Sparsentan for use in the treatment of IGA-mediated diseases

Abstract

A method is provided for the prevention or treatment of immunoglobulin A-mediated diseases, such as immunoglobulin A nephropathy, by treatment with sparnentan or a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] The present disclosure relates to a method for treating IgA-mediated diseases.

Background Art

[0002] Immunoglobulin A (IgA) is an antibody that plays a role in the immune function of mucous membranes. The amount of IgA produced in relation to mucous membranes is greater than the combined amount of all other types of antibodies. IgA is the major antibody component found in mucous secretions including tears, saliva, sweat, colostrum, and secretions from the urogenital tract, gastrointestinal tract, prostate, and respiratory epithelium.

[0003] IgA nephropathy (IgAN) (also called Berger's disease) is the most common form of primary glomerulonephritis and has the highest prevalence in Asian populations. IgAN is a rare autoimmune disease leading to kidney damage characterized by the accumulation of antibodies (IgA) in the glomeruli, which are collections of capillaries around the ends of the kidney tubules (where waste products are filtered from the blood). This IgA deposition occurs in the mesangial cells of the glomeruli, causing chronic inflammation and glomerular damage. The IgA that normally circulates and deposits in the glomeruli of IgAN patients is rich in a form (Gd-IgA1) with insufficient galactosylation due to abnormal production, which causes an autoimmune response and generates antibodies that recognize the abnormal IgA. The immune deposits contain Gd-IgA1 bound to autoantibodies. IgA nephropathy results in blood in the urine (hematuria) and protein in the urine (proteinuria). In some cases, it causes swelling, recurrent upper respiratory infections, and intestinal diseases, and patients often have flank pain and low-grade fever. Eventually, IgAN leads to kidney failure. Historically, in IgAN, 40% of patients progress to dialysis within 20 years after the diagnosis of IgA nephropathy, and the mortality rate after about 30 years is 50%.

[0004] The pathogenesis of IgAN is thought to occur through a "4-hit" mechanism, where the production of circulating Gd-IgA1, the generation of anti-Gd-IgA1 antibodies, the formation of immune complexes, and the deposition of these immune complexes in mesangial cells lead to glomerular injury (Non-Patent Literature 1). This is based on the observation that abnormalities in IgA1 production lead to elevated plasma levels of galactose-deficient IgA1 (Gd-IgA1) (hit #1). The increase in Gd-IgA1 triggers an autoimmune response, resulting in the production of anti-glycan antibodies that recognize the N-acetylgalactosamine epitope on Gd-IgA1 (hit #2). Gd-IgA1 and IgG autoantibodies form immune complexes in circulation (hit #3). These immune complexes can be deposited on mesangial cells of the kidney (hit #4), resulting in activation of the complement system and inflammatory pathways, and inducing renal injury.

[0005] Recent studies suggest that the deposition and composition of immune complexes on mesangial cells can be further controlled at the glomerular level with macrophage apoptosis inhibitors (AIMs) (Non-Patent Literature 2) and the generation of mesangial cell autoantigens (Non-Patent Literature 3).

[0006] IgA vasculitis is a disease characterized by the accumulation of IgA in small blood vessels, leading to inflammation and leakage (http: / / www.niddk.nih.gov / health-information / kidney-disease / iga-vasculitis). In many cases, IgA vasculitis is characterized by a red or purple rash. Some people with IgA vasculitis also experience problems with the gastrointestinal (GI) tract, joints, and kidneys, and sometimes with the lungs, nervous system, or other organs, due to inflammation of the blood vessels. In children and infants, IgA vasculitis can lead to further complications such as IgAN, occurring in approximately 3 to 27 cases per 100,000.

[0007] Linear IgA bullous dermatosis (LABD) is a mucocutaneous autoimmune disease characterized by linear deposition of IgA and destruction of the dermal epithelial junction, resulting in vesicles. The mucosal surface may also be affected. This condition occurs in children aged 6 months to 10 years and in the elderly population. LABD may be associated with lymphoproliferative disorders, infections, ulcerative colitis, and systemic lupus erythematosus.

[0008] Sparsentan is a monomolecule dual antagonist (DEARA) of endothelin and angiotensin receptors. ETAR and AT1R play important roles in IgAN. Biopsies of IgAN patients have shown that intrarenal levels of ET-1 and Ang II are associated with a higher risk of disease progression (Non-Patent Literature 4; Non-Patent Literature 5). The PROTECT trial (ClinicalTrials.gov, NCT03762850) was the basis for the United States Food and Drug Administration's expedited approval of sparsentan for reducing proteinuria in adults with IgA nephropathy at high risk of disease progression (Non-Patent Literature 6). [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Suzuki et al., Journal of the American Society of Nephrology (J Am Soc Nephrol), Vol. 22(10): pp. 1795-1803, 2011, doi:10.1681 / ASN.2011050464 [Non-Patent Document 2] Takahata et al., Journal of the American Society of Nephrology (JASN), Vol. 31(9): pp. 2013-2024, 2020, doi:10.1681 / ASN.2019100987 [Non-Patent Document 3] Nihei et al., Science Advances, Vol. 9(12):eadd6734, 2023, doi:10.1126 / sciadv.add6734 [Non-Patent Document 4] Tycova et al., Physiol Res., Vol. 67(1): pp. 93-105, 2018, doi:10.33549 / physiolres.933670 [Non-Patent Document 5] Lai et al., Kidney International, Vol. 66(4): pp. 1403-1416, 2004, doi:10.1111 / j.1523-1755.2004.00874.x [Non-Patent Document 6] Heerspink et al., The Lancet, Vol. 401 (10388): pp. 1584-1594, 2023 (published April 1, 2023), doi:10.1016 / S0140-6736(23)00569-X [Overview of the project]

[0010] Most treatments for IgAN and related IgA-mediated conditions only slow or hinder disease progression. Treatments or methods that prevent the onset or progression of kidney damage, or reverse the effects of these diseases, would be desirable.

[0011] This patent or application file contains at least one drawing created in color. A copy of this patent or patent application publication containing the color drawing will be provided by the Patent Office upon request and payment of the necessary fees. [Brief explanation of the drawing]

[0012] [Figure 1A]Figures 1A-1B show images of IgA content detected by immunofluorescence (IF) staining in immunodeposits in the kidney glomeruli of gddY mice treated for 8 weeks with a control diet or a diet containing 900 ppm or 1800 ppm of spalsentan. [Figure 1B] Same as above. [Figure 2] This shows the quantification of IgA content detected by IF staining in immunodeposits in the kidney glomeruli of gddY mice treated for 8 weeks with a control diet or a diet containing 900 ppm or 1800 ppm of sparnentan. Three glomeruli from each sample were semi-quantitatively scored based on the intensity of glomerular staining (0 negative, 1 weak, 2 medium, 3 strong). [Figure 3A] Figures 3A-3C show images and quantifications of IgA, IgG, and C3 content detected by IF staining in immunodeposits in the kidney glomeruli of gddY mice treated for 16 weeks with a control diet, a diet containing 900 ppm spalsentan, or losartan in drinking water delivered at a dose of 30 mg / kg per day. A shows the image and quantification of IgA content. B shows the image and quantification of IgG content. C shows the image and quantification of C3 content. [Figure 3B] Same as above. [Figure 3C] Same as above. [Figure 4A] Images 4A-4C show the IgA, IgG, and C3 content detected by IF staining in glomerular immunodeposits of gddY mice after 16 weeks of treatment with a control diet or a diet containing 900 ppm spalsentan. Images A and B show the binding of IgA and IgG in glomerular immunodeposits. Image C shows the C3 in glomerular immunodeposits. [Figure 4B] Same as above. [Figure 4C] Same as above. [Figure 5]Serum levels of IgA were evaluated in 12-week-old and 20-week-old gddY control mice (gddY C), or gddY mice treated with sparsentan in the diet at 900 ppm (gddY SP900), or gddY mice treated with losartan in the drinking water to deliver 30 mg / kg per day (gddY LS30) after 8 or 16 weeks of treatment. Individual animal data are shown as mean ± SD.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The present disclosure generally relates to the use of sparsentan, a compound having dual antagonist activity of angiotensin and endothelin receptors, in the prevention and / or treatment of diseases associated with immunoglobulin A (IgA), such as IgA nephropathy (IgAN), for example by preventing or reducing glomerular deposition of IgA.

[0014] In the following description, specific details are set forth in order to provide a thorough understanding of various embodiments of the invention. However, one skilled in the art will understand that the invention may be practiced without these details.

[0015] I. Glossary Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, certain terms may have the meanings defined below.

[0016] Unless the context requires otherwise, throughout this specification and the claims, the word "comprise", and variations such as "comprises" and "comprising", are to be construed in an open, inclusive sense, that is, as "including, but not limited to".

[0017] As used herein and in the claims, “including,” and its variations such as “include” and “includes,” should be interpreted in an open and inclusive sense, i.e., equivalent to “including, but not limited to.” As used herein, the terms “include” and “have” are used synonymously, and these terms and their variations are intended to be interpreted as non-restrictive.

[0018] As used herein, the phrase "such as" refers to non-restrictive examples. Throughout this specification, any reference to “one embodiment” or “embodiment” means that a particular feature, structure, or characteristic described in relation to that embodiment is included in at least one embodiment of the present invention. Therefore, occurrences of the phrase “in one embodiment” or “in an embodiment” in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, a particular feature, structure, or characteristic can be combined in any suitable manner in one or more embodiments.

[0019] As used herein and in the claims, the singular forms "a," "an," and "the" include multiple references unless the context clearly indicates otherwise. For example, the term "a cell" includes multiple cells, including mixtures thereof. Similarly, the use of "a compound" for the treatment or preparation of any agent described herein intends to use one or more of the compounds of the present invention for such treatment or preparation, unless the context clearly indicates otherwise.

[0020] The use of options (e.g., "or") should be understood to mean one of the options, both of them, or any combination thereof. "Optional" or "optionally" means that the event or situation described thereafter may or may not occur, and that the description includes both cases in which the event or situation occurs and cases in which it does not occur.

[0021] As used herein, “about” and “approximately” generally refer to the degree of acceptable error with respect to a measured quantity, taking into account the nature or precision of the measurement. Typically, exemplary degrees of error may be within 20%, 10%, or 5% of a given value or range of values. Alternatively, particularly in biological systems, the terms “about” and “approximately” may mean a value within one order of magnitude of a given value, potentially within five times or two times. Unless expressly stated otherwise, the terms “about” and “approximately” mean equal to a certain value or within 20% of that value.

[0022] Where used herein, quantities are precise to the extent that this is reflected in the number of significant figures reported. For example, a value of 0.1 is understood to mean between 0.05 and 0.14. As another example, the interval of values ​​between 0.1 and 0.2 includes the range of 0.05 to 0.24.

[0023] Sparsentan may also form salts, which are also included within the scope of this disclosure. References to sparsentan in this specification are generally understood to include references to its salts unless otherwise stated. As used herein, the term “salt” refers to an acidic or basic salt formed with an inorganic acid and a base, or an organic acid and a base. In addition, since sparsentan contains both a basic and an acidic moiety, zwitterions ("intramolecular salts") may be formed, which are included within the scope of the term “salt” as used herein. While pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, other salts may also be useful in isolation or purification steps that may be used, for example, during preparation. Salts of sparsentan can be formed, for example, by reacting sparsentan with a certain amount, for example, an equivalent amount of acid or base, in a medium such as a salt-precipitating medium or an aqueous medium, followed by freeze-drying.

[0024] The term "pharmaceutically acceptable salt" includes both acid addition salts and base addition salts. Prodrugs and solvates of sparsentan are also intended. The term "prodrug" refers to a compound that, upon administration to a subject, undergoes metabolic or chemical transformation through chemical processes to produce sparsentan or its salts or solvates. Sparsentan solvates may also be hydrates. All tautomers are also intended.

[0025] Crystallization may produce solvates of spalsentan or its salts. As used herein, the term “solvate” refers to aggregates comprising one or more molecules of the compounds disclosed herein and one or more molecules of a solvent. In some embodiments, the solvent is water, in which case the solvate is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Thus, the compounds of this disclosure may exist as hydrates, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and the corresponding solvated forms. In some embodiments, the compounds disclosed herein may be true solvates, but in other cases, the compounds disclosed herein may simply contain exogenous water or be a mixture of water and some exogenous solvent.

[0026] The inventions disclosed herein also encompass in vivo metabolites of the disclosed compounds. Such products may arise, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily due to enzymatic processes. Accordingly, the present invention includes compounds produced by processes comprising administering the compounds of the present invention to mammals for a period of time sufficient to yield their metabolites. Such products are typically identified by administering a detectable dose of the radiolabeled compound of the present invention to animals such as rats, mice, guinea pigs, monkeys, or humans, giving them sufficient time for metabolism to occur, and then isolating the conversion products from urine, blood, or other biological samples.

[0027] "Stable compound" and "stable structure" mean that the compound is robust enough to withstand isolation from a reaction mixture to a useful purity and formulation into an effective therapeutic agent. The term "subject" refers to a domestic pet (e.g., a dog or cat) or a mammal such as a human. Preferably, the subject is a human. In some embodiments, the subject is a patient diagnosed with a disease or disorder (e.g., IgAN).

[0028] The term "effective dose" refers to the amount administered to a subject or patient that is sufficient to treat a disease and bring about treatment for that disease. The term “unit dosage form” (or “dosage unit form”) refers to the form in which a drug is marketed for use, including but not limited to the form in which the drug is marketed. Examples include pills, tablets, capsules, and liquid solutions and suspensions. For example, as approved and available in the United States, spalsentan is available in 200 mg and 400 mg tablets, but other unit dosage forms are also intended.

[0029] "Treatment" or "treating" includes (1) suppressing the disease in a subject or patient experiencing or showing the pathophysiology or overall symptoms of the disease (e.g., preventing further manifestation of the pathophysiology or overall symptoms); or (2) improving the disease in a subject or patient experiencing or showing the pathophysiology or overall symptoms of the disease (e.g., reversing the pathophysiology or overall symptoms); or (3) resulting in a measurable reduction of the disease in a subject or patient experiencing or showing the pathophysiology or overall symptoms of the disease.

[0030] In the context of preventing a subject (e.g., a patient) from experiencing or exhibiting the pathophysiology or overall symptoms of a disease, “preventing” includes preventing the manifestation of the disease, disorder, or condition, or reducing the manifestation of signs or symptoms associated with such disease, disorder, or condition (e.g., in a clinically appropriate amount), or delaying the onset of signs or symptoms (e.g., by days, weeks, months, or years).

[0031] As used herein, “reversing the effects of the disease” means restoring a diseased tissue or object to a healthy state compared to its initial presentation by the disease. Reversing the effects of the disease does not necessarily require a complete recovery, nor does it mean a reversal of all (or any) symptoms, or a return of measurable results (i.e., clinical laboratory results) to statistically “normal” values. Reversing the effects of the disease means a relative recovery of function, a tendency toward or returning to normal, or recovery from the disease state.

[0032] As used herein, “achieving remission of disease” means restoring a diseased tissue or object to a healthy state. Therefore, in the case of tissue, remission means that necrosis and scarring are reduced and the tissue is restored to a healthy state with normal function. In the case of IgAN, achieving remission means that the lesion has healed and provides what appears to be a normal kidney with normal function.

[0033] As used herein, “restoration of function” of tissue means the return of function regardless of histological examination. For example, acute injury to an internal organ (including surgery) may not provide an organ without scar tissue, pre-injury angiogenesis, etc., but it may function as if the injury had not occurred. In some internal organs (e.g., the liver), the organ may regenerate and thus provide restoration of function even though histological evidence clearly shows that an injury occurred.

[0034] As used herein, “restoration of tissue integrity” means, from a histological standpoint, that tissue having necrosis, scarring, infarction, etc., returns to intact tissue, as commonly occurs in wound healing. The process of restoring integrity may be simple tissue reconstruction facilitated by the removal of inflammation, a reduction in the deposition of various types of plaque (including IgA-associated plaque), etc. Healing of damage in IgA-associated nephropathy is a combination of the restoration of tissue integrity and the restoration of function of the associated organ.

[0035] As used herein, “normal diet” means an unmonitored or restricted diet. For example, patients with kidney disease and proteinuria are often subjected to dietary restrictions to avoid systemic imbalances, muscle fatigue, etc. In this context, returning to a normal diet means that the need to continue the restrictions imposed for the purpose of treating IgA-mediated disease is reduced.

[0036] Additional definitions are provided throughout this disclosure. II. Sparsentan Sparsentan (CAS 254740-64-2, 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]nona-1-en-3-yl)methyl]-2-(ethoxymethyl)phenyl]-N-(4,5-dimethyl-1,2-oxazole-3-yl)benzenesulfonamide) has structure (I)

[0037] [ka]

[0038] It is a biphenylsulfonamide compound having [a specific characteristic]. Sparsentan is an endothelin (type A) receptor ("ET"). A It is a selective dual-acting receptor antagonist that has affinity for the "AT1" receptor and angiotensin II receptor (type 1) ("AT1" receptor) (Kowala et al., Journal of Pharmacology and Experimental Therapeutics (JPET), Vol. 309: pp. 275-284, 2004).

[0039] Spalcentan may be prepared by methods such as those described in International Publication No. 2018 / 071784A1. Furthermore, spalcentan may be prepared by methods described in U.S. Patent Application Publication No. 2015 / 0164865 and U.S. Patent No. 6,638,937.

[0040] III. Pharmaceutical Compositions and Methods of Use In some embodiments, this disclosure relates to the administration of pharmaceutical compositions comprising spalsentan or a pharmaceutically acceptable salt thereof. As used herein, the term “pharmaceutical composition” means a composition comprising an active ingredient and pharmaceutically acceptable excipients. Pharmaceutical compositions may be used to facilitate the administration of an active ingredient to a living organism. Several techniques for administering compounds exist in the art, including oral administration, injection administration, aerosol administration, parenteral administration, and topical administration. Pharmaceutical compositions can be obtained, for example, by reacting a compound with an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, or salicylic acid. As used herein, the terms “physiologically acceptable excipient” or “pharmaceutically acceptable excipient” refer to any physiologically and pharmaceutically appropriate, non-toxic, and inert material or component that does not interfere with the activity of the active ingredient, and include any auxiliaries, carriers, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers approved by the U.S. Food and Drug Administration as acceptable for use in humans or livestock.

[0041] In some embodiments, the pharmaceutical composition may be formulated as described below. Furthermore, methods for preventing or treating IgA-mediated diseases such as IgAN, including administering spalsentan or a pharmaceutically acceptable salt thereof, are included within the scope of this disclosure. In some embodiments, methods for preventing or treating IgA-mediated diseases such as IgAN are provided, including administering a pharmaceutical composition comprising spalsentan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0042] In some embodiments, a method is provided for preventing further deposition of IgA in the kidneys, comprising administering spalsentan (or a pharmaceutically acceptable salt thereof) to a subject in need thereof.

[0043] In some embodiments, methods are provided for reversing the effects of an IgA-mediated disease or achieving remission of an IgA-mediated disease, comprising administering spalsentan (or a pharmaceutically acceptable salt thereof) to a subject in need thereof.

[0044] In some embodiments, a method is provided for restoring tissue function and integrity in a subject with an IgA-mediated disease, the method comprising administering spalsentan (or a pharmaceutically acceptable salt thereof) to the subject.

[0045] In some embodiments, a method is provided for healing damage in IgA-associated nephropathy, comprising administering spalsentan (or a pharmaceutically acceptable salt thereof) to a subject in need thereof. In some such embodiments, the subject has an IgA-mediated disease.

[0046] In some embodiments of the above-described method, normal tissue function and integrity are restored. In some embodiments of the above-described method, further deposition of IgA in the kidneys is prevented. In further embodiments, spalsentan or a pharmaceutically acceptable salt thereof may be useful in reducing overall morbidity or mortality as a result of the above-mentioned benefits.

[0047] In some embodiments, a pharmaceutical composition comprising sparsentan or a pharmaceutically acceptable salt thereof, or sparsentan or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient, is useful in extending the time to end-stage renal disease or reducing the risk of end-stage renal disease in patients diagnosed with IgAN.

[0048] In some embodiments, spalsentan or a pharmaceutically acceptable salt thereof is useful in reducing proteinuria. As used herein, “proteinuria” refers to a condition in which the urine contains an abnormal amount of protein (i.e., urinary protein excretion per day exceeds 300 mg). The urinary protein to creatinine ("UP / C") ratio provides a measure of total urinary protein relative to the amount of creatinine in a urine sample (for example, dividing 1 g of protein in urine (dl) by 1 g of creatinine in urine (dl) results in a UP / C ratio of 1). As used herein, a UP / C ratio greater than 0.3 g / g indicates proteinuria. In some embodiments, spalsentan or a pharmaceutically acceptable salt thereof is useful in reducing proteinuria to 1.0 g / g or less. In some embodiments, spalsentan or a pharmaceutically acceptable salt thereof is useful in reducing proteinuria to 0.5 g / g or less. In some embodiments, spalsentan or a pharmaceutically acceptable salt thereof is useful in reducing proteinuria to 0.3 g / g or less (i.e., complete remission of proteinuria). Accordingly, the disclosure also provides a method for inducing complete remission in a subject having IgAN by administering spalsentan or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, a method is provided for treating subjects requiring treatment for IgAN, which involves administering a pharmaceutical composition containing spalsentan or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a UP / C ratio of 1.0 g / g or less. In some embodiments, a method is provided for treating subjects requiring treatment for IgAN, which involves administering a pharmaceutical composition containing spalsentan or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve or maintain a UP / C ratio of 1.0 g / g or less. In some embodiments, a method is provided for treating subjects requiring treatment for IgAN, which involves administering a pharmaceutical composition containing spalsentan or a pharmaceutically acceptable salt thereof in a dosage schedule sufficient to achieve or maintain a UP / C ratio of 1.0 g / g or less. In some of the embodiments described above, treatment with spalsentan reduces proteinuria to 0.5 g / g or less. In some of the embodiments described above, treatment with spalsentan reduces proteinuria to 0.3 g / g or less (i.e., treatment with spalsentan induces complete remission of proteinuria). In some embodiments, the dosing regimen includes administering 100 mg / day of spalsentan or a pharmaceutically acceptable salt thereof. In some embodiments, the dosing regimen includes administering 200 mg / day of spalsentan or a pharmaceutically acceptable salt thereof. In some embodiments, the dosing regimen includes administering 400 mg / day of spalsentan or a pharmaceutically acceptable salt thereof. In some embodiments, the dosing regimen includes administering 800 mg / day of spalsentan or a pharmaceutically acceptable salt thereof. In some embodiments, the dosing regimen includes administering 200 mg / day of spalsentan or a pharmaceutically acceptable salt thereof over 8 weeks, 26 weeks, 36 weeks, 6 months, 8 months, 1 year, or 108 weeks. In some embodiments, the administration plan includes administering 400 mg / day of spalsentan or a pharmaceutically acceptable salt thereof over 8 weeks, 26 weeks, 36 weeks, 6 months, 8 months, 1 year, or 108 weeks.In some embodiments, the dosing regimen includes administering 800 mg / day of spalsentan or a pharmaceutically acceptable salt thereof over 8 weeks, 26 weeks, 36 weeks, 6 months, 8 months, 1 year, or 108 weeks. In some embodiments, the dosing regimen includes administering 200 mg / day of spalsentan or a pharmaceutically acceptable salt thereof over 6 weeks, 36 weeks, 6 months, 1 year, 58 weeks, or 110 weeks. In some embodiments, the dosing regimen includes administering 400 mg / day of spalsentan or a pharmaceutically acceptable salt thereof over 6 weeks, 36 weeks, 6 months, 1 year, 58 weeks, or 110 weeks.

[0050] In some embodiments, if the subject's weight is between 20 kg and 50 kg, the amount of spalsentan or its pharmaceutically acceptable salt administered to the subject is 200 mg / day for the first two weeks, and 400 mg / day thereafter. In some embodiments, if the subject's weight is greater than 50 kg, the amount of spalsentan or its pharmaceutically acceptable salt administered to the subject is 400 mg / day for the first two weeks, and 800 mg / day thereafter.

[0051] In some embodiments, methods are provided for treating subjects requiring treatment for IgAN, the method comprising administering to the subject over a period of administration a pharmaceutical composition containing spalsentan or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve or maintain a UP / C ratio of 1.0 g / g or less for at least part of the administration period. “Administration period” refers to the period during which the pharmaceutical composition is administered to the subject at least daily. In some embodiments, the administration period is 6 weeks. In some embodiments, the administration period is 8 weeks. In some embodiments, the administration period is 26 weeks. In some embodiments, the administration period is 36 weeks. In some embodiments, the administration period is 6 months. In some embodiments, the administration period is 108 weeks. In some embodiments, the administration period is 110 weeks. In some embodiments, the administration period is 8 months.

[0052] In some embodiments, methods are provided for subjects that require maintaining a UP / C ratio of 1.0 g / g or less, the method comprising administering a pharmaceutical composition to a subject containing a sufficient amount of spalsentan or a pharmaceutically acceptable salt thereof to maintain a UP / C ratio of 1.0 g / g or less.

[0053] In some embodiments, methods are provided for reducing the UP / C ratio to 1.0 g / g or less in subjects where this is required, and the methods include administering a pharmaceutical composition to the subject containing a sufficient amount of spalsentan or a pharmaceutically acceptable salt thereof to reduce the UP / C ratio of the subject to 1.0 g / g or less. In some embodiments, the subject had, or had, a UP / C ratio greater than 1.0 g / g prior to administration of the pharmaceutical composition.

[0054] In some embodiments, spalsentan or a pharmaceutically acceptable salt thereof is useful in maintaining glomerular filtration rate. As used herein, “glomerular filtration rate” (“GFR”) is a measure of renal function and refers to the amount of fluid filtered by the glomeruli of the kidney per unit time. GFR can be estimated by measuring serum creatinine levels and using the creatinine formula of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). As used herein, “estimated glomerular filtration rate” (“eGFR”) refers to an estimate of GFR obtained by using the CKD-EPI creatinine formula. In some embodiments, spalsentan or a pharmaceutically acceptable salt thereof is useful in maintaining eGFR levels (e.g., preventing a decline in eGFR associated with IgAN or slowing the rate of decline of eGFR in patients with IgAN). In some embodiments, administration of spalsentan or a pharmaceutically acceptable salt thereof to a subject results in maintaining the eGFR at or above the eGFR level immediately prior to administration of spalsentan or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing them (e.g., within one month prior to administration). In some embodiments, administration of spalsentan or a pharmaceutically acceptable salt thereof to a subject results in maintaining the eGFR at or above the baseline eGFR level. Here, “baseline eGFR level” refers to the most recent eGFR level calculated before the initiation of treatment. As used herein, “maintaining eGFR” means that there is no clinically significant decrease in the baseline eGFR level. Thus, as used herein in relation to the treatment of a patient with IgAN, the phrase “maintaining constant eGFR” means treatment that maintains the subject’s eGFR at a level clinically equivalent to or better than its baseline eGFR (i.e., the most recent eGFR level calculated before the initiation of treatment). In some embodiments, eGFR is maintained for several months or years after administration. The period during which the target eGFR level remains constant is typically at least 12 months.

[0055] In some embodiments, any of the above-described methods of use or treatment may involve administering spalsentan or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing them, in combination with one or more other active ingredients, such as other therapeutic or diagnostic agents. For example, in some embodiments, one or more other therapeutic agents may be administered before, concurrently with, or after administration of a pharmaceutical composition containing an effective amount of spalsentan or a pharmaceutically acceptable salt thereof. When formulated as a fixed dose, such combination product may use spalsentan or a pharmaceutically acceptable salt thereof within the dosage range described below, along with other active ingredients within the approved dosage range.

[0056] In some embodiments, spalsentan or a pharmaceutically acceptable salt thereof is used in conjunction with hemodialysis. In some embodiments of the above-described methods of use and treatment, the dosage regimen includes administering 50 mg / day of spalsentan or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage regimen includes administering 100 mg / day of spalsentan or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage regimen includes administering 200 mg / day of spalsentan or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage regimen includes administering 300 mg / day of spalsentan or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage regimen includes administering 400 mg / day of spalsentan or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage regimen includes administering 500 mg / day of spalsentan or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage regimen includes administering 600 mg / day of spalsentan or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage regimen includes administering 700 mg / day of spalsentan or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage regimen includes administering 800 mg / day of spalsentan or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage regimen includes administering 900 mg / day of spalsentan or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage regimen includes administering 1000 mg / day of spalsentan or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments of the above-described methods of use and treatment, the dosing plan includes administering 100 mg / day of spalsentan or a pharmaceutically acceptable salt thereof over 6 weeks, 8 weeks, 26 weeks, 36 weeks, 8 months, 108 weeks, or 110 weeks. In some embodiments of the above-described methods of use and treatment, the dosing plan includes administering 200 mg / day of spalsentan or a pharmaceutically acceptable salt thereof over 6 weeks, 8 weeks, 26 weeks, 36 weeks, 8 months, 108 weeks, or 110 weeks. In some embodiments of the above-described methods of use and treatment, the dosing plan includes administering 400 mg / day of spalsentan or a pharmaceutically acceptable salt thereof over 6 weeks, 8 weeks, 26 weeks, 36 weeks, 8 months, 108 weeks, or 110 weeks. In further embodiments, the administration plan includes administering 800 mg / day of spalsentan or a pharmaceutically acceptable salt thereof over a period of 6 weeks, 8 weeks, 26 weeks, 36 weeks, 8 months, 108 weeks, or 110 weeks.

[0058] In any of the embodiments described above, the amount of spalsentan or its pharmaceutically acceptable salt administered to the subject may be about 50 mg / day to about 1000 mg / day. For example, in some embodiments, the amount of spalsentan or its pharmaceutically acceptable salt administered to the subject is about 200 mg / day to about 800 mg / day. In other embodiments, the amount of spalsentan or its pharmaceutically acceptable salt administered to the subject is about 50 mg / day. In other embodiments, the amount of spalsentan or its pharmaceutically acceptable salt administered to the subject is about 100 mg / day. In other embodiments, the amount of spalsentan or its pharmaceutically acceptable salt administered to the subject is about 200 mg / day. In other embodiments, the amount of spalsentan or its pharmaceutically acceptable salt administered to the subject is about 300 mg / day. In other embodiments, the amount of spalsentan or its pharmaceutically acceptable salt administered to the subject is about 400 mg / day. In other embodiments, the amount of spalsentan or its pharmaceutically acceptable salt administered to the subject is approximately 500 mg / day. In other embodiments, the amount of spalsentan or its pharmaceutically acceptable salt administered to the subject is approximately 600 mg / day. In other embodiments, the amount of spalsentan or its pharmaceutically acceptable salt administered to the subject is approximately 700 mg / day. In other embodiments, the amount of spalsentan or its pharmaceutically acceptable salt administered to the subject is approximately 800 mg / day. In other embodiments, the amount of spalsentan or its pharmaceutically acceptable salt administered to the subject is approximately 900 mg / day. In other embodiments, the amount of spalsentan or its pharmaceutically acceptable salt administered to the subject is approximately 1000 mg / day.

[0059] In any of the embodiments described above, the method may further include administering one or more additional therapeutic agents to the subject. In any of the embodiments described above, the subject may be an adult or a child under 18 years of age. In some embodiments, the subject is under 18 years of age. In some embodiments, the subject is between 5 and 10 years of age. In some embodiments, the subject is between 6 and 12 years of age. In some embodiments, the subject is between 2 and 6 years of age. In some embodiments of the method described above, the subject is 8 years of age or older.

[0060] In some embodiments, the target population is children aged 2 to 4 years, 5 to 7 years, or 8 to 17 years. In some embodiments of the above-described methods of use and treatment, the amount of spalsentan or its pharmaceutically acceptable salt administered to the subject is 1 mg / kg to 15 mg / kg per day. In some embodiments, the amount of spalsentan or its pharmaceutically acceptable salt administered to the subject is 3 mg / kg to 12 mg / kg per day. In some embodiments, the amount of spalsentan or its pharmaceutically acceptable salt administered to the subject is 3 mg / kg to 6 mg / kg per day. In some of these embodiments, the subject is a child (e.g., under 18 years, 2-6 years, 5-10 years, 6-12 years).

[0061] In any of the methods described above, the subject may have primary IgAN confirmed or definitively diagnosed by biopsy. In any of the methods described above, the subject may have an IgAN that is not secondary to another condition.

[0062] In any of the methods described above, the subject may currently be receiving a stable dose of ACEI and / or ARB therapy for at least 12 weeks prior to treatment with, for example, spalsentan. In some embodiments, the subject may be receiving ACEI and / or ARBs at a maximum tolerated dose and at least half of the maximum indicated dose.

[0063] In any of the methods described above, the subject may have a systolic blood pressure of ≤ 150 mmHg and a diastolic blood pressure of ≤ 100 mmHg prior to treatment with spalsentan. In some embodiments of the methods described above, the subjects are not pregnant or breastfeeding women. In some embodiments, if a subject may be pregnant, the subject is also given a monthly pregnancy test, and if the pregnancy test indicates that the subject is pregnant, administration of spalsentan or a pharmaceutically acceptable salt thereof is discontinued. In some embodiments, if a subject may be pregnant, the subject is also administered oral contraceptives, implantable contraceptives, injectable contraceptives, or intrauterine devices.

[0064] In some embodiments of the method described above, subjects do not show cellular glomerular crescent formation in more than 25% of glomeruli in kidney biopsies, for example, within 6 months of initiation of treatment with spalsentan.

[0065] In some embodiments of the method described above, the subjects have no history of organ transplantation other than corneal transplantation. In some embodiments of the method described above, the subjects are not treated with systemic immunosuppressive drug therapy (including corticosteroids) for more than two weeks within three months of initiating treatment with spalsentan.

[0066] In some embodiments of the method described above, the subjects do not have a history of heart failure, a history of hospitalization for heart failure, or unexplained dyspnea, orthopnea, paroxysmal nocturnal dyspnea, ascites, and / or peripheral edema.

[0067] In some embodiments of the method described above, the subjects do not have clinically significant cerebrovascular disease or coronary artery disease within six months of the initiation of treatment with spalsentan. In some embodiments of the method described above, the subjects do not have a significant hepatic condition or severe hepatic impairment. In some embodiments, the subjects do not have severe hepatic impairment (i.e., Child-Pugh classification C). In some embodiments, the subjects do not have jaundice, hepatitis, or a known hepatobiliary disease, or an elevation of transaminases (ALT / AST) more than twice the upper limit of normal, prior to the initiation of treatment with spalsentan.

[0068] In some embodiments of the method described above, the subjects have no history of malignant tumors other than basal cell carcinoma, squamous cell carcinoma, or cervical cancer that have been appropriately treated within the two years prior to the initiation of treatment with spalsentan.

[0069] In some embodiments of the above-described method, the subjects do not have a hematocrit value of less than 27% (0.27 V / V), a hemoglobin value of less than 9 g / dL (90 g / L), and / or a potassium level greater than 5.5 mEq / L (5.5 mmol / L) before initiating treatment with spalsentan.

[0070] In any of the above methods, the subject is 30 mL / min / 1.73 m 2 The patient may have a baseline eGFR of the above and a baseline urinary protein-to-creatinine ratio (UP / C) of 1.0 g / g or higher.

[0071] In some embodiments, the Disclosure provides pharmaceutical compositions comprising spalsentan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for use in any of the methods described above.

[0072] In some embodiments, the disclosure provides the use of a pharmaceutical composition comprising spalsentan or a pharmaceutically acceptable salt thereof in the manufacture of a drug for use in any of the therapeutic methods described above.

[0073] IV. Pharmaceutical preparations In one embodiment, the present disclosure relates to the administration of a pharmaceutical composition comprising spalsentan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Formulation and administration techniques for spalsentan or a pharmaceutically acceptable salt thereof can be found, for example, in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990, which is incorporated herein by reference for teachings relating to such techniques. In some embodiments, the pharmaceutical composition is formulated as described below.

[0074] In some embodiments, excipients include any substance that is not a therapeutic agent itself, which is used as a carrier, diluent, adjuvant, or medium to deliver a therapeutic agent to a target, or to improve its handling or storage properties, or to enable or facilitate the formation of the composition's dosage units into individual articles such as capsules, tablets, film-coated tablets, caplets, gel caps, pills, pellets, beads, etc., suitable for oral administration. For example, excipients may be surfactants (or "surfactants"), carriers, diluents, disintegrants, binders, wetting agents, polymers, lubricants, flow aids, coatings or coating aids, film coating substances, sweeteners, solubilizers, smoothing agents, suspending agents, substances added to mask or neutralize unpleasant tastes or odors, flavors, colorants, fragrances, or substances added to improve the appearance of the composition, or combinations thereof.

[0075] Acceptable excipients include, for example, microcrystalline cellulose, lactose, sucrose, starch powder, corn starch or its derivatives, cellulose esters of alkanates, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfate, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, polyvinyl alcohol, physiological saline, dextrose, mannitol, lactose monohydrate, lecithin, albumin, monosodium glutamate, cysteine ​​hydrochloride, and croscarmellose. It contains melose sodium, sodium starch glycolate, hydroxypropyl cellulose, poloxamers (e.g., poloxamer 101, 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, 403, and 407, as well as poloxamer 105 benzoate, poloxamer 182 dibenzoate 407, etc.), sodium lauryl sulfate, colloidal silicon dioxide, and the like. Examples of excipients suitable for tablets and capsules include microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, sodium starch, hydroxypropyl cellulose, poloxamer 188, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. Examples of excipients suitable for soft gelatin capsules include vegetable oils, waxes, fats, and semi-solid and liquid polyols. Excipients suitable for the preparation of solutions and syrups include, for example, water, polyols, sucrose, invert sugar, and glucose. Compounds can also be encapsulated in microencapsulated forms. Absorption-enhancing preparations (e.g., liposomes) can be used as needed.Excipients acceptable for therapeutic use are well known in the pharmaceutical technology field, and are described, for example, in the “Handbook of Pharmaceutical Excipients,” 5th edition (edited by Raymond C Rowe, Paul J Sheskey, and Sian C Owen, 2005), which are incorporated herein by reference for teachings relating to such excipients, and in “Remington: The Science and Practice of Pharmacy,” 21st edition (Lippincott Williams & Wilkins, 2005).

[0076] In some embodiments, surfactants are used. The use of surfactants as wetting agents in oral drug forms, or to improve the penetration and bioavailability of pharmacoactive compounds, is described in the literature, for example, H. Sucker, P. Fuchs, and P. Speiser, *Pharmazeutische Technologie*, 2nd edition, Thieme, 1989, p. 260, and *Advanced Drug Delivery Reviews* (1997), Vol. 23, pp. 163-183, which are incorporated herein by reference for such teaching. Examples of surfactants include anionic surfactants, nonionic surfactants, amphoteric surfactants, and mixtures thereof. In some embodiments, the surfactant is selected from the group consisting of poly(oxyethylene)sorbitan fatty acid esters, poly(oxyethylene) stearates, poly(oxyethylene) alkyl ethers, polyglycolated glycerides, poly(oxyethylene) castor oil, sorbitan fatty acid esters, poloxamers, fatty acid salts, bile salts, alkyl sulfates, lecithin, mixed micelles of bile salts and lecithin, glucose ester vitamin E TPGS (D-α-tocopheryl polyethylene glycol 1000 succinate), sodium lauryl sulfate, and mixtures thereof.

[0077] As used herein, the term “carrier” defines a compound that facilitates the uptake of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a widely used carrier to facilitate the uptake of many organic compounds into the cells or tissues of living organisms. As used herein, the term “diluent” defines a compound diluted in water that can dissolve a compound of interest and stabilize the biologically active form of that compound. Salts dissolved in buffer solutions are widely used as diluents in the art. One widely used buffer solution is phosphate-buffered saline, which mimics the salt state of human blood. Because buffer salts can control the pH of a solution at low concentrations, buffer diluents hardly alter the biological activity of a compound. In some embodiments, diluents are used that are selected from one or more of the following: sucrose, fructose, glucose, galactose, lactose, maltose, invert sugar, calcium carbonate, lactose, starch, microcrystalline cellulose, lactose monohydrate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, pharmaceutically acceptable polyols such as xylitol, sorbitol, maltitol, mannitol, isomalt, and compounds such as glycerol, polydextrose, starch, or any mixture thereof. Carriers or diluents acceptable for therapeutic use are well known in the pharmaceutical art, and are described, for example, in "Remington's Pharmaceutical Sciences," 18th edition, Mack Publishing Co., Easton, PA (1990), which is incorporated herein by reference for teachings relating to such carriers or diluents.

[0078] In some embodiments, disintegrants such as starch, clay, cellulose, algin, gum, or cross-linked polymers are used, for example, to promote the disintegration of the tablet after administration. Suitable disintegrants include, for example, cross-linked polyvinylpyrrolidone (PVP-XL), sodium starch glycolate, alginic acid, DYB methacrylate, microcrystalline cellulose, crospovidone, potassium polaritrin, sodium starch glycolate, starch, pregelatinized starch, and croscarmellose sodium. In some embodiments, the formulation may also contain small amounts of non-toxic auxiliary substances such as wetting agents or emulsifiers, pH buffers, for example, sodium acetate, sorbitan monolaurate, sodium triethanolamine acetate, triethanolamine oleate, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and polyoxyethylene sorbitan fatty acid esters.

[0079] In some embodiments, binders are used, for example, to impart tackiness to the formulation and thus ensure that the resulting dosage form remains intact after compression. Suitable binder materials include, but are not limited to, microcrystalline cellulose, gelatin, sugars (e.g., sucrose, glucose, dextrose, and maltodextrin), polyethylene glycol, waxes, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, povidone, and cellulose polymers (e.g., hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), methylcellulose, hydroxyethylcellulose, etc.). Accordingly, in some embodiments, the formulations disclosed herein include at least one binder to enhance the compressibility of the main excipients. For example, a formulation may contain at least one of the following binders within the following ranges: about 2% to about 6% w / w hydroxypropyl cellulose (Klucel); about 2% to about 5% w / w polyvinylpyrrolidone (PVP); about 1% to about 5% w / w methyl cellulose; about 2% to about 5% hydroxypropyl methyl cellulose; about 1% to about 5% w / w ethyl cellulose; about 1% to about 5% w / w carboxymethylcellulose sodium, etc. Those skilled in the art will recognize additional binders and / or amounts that may be used in the formulations described herein. As will be recognized by those skilled in the art, when incorporated into the formulations disclosed herein, the amounts of major fillers and / or other excipients may be appropriately reduced to match the amount of binder added in order to maintain a constant unit weight of the overall dosage form. In some embodiments, the binder is sprayed from a solution (e.g., wet granulation) to enhance binding activity.

[0080] In some embodiments, lubricants are used in the manufacture of a particular dosage form. For example, lubricants may be used when manufacturing tablets. In some embodiments, lubricants can be added immediately before the tableting process and mixed with other components in the shortest possible time to obtain good dispersion. In some embodiments, one or more lubricants may be used. Examples of suitable lubricants include magnesium stearate, calcium stearate, zinc stearate, stearic acid, talc, glyceryl behenate, polyethylene glycol, polyethylene oxide polymer (for example, available from Dow Chemical Company, Midland, Michigan, under the registered trademarks Carbowax® for polyethylene glycol and Polyox® for polyethylene oxide), sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silica, and others known in the art. Typical lubricants are magnesium stearate, calcium stearate, zinc stearate, and mixtures of magnesium stearate and sodium lauryl sulfate. The lubricant can constitute about 0.25% to about 50% of the tablet weight, generally about 1% to about 40%, more commonly about 5% to about 30%, and most commonly 20% to 30%. In some embodiments, magnesium stearate can be added as a lubricant, for example, to improve the flow of the powder, to prevent the blend from sticking to the tablet press and punch surface, and to provide lubrication so that the tablets can be ejected cleanly from the tablet mold.In some embodiments, magnesium stearate may be added to pharmaceutical formulations at concentrations ranging from about 0.1% to about 5.0% w / w, or about 0.25% to about 4% w / w, or about 0.5% w / w to about 3% w / w, or about 0.75% to about 2% w / w, or about 0.8% to about 1.5% w / w, or about 0.85% to about 1.25% w / w, or about 0.9% to about 1.20% w / w, or about 0.85% to about 1.15% w / w, or about 0.90% to about 1.1% w / w, or about 0.95% to about 1.05% w / w, or about 0.95% to about 1% w / w. The above ranges are examples of typical ranges. Those skilled in the art will recognize additional lubricants and / or amounts that can be used in the formulations described herein. As can be recognized by those skilled in the art, when incorporated into the pharmaceutical compositions disclosed herein, the amounts of the main fillers and / or other excipients can be appropriately reduced to match the amount of lubricant added in order to maintain a constant unit weight of the entire dosage form.

[0081] In some embodiments, one or more fluidizing agents are used. Examples of fluidizing agents include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and calcium phosphate, as well as mixtures thereof.

[0082] In some embodiments, the formulation may include a coating, such as a film coating. If a film coating is included, the coating preparation may include, for example, a film-forming polymer, a plasticizer, and so on. The coating may also include a pigment or an opacifier. Examples of film-forming polymers include hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinyl pyrrolidine, and starch. Examples of plasticizers include polyethylene glycol, tributyl citrate, dibutyl sebecate, castor oil, and acetylated monoglycerides. Furthermore, examples of pigments and opacifiers include iron oxides of various colors, lake dyes of many colors, and titanium dioxide.

[0083] In some embodiments, one or more coloring additives are included. The coloring agent may be used in an amount sufficient to distinguish the strength of the dosage form. In some embodiments, coloring additives approved for use in drugs (see 21C.FRpt.74) are added to commercially available formulations to distinguish the strength of tablets. The use of other pharmaceutically acceptable coloring agents and combinations thereof is also encompassed by this disclosure.

[0084] The pharmaceutical compositions disclosed herein may include any other agents that provide improved transfer, delivery, tolerance, etc. These compositions may include, for example, powders, pastes, jellies, waxes, oils, lipids, lipid (cationic or anionic)-containing vesicles (e.g., Lipofectin®), DNA conjugates, anhydrous absorbent pastes, oil-in-water and water-in-oil emulsions, Carbowax (polyethylene glycol of various molecular weights) emulsions, semi-solid gels, and semi-solid mixtures containing Carbowax.

[0085] In various embodiments, alcohols, esters, sulfated aliphatic alcohols, etc., may be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium aluminometasilicate, synthetic aluminum silicate, calcium carbonate, acidic sodium carbonate, calcium hydrogen phosphate, calcium carboxymethylcellulose, etc., may be used as excipients; magnesium stearate, talc, hydrogenated oils, etc., may be used as smoothing agents; coconut oil, olive oil, sesame oil, peanut oil, and soybeans may be used as suspending agents or lubricants; plasticizers such as cellulose phthalate acetate as a derivative of carbohydrates such as cellulose or sugar, methyl methacrylate acetate copolymer as a derivative of polyvinyl, or phthalate esters may be used as suspending agents.

[0086] In some embodiments, the pharmaceutical compositions disclosed herein further include one or more of the following: preservatives, stabilizers, dyes, sweeteners, fragrances, flavorings, etc. For example, esters of sodium benzoate, ascorbic acid, and p-hydroxybenzoic acid may be included as preservatives. Antioxidants and suspending agents may also be included in the pharmaceutical compositions.

[0087] In addition to their use as monotherapies, the compounds and pharmaceutical compositions disclosed herein may also be used in combination therapies. Effective combination therapies may be achieved using a single pharmaceutical composition containing multiple active ingredients, or two or more separate pharmaceutical compositions. Alternatively, each therapy may precede or follow the other with intervals ranging from minutes to months.

[0088] In some embodiments, one or more of the described excipients, or any combination thereof, may be specifically included in or excluded from the pharmaceutical compositions or methods disclosed herein.

[0089] Any of the aforementioned formulations may be suitable for treatments and therapies as disclosed herein, provided that one or more active ingredients in the pharmaceutical composition are not inactivated by formulation and that the formulation is physiologically compatible and tolerable to the route of administration (see also Baldrick, Regulatory Toxicology and Pharmacology, Vol. 32(2): pp. 210-218, 2000; Charman, Journal of Pharmaceutical Sciences, Vol. 89(8): pp. 967-978, 2000, and the references therein; these references are incorporated herein by reference for teachings on formulations, excipients, and carriers well known to pharmaceutical chemists).

[0090] In some embodiments, the above-mentioned excipients may be present in amounts of up to about 95% of the total composition weight, or up to about 85% of the total composition weight, or up to about 75% of the total composition weight, or up to about 65% of the total composition weight, or up to about 55% of the total composition weight, or up to about 45% of the total composition weight, or up to about 43% of the total composition weight, or up to about 40% of the total composition weight, or up to about 35% of the total composition weight, or up to about 30% of the total composition weight, or up to about 25% of the total composition weight, or up to about 20% of the total composition weight, or up to about 15% of the total composition weight, or up to about 10% of the total composition weight, or less.

[0091] As will be apparent to those skilled in the art, the amount of excipients will be determined by the drug dosage and dosage size. In some embodiments disclosed herein, the dosage size is approximately 100 mg to 800 mg. In some embodiments disclosed herein, the dosage size is approximately 100 mg. In some embodiments disclosed herein, the dosage size is approximately 200 mg. In some embodiments disclosed herein, the dosage size is approximately 400 mg. In some embodiments disclosed herein, the dosage size is approximately 800 mg. Those skilled in the art will understand that various weights can be made and are included in this disclosure.

[0092] The pharmaceutical compositions of this disclosure may be produced by methods known in themselves, for example, by conventional mixing, dissolving, granulation, sugar-coated tablet production, grinding, emulsification, encapsulation, encapsulation, or tableting processes.

[0093] The pharmaceutical compositions disclosed herein may provide low-dose formulations of spalsentan or a pharmaceutically acceptable salt thereof in dosage forms such as tablets, film-coated tablets, capsules, caplets, pills, gel caps, pellets, beads, or sugar-coated tablets. The formulations disclosed herein can provide advantageous drug handling qualities, including, for example, rapid tableting speed, reduced compressive force, reduced ejection force, uniformity of blend, uniformity of content, uniform dispersion of color, accelerated disintegration time, rapid dissolution, low abrasion (preferred for downstream processing such as packaging, shipping, and pick-and-pack), and less variable physical properties of the dosage form (e.g., weight, hardness, thickness, abrasion).

[0094] The appropriate formulation depends on the chosen route of administration. Suitable routes for administering spalsentan or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing them, may include, for example, oral administration, rectal administration, transmucosal administration, topical administration, or intestinal administration; and parenteral delivery including intramuscular injection, subcutaneous injection, intravenous injection, intramedullary injection, subarachnoid injection, direct intraventricular injection, intraperitoneal injection, intranasal injection, or intraocular injection. Spalsentan or a pharmaceutically acceptable salt thereof may be administered in sustained-release or controlled-release formulations, including depot injections, osmotic pumps, pills, and transdermal (including electrotransport) patches, for long-term or timely pulsed administration at a predetermined rate.

[0095] Injectable preparations can be prepared in conventional forms, either as a liquid solution or suspension, as a solid suitable for dissolution or suspension in a liquid before injection, or as an emulsion. Suitable excipients may include, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, monosodium glutamate, cysteine ​​hydrochloride, etc. In addition, the injectable pharmaceutical composition may optionally contain small amounts of non-toxic adjuncts, such as wetting agents and pH buffers. Physiologically compatible buffers include Hanks' solution, Ringer's solution, or saline buffer. Absorption-enhancing preparations (e.g., liposomes) may be used as needed.

[0096] For transmucosal administration, a penetrating agent suitable for permeating the barrier may be used in the formulation. For example, pharmaceutical formulations for parenteral administration, such as by bolus injection or continuous infusion, contain aqueous solutions of the active compound in a water-soluble form. Furthermore, suspensions of the active compound can be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or media include fatty oils such as sesame oil, or other organic oils such as soybean oil, grapefruit oil, or almond oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to enable the preparation of high-concentration solutions. Injectable formulations may be supplied in unit dosage forms, such as ampoules, or in multi-dose containers, with the addition of preservatives. Compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous media and may contain formulation agents such as suspending agents, stabilizers, or dispersants. Alternatively, the active ingredient may be in powder form for preparation in a suitable medium, such as sterile pyrogen-free water, before use.

[0097] For oral administration, spalsentan or a pharmaceutically acceptable salt thereof can be formulated by combining the active compound with a pharmaceutically acceptable carrier known in the art. Such carriers enable the compound to be formulated as tablets, film-coated tablets, pills, sugar-coated tablets, capsules, liquids, gels, gel caps, pellets, beads, syrups, slurries, suspensions, etc., for oral intake by the patient being treated.

[0098] Pharmaceutical preparations for oral use can be obtained by combining an active compound with a solid excipient, optionally grinding the resulting mixture, adding appropriate adjuvants as needed, and then processing the granular mixture to obtain tablets or sugar-coated tablet cores. Suitable excipients may include fillers such as sugars containing lactose, sucrose, mannitol, or sorbitol, and cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). Disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, may be added as needed. Sugar-coated tablet cores having a suitable coating are also included within the scope of this disclosure. For this purpose, a concentrated sugar solution may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol, titanium dioxide, lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablet or sugar-coated tablet coating for identification or to characterize different combinations of active compound doses. In addition, stabilizers may be added. In some embodiments, formulations for oral administration are doses suitable for such administration. In some embodiments, formulations of spalsentan or its pharmaceutically acceptable salts have an acceptable immediate-release dissolution profile and a robust and scalable manufacturing method.

[0099] Orally administered pharmaceutical preparations include push-fit capsules made of gelatin and soft-seal capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules may contain an active ingredient mixed with a filler such as lactose, a binder such as starch, or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers may be added.

[0100] For buccal administration, the composition can take the form of tablets or lozenges formulated using conventional methods. For administration by inhalation, spalsentan or a pharmaceutically acceptable salt thereof is conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer using a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of pressurized aerosols, the dose unit may be determined by providing a valve for delivering a fixed quantity. Capsules and cartridges, e.g., gelatin capsules and cartridges for use in inhalers or insufflers may be formulated to contain a powder mixture of the compound with a suitable powder base such as lactose or starch.

[0101] This specification further discloses various pharmaceutical compositions well known in the pharmaceutical art for use including intraocular, intranasal, and intraauricular delivery. Suitable penetrating agents for these uses are generally known in the art. Pharmaceutical compositions for intraocular delivery include aqueous ophthalmic solutions of the active compound in water-soluble forms such as eye drops, or in gellan gum (Shedden et al., Clinical Therapeutics (Clin.Ther.), Vol. 23(3): pp. 440-450, 2001) or hydrogel (Mayer et al., Ophthalmologica, Vol. 210(2): pp. 101-103, 1996); ophthalmic ointments; and liquid carrier media (Joshi, Journal of Ocular Pharmacology (J.Ocul.Pharmacol.), Vol. 10(1): pp. 29-45). This includes eye drop suspensions such as fine particles suspended in lipid-soluble formulations (Alm et al., Progress in Clinical and Biological Research, Vol. 312: pp. 447-458, 1989), and microspheres (Mordenti, Toxicol. Sci., Vol. 52(1): pp. 101-106, 1999), drug-containing polymer particles, and other ophthalmic suspensions; and eyeball inserts (these references are incorporated herein by reference for teachings relating to such compositions). Such suitable pharmaceutical formulations may be formulated to be sterile, isotonic, and buffered for stability and comfort. Pharmaceutical compositions for intranasal delivery may include nasal drops and sprays, which are often formulated to mimic nasal discharge in many ways to ensure the maintenance of normal ciliary action.As disclosed in "Remington's Pharmaceutical Sciences," 18th edition, Mack Publishing Co., Easton, PA (1990) (incorporated herein by reference for teachings relating to such formulations), and as is well known to those skilled in the art, suitable formulations are in most cases preferably isotonic, slightly buffered to maintain a pH of 5.5–6.5, and in most cases preferably contain an antimicrobial preservative and a suitable drug stabilizer. Pharmaceutical formulations for intraauricular delivery include suspensions and ointments for topical application in the ear. Common solvents for such ear formulations include glycerin and water.

[0102] Sparsentan or its pharmaceutically acceptable salts can also be formulated into rectal compositions such as suppositories or retained enemas, which may contain conventional suppository bases such as cocoa butter or other glycerides.

[0103] In addition to the above formulations, spalsentan or a pharmaceutically acceptable salt thereof may be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Therefore, for example, spalsentan or a pharmaceutically acceptable salt thereof may be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or as a sparingly soluble derivative, such as a sparingly soluble salt.

[0104] For hydrophobic compounds, a suitable pharmaceutical carrier may be a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. A common cosolvent system used is the VPD cosolvent system, which is a solution of 3% w / v benzyl alcohol, 8% w / v nonpolar surfactant Polysorbate 80™, and 65% w / v polyethylene glycol 300 in anhydrous ethanol at a fixed volume. The proportions of the cosolvent system can be changed significantly without impairing its solubility and toxicity properties. Furthermore, the identity of the cosolvent components can be changed: for example, other low-toxicity nonpolar surfactants may be used instead of Polysorbate 80™; the proportion of polyethylene glycol may be changed; other biocompatible polymers, such as polyvinylpyrrolidone, may be used instead of polyethylene glycol; and other sugars or polysaccharides may be used instead of dextrose.

[0105] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds can be used. Liposomes and emulsions are well-known examples of delivery media or carriers for hydrophobic drugs. In some embodiments, certain organic solvents, such as dimethyl sulfoxide, may also be used.

[0106] Furthermore, the compounds can be delivered using sustained-release systems such as a semipermeable matrix of a solid hydrophobic polymer containing the therapeutic agent. Various sustained-release materials have been established and are known to those skilled in the art. Depending on their chemical properties, sustained-release capsules can release compounds over a period ranging from several weeks to up to 100 days. Depending on the chemical properties and biological stability of the therapeutic reagent, additional strategies for protein stabilization may be used.

[0107] Drugs intended for intracellular administration can be administered using techniques well known to those skilled in the art. For example, such drugs can be encapsulated in liposomes. Molecules present in the aqueous solution at the time of liposome formation are incorporated into the aqueous interior. The liposome contents are protected from the external microenvironment and efficiently delivered into the cytoplasm for the liposome to fuse with the cell membrane. Liposomes can be coated with tissue-specific antibodies. Liposomes can be targeted to desired organs and selectively taken up. Alternatively, hydrophobic small organic molecules can be administered directly into cells.

[0108] In some embodiments, solid unit dosage forms comprising spalsentan or a pharmaceutically acceptable salt thereof are provided for use in the compositions and methods described herein. In some embodiments, the solid unit dosage form comprises spalsentan or a pharmaceutically acceptable salt thereof in amounts of 100 mg; about 100 mg; 200 mg; about 200 mg; 400 mg; or about 400 mg. In some embodiments, the solid unit dosage form comprises spalsentan or a pharmaceutically acceptable salt thereof in amounts of 400 mg; or about 400 mg.

[0109] In some embodiments, liquid formulations of sparnentan or a pharmaceutically acceptable salt thereof are provided for use in the compositions and methods described herein. In some embodiments, the liquid formulation comprises sparnentan and a diluent or medium, such as water. In some embodiments, the liquid formulation further comprises (a) a preservative such as potassium sorbate or sodium benzoate; (b) a sweetener such as sucralose or sodium saccharin; (c) a flavoring agent; (d) a viscosity modifier such as xanthan gum, microcrystalline cellulose / sodium carboxymethylcellulose complex, methylcellulose, or hydroxyethylcellulose; or (e) a pH modifier such as citric acid, tartaric acid, or sodium citrate; or a combination thereof. For example, in some embodiments, a liquid formulation of sparnentan is provided comprising sparnentan, water as a diluent or medium, sodium benzoate, sucralose, a flavoring agent, xanthan gum, and citric acid. In some embodiments, the liquid formulation is administered orally to subjects under 18 years of age, under 12 years of age, 6 to 12 years of age, or 2 to 6 years of age.

[0110] V. Administration Method Sparsentan or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions containing them, may be administered to a subject (e.g., a human patient) by any suitable means. Examples of administration methods include, where it is deemed appropriate by those skilled in the art to bring sparsentan or a pharmaceutically acceptable salt thereof into contact with living tissue, (a) oral administration, including administration in capsules, tablets, granules, sprays, syrups, and other such forms; (b) parenteral administration, including administration as an aqueous suspension, oily preparation, etc., in infusion, spray, suppository, ointment, etc., such as rectal, vaginal, urethral, ​​intraocular, nasal, and auricular; (c) injection, including subcutaneous, intraperitoneal, intravenous, intramuscular, intradermal, intraorbital, intracapsular, intrastellar, intrasternal, etc., including infusion pump delivery; (d) topical administration, such as direct injection into the renal or cardiac region, for example, by depot implantation; and (e) topical administration.

[0111] Suitable pharmaceutical compositions for administration include compositions containing spalsentan or a pharmaceutically acceptable salt thereof in an effective amount to achieve its intended purpose. The dosage may be adjusted to achieve the desired effect, but will depend on factors such as body weight, diet, concomitant drug therapy, and other factors that a person skilled in the art of medicine can recognize.

[0112] In some embodiments, the administration plan of sparsentan or a pharmaceutically acceptable salt thereof is administered for a certain period, which may be, for example, at least about 4 weeks to at least about 8 weeks, at least about 4 weeks to at least about 12 weeks, at least about 4 weeks to at least about 16 weeks, or longer. In some embodiments, the administration plan of sparsentan or a pharmaceutically acceptable salt thereof is administered for 36 weeks or more. In some embodiments, the administration plan of sparsentan or a pharmaceutically acceptable salt thereof is administered for 36 weeks. In some embodiments, the administration plan of sparsentan or a pharmaceutically acceptable salt thereof is administered for 6 months. In some embodiments, the administration plan of sparsentan or a pharmaceutically acceptable salt thereof is administered for 1 year. In some embodiments, the administration plan of sparsentan or a pharmaceutically acceptable salt thereof is administered for 108 weeks. In some embodiments, the administration plan of sparsentan or a pharmaceutically acceptable salt thereof is administered for 110 weeks. The administration schedule for spalsentan or its pharmaceutically acceptable salts may be three times a day, twice a day, daily, every other day, three times a week, every other week, three times a month, once a month, substantially continuously or continuously.

[0113] In some embodiments, the present disclosure relates to a method for using spalsentan or a pharmaceutically acceptable salt thereof in the treatment of IgAN, comprising orally administering to a patient a dose of spalsentan or a pharmaceutically acceptable salt thereof containing approximately 10 mg to approximately 1000 mg of the drug per dose, substantially continuously or consecutively, at frequencies of three times a month, once a month, once a week, once every three days, once every two days, once a day, twice a day, or three times a day, over a desired treatment period.

[0114] In some embodiments, the Disclosure provides a method for using spalsentan or a pharmaceutically acceptable salt thereof in the treatment of a patient's IgAN, comprising orally administering to the patient a dose of the drug containing about 100 mg to about 1000 mg per dose at a frequency of three times a month, once a month, once a week, once every three days, once every two days, once a day, twice a day, or three times a day, over a desired treatment period.

[0115] In some further embodiments, the Disclosure provides a method for using spalsentan or a pharmaceutically acceptable salt thereof in the treatment of a patient's IgAN, comprising orally administering to the patient a dose of the drug containing about 200 mg per dose at a frequency of three times a month, once a month, once a week, once every three days, once every two days, once a day, twice a day, or three times a day, over a desired treatment period.

[0116] In some embodiments, the Disclosure provides a method for using spalsentan or a pharmaceutically acceptable salt thereof in the treatment of a patient's IgAN, comprising orally administering to the patient a dose of the drug containing about 400 mg per dose at a frequency of three times a month, once a month, once a week, once every three days, once every two days, once a day, twice a day, or three times a day, over a desired treatment period.

[0117] In some embodiments, the Disclosure provides a method for using spalsentan or a pharmaceutically acceptable salt thereof in the treatment of a patient's IgAN, comprising orally administering to the patient a dose of the drug containing about 800 mg per dose at a frequency of three times a month, once a month, once a week, once every three days, once every two days, once a day, twice a day, or three times a day, over a desired treatment period.

[0118] In some embodiments, the Disclosure provides a method for using spalsentan or a pharmaceutically acceptable salt thereof in the treatment of a patient's IgAN, comprising administering to the patient an active compound in a dose of approximately 0.1 mg / kg to approximately 100 mg / kg, or approximately 0.2 mg / kg to approximately 50 mg / kg, or approximately 0.5 mg / kg to approximately 25 mg / kg body weight per day (or approximately 1 mg to approximately 2500 mg, or approximately 100 mg to approximately 800 mg) (which may be administered as a single dose or in the form of individual doses divided into 1 to 4 times per day, etc.). In some embodiments, the amount of spalsentan or a pharmaceutically acceptable salt thereof administered to the patient is approximately 1 mg / kg to approximately 15 mg / kg, approximately 3 mg / kg to approximately 12 mg / kg, or approximately 3 mg / kg to approximately 6 mg / kg per day, which may be administered as a single dose or in the form of individual doses divided into 1 to 4 times per day, etc.

[0119] In some embodiments of the pharmaceutical compositions and methods described above, the pharmaceutical composition is a solid unit dosage form. In some embodiments, the solid unit dosage form contains 100 mg, 200 mg, or 400 mg, or about 100 mg, about 200 mg, or about 400 mg of spalsentan or a pharmaceutically acceptable salt thereof. In some embodiments, the solid unit dosage form contains 400 mg, or about 400 mg of spalsentan or a pharmaceutically acceptable salt thereof. In some embodiments, the solid unit dosage form is administered once daily. In some embodiments, the solid unit dosage form is administered orally.

[0120] In some embodiments of the pharmaceutical compositions and methods described above, the pharmaceutical composition is a liquid formulation for oral administration. In some specific embodiments, the liquid formulation is administered to subjects under 18 years of age (e.g., 2 to 6 years of age).

[0121] In some embodiments of the pharmaceutical compositions and methods described above, the pharmaceutical compositions are formulated for oral administration and administered with or without food. The composition may be provided in a pack or dispenser device that may contain one or more unit dosage forms containing the active ingredient, as necessary. The pack may include, for example, metal foil or plastic foil, such as a blister pack. Instructions for administration may be attached to the pack or dispenser device. The pack or dispenser may also be attached to a notice related to the container, in the form prescribed by the government agency that regulates the manufacture, use, or sale of the drug. This notice reflects the government agency's approval of the form of the drug for human or animal administration. Such a notice may be, for example, a label or product insert approved by the U.S. Food and Drug Administration as a prescription drug. Compositions containing spalsentan or a pharmaceutically acceptable salt thereof formulated in a suitable pharmaceutical carrier may also be prepared, placed in a suitable container, and labeled for use in the indicated state. [Examples]

[0122] VI. Examples Example 1 - Effect of spalsentan on immunoprecipitates in the gddY mouse model This study was conducted using "grouped ddY" (gddY) mice. This is a model based on the original uninbred ddY mouse strain that spontaneously expresses IgAN at various ages of onset. gddY mice were established by selectively breeding ddY mice with an early onset phenotype for more than 20 generations.

[0123] 8-week treatment In one study, gddY mice were administered 900 or 1800 ppm (approximately 180 or 360 mg / kg per day, respectively) of spalsentan in their diet from 4 to 12 weeks of age. After the study ended 8 weeks after treatment, kidney samples were taken from the mice, and the composition of immunodeposits in the kidneys was determined using immunofluorescence (IF) antibodies against IgA (Myette et al., Kidney International, Vol. 96(1): pp. 104-116, 2019, doi:10.1016 / j.kint.2019.01.031).

[0124] IgA content levels in immunodeposits were significantly reduced in mice treated with 900 or 1800 ppm spalsentan (P=0.003 and P=0.007, respectively) (Figures 1A-1B, Figure 2). In this study, circulating levels of IgA or abnormally glycosylated IgA were not altered by spalsentan. Proteinuria was significantly reduced and glomerulosclerosis was attenuated in gddY mice treated with spalsentan (Nagasawa et al., Journal of the American Society of Nephrology (J Am Soc Nephrol), Vol. 31, PO1808 (poster), ASN Kidney Week, October 22-25, p. 564, 2020).

[0125] 16-week treatment In another study, gddY mice were administered 900 ppm sparsentan in their diet and losartan was provided in drinking water at a dose of 30 mg / kg for 16 weeks from 4 to 20 weeks of age. Sparsentan significantly prevented the deposition of IgA, IgG, and C3, while losartan did not (P<0.01, P<0.0001, and P<0.05, respectively) (Figures 3A-3C, 4A-4C). Furthermore, the deposition of IgA, IgG, and C3 in the renal mesangium of gddY mice treated with losartan was significantly higher than in mice treated with sparsentan (P<0.01, P<0.01, and P<0.05, respectively). The signal intensity obtained by concatenating images of immunofluorescence (IF) using anti-IgA and anti-IgG antibodies in control gddY mice was significantly attenuated after IF using the same antibodies in kidney sections of sparsentan-treated gddY mice (Figures 4A and 4B). Further images of IF performed using anti-C3 antibodies in kidney sections of control gddY mice or sparsentan-treated gddY mice showed that sparsentan treatment also attenuated the amount of C3 in the immunodeposits (Figure 4C).

[0126] As observed in shorter-term studies, there was no change in circulating IgA levels (Figure 5). Serum IgA levels were measured by sandwich enzyme-linked immunosorbent assay (ELISA) (Bethyl Laboratories, Montgomery, TX, USA) using a modified method previously described (Suzuki et al., Kidney International, Vol. 72: pp. 319-327, 2007, doi: 0.1038 / sj.ki.5002300).

[0127] Spalsentan treatment rapidly reduced proteinuria, prevented increases in ET-1, ETAR, and AT1R, and prevented upcontrol of inflammatory pathways. It also protected glomeruli from glomerulosclerosis and podocyte loss, while protecting the glycocalyx layer of endothelial cells (Nagasawa et al., ERA-EDTA Paris (oral presentation), May 19-22, 2022).

[0128] Further embodiments can be provided by combining the various embodiments described above. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications referenced herein and / or described in application data sheets, including U.S. Provisional Patent Application No. 63 / 505,314 filed on 31 May 2023, which are incorporated herein by reference, are incorporated herein by reference in their entirety unless otherwise stated. The aspects of the embodiments can be modified as needed to provide further embodiments using concepts from various patents, applications, and publications.

[0129] In consideration of the detailed description above, these and other variations may be made to the embodiments. In general, the terms used in the following claims should not be construed as limiting the claims to the specific embodiments disclosed herein and therein, but rather as encompassing all possible embodiments, along with the entire scope of equivalents for which such claims are entitled. Thus, the claims are not limited by this disclosure.

Claims

1. A method for preventing IgA-mediated diseases, comprising administering spalsentan to a subject in need thereof.

2. The method according to claim 1, wherein the prevention of the IgA-mediated disease includes preventing further deposition of IgA in the kidneys.

3. A method for reversing the effects of an IgA-mediated disease or achieving remission of an IgA-mediated disease, comprising administering spalsentan to a subject in need thereof.

4. A method for restoring tissue function and integrity in a subject with an IgA-mediated disease, comprising administering spalsentan to the subject.

5. A method for healing damage in IgA-associated nephropathy, comprising administering spalsentan to a subject in need thereof.

6. The method according to claim 4, wherein the subject has an IgA-mediated disease.

7. A method for treating an IgA-mediated disease, comprising administering spalsentan to a subject in need thereof.

8. The method according to any one of claims 1 to 4, 6, and 7, wherein the IgA-mediated disease is IgA nephropathy.

9. The method according to any one of claims 1 to 4, 6, and 7, wherein the IgA-mediated disease is IgA vasculitis.

10. The method according to any one of claims 1 to 4, 6, and 7, wherein the IgA-mediated disease is IgA-related dermatitis.

11. The method according to any one of claims 1 to 4, 6, and 7, wherein the IgA-mediated disease is linear IgA bullous dermatosis (LABD).

12. The method according to any one of claims 1 to 4 and 6 to 7, wherein the subject has been diagnosed with an IgA-mediated disease based on the analysis of a tissue biopsy.

13. The method according to any one of claims 1 to 12, wherein the normal function and integrity of the tissue are restored.

14. The method according to any one of claims 1 to 13, wherein further deposition of IgA in the kidneys is prevented.

15. The method according to any one of claims 1 to 14, wherein the administration comprises providing daily administration of spalsentan for a period of at least six months, and the subject returns to a normal diet after the period of six months.

16. The method according to any one of claims 1 to 15, wherein the administration first provides spalsentan at a daily dose of 200 mg to 400 mg over a period of six months, and then provides spalsentan at a daily dose of 200 mg or less.

17. The method according to any one of claims 1 to 15, wherein the administration first provides 400 mg of spalsentan per day over a period of one year, and then provides spalsentan in a daily dose of 200 mg or less.

18. The method according to any one of claims 1 to 17, further comprising administering a second therapeutic agent to the subject.

19. Spalsentan for use in the method according to any one of claims 1 to 18.

20. A pharmaceutical composition comprising spalsentan for use in the method according to any one of claims 1 to 18.

21. Use of spalsentan in the method according to any one of claims 1 to 18, or use of a pharmaceutical composition containing spalsentan.

22. Use of spalsentan in the manufacture of a drug for use in the method according to any one of claims 1 to 18.

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