamethasone, betamethasone, fluorometholone, prednisone, prednisolone, methylprednisolone, hydrocortisone, fluocinolone, fluticasone, mometasone, loteprednol etabonate, rimexalone, fluticasone, beclomethasone, ciclesonide, budesonide, triamcinolone acetonide, prednicarbate, butixocort, tipredane and tixocortol or their pharmaceutically acceptable salts or any combination thereof.

[0011] In a preferred technical solution of the present invention, the glucocorticoid is selected from budesonide and methylprednisolone or their pharmaceutically acceptable salts.

[0012] In a preferred technical solution of the present invention, the endothelin receptor antagonist is administered in a dosage form given orally, buccally or parenterally. For example, the oral dosage form may be a tablet, capsule, powder, pill, granule, suspension, solution and solution preconcentrate or emulsion and emulsion preconcentrate, and the parenteral dosage form may be, for example, a dosage form administered intravenously, intraperitoneally, intradermally, subcutaneously, intramuscularly, intracranially, intrathecally, intratumorally, transdermally or transmucosally.

[0013] In a preferred technical solution of the present invention, the endothelin receptor antagonist is administered once or twice a day, or the endothelin receptor antagonist is administered once every 2, 3, 4, 5, 6, 7, 8, 9, or 10 days, or once every 1, 2, or 3 weeks, or the endothelin receptor antagonist is administered once a day for 5 consecutive days per week, followed by an interval of 2 days.

[0014] In a preferred technical solution of the present invention, the endothelin receptor antagonist is administered to a subject at an effective dose of about 0.5 to about 250 mg / kg, 1 to about 250 mg / kg, about 2 to about 200 mg / kg, about 3 to about 120 mg / kg, about 5 to about 250 mg / kg, about 10 to about 200 mg / kg, or about 20 to about 120 mg / kg.

[0015] In a preferred technical solution of the present invention, the glucocorticoid is administered in a dosage form given orally, bucally or parenterally. For example, oral dosage forms may be tablets, capsules, powders, pills, granules, suspensions, solutions and solution preconcentrates or emulsions and emulsion preconcentrates, and parenteral dosage forms may be, for example, dosage forms administered intravenously, intraperitoneally, intradermally, subcutaneously, intramuscularly, intracranially, intrathecally, intratumorally, transdermally or transmucosally.

[0016] In the preferred technical solutions of the present invention, the glucocorticoid is administered once or twice a day, or the glucocorticoid is administered once every 2, 3, 4, 5, 6, 7, 8, 9 or 10 days, or once every 1, 2 or 3 weeks, or the glucocorticoid is administered once a day for 5 consecutive days per week, followed by an interval of 2 days.

[0017] In a preferred technical solution of the present invention, the glucocorticoid is administered to the subject at an effective dose of about 0.5 to about 250 mg / kg, 1 to about 250 mg / kg, about 2 to about 200 mg / kg, about 3 to about 120 mg / kg, about 5 to about 250 mg / kg, about 10 to about 200 mg / kg, or about 20 to about 120 mg / kg.

[0018] In a preferred embodiment of the invention, the method may optionally further comprise administering to the subject an effective amount of a third therapeutically active agent.

[0019] In a preferred technical solution of the present invention, the third therapeutically active substance is selected from SGLT-2 inhibitors.

[0020] In a preferred technical solution of the present invention, the SGLT-2 inhibitor is selected from any one of empagliflozin, canagliflozin, remogliflozin, ipragliflozin, HM41322, dapagliflozin, bexagliflozin, ertugliflozin, sotagliflozin, luseogliflozin and tofogliflozin, or any combination thereof.

[0021] In a preferred technical solution of the present invention, the SGLT-2 inhibitor is administered in a dosage form given orally, bucally or parenterally. For example, oral dosage forms may be tablets, capsules, powders, pills, granules, suspensions, solutions and solution preconcentrates or emulsions and emulsion preconcentrates, and parenteral dosage forms may be, for example, dosage forms administered intravenously, intraperitoneally, intradermally, subcutaneously, intramuscularly, intracranially, intrathecally, intratumorally, transdermally or transmucosally.

[0022] In the preferred technical solutions of the present invention, the SGLT-2 inhibitor is administered once or twice a day, or the SGLT-2 inhibitor is administered once every 2, 3, 4, 5, 6, 7, 8, 9 or 10 days or once every 1, 2 or 3 weeks, or the SGLT-2 inhibitor is administered once a day for 5 consecutive days per week, followed by an interval of 2 days.

[0023] In a preferred technical solution of the present invention, the SGLT-2 inhibitor is administered to the subject at an effective dose of about 0.5 to about 250 mg / kg, 1 to about 250 mg / kg, about 2 to about 200 mg / kg, about 3 to about 120 mg / kg, about 5 to about 250 mg / kg, about 10 to about 200 mg / kg, or about 20 to about 120 mg / kg.

[0024] In a preferred technical solution of the present invention, the third therapeutically active substance is selected from APRIL neutralizing antibodies.

[0025] In a preferred technical solution of the present invention, the APRIL neutralizing antibody is the BION-1301 monoclonal antibody.

[0026] In a preferred technical solution of the present invention, the APRIL neutralizing antibody is formulated into a solution or a lyophilized agent.

[0027] In a preferred technical solution of the present invention, when the APRIL neutralizing antibody is administered as an intravenous injection, the pH is 5 to 8, preferably 5.5, the concentration of the buffer solution is 1 to 50 mM, preferably 5 to 40 mM, more preferably 10 to 20 mM, the buffer solution is preferably a histidine buffer solution, the concentration of the APRIL neutralizing antibody is 10 to 60 mg / mL, preferably 20 to 50 mg / mL, more preferably 25 mg / mL, the concentration of sucrose is 1 to 10% (w / v), preferably 2 to 8% (w / v), and the concentration of polysorbate 80 is 0.01% to 1% (w / v), preferably 0.01% to 1% (w / v).

[0028] In a preferred technical solution of the present invention, the APRIL neutralizing antibody is administered once every 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days or once every 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks, or the APRIL neutralizing antibody is administered once a day for 5 consecutive days in a week, followed by an interval of 2 days.

[0029] In a preferred technical solution of the present invention, the APRIL neutralizing antibody is administered at an effective dose of 0.05 mg / kg, 0.1 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg or 8 mg / kg.

[0030] Additionally, the present invention further provides a pharmaceutical composition comprising effective amounts of an endothelin receptor antagonist and a glucocorticoid, wherein the endothelin receptor antagonist and the glucocorticoid can be administered separately or sequentially in a single dosage form.

[0031] In a preferred technical solution of the present invention, the endothelin receptor antagonist can be formulated into a dosage form for oral, buccal or parenteral administration. For example, the oral dosage form can be a tablet, capsule, powder, pill, granule, suspension, solution and solution preconcentrate or emulsion and emulsion preconcentrate, and the parenteral dosage form can be, for example, a dosage form for intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, transdermal or transmucosal administration, such as a solution or lyophilized agent; and / or

[0032] The glucocorticoid may be formulated into a dosage form for parenteral administration, for example, intravenously, intraperitoneally, intradermally, subcutaneously, intramuscularly, intracranially, intrathecally, intratumorally, transdermally, or transmucosally, and may be, for example, a solution or a lyophilized agent.

[0033] In a preferred technical solution of the present invention, the endothelin receptor antagonist is selected from any one of tezosentan, sparsentan, bosentan, macitentan, ambrisentan, sitaxsentan, aprocitentan and atrasentan or their pharmaceutically acceptable salts, or any combination thereof.

[0034] In a preferred technical solution of the present invention, the endothelin receptor antagonist is selected from atrasentan or a pharmaceutically acceptable salt thereof.

[0035] In a preferred technical solution of the present invention, the glucocorticoid is selected from any one of dexamethasone, betamethasone, fluorometholone, prednisone, prednisolone, methylprednisolone, hydrocortisone, fluocinolone, fluticasone, mometasone, loteprednol etabonate, rimexalone, fluticasone, beclomethasone, ciclesonide, budesonide, triamcinolone acetonide, prednicarbate, butixocort, tipredane and tixocortol or their pharmaceutically acceptable salts or any combination thereof.

[0036] In a preferred technical solution of the present invention, the glucocorticoid is selected from budesonide and methylprednisolone or their pharmaceutically acceptable salts.

[0037] In a preferred technical solution of the present invention, each unit dosage form contains an endothelin receptor antagonist at a dose of 1 to 1000 mg, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 250, 300, 350, 400, 450, 500, 600, 700, 750, 800, 900, 1000 mg, or a value between any two of the above values.

[0038] In a preferred technical solution of the present invention, each unit dosage form contains 1 to 5000 mg, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 250, 300, 350, 400, 550, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1250, 1300, 1400, 1500, 1600, 1700, 1750, 1800, 1900, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 7000, 7500, 8000, 8000, 9000, 10000, 11000, 12000, 13000, 14000, 15000, 16000, 17000, 17500, 18000, 19000, 20000, 25000, 30000, 35 2000, 2200, 2400, 2500, 2600, 2700, 2750, 2800, 3000, 3500, 4000, 4500, 5000 mg or a value between any two of the above values.

[0039] In a preferred technical solution of the present invention, the pharmaceutical composition may also optionally contain an effective amount of a third therapeutically active substance.

[0040] In a preferred technical solution of the present invention, the third therapeutically active substance is selected from SGLT-2 inhibitors.

[0041] In a preferred technical solution of the present invention, the SGLT-2 inhibitor is selected from any one of empagliflozin, canagliflozin, remogliflozin, ipragliflozin, HM41322, dapagliflozin, bexagliflozin, ertugliflozin, sotagliflozin, luseogliflozin and tofogliflozin, or any combination thereof.

[0042] In a preferred technical solution of the present invention, the SGLT-2 inhibitor is selected from dapagliflozin.

[0043] In a preferred technical solution of the present invention, each unit dosage form contains an SGLT-2 inhibitor at a dose of 1 to 1000 mg, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 250, 300, 350, 400, 450, 500, 600, 700, 750, 800, 900, 1000 mg or a value between any two of the above values.

[0044] In a preferred technical solution of the present invention, the third therapeutically active substance is selected from APRIL neutralizing antibodies.

[0045] In a preferred technical solution of the present invention, the APRIL neutralizing antibody is the BION-1301 monoclonal antibody.

[0046] In a preferred technical solution of the present invention, each unit dosage form contains 1 to 5000 mg, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 250, 300, 350, 400, 550, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1250, 1300, 1400, 1500, 1600, 1700, 1750, 1800, 1900, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 7000, 7500, 8000, 8000, 9000, 10000, 11000, 12000, 13000, 14000, 15000, 16000, 17000, 17500, 18000, 19000, 20000, 25000, 30000, 35 00, 450, 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2400, 2500, 2600, 2700, 2750, 2800, 3000, 3500, 4000, 4500, 5000 mg or a value between any two of the above values.

[0047] In a preferred technical solution of the present invention, when the APRIL neutralizing antibody is administered as an intravenous injection, the pH is 5 to 8, preferably 5.5, the concentration of the buffer solution is 1 to 50 mM, preferably 5 to 40 mM, more preferably 10 to 20 mM, the buffer solution is preferably a histidine buffer solution, the concentration of the APRIL neutralizing antibody is 10 to 60 mg / mL, preferably 20 to 50 mg / mL, more preferably 25 mg / mL, the concentration of sucrose is 1 to 10% (w / v), preferably 2 to 8% (w / v), and the concentration of polysorbate 80 is 0.01% to 1% (w / v), preferably 0.01% to 1% (w / v).

[0048] Additionally, the present invention further provides a pharmaceutical kit containing any of the above pharmaceutical compositions of the present invention and instructions for use. [Brief explanation of the drawings]

[0049] [Figure 1] Figure 1: Renal glomerular changes in mice before and after IgAN modeling. [Figure 2] Figure 2: Changes in mouse hIgA1, IgG, IgM, etc. before and after IgAN modeling. [Figure 3] Figure 3-1, Figure 3-2: Comparison of changes in hlgA1 index in IgAN mice administered blank control (Ctrl), atrasentan (A), methylprednisolone (MP), a combination of atrasentan (A) + methylprednisolone (MP), or a combination of atrasentan (A) + methylprednisolone (MP) + dapagliflozin (Dapa). [Figure 4] Figure 4-1, Figure 4-2: Comparison of changes in IgG index in IgAN mice administered blank control (Ctrl), atrasentan (A), methylprednisolone (MP), a combination of atrasentan (A) + methylprednisolone (MP), or a combination of atrasentan (A) + methylprednisolone (MP) + dapagliflozin (Dapa). [Figure 5]Figure 5-1, Figure 5-2: Comparison of changes in IgM index in IgAN mice administered blank control (Ctrl), atrasentan (A), methylprednisolone (MP), a combination of atrasentan (A) + methylprednisolone (MP), or a combination of atrasentan (A) + methylprednisolone (MP) + dapagliflozin (Dapa). DETAILED DESCRIPTION OF THE INVENTION

[0050] Definitions of terms: Unless otherwise specified herein, terms used herein have their conventional meaning in the art to which they belong.

[0051] "Treating" or "treatment" refers to reducing, inhibiting, and / or reversing the progression of a disease in a subject in need thereof. The term "treatment" includes any indicator of successful treatment or improvement of a disease, including any objective or subjective parameter, such as alleviation, reduction, or reduction of symptoms, or making an injury, condition, or disorder more tolerable to a subject, or slowing or retarding the rate of progression. Measurement of treatment or improvement may be based, for example, on the results of physical, pathological, and / or diagnostic tests known in the art. For example, in one embodiment, "treating" IgA nephropathy as contemplated by the present invention refers to treating a subject with IgA nephropathy using a combination of an endothelin receptor antagonist and a glucocorticoid to achieve at least one positive therapeutic outcome.

[0052] Treatment can also refer to reducing the risk of disease onset or attack or reducing disease recurrence (e.g., prolonging the time until recurrence) compared to what would occur if no treatment was administered. In the medical field, treatment is also known as "prophylaxis."

[0053] The term "effective amount" or "therapeutically effective amount" refers to an amount effective to treat a disease, as documented through clinical trials and evaluations, patient observations, and the like. "Effective amount" may further refer to an amount that causes a detectable change in biological or chemical activity. A detectable change can be detected and / or further quantified by a person skilled in the art who is familiar with the relevant mechanism or methodology. Additionally, "effective amount" may refer to an amount that maintains a desired physiological state (i.e., reduces or prevents a significant deterioration of the state and / or promotes improvement of the state). "Effective amount" may further refer to a therapeutically effective amount.

[0054] In some embodiments, the endothelin receptor antagonist is administered to a subject in an effective amount. Effective doses are typically 0.01 mg / kg to 500 mg / kg of body weight per day. In some embodiments, pharmaceutically acceptable compositions can be formulated to provide a dose of 0.01 mg / kg to 200 mg / kg of body weight or 0.01 mg / kg to 100 mg / kg of body weight per day to a subject receiving these compositions (e.g., a dose of 0.75 mg to 7.5 g or 15 g for a 75 kg human). In certain embodiments, the active pharmaceutical ingredient of the present invention is formulated to provide a dose of 0.01 mg / kg to 70 mg / kg of body weight (e.g., a dose of 0.75 mg to 5.25 g for a 75 kg human).

[0055] In some embodiments, an effective dose of the endothelin receptor antagonist is about 0.5 to about 250 mg / kg, 1 to about 250 mg / kg, about 2 to about 200 mg / kg, about 3 to about 120 mg / kg, about 5 to about 250 mg / kg, about 10 to about 200 mg / kg, or about 20 to about 120 mg / kg. In some embodiments, effective doses include about 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg, 20 mg / kg, 25 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 75 mg / kg, 100 mg / kg, 120 mg / kg, 150 mg / kg, 175 mg / kg, 200 mg / kg, 225 mg / kg, 250 mg / kg, and 300 mg / kg. The dosage form can take a variety of suitable forms, such as tablets or capsules, and the effective dose can be provided in one or more unit dosage forms (e.g., tablets or capsules) and administered one, two, or three times daily, or at, for example, 4-, 8-, or 12-hour intervals throughout the day. A tablet or capsule can contain, for example, 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, or 1,250 mg of the compound. For example, in some embodiments, administration of an endothelin receptor antagonist to a human subject can include a daily dose of the endothelin receptor antagonist in the range of 100-1,250, 150-1,000, 200-800, or 250-750 mg. The daily dose can be administered once a day as a whole or in multiple doses administered at regular intervals throughout the day. Liquid formulations can also be prepared, allowing for easy and convenient dispensing of any dosage.

[0056] Antibodies are typically mixed with a pharmaceutically acceptable, non-toxic carrier material (e.g., saline or phosphate-buffered saline) prior to administration and may be administered using any medically appropriate procedure, including, but not limited to, intravenous or intraarterial administration and injection into the cerebrospinal fluid.

[0057] In some embodiments, an effective dose of antibody is about 5 to about 250 mg / kg, about 10 to about 200 mg / kg, or about 20 to about 120 mg / kg. In some embodiments, effective doses include 5 mg / kg, 10 mg / kg, 20 mg / kg, 25 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 75 mg / kg, 100 mg / kg, 120 mg / kg, 150 mg / kg, 175 mg / kg, 200 mg / kg, 225 mg / kg, 250 mg / kg, and 300 mg / kg. Dosage forms may be, for example, tablets or capsules, and an effective dose may be provided in one or more tablets or capsules, once daily or at intervals throughout the day, for example, at 4-, 8-, or 12-hour intervals. Tablets or capsules can contain, for example, 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1,000 mg of antibody. Liquid formulations can also be prepared, allowing for easy and convenient dispensing of any dosage.

[0058] In some embodiments, the antibody is administered to a subject in an effective amount. Effective doses are typically 0.01 mg / kg to 500 mg / kg of body weight per day. In some embodiments, pharmaceutically acceptable compositions can be formulated so that 0.01 mg / kg to 200 mg / kg of body weight or 0.01 mg / kg to 100 mg / kg of body weight per day can be administered to a patient receiving these compositions (e.g., a dose of 0.75 mg to 7.5 g or 15 g for a 75 kg human). In certain embodiments, compositions of the invention are formulated to provide a dose of 0.01 mg / kg to 70 mg / kg of body weight (e.g., a dose of 0.75 mg to 5.25 g for a 75 kg human).

[0059] An effective amount of an antibody can be, for example, 0.05 mg / kg, 0.1 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, or 8 mg / kg per dose (e.g., a dose of 3.75 mg to 600 mg for a 75 kg human).

[0060] The antibody dose can be administered once, twice, three times, four times, five or more times per week, once per week, once every two weeks, or even once every three weeks during the course of treatment. Administration can be once daily, once every two days, once every three days, once every four days, once every five days, once per week, once every two weeks, or once every three weeks. Formulations containing the antibody can be prepared to allow for easy and convenient dispensing of any dosage.

[0061] The term "subject" refers to a mammalian subject, particularly a human subject, including a male or female subject, and may be a neonate, infant, toddler, adolescent, adult, or geriatric subject, and further includes various human races and ethnicities, e.g., Caucasian, African, and Asian. As used herein, the subject is afflicted with IgA nephropathy.

[0062] The term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic or organic acid salt of a compound. These salts can be prepared in situ during the final isolation and purification of the compound or by reacting the purified free form of the compound with a suitable organic or inorganic acid, respectively, and isolating the salt thus formed. Representative acid salts include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, dextro-camphorsulfonate, citrate, cyclosulfonate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, hydroxybenzo ... phosphate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, glycolate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinafoate. In one embodiment, the pharmaceutically acceptable salt is a hydrochloride / chloride salt.

[0063] As used herein, the term "pharmaceutically acceptable" refers to the types generally accepted by those skilled in the pharmaceutical arts, e.g., pharmaceutically acceptable salts, pharmaceutically acceptable carriers, etc.

[0064] "Oral dosage form" refers to a pharmaceutical preparation prepared for administration to an individual via the oral administration route. Examples of known oral dosage forms include, but are not limited to, tablets, capsules, powders, pills, granules, suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates, etc. In some cases, for example, to achieve higher stability in the gastrointestinal tract or to achieve a desired release rate, powders, pills, granules, capsules, and tablets can be coated with a suitable polymer or conventional coating material. In addition, the capsule shell of powders, pills, or granules can be further coated. Tablets can be scored to facilitate administration.

[0065] When the endothelin receptor antagonist or glucocorticoid of the present invention is administered as an oral preparation, it is preferably film-coated. Suitable films are known in the art and are commercially available or can be prepared according to known methods. Typically, film-coating materials include hydrophilic polymers such as polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, hydroxymethyl cellulose, and hydroxypropyl methyl cellulose. Components of the film-coating composition may include conventional amounts of plasticizers such as polyethylene glycol, triethyl citrate, diethyl phthalate, propylene glycol, and glycerin, opacifiers such as titanium dioxide, and colorants such as iron oxide and aluminum lake. Typically, the film-coating material is applied in an amount that provides a film coating covering, for example, 1% to 6% of the solid oral dosage form.

[0066] When the endothelin receptor antagonist of the present invention is administered as an oral preparation, it may optionally further comprise at least one pharmaceutically acceptable carrier used in pharmaceuticals. "Pharmaceutically acceptable carrier" refers to any pharmaceutically inactive material that is substantially inert and forms a substantial part of the formulation. Examples of such carriers include, but are not limited to, diluents and fillers, disintegrants, glidants, binders, stabilizers, colorants, flavoring agents, and preservatives.

[0067] As diluents, examples of options include, but are not limited to, microcrystalline cellulose, mannitol, powdered sugar, compressible sugar, dextran, dextrin, dextrose, lactose, cellulose powder, sorbitol, sucrose, and talc, or combinations thereof. The diluent may be 5% to 90%, preferably 10% to 80%, 20% to 70%, 30% to 60%, or 40% to 50% of the total weight of the oral preparation.

[0068] Disintegrants, examples of options include, but are not limited to, cellulose, alginic acid, gums, cross-linked polymers such as cross-linked polyvinylpyrrolidone or crospovidone, croscarmellose sodium, croscarmellose calcium, soy polysaccharides, sodium starch glycolate, guar gum, or any combination thereof.

[0069] In this case, the disintegrant may be present in an amount of about 1% to 15%, preferably 2% to 10%, based on the total weight of the oral preparation.

[0070] Examples of binder options include, but are not limited to, starch, cellulose or its derivatives, such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropyl methyl cellulose, sucrose, dextrose, corn syrup, polysaccharides, gelatin, or any combination thereof, in which case the binder may be present in an amount of 0.01 to 10%, preferably 1% to 10%, based on the total weight of the preparation.

[0071] Glidant options include, but are not limited to, colloidal silica, magnesium trisilicate, cellulose powder, talc, or combinations thereof. The glidant may be present in an amount of 0.1% to 10%, preferably 0.1% to 0.5%, based on the total weight of the composition.

[0072] Unless otherwise specified, the terms "comprising" and "including" as used herein mean an open-ended and non-limiting inclusion. For example, in addition to the pharmaceutical combination formed by the endothelin receptor antagonist and APRIL neutralizing antibody of the present invention, other therapeutic agents such as "biological agents" and "chemotherapeutic agents" may also be included.

[0073] The choice of dosing regimen for the combination therapy of the present invention depends on factors such as the subject's serum or tissue turnover rate, the level of symptoms, overall immunogenicity, and the accessibility of target cells, tissues, or organs in the individual being treated. Preferably, the dosing regimen maximizes the amount of each therapeutic agent delivered to the patient without compromising acceptable side effect levels. Thus, the dosage and frequency of administration of each biologic and chemotherapeutic agent in the combination therapy will depend in part on the specific therapeutic agent, the severity of the IgA nephropathy being treated, and the characteristics of the patient.

[0074] Sequential administration is particularly useful when the therapeutic agents in the combination therapy are administered in different dosage forms (e.g., one active agent is oral and the other active agent is a sterile solution) and / or in different dosing regimens (e.g., an endothelin receptor antagonist is administered as the active ingredient at least daily, while an APRIL neutralizing antibody is administered less frequently, e.g., weekly, biweekly, or every three weeks).

[0075] WO2016110587A1 describes the sequence and preparation of the BION-1301 monoclonal antibody, which is incorporated herein by reference in its entirety, wherein the full-length heavy chain amino acid sequence, heavy chain variable region sequence, and CDR sequences of BION-1301 correspond to SEQ ID NO:52, SEQ ID NO:40, SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7, respectively, in the present patent application, while the full-length light chain amino acid sequence, light chain variable region sequence, and CDR sequences correspond to SEQ ID NO:50, SEQ ID NO:30, SEQ ID NO:8, SEQ ID NO:9, and SEQ ID NO:10, respectively.

[0076] The present invention is further illustrated below through examples, which are not meant to limit the scope of the invention in any way. For the measurement methods of various parameters in the examples, see Wan F, Wang H, Wang M, Lue J, Zhao M, Zhang H. Sustained release of Lactobacillus casei cell wall extract can induce a continuous and stable IgA deposition model. J Pathol. 2022; 257(3): 262-273. doi: 10.1002 / path.5884 and Xie X, Li J, Liu P, et al. Chimeric fusion between Clostridium ramosum IgA protease and IgG Fc provides long-lasting clearance of IgA deposits in mouse models of IgA nephropathy. J Am Soc Nephrol. 2022; 33(5): 918-935. doi: 10.1681 / ASN.2021030372. The above-mentioned documents are incorporated herein in their entirety.

[0077] Example 1: Construction of an IgAN animal model (a) Construction of a humanized IGHA1 mouse model; (b) Construction of a renal IgA deposition model with high-level expression of IgA in serum. The mouse model of the present invention can efficiently express human IgA1 protein, ensuring the functionality of the human IgA1 molecule in mice. It is more specific and closer to the natural characteristics of human IgA1 than existing conventional construction methods. In addition, the modeling method of the CFA stimulation model is simple and easy to perform, has a high success rate, is highly reproducible, and causes minimal damage to the body. This provides an effective experimental animal platform for exploring the pathogenesis of IgA nephropathy and new therapeutic strategies.

[0078] procedure: I. Construction of a humanized IGHA1 mouse model (for specific methods, please refer to Chinese Patent No. 115197942A, the entire text of which is incorporated herein by reference) 1. The entire human IGHA1 gene sequence was introduced into the IGHA gene region of C57BL / 6Jju mice, and the heavy chain region of mouse IgA was replaced with that of human IgA1 to construct humanized IgA1 mice with an O-glycosylated hinge region. 2. After verifying the gene sequence of the first mice, homozygous humanized IGHA1 mice were obtained through multiple generations of backcrossing and self-crossing.

[0079] II. Construction of a renal IgA deposition model 1. Complete Freund's adjuvant (CFA) and phosphate buffered saline (PBS) were thoroughly mixed and emulsified at a 1:1 ratio to obtain a CFA injection, which was then intraperitoneally injected into the 8-week-old humanized IGHA1 mice constructed in step 1. Four times the mouse's body weight (4 μl) was injected every two weeks, for a total of six injections over a period of approximately 2.5 months. 2. In this experiment, 8-week-old humanized IgA1 mice underwent an induction period of 2–5 months after the final injection of CFA.

[0080] Table 1

[0081] [Table 1]

[0082] The test results showed that the hIgA1, IgG, and IgM levels in IgAN mice after modeling were significantly higher than those in unstimulated humanized IGHA1 transgenic mice (non-IgAN transgenic mice).

[0083] Example 2: Study on the efficacy and safety of atrasentan (A) in combination with methylprednisolone (MP) and dapagliflozin (Dapa) for IgA nephropathy Methods: Forty-one IgA nephropathy model mice were randomly assigned to the atrasentan + methylprednisolone + dapagliflozin group (n = 9), the atrasentan + methylprednisolone group (n = 8), the methylprednisolone group (n = 8), the atrasentan group (n = 8), and the treatment control group (n = 8). Each group received an intraperitoneal injection of CFA to create the model. Once the model was established, atrasentan, methylprednisolone, and / or dapagliflozin were administered as outlined below. The control group received an equal volume of vehicle (aqueous solution of 0.5% (w / v) methylcellulose and 0.5% (v / v) Tween 80) by oral gavage for 30 days.

[0084] Administration method: Atrasentan (15 mg / kg / day), methylprednisolone (5 mg / kg / day), and dapagliflozin (1 mg / kg / day) were administered by oral gavage every morning for 30 days. For simultaneous administration, the required drugs were mixed in the appropriate ratio (the dose of each drug was calculated according to the mouse's body weight) and then administered by gavage.

[0085] Before the start of treatment, once a week during the treatment period, and on day 30 of treatment, mice were weighed and their blood pressure was measured, and blood levels of hlgA1, Gd-IgA1, IgA-containing complexes, IgG, IgM, C3, BUN, Scr, Hb, BNP, and ET-1 were measured. Before treatment, once every two weeks during the treatment period, and on day 30 of treatment, urinary creatinine, urinary protein level, and albumin-to-creatinine ratio (ACR) were measured, and mice were checked for the presence of hematuria. Before treatment and on day 30 of treatment, renal tissue lesions were scored according to the Oxford classification system, IgA and C3 deposition in renal tissue was measured by immunofluorescence assay, and mice from each group were examined for cardiac lesions.

[0086] Features of the IgAN mouse model: IGHA1+ / + mice stimulated intraperitoneally with CFA: Increased levels of IgA1, Gd-IgA1, and IgA1 complexes in serum and intestinal mucus Emergence of IgAN renal pathological phenotype: -IgA1 and C3 were co-deposited in the mesangial region and the extent of complement activation was stronger compared to stimulated wild-type mice. -Mesangial matrix, mesangial cells, and endothelial cells proliferated, and some mice developed severe lesions in the form of focal sclerosis and tubulointerstitial fibrosis.

[0087] Analysis of the test results, as shown in Table 2 and Figures 3-1 and 3-2, reveals that there is no statistically significant difference in the changes in hIgA1 between the groups, but that the MP-only group showed a tendency for hIgA1 to decrease compared to the control treatment group (which showed a tendency for hIgA1 to increase after 30 days). This decrease in hIgA1 after administration was more pronounced in the A+MP group than in the MP-only group, and even more pronounced in the A+Dapa+MP group.

[0088] Table 2

[0089] [Table 2]

[0090] Analysis of the test results, based on the data in Table 3 and Figures 4-1 and 4-2, showed that there was no statistically significant difference between the groups in the changes in IgG, but in the MP alone group, IgG tended to decrease after administration compared to the treatment control group (in which IgG tended to increase after 30 days), and this decrease in IgG after administration was more pronounced in the A+MP group than in the MP alone group.

[0091] Table 3

[0092] [Table 3]

[0093] Analysis of the test results (Table 4 and Figures 5-1 and 5-2) showed that there was no statistically significant difference between the groups in the changes in IgM, but the decrease in IgM after administration was more pronounced in the A+MP group compared to the MP alone group (IgM showed a gradual downward trend after 30 days).

[0094] Table 4

[0095] [Table 4]

Claims

1. A method for treating IgA nephropathy in a subject in need thereof, comprising administering to the subject effective amounts of an endothelin receptor antagonist and a glucocorticoid, wherein the endothelin receptor antagonist and the glucocorticoid may be administered separately in a single dosage form or sequentially.

2. 2. The method of claim 1, wherein the endothelin receptor antagonist is selected from any one of tezosentan, sparsentan, bosentan, macitentan, ambrisentan, sitaxsentan, aprocitentan, and atrasentan, or a pharmaceutically acceptable salt thereof, or any combination thereof.

3. 3. The method of claim 1 or 2, wherein the endothelin receptor antagonist is selected from atrasentan or a pharmaceutically acceptable salt thereof.

4. 2. The method of claim 1, wherein the glucocorticoid is selected from any one of dexamethasone, betamethasone, fluorometholone, prednisone, prednisolone, methylprednisolone, hydrocortisone, fluocinolone, fluticasone, mometasone, loteprednol etabonate, rimexalone, fluticasone, beclomethasone, ciclesonide, budesonide, triamcinolone acetonide, prednicarbate, butixocort, tipredane, and tixocortol, or a pharmaceutically acceptable salt thereof, or any combination thereof.

5. 5. The method of claim 4, wherein the glucocorticoid is selected from any one of budesonide and methylprednisolone or a pharmaceutically acceptable salt thereof.

6. 2. The method of claim 1, wherein the endothelin receptor antagonist is administered in a dosage form given orally, buccally, or parenterally, and the oral dosage form may be, for example, a tablet, capsule, powder, pill, granule, suspension, solution and solution preconcentrate or emulsion and emulsion preconcentrate, and the parenteral dosage form may be, for example, a dosage form administered intravenously, intraperitoneally, intradermally, subcutaneously, intramuscularly, intracranially, intrathecally, intratumorally, transdermally, or transmucosally.

7. 10. The method of claim 1, wherein the method optionally further comprises administering to the subject an effective amount of a third therapeutically active agent.

8. 8. The method of claim 7, wherein the third therapeutically active agent is selected from an SGLT-2 inhibitor.

9. The method of claim 8, wherein the SGLT-2 inhibitor is selected from any one of empagliflozin, canagliflozin, remogliflozin, ipragliflozin, HM41322, dapagliflozin, bexagliflozin, ertugliflozin, sotagliflozin, luseogliflozin, and tofogliflozin, or any combination thereof.

10. A pharmaceutical composition comprising effective amounts of an endothelin receptor antagonist and a glucocorticoid, wherein the endothelin receptor antagonist and the glucocorticoid can be administered separately or sequentially in a single dosage form.

11. 11. The pharmaceutical composition of claim 10, wherein the endothelin receptor antagonist is selected from any one of tezosentan, sparsentan, bosentan, macitentan, ambrisentan, sitaxsentan, aprocitentan, and atrasentan, or pharmaceutically acceptable salts thereof, or any combination thereof.

12. The pharmaceutical composition of claim 10, wherein the endothelin receptor antagonist is selected from atrasentan or a pharmaceutically acceptable salt thereof.

13. 11. The pharmaceutical composition of claim 10, wherein the glucocorticoid is selected from any one of dexamethasone, betamethasone, fluorometholone, prednisone, prednisolone, methylprednisolone, hydrocortisone, fluocinolone, fluticasone, mometasone, loteprednol etabonate, rimexalone, fluticasone, beclomethasone, ciclesonide, budesonide, triamcinolone acetonide, prednicarbate, butixocort, tipredane, and tixocortol, or a pharmaceutically acceptable salt thereof, or any combination thereof.

14. 14. The pharmaceutical composition of claim 13, wherein the glucocorticoid is selected from any one of budesonide and methylprednisolone or a pharmaceutically acceptable salt thereof.

15. 11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition may optionally further comprise an effective amount of a third therapeutically active agent.

16. 16. The pharmaceutical composition of claim 15, wherein the third therapeutically active agent is selected from an SGLT-2 inhibitor.

17. 17. The pharmaceutical composition of claim 16, wherein the SGLT-2 inhibitor is selected from any one of empagliflozin, canagliflozin, remogliflozin, ipragliflozin, HM41322, dapagliflozin, bexagliflozin, ertugliflozin, sotagliflozin, luseogliflozin, and tofogliflozin, or any combination thereof.

18. 18. The pharmaceutical composition of claim 17, wherein the SGLT-2 inhibitor is selected from dapagliflozin.

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