Sparsentan for use in a method of treating iga-mediated diseases

Abstract

Methods of preventing or treating immunoglobulin A-mediated diseases, such as immunoglobulin A nephropathy, by treatment with sparsentan, or a pharmaceutically acceptable salt thereof, are provided.

Description

METHOD OF TREATING IGA-MEDIATED DISEASESBACKGROUND

[0001] Immunoglobulin A (IgA) is an antibody that plays a role in the immune function of mucous membranes. The amount of IgA produced in association with mucosal membranes is greater than all other types of antibody combined. It is a major antibody component found in mucous secretions, including tears, saliva, sweat, colostrum, and secretions from the genitourinary tract, gastrointestinal tract, prostate, and respiratory epithelium.

[0002] IgA nephropathy (IgAN) (also called Berger's disease) is the most common form of primary glomerulonephritis, with the highest prevalence in the Asian population. IgAN is a rare autoimmune disease leading to a kidney disorder that is characterized by the build up of antibodies (IgA) in kidney tissue, specifically the glomeruli, which are a cluster of capillaries around the end of a kidney tubule, where waste products are filtered from the blood. This IgA deposition occurs in the mesangial cells of glomeruli and results in chronic inflammation and glomerular damage. The IgA that typically circulates and is deposited in the glomeruli of IgAN patients is enriched in a form that is under-galactosylated (Gd-IgAl) due to abnormal production, which triggers an auto-immune response to generate antibodies that recognize the abnormal IgA. The immunodeposits contain Gd-IgAl bound to the auto-antibodies. IgA nephropathy results in blood in the urine (hematuria) and protein in the urine (proteinuria). In some cases, swelling, recurrent upper respiratory infections, and intestinal disease, with patients frequently having flank pain and low fever. Ultimately IgAN leads to kidney failure. Historically, IgAN led to 40% patients progressing to dialysis in less than 20 years, and 50% mortality at about 30 years after diagnosis of IgA nephropathy.

[0003] The pathogenesis of IgAN is thought to occur via a "4-hit" mechanism with production of circulating Gd-IgAl, generation of anti-Gd-IgAl antibodies, formation of immune complexes, and deposition of the immune complexes in mesangial cells leading to glomerular injury (Suzuki et al., J Am Soc Nephrol 22(10): 1795-1803, 2011, doi:10.1681 / ASN.2011050464). It is based on the observation that abnormalities in the production of IgAl lead to elevated plasma levels of galactose-deficient IgAl (Gd-IgAl) (hit #1). The increased Gd-IgAl elicits an autoimmune response, resulting in generation of anti-glycan antibodies that recognize N-acetylgalactosamine epitopes on Gd-IgAl (hit #2). The Gd-IgAl and the IgG autoantibodies form immune complexes in the circulation (hit #3). These immunecomplexes can deposit on the mesangial cells in the kidney (hit #4), resulting in activation of the complement system and inflammatory pathways and inducing kidney injury.

[0004] More recent research has suggested that the deposition and composition of the immune complexes onto the mesangial cells may be more regulated at the glomerular level involving apoptosis inhibitor of macrophage (AIM) (Takahata et al., JASN 31(9): 2013 -2024, 2020, doi: 10.1681 / ASN.2019100987) and generation of mesangial cell auto-antigens (Nihei et al., SciAdv. 9(12):eadd6734, 2023, doi: 10.1126 / sciadv.add6734).

[0005] IgA vasculitis, is a disease that causes IgA to collect in small blood vessels, triggering inflammation and leakage (http: / / www.niddk.nih.gov / health-information / kidney- disease / iga-vasculitis). Often IgA vasculitis is apparent by a red or purple rash. Some people with IgA vasculitis also develop problems with their gastrointestinal (GI) tractjoints, and kidneys, and occasionally, lungs, nervous system, or other organs because of blood vessel inflammation. In approximately 3 to 27 cases per 100,000 in children and infants, IgA vasculitis may lead to further complications like IgAN.

[0006] Linear IgA bullous dermatosis (LABD) is a mucocutaneous autoimmune disease, characterized by linear deposition of IgA and disruption of the dermo-epidermal junction, resulting in blisters. Mucosal surfaces may also be affected. The condition occurs in children between 6 months and 10 years of age, and in geriatric populations. LABD may be related to lymphoproliferative disorders, infections, ulcerative colitis, and systemic lupus erythematosis.

[0007] Sparsentan is a single-molecule dual antagonist of the endothelin and angiotensin receptors (DEARA). ETAR and AT1R play an important role in IgAN. IgAN patient biopsies have shown that intra-renal levels of ET-1 and Ang II are associated with a higher risk of progression (Tycova et al., Physiol Res. 67(1):93-105, 2018, doi: 10.33549 / physiolres.933670; Lai Kidney Int. 66(4): 1403-1416, 2004, doi: 10.1111 / j .1523-1755.2004.00874.x). The PROTECT trial (ClinicalTrials.gov, NCT03762850) was the basis for accelerated approval of sparsentan by United States Food and Drug Administration for the reduction of proteinuria in adults with IgA nephropathy at high risk of disease progression (Heerspink et al., Lancet 401(10388): 1584-1594, 2023 (published April 1, 2023), doi: 10.1016 / S0140-6736(23)00569-X).

[0008] Most therapies for IgAN and related IgA-mediated pathologies only slow or impede progression of disease. Therapies or methods for preventing the initiation of kidney damage or progression of damage, or reversing the effects of these diseases, would be desirable.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] The patent or application file contains at least one drawing executed in color.Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0010] FIGS. 1A-1B show images of IgA content detected by immunofluorescence (IF) staining in immune deposits in kidney glomeruli of gddY mice treated for 8 weeks with a control diet or a diet containing sparsentan at 900 or 1800 ppm.

[0011] FIG. 2 shows quantitation of IgA content as detected by IF staining in immune deposits in kidney glomeruli of gddY mice treated for 8 weeks with a control diet or a diet containing sparsentan at 900 or 1800 ppm. Three glomeruli from each specimen were scored semi quantitatively for the brightness of glomeruli staining (0, negative 1, weak 2, medium 3, strong).

[0012] FIGS. 3A-3C show images and quantitation of IgA, IgG, and C3 content detected by IF staining in immune deposits in kidney glomeruli of gddY mice treated for 16 weeks with a control diet or a diet containing sparsentan at 900 ppm or with losartan in the drinking water to deliver 30 mg / kg per day FIG. 3 A shows images and quantitation of IgA content. FIG. 3B shows images and quantitation of IgG content. FIG. 3C shows images and quantitation of C3 content.

[0013] FIGS. 4A-4C show images of IgA, IgG, and C3 content detected by IF staining in immune deposits in glomeruli of gddY mice following 16 weeks of treatment with a control diet or a diet containing sparsentan at 900 ppm. FIG. 4A and FIG. 4B show a merge of IgA and IgG in immune deposits in glomeruli. FIG. 4C shows images of C3 in glomerular immune deposits.

[0014] FIG. 5 shows serum levels of IgA assessed in gddY control mice (gddY C), or gddY mice treated with sparsentan in chow at 900 ppm (gddY SP900) or losartan in the drinking water to deliver 30 mg / kg per day (gddY LS30) at 12 and 20 weeks of age following 8 or 16 weeks of treatment. Individual animal data are shown with mean ± SD.DETAILED DESCRIPTION

[0015] The present disclosure generally relates to the use of sparsentan, a compound having dual angiotensin and endothelin receptor antagonist activity, in the prevention and / or treatment of diseases related to immunoglobulin A (IgA), such as IgA nephropathy (IgAN), e.g., by preventing or reducing the glomerular deposition of IgA.

[0016] In the following description, certain 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.I. Glossary

[0017] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. As used herein, certain terms may have the following defined meanings.

[0018] Unless the context requires otherwise, throughout the present specification and claims, the word "comprise" and variations thereof, such as "comprises" and "comprising," are to be construed in an open, inclusive sense, that is, as "including, but not limited to."

[0019] As used in the specification and claims, "including" and variants thereof, such as "include" and "includes," are to be construed in an open, inclusive sense; z.e., it is equivalent to "including, but not limited to." As used herein, the terms "include" and "have" are used synonymously, which terms and variants thereof are intended to be construed as non-limiting.

[0020] As used in herein, the phrase "such as" refers to non-limiting examples.

[0021] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0022] As used in the specification and claims, the singular for "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a cell" includes a plurality of cells, including mixtures thereof. Similarly, use of "a compound" for treatment of preparation of medicaments as described herein contemplates using one or more compounds of the invention for such treatment or preparation unless the context clearly dictates otherwise.

[0023] The use of the alternative (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives.

[0024] "Optional" or "optionally" means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not occur.

[0025] As used herein, "about" and "approximately" generally refer to an acceptable degree of error for the quantity measured, given the nature or precision of the measurements. Typical, exemplary degrees of error may be within 20%, 10%, or 5% of a given value or range of values. Alternatively, and particularly in biological systems, the terms "about" and "approximately" may mean values that are within an order of magnitude, potentially within 5- fold or 2-fold of a given value. When not explicitly stated, the terms "about" and "approximately" mean equal to a value, or within 20% of that value.

[0026] As used herein, numerical quantities are precise to the degree reflected in the number of significant figures reported. For example, a value of 0.1 is understood to mean from 0.05 to 0.14. As another example, the interval of values 0.1 to 0.2 includes the range from 0.05 to 0.24.

[0027] Sparsentan may form salts, which are also within the scope of this disclosure. Reference to sparsentan herein is generally understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)," as employed herein, denotes acidic, or basic salts formed with inorganic or organic acids and bases. In addition, as sparsentan contains both a basic moiety and an acidic moiety, zwitterions ("inner salts") may be formed and are included within the term "salt(s)," as used herein. Pharmaceutically acceptable (z.e., non-toxic, physiologically acceptable) salts are preferred, although other salts may be useful, e.g., in isolation or purification steps which may be employed during preparation. Salts of sparsentan may be formed, for example, by reacting sparsentan with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0028] The term "pharmaceutically acceptable salt" includes both acid and base addition salts.

[0029] Prodrugs and solvates of sparsentan are also contemplated. The term "prodrug" denotes a compound that, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield sparsentan, or a salt or solvate thereof. Solvates of sparsentan may be hydrates. Any tautomers are also contemplated.

[0030] Crystallizations may produce a solvate of sparsentan, or a salt thereof. As used herein, the term "solvate" refers to an aggregate that comprises one or more molecules of acompound as disclosed herein with one or more molecules of 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 the present disclosure may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. In some embodiments, the compounds disclosed herein may be a true solvate, while in other cases, the compounds disclosed herein merely retain adventitious water or are mixtures of water plus some adventitious solvent.

[0031] The invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising administering a compound of this invention to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the invention in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood, or other biological samples.

[0032] Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0033] The term "subject" refers to a mammal, such as a domestic pet (for example, a dog or cat), or human. Preferably, the subject is a human. In some embodiments, the subject is a patient that has been diagnosed as having a disease or disorder (e.g., IgAN).

[0034] The phrase "effective amount" refers to the amount which, when administered to a subject or patient for treating a disease, is sufficient to effect such treatment for the disease.

[0035] The term "dosage unit form" (or "dose unit form") is the form of a pharmaceutical product, including, but not limited to, the form in which the pharmaceutical product is marketed for use. Examples include pills, tablets, capsules, and liquid solutions and suspensions. For example, as approved and available in the United States, sparsentan is available in 200 mg and 400 mg tablets, though other dosage unit forms are contemplated.

[0036] Treatment" or "treating" includes (1) inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease (e.g., arresting further development of the pathology or symptomatology); or (2) ameliorating a disease in asubject or patient that is experiencing or displaying the pathology or symptomatology of the disease (e.g., reversing the pathology or symptomatology); or (3) effecting any measurable decrease in a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease.

[0037] "Preventing" in the context of preventing a subject (e.g.sa patient) from experiencing or displaying the pathology or symptomology of a disease includes the failure to develop a disease, disorder, or condition, or the reduction in the development of a sign or symptom associated with such a disease, disorder, or condition (e.g., by a clinically relevant amount), or the exhibition of delayed signs or symptoms delayed (e.g., by days, weeks, months, or years).

[0038] As used herein, "reversing an effect of a disease" means to return the tissue or subject afflicted with the disease to a state of health relative to the initial presentment with the disease. Reversing an effect of the disease need not require complete recovery, and need not mean reversal of all (or each and every of the) symptoms or measurable results (i.e., laboratory results) returning to statistically "normal" values. Reversing an effect of a disease means a relative recovery of function, tending toward or returning to normalcy or recovering from a disease state.

[0039] As used herein, "achieving remission of a disease" refers to return the tissue or subject afflicted with the disease to a state of health. Thus for a tissue, remission would return the tissue to a healthy state, with reduced necrosis and scarring and with normal function. In the case of IgAN, achieving remission means healing of lesions to provide what may appear to be a normal kidney, with normal function.

[0040] As used herein, "restoring function" of a tissue means a return of function, regardless of histology. For example, acute injury (including surgery) to an internal organ may not provide an organ free of scar tissue, pre-injury vascularization, etc., but it may function as if the injury had not occurred. In some internal organs (e.g., the liver), organs may regenerate thus providing restored function, though it is histologically apparent that injury had occurred.

[0041] As used herein, "restoring integrity" of a tissue means that from a histological standpoint, tissue with necrosis, scarring, infarct, and the like, are returned to intact tissue, as commonly occurs in wound healing. The processes of restoring integrity may be simple tissue remodeling facilitated by removal of inflammation, reduction in depositions of plaques of various types (including IgA-related plaques), and the like. The healing of IgA-relatednephropathic damage is a combination of restoring integrity of the tissue and restoring function of the organ involved.

[0042] As used herein, "normal diet" means a diet that is unsupervised or restricted. For example, in many cases individuals with kidney diseases and proteinurea are put on restrictive diets to avoid systemic imbalances, muscle wasting, etc. Returning to a normal diet, in this context, means alleviating the need to continue restictions imposed for the purpose of treating the IgA-mediated disease.

[0043] Additional definitions are set forth throughout this disclosure.II. Sparsentan

[0044] Sparsentan (CAS 254740-64-2, 2-[4-[(2-butyl-4-oxo-l,3-diazaspiro[4.4]non-l-en-3-yl)methyl]-2-(ethoxymethyl)phenyl]-N-(4,5-dimethyl-l,2-oxazol-3-yl)benzenesulfonamide) is a biphenyl sulfonamide compound having structure (I),

[0045] Sparsentan is a selective dual-acting receptor antagonist with affinity for endothelin (A type) receptors ("ETA" receptors) and angiotensin II receptors (Type 1) ("ATi" receptors) (Kowala et al., JPET 309:275-284, 2004).

[0046] Sparsentan may be prepared by methods such as those described in International Patent Application Publication No. WO2018 / 071784 Al. Additionally, sparsentan may be prepared by the methods recited in U.S. Patent Application Publication No. US 2015 / 0164865 Al and U.S. Patent No. US 6,638,937 B2.III. Pharmaceutical Compositions and Methods of Use

[0047] In some embodiments, the present disclosure relates to the administration of a pharmaceutical composition comprising sparsentan, or a pharmaceutically acceptable salt thereof. The term "pharmaceutical composition" as used herein refers to a composition comprising an active ingredient and a pharmaceutically acceptable excipient. Pharmaceutical compositions may be used to facilitate administration of an active ingredient to an organism. Multiple techniques of administering a compound exist in the art, such as oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can be obtained, for example, by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methane sulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. As used herein, the term "physiologically acceptable excipient" or "pharmaceutically acceptable excipient" refers to a physiologically and pharmaceutically suitable non-toxic and inactive material or ingredient that does not interfere with the activity of the active ingredient, including any adjuvant, carrier, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0048] In some embodiments, the pharmaceutical composition may be formulated as described below.

[0049] Additionally, methods of preventing or treating IgA-mediated diseases, such as IgAN, comprising administering sparsentan, or a pharmaceutically acceptable salt thereof, are within the scope of the present disclosure. In some embodiments, methods of preventing or treating IgA-mediated diseases, such as IgAN, comprising administering a pharmaceutical composition comprising sparsentan, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, are provided.

[0050] In some embodiments, methods of preventing further deposition of IgA in the kidney, comprising administering sparsentan (or a pharmaceutically acceptable salt thereof) to a subject in need thereof are provided.

[0051] In some embodiments, methods of reversing an effect of an IgA-mediated disease, or achieving remission of an IgA-mediated disease, comprising administering sparsentan (or a pharmaceutically acceptable salt thereof) to a subject in need thereof are provided.

[0052] In some embodiments, methods of restoring function and integrity of a tissue in a subject having an IgA-mediated disease, comprising administering sparsentan (or a pharmaceutically acceptable salt thereof) to the subject are provided.

[0053] In some embodiments, methods of healing IgA-related nephropathic damage, comprising administering sparsentan (or a pharmaceutically acceptable salt thereof) to a subject in need thereof are provided. In some such embodiment, the subject has an IgA-mediated disease.

[0054] In some embodiments of the aforementioned methods, normal function and integrity of a tissue is restored. In some embodiments of the aforementioned methods, further deposition of IgA in the kidney is prevented.

[0055] In still further embodiments, sparsentan, or a pharmaceutically acceptable salt thereof, is useful in the reduction of general morbidity or mortality as a result of the above utilities.

[0056] In some embodiments, sparsentan, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising sparsentan, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, are useful in prolonging the time to end stage renal disease or reducing a risk of end stage renal disease in a patient diagnosed with IgAN.

[0057] In some embodiments, sparsentan, 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 (z.e., urine protein excretion of greater than 300 mg per day). A urinary protein to creatinine ("UP / C") ratio provides a measurement of total urine protein relative to the amount of creatinine in a urine sample (e.g., 1 g of protein in urine (dl) divided by 1 g of creatinine in urine (dl) = a UP / C ratio of 1). As used herein, a UP / C ratio of more than 0.3 g / g indicates proteinuria. In some embodiments, sparsentan, or a pharmaceutically acceptable salt thereof, is useful in reducing proteinuria to less than or equal to 1.0 g / g. In some embodiments, sparsentan, or a pharmaceutically acceptable salt thereof, is useful in reducing proteinuria to less than or equal to 0.5 g / g. In some embodiments, sparsentan, or a pharmaceutically acceptable salt thereof, is useful in reducing proteinuria to less than or equal to 0.3 g / g (z.e., complete remission of proteinuria). Accordingly, the present disclosure also provides methods of inducing complete remission in a subject having IgAN, by administering sparsentan, or a pharmaceutically acceptable salt thereof, to the subject.

[0058] In some embodiments, a method of treating IgAN in a subject in need thereof is provided, the method comprising administering to the subject a pharmaceutical compositioncomprising sparsentan, or a pharmaceutically acceptable salt thereof, in an amount sufficient to achieve a UP / C ratio of less than or equal to 1.0 g / g. In some embodiments, a method of treating IgAN in a subject in need thereof is provided, the method comprising administering to the subject a pharmaceutical composition comprising sparsentan, or a pharmaceutically acceptable salt thereof, in an amount sufficient to achieve or maintain a UP / C ratio of less than or equal to 1.0 g / g. In some embodiments, a method of treating IgAN in a subject in need thereof is provided, the method comprising administering to the subject a pharmaceutical composition comprising sparsentan, or a pharmaceutically acceptable salt thereof, at a dosing regimen sufficient to achieve or maintain a UP / C ratio of less than or equal to 1.0 g / g. In some of the foregoing embodiments, treatment with sparsentan reduces proteinuria to less than or equal to 0.5 g / g. In some of the foregoing embodiments, treatment with sparsentan reduces proteinuria to less than or equal to 0.3 g / g (z.e., treatment with sparsentan induces complete remission of proteinuria). In some embodiments, the dosing regimen comprises administering sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 100 mg / day. In some embodiments, the dosing regimen comprises administering sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 200 mg / day. In some embodiments, the dosing regimen comprises administering sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 400 mg / day. In some embodiments, the dosing regimen comprises administering sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 800 mg / day. In some embodiments, the dosing regimen comprises administering sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 200 mg / day for 8 weeks, 26 weeks, 36 weeks, 6 months, 8 months, 1 year, or 108 weeks. In some embodiments, the dosing regimen comprises administering sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 400 mg / day for 8 weeks, 26 weeks, 36 weeks, 6 months, 8 months, 1 year, or 108 weeks. In some embodiments, the dosing regimen comprises administering sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 800 mg / day for 8 weeks, 26 weeks, 36 weeks, 6 months, 8 months, 1 year, or 108 weeks. In some embodiments, the dosing regimen comprises administering sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 200 mg / day for 6 weeks, 36 weeks, 6 months, 1 year, 58 weeks, or 110 weeks. In some embodiments, the dosing regimen comprises administering sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 400 mg / day for 6 weeks, 36 weeks, 6 months, 1 year, 58 weeks, or 110 weeks.

[0059] In some embodiments, if the subject's weight is from 20 kg to 50 kg, the amount of sparsentan, or a pharmaceutically acceptable salt thereof, administered to the subject is 200mg / day for the first 2 weeks and thereafter is 400 mg / day. In some embodiments, if the subject's weight is greater than 50 kg, the amount of sparsentan, or a pharmaceutically acceptable salt thereof, administered to the subject is 400 mg / day for the first 2 weeks and thereafter is 800 mg / day.

[0060] In some embodiments, a method of treating IgAN in a subject in need thereof is provided, the method comprising administering to the subject, over an administration period, a pharmaceutical composition comprising sparsentan, or a pharmaceutically acceptable salt thereof, in an amount sufficient to achieve or maintain a UP / C ratio of less than or equal to 1.0 g / g for at least a portion of the administration period. "Administration period" refers to the time period during which the pharmaceutical composition is administered to the subject as 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.

[0061] In some embodiments, a method of maintaining a UP / C ratio at less than or equal to 1.0 g / g in a subject in need thereof is provided, the method comprising administering to the subject a pharmaceutical composition comprising sparsentan, or a pharmaceutically acceptable salt thereof, in an amount sufficient to maintain a UP / C ratio of less than or equal to 1.0 g / g.

[0062] In some embodiments, a method of reducing a UP / C ratio to less than or equal to 1.0 g / g in a subject in need thereof is provided, comprising administering to the subject a pharmaceutical composition comprising sparsentan, or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce said subject's UP / C ratio to less than or equal to 1.0 g / g. In some embodiments, the subject has, or has had, a UP / C ratio greater than 1.0 g / g prior to administration of the pharmaceutical composition.

[0063] In some embodiments, sparsentan, or a pharmaceutically acceptable salt thereof, is useful in maintaining glomerular filtration rate. As used herein, "glomerular filtration rate" ("GFR") is a measure of kidney function and refers to the amount of fluid filtered through the glomeruli of the kidney per unit of time. GFR may be estimated by measuring serum creatinine levels and using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation. As used herein, "estimated glomerular filtration rate" ("eGFR") refers to an estimate of GFR obtained from using the CKD-EPI creatinine equation. In some embodiments, sparsentan,or a pharmaceutically acceptable salt thereof, is useful in maintaining eGFR levels e.g., preventing a reduction in eGFR associated with IgAN or reducing the rate of decline in eGFR in a patient having IgAN). In some embodiments, administering sparsentan, or a pharmaceutically acceptable salt thereof, to a subject results in eGFR being maintained at or above eGFR levels immediately prior to (e.g., within a month prior to) administration of sparsentan, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition comprising the same. In some embodiments, administering sparsentan, or a pharmaceutically acceptable salt thereof, to a subject results in eGFR being maintained at or above baseline eGFR level, where "baseline eGFR level" refers to their most recently calculated eGFR level prior to onset of treatment. As used herein, "maintenance of eGFR" refers to no clinically meaningful reduction in baseline eGFR levels. Thus, as used herein, in reference to treatment of a patient having IgAN, the phrase “maintain eGFR constant” means treatment that maintains the subject's eGFR at a level that is clinically equivalent to or better than their baseline eGFR (i.e., most recently calculated eGFR level prior to onset of treatment). In some embodiments, the eGFR is maintained for months or years after administration. The period of time during which the subject's eGFR level is maintained constant typically is at least 12 months.

[0064] In some embodiments, any of the aforementioned uses or methods of treatment may comprise administering sparsentan, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition comprising the same, 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 prior to, simultaneously with, or following the administration of the pharmaceutical composition comprising an effective amount of sparsentan, or a pharmaceutically acceptable salt thereof. If formulated as a fixed dose, such combination products may employ sparsentan, or a pharmaceutically acceptable salt thereof, within the dosage range described below, and the other active ingredient within its approved dosage range.

[0065] In some embodiments, sparsentan, or a pharmaceutically acceptable salt thereof, is used in conjunction with hemodialysis.

[0066] In some embodiments of the aforementioned uses and methods of treatment, the dosing regimen comprises administering sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 50 mg / day. In some embodiments, the dosing regimen comprises administering sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 100 mg / day. In some embodiments, the dosing regimen comprises administering sparsentan, or apharmaceutically acceptable salt thereof, in an amount of 200 mg / day. In some embodiments, the dosing regimen comprises administering sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 300 mg / day. In some embodiments, the dosing regimen comprises administering sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 400 mg / day. In some embodiments, the dosing regimen comprises administering sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 500 mg / day. In some embodiments, the dosing regimen comprises administering sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 600 mg / day. In some embodiments, the dosing regimen comprises administering sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 700 mg / day. In some embodiments, the dosing regimen comprises administering sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 800 mg / day. In some embodiments, the dosing regimen comprises administering sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 900 mg / day. In some embodiments, the dosing regimen comprises administering sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 1000 mg / day.

[0067] In some embodiments of the aforementioned uses and methods of treatment, the dosing regimen comprises administering sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 100 mg / day for 6 weeks, 8 weeks, 26 weeks, 36 weeks, 8 months, 108 weeks, or 110 weeks. In some embodiments of the aforementioned uses and methods of treatment, the dosing regimen comprises administering sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 200 mg / day for 6 weeks, 8 weeks, 26 weeks, 36 weeks, 8 months, 108 weeks, or 110 weeks. In some embodiments of the aforementioned uses and methods of treatment, the dosing regimen comprises administering sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 400 mg / day for 6 weeks, 8 weeks, 26 weeks, 36 weeks, 8 months, 108 weeks, or 110 weeks. In still further embodiments, the dosing regimen comprises administering sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 800 mg / day for 6 week, 8 weeks, 26 weeks, 36 weeks, 8 months, 108 weeks, or 110 weeks.

[0068] In any of the aforementioned embodiments, the amount of sparsentan, or a pharmaceutically acceptable salt thereof, administered to the subject may be from about 50 mg / day to about 1000 mg / day. For example, in some embodiments, the amount of sparsentan, or a pharmaceutically acceptable salt thereof, administered to the subject is from about 200 mg / day to about 800 mg / day. In other embodiments, the amount of sparsentan, or a pharmaceuticallyacceptable salt thereof, administered to the subject is about 50 mg / day. In other embodiments, the amount of sparsentan, or a pharmaceutically acceptable salt thereof, administered to the subject is about 100 mg / day. In other embodiments, the amount of sparsentan, or a pharmaceutically acceptable salt thereof, administered to the subject is about 200 mg / day. In other embodiments, the amount of sparsentan, or a pharmaceutically acceptable salt thereof, administered to the subject is about 300 mg / day. In other embodiments, the amount of sparsentan, or a pharmaceutically acceptable salt thereof, administered to the subject is about 400 mg / day. In other embodiments, the amount of sparsentan, or a pharmaceutically acceptable salt thereof, administered to the subject is about 500 mg / day. In other embodiments, the amount of sparsentan, or a pharmaceutically acceptable salt thereof, administered to the subject is about 600 mg / day. In other embodiments, the amount of sparsentan, or a pharmaceutically acceptable salt thereof, administered to the subject is about 700 mg / day. In other embodiments, the amount of sparsentan, or a pharmaceutically acceptable salt thereof, administered to the subject is about 800 mg / day. In other embodiments, the amount of sparsentan, or a pharmaceutically acceptable salt thereof, administered to the subject is about 900 mg / day. In other embodiments, the amount of sparsentan, or a pharmaceutically acceptable salt thereof, administered to the subject is about 1000 mg / day.

[0069] In any of the aforementioned embodiments, the method may further comprise administering to said subject one or more additional therapeutic agents.

[0070] In any of the aforementioned embodiments, the subject may be an adult or may be a child of less than 18 years of age. In some embodiments, the subject is younger than 18 years of age. In some embodiments, the subject is from 5 to 10 years of age. In some embodiments, the subject is from 6 to 12 years of age. In some embodiments, the subject is from 2 to 6 years of age. In some embodiments of the aforementioned methods, the subject is 8 years old or older.

[0071] In some embodiments, the subject is a pediatric subject who is from 2 years of age up to 4 years of age; from 5 years of age up to 7 years of age; or from 8 to 17 years of age.

[0072] In some embodiments of the aforementioned uses and methods of treatment, the amount of sparsentan, or a pharmaceutically acceptable salt thereof, administered to the subject is from 1 mg / kg to 15 mg / kg per day. In some embodiments, the amount of sparsentan, or a pharmaceutically acceptable salt thereof, administered to the subject is from 3 mg / kg to 12 mg / kg per day. In some embodiments, the amount of sparsentan, or a pharmaceutically acceptable salt thereof, administered to the subject is from 3 mg / kg to 6 mg / kg per day. In someof these embodiments, the subject is a child e.g., less than 18 years of age; from 2 to 6 years of age; from 5 to 10 years of age; from 6 to 12 years of age).

[0073] In any of the aforementioned methods, the subject may have biopsy-confirmed or biopsy-proven primary IgAN.

[0074] In any of the aforementioned methods, the subject may have IgAN that is not secondary to another condition.

[0075] In any of the aforementioned methods, the subject may be currently on a stable dose of ACEI and / or ARB therapy, e.g., for at least 12 weeks prior to treatment with sparsentan. In some embodiments, the subject may be receiving an ACEI and / or ARB at the maximum tolerated dose and at least one-half of the maximum labeled dose.

[0076] In any of the aforementioned methods, the subject may have a systolic BP <150 mmHg and diastolic BP <100 mmHg prior to treatment with sparsentan.

[0077] In some embodiments of the aforementioned methods, the subject is not a pregnant or breastfeeding female. In some embodiments, if the subject is of childbearing potential, the subject is also administered monthly pregnancy tests, and if a pregnancy test indicates that the subject is pregnant, administration of sparsentan or a pharmaceutically acceptable salt thereof, is discontinued. In some embodiments, if the subject is of childbearing potential, the subject is also administered an oral contraceptive, an implanted contraceptive, an injected contraceptive, or an intrauterine device.

[0078] In some embodiments of the aforementioned methods, the subject does not exhibit cellular glomerular crescents in >25% of glomeruli on renal biopsy, e.g., within 6 months of beginning treatment with sparsentan.

[0079] In some embodiments of the aforementioned methods, the subject does not have a history of organ transplantation, with the exception of corneal transplants.

[0080] In some embodiments of the aforementioned methods, the subject is not treated with systemic immunosuppressive medications (including corticosteroids) for >2 weeks within 3 months of beginning treatment with sparsentan.

[0081] In some embodiments of the aforementioned methods, the subject does not have a history of heart failure or previous hospitalization for heart failure or unexplained dyspnea, orthopnea, paroxysmal nocturnal dyspnea, ascites, and / or peripheral edema.

[0082] In some embodiments of the aforementioned methods, the subject does not have clinically significant cerebrovascular disease or coronary artery disease within 6 months of beginning treatment with sparsentan.

[0083] In some embodiments of the aforementioned methods, the subject does not have a significant hepatic condition or severe hepatic impairment. In some embodiments, the subject does not have severe hepatic impairment (i.e. ,Child-Pugh class C). In some embodiments, the subject does not have jaundice, hepatitis, or known hepatobiliary disease or elevations of transaminases (ALT / AST) >2 times upper limit of normal prior to beginning treatment with sparsentan.

[0084] In some embodiments of the aforementioned methods, the subject does not have a history of malignancy other than adequately treated basal cell or squamous cell skin cancer or cervical carcinoma within the past 2 years prior to beginning treatment with sparsentan.

[0085] In some embodiments of the aforementioned methods, the subject does not have a hematocrit value <27% (0.27 V / V), a hemoglobin value <9 g / dL (90 g / L), and / or potassium >5.5 mEq / L (5.5 mmol / L) prior to beginning treatment with sparsentan.

[0086] In any of the aforementioned methods, the subject may have a baseline eGFR greater than or equal to 30 mL / min / 1.73 m2and a baseline urinary protein to creatinine ratio (UP / C) greater than or equal to 1.0 g / g.

[0087] In some embodiments, the present disclosure provides a pharmaceutical composition comprising sparsentan, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient for use in any of the aforementioned methods.

[0088] In some embodiments, the present disclosure provides for the use of a pharmaceutical composition comprising sparsentan, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in any of the aforementioned therapeutic methods.IV. Pharmaceutical Formulations

[0089] In one aspect, the present disclosure relates to the administration of a pharmaceutical composition comprising sparsentan, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient. Techniques for formulation and administration of sparsentan, or a pharmaceutically acceptable salt thereof, may 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 relevant to such techniques. In some embodiments, the pharmaceutical composition is formulated as described below.

[0090] In some embodiments, an excipient includes any substance, not itself a therapeutic agent, used as a carrier, diluent, adjuvant, or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition into a discrete article such as a capsule, tablet, film coated tablet, caplet, gel cap, pill, pellet, bead, and the like suitable for oral administration. For example, an excipient may be a surface active agent (or "surfactant"), carrier, diluent, disintegrant, binding agent, wetting agent, polymer, lubricant, glidant, coating or coating assistant, film forming substance, sweetener, solubilizing agent, smoothing agent, suspension agent, substance added to mask or counteract a disagreeable taste or odor, flavor, colorant, fragrance, or substance added to improve appearance of the composition, or a combination thereof.

[0091] Acceptable excipients include, for example, microcrystalline cellulose, lactose, sucrose, starch powder, maize starch or derivatives thereof, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, polyvinyl alcohol, saline, dextrose, mannitol, lactose monohydrate, lecithin, albumin, sodium glutamate, cysteine hydrochloride, croscarmellose sodium, sodium starch glycolate, hydroxypropyl cellulose, poloxamer (e.g., poloxamers 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, and poloxamer 105 benzoate, poloxamer 182 dibenzoate 407, and the like), sodium lauryl sulfate, colloidal silicon dioxide, and the like. Examples of suitable excipients 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 suitable excipients for soft gelatin capsules include vegetable oils, waxes, fats, and semisolid and liquid polyols. Suitable excipients for the preparation of solutions and syrups include, for example, water, polyols, sucrose, invert sugar, and glucose. The compound can also be made in microencapsulated form. If desired, absorption enhancing preparations (for example, liposomes), can be utilized. Acceptable excipients for therapeutic use are well known in the pharmaceutical art, and are described, for example, in "Handbook of Pharmaceutical Excipients," 5th edition (Raymond C Rowe, Paul J Sheskey and Sian C Owen, eds. 2005), and "Remington: The Science and Practice of Pharmacy," 21st edition (LippincottWilliams & Wilkins, 2005), which are incorporated herein by reference for teachings relevant to such excipients.

[0092] In some embodiments, surfactants are used. Use of surfactants as wetting agents in oral drug forms or to improve the permeation and bioavailability of pharmaceutical active compounds is described in the literature, for example in H. Sucker, P. Fuchs, P. Speiser, Pharmazeutische Technologic, 2nd edition, Thieme 1989, page 260, and Advanced Drug Delivery Reviews (1997), 23, pages 163-183, which are incorporated herein by reference for such teachings. Examples of surfactants include anionic surfactants, non-ionic surfactants, zwitterionic surfactants, and a mixture thereof. In some embodiments, the surfactant is selected from the group consisting of poly(oxyethylene) sorbitan fatty acid ester, poly(oxyethylene) stearate, poly(oxyethylene) alkyl ether, polyglycolated glyceride, poly(oxyethylene) castor oil, sorbitan fatty acid ester, poloxamer, fatty acid salt, bile salt, alkyl sulfate, lecithin, mixed micelle of bile salt and lecithin, glucose ester vitamin E TPGS (D-a-tocopheryl polyethylene glycol 1000 succinate), sodium lauryl sulfate, and the like, and a mixture thereof.

[0093] As used herein, the term "carrier" defines a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly utilized carrier, as it facilitates the uptake of many organic compounds into the cells or tissues of an organism. As used herein, the term "diluent" defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are commonly utilized as diluents in the art. One commonly used buffered solution is phosphate buffered saline because it mimics the salt conditions of human blood. Because buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound. In some embodiments, a diluent selected from one or more of the compounds sucrose, fructose, glucose, galactose, lactose, maltose, invert sugar, calcium carbonate, lactose, starch, microcrystalline cellulose, lactose monohydrate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, a pharmaceutically acceptable polyol such as xylitol, sorbitol, maltitol, mannitol, isomalt, and glycerol, polydextrose, starch, and the like, or any mixture thereof, is used. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in "Remington's Pharmaceutical Sciences," 18th Ed., Mack Publishing Co., Easton, PA (1990), which is incorporated herein by reference for teachings relevant to such carriers or diluents.

[0094] In some embodiments, disintegrants such as starches, clays, celluloses, algins, gums, or crosslinked polymers are used, for example, to facilitate tablet disintegration after administration. Suitable disintegrants include, for example, crosslinked polyvinylpyrrolidone (PVP-XL), sodium starch glycolate, alginic acid, methacrylic acid DYB, microcrystalline cellulose, crospovidone, polacriline potassium, sodium starch glycolate, starch, pregelatinized starch, croscarmellose sodium, and the like. In some embodiments, the formulation can also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and the like; for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polyoxyethylene sorbitan fatty acid esters, and the like.

[0095] In some embodiments, binders are used, for example, to impart cohesive qualities to a formulation, and thus ensure that the resulting dosage form remains intact after compaction. Suitable binder materials include, but are not limited to, microcrystalline cellulose, gelatin, sugars (including, for example, sucrose, glucose, dextrose and maltodextrin), polyethylene glycol, waxes, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, povidone, cellulosic polymers (including, for example, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), methyl cellulose, hydroxyethyl cellulose, and the like), and the like. Accordingly, in some embodiments, a formulations disclosed herein includes at least one binder to enhance the compressibility of the major excipient(s). For example, the formulation can include at least one of the following binders in the following ranges: from about 2% to about 6% w / w hydroxypropyl cellulose (Klucel); from about 2% to about 5% w / w polyvinylpyrrolidone (PVP); from about 1% to about 5% w / w methylcellulose; from about 2% to about 5% hydroxypropyl methylcellulose; from about 1% to about 5% w / w ethylcellulose; from about 1% to about 5% w / w sodium carboxy methylcellulose; and the like. One of ordinary skill in the art would recognize additional binders and / or amounts that can be used in the formulations described herein. As would be recognized by one of ordinary skill in the art, when incorporated into the formulations disclosed herein, the amounts of the major filler(s) and / or other excipients can be reduced accordingly to accommodate the amount of binder added in order to keep the overall unit weight of the dosage form unchanged. In some embodiments, a binder is sprayed on from solution, e.g., wet granulation, to increase binding activity.

[0096] In some embodiments, a lubricant is employed in the manufacture of certain dosage forms. For example, a lubricant may be employed when producing tablets. In some embodiments, a lubricant can be added just before the tableting step, and can be mixed with theother ingredients for a minimum period of time to obtain good dispersal. 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 polymers (for example, available under the registered trademarks of Carbowax® for polyethylene glycol and Polyox® for polyethylene oxide from Dow Chemical Company, Midland, Mich.), sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silica, and others as known in the art. Typical lubricants are magnesium stearate, calcium stearate, zinc stearate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants may comprise from about 0.25% to about 50% of the tablet weight, typically from about 1% to about 40%, more typically from about 5% to about 30%, and most typically from 20% to 30%. In some embodiments, magnesium stearate can be added as a lubricant, for example, to improve powder flow, prevent the blend from adhering to tableting equipment and punch surfaces, and provide lubrication to allow tablets to be cleanly ejected from tablet dies. 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 from about 0.25% to about 4% w / w, or from about 0.5% w / w to about 3% w / w, or from about 0.75% to about 2% w / w, or from about 0.8% to about 1.5% w / w, or from about 0.85% to about 1.25% w / w, or from about 0.9% to about 1.20% w / w, or from about 0.85% to about 1.15% w / w, or from about 0.90% to about 1.1.% w / w, or from about 0.95% to about 1.05% w / w, or from about 0.95% to about 1% w / w. The above ranges are examples of typical ranges. One of ordinary skill in the art would recognize additional lubricants and / or amounts that can be used in the formulations described herein. As would be recognized by one of ordinary skill in the art, when incorporated into the pharmaceutical compositions disclosed herein, the amounts of the major filler(s) and / or other excipients may be reduced accordingly to accommodate the amount of lubricant(s) added in order to keep the overall unit weight of the dosage form unchanged.

[0097] In some embodiments, one or more glidants are used. Examples of glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and calcium phosphate, and the like, and mixtures thereof.

[0098] In some embodiments, the formulations can include a coating, for example, a film coating. Where film coatings are included, coating preparations may include, for example, a film-forming polymer, a plasticizer, or the like. Also, the coatings may include pigments or opacifiers. Examples of film-forming polymers include hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinyl pyrrolidine, and starches. Examples ofplasticizers include polyethylene glycol, tributyl citrate, dibutyl sebecate, castor oil, and acetylated monoglyceride. Furthermore, examples of pigments and opacifiers include iron oxides of various colors, lake dyes of many colors, titanium dioxide, and the like.

[0099] In some embodiments, one or more color additives are included. The colorants can be used in amounts sufficient to distinguish dosage form strengths. In some embodiments, color additives approved for use in drugs (see 21 C.F.R. pt. 74) are added to the commercial formulations to differentiate tablet strengths. The use of other pharmaceutically acceptable colorants and combinations thereof is also encompassed by the current disclosure.

[0100] The pharmaceutical compositions as disclosed herein may include any other agents that provide improved transfer, delivery, tolerance, and the like. These compositions may include, for example, powders, pastes, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as Lipofectin®), DNA conjugates, anhydrous absorption pastes, oil-in- water and water-in-oil emulsions, emulsions of Carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semisolid mixtures containing Carbowax.

[0101] In various embodiments, alcohols, esters, sulfated aliphatic alcohols, and the like may be used as surface active agents; sucrose, glucose, lactose, starch, crystallized cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium methasilicate aluminate, synthetic aluminum silicate, calcium carbonate, sodium acid carbonate, calcium hydrogen phosphate, calcium carboxymethyl cellulose, and the like may be used as excipients; magnesium stearate, talc, hardened oil, and the like may be used as smoothing agents; coconut oil, olive oil, sesame oil, peanut oil, and soya may be used as suspension agents or lubricants; cellulose acetate phthalate as a derivative of a carbohydrate such as cellulose or sugar, methyl acetatemethacrylate copolymer as a derivative of polyvinyl, or plasticizers such as ester phthalate may be used as suspension agents.

[0102] In some embodiments, a pharmaceutical composition as disclosed herein further comprises one or more of preservatives, stabilizers, dyes, sweeteners, fragrances, flavoring agents, and the like. For example, sodium benzoate, ascorbic acid, and esters of p- hydroxybenzoic acid may be included as preservatives. Antioxidants and suspending agents may also be included in the pharmaceutical composition.

[0103] In addition to being used as a monotherapy, the compounds and pharmaceutical compositions disclosed herein may also find use in combination therapies. Effective combination therapy may be achieved with a single pharmaceutical composition that includes multiple activeingredients, or with two or more distinct pharmaceutical compositions. Alternatively, each therapy may precede or follow the other by intervals ranging from minutes to months.

[0104] In some embodiments, one or more of, or any combination of, the listed excipients can be specifically included or excluded from the pharmaceutical compositions or methods disclosed herein.

[0105] Any of the foregoing formulations may be appropriate in treatments and therapies in accordance with the disclosure herein, provided that the one or more active ingredient in the pharmaceutical composition is not inactivated by the formulation and the formulation is physiologically compatible and tolerable with the route of administration (see also Baldrick, Regul. Toxicol. Pharmacol. 32(2):210-218, 2000; Charman, J. Pharm. Sci. 89(8):967-978, 2000, and the citations therein; which references are incorporated herein by reference for teachings relevant to formulations, excipients, and carriers well known to pharmaceutical chemists).

[0106] In some embodiments, the above excipients can be present in an amount 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.

[0107] As will be appreciated by those of skill in the art, the amounts of excipients will be determined by drug dosage and dosage form size. In some embodiments disclosed herein, the dosage form size is about 100 mg to 800 mg. In some embodiments disclosed herein, the dosage form size is about 100 mg. In some embodiments disclosed herein, the dosage form size is about 200 mg. In some embodiments disclosed herein, the dosage form size is about 400 mg. In some embodiments disclosed herein, the dosage form size is about 800 mg. One skilled in the art will realize that a range of weights may be made and are encompassed by this disclosure.

[0108] The pharmaceutical compositions of the present disclosure may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or tableting processes.

[0109] The pharmaceutical compositions of the present disclosure may provide low-dose formulations of sparsentan, or a pharmaceutically acceptable salt thereof, in tablets, film coatedtablets, capsules, caplets, pills, gel caps, pellets, beads, or dragee dosage forms. The formulations disclosed herein can provide favorable drug processing qualities, including, for example, rapid tablet press speeds, reduced compression force, reduced ejection forces, blend uniformity, content uniformity, uniform dispersal of color, accelerated disintegration time, rapid dissolution, low friability (preferable for downstream processing such as packaging, shipping, pick-and-pack, etc.) and dosage form physical characteristics (e.g., weight, hardness, thickness, friability) with little variation.

[0110] Proper formulation is dependent upon the route of administration chosen. Suitable routes for administering sparsentan, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, may include, for example, oral, rectal, transmucosal, topical, or intestinal administration; and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections. Sparsentan, or a pharmaceutically acceptable salt thereof, may also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for prolonged or timed, pulsed administration at a predetermined rate.

[0111] Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients may include, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, and the like. In addition, if desired, the injectable pharmaceutical compositions may contain minor amounts of nontoxic auxiliary substances, such as wetting agents, pH buffering agents, and the like. Physiologically compatible buffers include Hanks' solution, Ringer's solution, or physiological saline buffer. If desired, absorption enhancing preparations (for example, liposomes), may be utilized.

[0112] For transmucosal administration, penetrants appropriate to the barrier to be permeated may be used in the formulation.

[0113] Pharmaceutical formulations for parenteral administration, e.g., by bolus injection or continuous infusion, include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or other organic oils such as soybean, grapefruit, or almond oils, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions maycontain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi -dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use.

[0114] For oral administration, sparsentan, or a pharmaceutically acceptable salt thereof can be formulated by combining the active compound with pharmaceutically acceptable carriers known in the art. Such carriers enable the compound to be formulated as tablets, film coated tablets, pills, dragees, capsules, liquids, gels, get caps, pellets, beads, syrups, slurries, suspensions, and the like, for oral ingestion by a patient to be treated.

[0115] Pharmaceutical preparations for oral use can be obtained by combining the active compound with solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients may be, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl- cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Dragee cores having suitable coatings are also within the scope of the disclosure. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions, or suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. In addition, stabilizers can be added. In some embodiments, formulations fororal administration are in dosages suitable for such administration. In some embodiments, formulations of sparsentan, or a pharmaceutically acceptable salt thereof have an acceptable immediate release dissolution profile and a robust, scalable method of manufacture.

[0116] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, or lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.

[0117] For buccal administration, the compositions may take the form of tablets or lozenges formulated in a conventional manner.

[0118] For administration by inhalation, sparsentan, or a pharmaceutically acceptable salt thereof is conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin, for use in an inhaler or insufflator, may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0119] Further disclosed herein are various pharmaceutical compositions well known in the pharmaceutical art for uses that include intraocular, intranasal, and intraauricular delivery. Suitable penetrants for these uses are generally known in the art. Pharmaceutical compositions for intraocular delivery include aqueous ophthalmic solutions of the active compounds in water- soluble form, such as eye drops, or in gellan gum (Shedden et al., Clin. Ther. 23(3):440-450, 2001) or hydrogels (Mayer et al., Ophthalmol ogica 210(2): 101-103, 1996); ophthalmic ointments; ophthalmic suspensions, such as microparticulates, drug-containing small polymeric particles that are suspended in a liquid carrier medium (Joshi, J. OcuL Pharmacol. 10(l):29-45, 1994), lipid-soluble formulations (Alm et al., Prog. Clin. Biol. Res. 312:447-458, 1989), and microspheres (Mordenti, Toxicol. Sci. 52(1): 101-106, 1999); and ocular inserts (which references are incorporated herein by reference for teachings relevant 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 also include drops andsprays often prepared to simulate in many respects nasal secretions, to ensure maintenance of normal ciliary action. As disclosed in "Remington's Pharmaceutical Sciences," 18th Ed., Mack Publishing Co., Easton, PA (1990) (incorporated herein by reference for teachings relevant to such formulations), and well known to those skilled in the art, suitable formulations are most often and preferably isotonic, slightly buffered to maintain a pH of 5.5 to 6.5, and most often and preferably include antimicrobial preservatives and appropriate drug stabilizers. Pharmaceutical formulations for intraauricular delivery include suspensions and ointments for topical application in the ear. Common solvents for such aural formulations include glycerin and water.

[0120] Sparsentan, or a pharmaceutically acceptable salt thereof may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., those containing conventional suppository bases such as cocoa butter or other glycerides.

[0121] In addition to the formulations described previously, sparsentan, or a pharmaceutically acceptable salt thereof, may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, sparsentan, or a pharmaceutically acceptable salt thereof may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0122] 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 co-solvent system, which is a solution of 3% w / v benzyl alcohol, 8% w / v of the nonpolar surfactant Polysorbate 80™, and 65% w / v polyethylene glycol 300, made up to volume in absolute ethanol. The proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of Polysorbate 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.

[0123] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well-known examples of delivery vehicles or carriers for hydrophobic drugs. In some embodiments, certain organic solvents such as dimethylsulfoxide also may be employed.

[0124] Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

[0125] Agents intended to be administered intracellularly may be administered using techniques well known to those of ordinary skill in the art. For example, such agents may be encapsulated into liposomes. Molecules present in an aqueous solution at the time of liposome formation are incorporated into the aqueous interior. The liposomal contents are both protected from the external micro-environment and, because liposomes fuse with cell membranes, are efficiently delivered into the cell cytoplasm. The liposome may be coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the desired organ. Alternatively, small hydrophobic organic molecules may be directly administered intracellularly.

[0126] In some embodiments, a solid dosage unit form comprising sparsentan, or a pharmaceutically acceptable salt thereof, is provided for use in the compositions and methods described herein. In some embodiments, the solid dosage unit form includes sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 100 mg; about 100 mg; 200 mg; about 200 mg; 400 mg; or about 400 mg. In some embodiments, the solid dosage unit form includes sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 400 mg; or about 400 mg.

[0127] In some embodiments, a liquid formulation of sparsentan, or a pharmaceutically acceptable salt thereof, is provided for use in the compositions and methods described herein. In some embodiments, the liquid formulation comprises sparsentan and a diluent or vehicle, 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 composite, methyl cellulose, or hydroxyethyl cellulose; or (e) a pH modifier, such as citric acid, tartaric acid, or sodium citrate; or combinations thereof. For example, in some embodiments, a liquid formulation of sparsentan is provided, which comprises sparsentan, water as a diluent or vehicle, sodium benzoate, sucralose, a flavoring agent, xanthan gum, and citric acid. In some embodiments, the liquid formulation isadministered orally to a subject who is 18 years old or younger, 12 years old or younger, from 6 to 12 years of age, or from 2 to 6 years of age.V. Methods of Administration

[0128] Sparsentan, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions comprising the same may be administered to the subject (e.g., a human patient) by any suitable means. Examples of methods of administration include (a) administration though oral pathways, which includes administration in capsule, tablet, granule, spray, syrup, and other such forms; (b) administration through non-oral pathways such as rectal, vaginal, intraurethral, intraocular, intranasal, and intraauricular, which includes administration as an aqueous suspension, an oily preparation, or the like as a drip, spray, suppository, salve, ointment, or the like; (c) administration via injection, subcutaneously, intraperitoneally, intravenously, intramuscularly, intradermally, intraorbitally, intracapsularly, intraspinally, intrasternally, or the like, including infusion pump delivery; (d) administration locally such as by injection directly in the renal or cardiac area, e.g., by depot implantation; and (e) administration topically; as deemed appropriate by those of skill in the art for bringing sparsentan, or a pharmaceutically acceptable salt thereof into contact with living tissue.

[0129] Pharmaceutical compositions suitable for administration include compositions where sparsentan, or a pharmaceutically acceptable salt thereof, is contained in an amount effective to achieve its intended purpose. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication, and other factors that those skilled in the medical arts will recognize.

[0130] In some embodiments, the dosing regimen of sparsentan, or a pharmaceutically acceptable salt thereof, is administered for a period of time, which time period can be, for example, from at least about 4 weeks to at least about 8 weeks, from at least about 4 weeks to at least about 12 weeks, from at least about 4 weeks to at least about 16 weeks, or longer. In some embodiments, the dosing regimen of sparsentan, or a pharmaceutically acceptable salt thereof, is administered for 36 weeks or longer. In some embodiments, the dosing regimen of sparsentan, or a pharmaceutically acceptable salt thereof, is administered for 36 weeks. In some embodiments, the dosing regimen of sparsentan, or a pharmaceutically acceptable salt thereof, is administered for 6 months. In some embodiments, the dosing regimen of sparsentan, or a pharmaceutically acceptable salt thereof, is administered for 1 year. In some embodiments, the dosing regimen of sparsentan, or a pharmaceutically acceptable salt thereof, is administered for 108 weeks. In someembodiments, the dosing regimen of sparsentan, or a pharmaceutically acceptable salt thereof, is administered for 110 weeks. The dosing regimen of sparsentan, or a pharmaceutically acceptable salt thereof can be administered three times a day, twice a day, daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously, or continuously.

[0131] In some embodiments, the present disclosure relates to a method of using sparsentan, or a pharmaceutically acceptable salt thereof, in the treatment of IgAN comprising administering to the patient a dosage of sparsentan, or a pharmaceutically acceptable salt thereof containing an amount of about 10 mg to about 1000 mg, of drug per dose, orally, at a frequency of three times per month, once monthly, once weekly, once every three days, once every two days, once per day, twice per day, three times per day, substantially continuously, or continuously, for the desired duration of treatment.

[0132] In some embodiments, the present disclosure provides a method of using sparsentan, or a pharmaceutically acceptable salt thereof, in the treatment of IgAN in a patient comprising administering to the patient a dosage containing an amount of about 100 mg to about 1000 mg, of drug per dose, orally, at a frequency of three times per month, once monthly, once weekly, once every three days, once every two days, once per day, twice per day, or three times per day, for the desired duration of treatment.

[0133] In some further embodiments, the present disclosure provides a method of using sparsentan, or a pharmaceutically acceptable salt thereof, in the treatment of IgAN in a patient comprising administering to the patient a dosage containing an amount of about 200 mg of drug per dose, orally, at a frequency of three times per month, once monthly, once weekly, once every three days, once every two days, once per day, twice per day, or three times per day, for the desired duration of treatment.

[0134] In some embodiments, the present disclosure provides a method of using sparsentan, or a pharmaceutically acceptable salt thereof, in the treatment of IgAN in a patient comprising administering to the patient a dosage containing an amount of about 400 mg of drug per dose, orally, at a frequency of three times per month, once monthly, once weekly, once every three days, once every two days, once per day, twice per day, or three times per day, for the desired duration of treatment.

[0135] In some embodiments, the present disclosure provides a method of using sparsentan, or a pharmaceutically acceptable salt thereof, in the treatment of IgAN in a patient comprising administering to the patient a dosage containing an amount of about 800 mg of drugper dose, orally, at a frequency of three times per month, once monthly, once weekly, once every three days, once every two days, once per day, twice per day, or three times per day, for the desired duration of treatment.

[0136] In some embodiments, the present disclosure provides a method of using sparsentan, or a pharmaceutically acceptable salt thereof, in the treatment of IgAN in a patient comprising administering to the patient a dosage from about 0.1 mg / kg to about 100 mg / kg, or from about 0.2 mg / kg to about 50 mg / kg, or from about 0.5 mg / kg to about 25 mg / kg of body weight (or from about 1 mg to about 2500 mg, or from about 100 mg to about 800 mg) of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day. In some embodiments, the amount of sparsentan, or a pharmaceutically acceptable salt thereof, administered to the patient is from about 1 mg / kg to about 15 mg / kg, from about 3 mg / kg to about 12 mg / kg, or from about 3 mg / kg to about 6 mg / kg, per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day.

[0137] In some embodiments of the aforementioned pharmaceutical compositions and methods, the pharmaceutical composition is a solid dosage unit form. In some embodiments, the solid dosage unit form includes sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 100 mg, 200 mg, or 400 mg, or about 100 mg, about 200 mg, or about 400 mg. In some embodiments, the solid dosage unit form includes sparsentan, or a pharmaceutically acceptable salt thereof, in an amount of 400 mg, or about 400 mg. In some embodiments, the solid dosage unit form is administered once daily. In some embodiments, the solid dosage unit form is administered orally.

[0138] In some embodiments of the aforementioned pharmaceutical compositions and methods, the pharmaceutical composition is a liquid formulation for oral administration. In some particular embodiments, the liquid formulation is administered to a subject who is less than 18 years of age (e.g., from 2 to 6 years of age).

[0139] In some embodiments of the aforementioned pharmaceutical compositions and methods, the pharmaceutical composition is formulated for oral administration and is administered with or without food.

[0140] The compositions may, if desired, be presented in a pack or dispenser device that may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also beaccompanied with a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions comprising sparsentan, or a pharmaceutically acceptable salt thereof, formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.VI, ExamplesEXAMPLE 1 - Effects of Spar sentan on Immunoprecipitates in a gddY Mouse Model

[0141] Studies were conducted using "grouped ddY" (gddY) mice, which are a model based on the original outbred ddY mouse that spontaneously develops IgAN with a variable age of onset. gddY mice were established by the selective mating of ddY mice with the early-onset phenotype for >20 generations.8-Week Treatment

[0142] In one study, sparsentan was adminstered in the diet to gddY at 900 or 1800 ppm (approximately 180 or360 mg / kg per day respectively) from 4 to 12 weeks of age. Following the end of the study after 8 weeks of treatment, kidney samples were taken from the mice and the composition of the immune deposits in the kidney was determined using immunofluorescent (IF) antibodies to IgA, (Myette et al., Kidney International 96(1): 104-116, 2019, doi:10.1016 / j .kint.2019.01.031).

[0143] IgA content levels of the immunodeposits were significantly reduced in mice treated with sparsentan at 900 or 1800 ppm (P=0.003 and P=0.007, respectively) (FIGS. 1A-1B, FIG. 2). Circulating levels of IgA or aberrantly glycosylated IgA were not altered by sparsentan in the study. Proteinuria was significantly reduced and glomerulosclerosis was attenuated in gddY mice treated with sparsentan (Nagasawa et al., J Am Soc Nephrol 31, PO1808 (poster) ASN Kidney Week, October 22-25, p. 564, 2020).16-Week Treatment

[0144] In another study in which sparsentan was administered in the diet to gddY mice at 900 ppm and losartan was provided in the drinking water at 30 mg / kg for 16 weeks, from 4 to 20 weeks of age, sparsentan, but not losartan, significantly prevented the deposition of IgA, IgG, and C3 (P<0.01, P<0.0001, and P<0.05, respectively) (FIGS. 3A-3C, FIGS. 4A-4C). Moreover, the deposition of IgA, IgG, and C3 in the kidney mesangium of gddY treated with losartan was significantly greater than that in mice treated with sparsentan (P<0.01, P<0.01, and P<0.05, respectively). The signal intensity resulting from merging of the images from IF using anti -IgA and anti-IgG antibodies in the control gddY mice was greatly attenuated following IF using the same antibodies in kidney sections from sparsentan-treated gddY mice (FIG. 4A, FIG. 4B). Further images from IF performed with an anti-C3 antibody in kidney sections from control or sparsentan treated gddY mice illustrate that sparsentan treatment also attenuates the extent of C3 in the immunodeposits (FIG. 4C).

[0145] As was observed in the shorter study, there was no alteration in the circulating levels of IgA (FIG. 5). Serum IgA levels were measured by sandwich enzyme-linked immunosorbent assay (ELISA) (Bethyl Laboratories, Montgomery, TX, USA) using a modified method described previously (Suzuki et al., Kidney International 72:319-327, 2007, doi: 0.1038 / sj.ki.5002300).

[0146] Sparsentan treatment rapidly reduced proteinuria, prevented the increase in ET-1, ETAR, and AT1R and upregulation of inflammatory pathways, and protected the glomeruli from glomerulosclerosis and loss of podocytes while also protecting the glycocalyx layer in the endothelial cells (Nagasawa et al., ERA-EDTA Paris (oral presentation), May 19-22, 2022).

[0147] The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and / or listed in the Application Data Sheet are incorporated herein by reference, including U.S. Provisional Patent Application No. 63 / 505,314 filed May 31, 2023, are incorporated herein by reference, in their entirety, unless otherwise stated. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications, and publications to provide yet further embodiments.

[0148] These and other changes can be made to the embodiments in light of the abovedetailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, butshould be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

CLAIMSWhat is claimed is:

1. A method of preventing an IgA-mediated disease, comprising administering sparsentan to a subject in need thereof.

2. The method of claim 1, wherein preventing an IgA-mediated disease comprises preventing further deposition of IgA in the kidney.

3. A method of reversing an effect of an IgA-mediated disease, or achieving remission of an IgA-mediated disease, comprising administering sparsentan to a subject in need thereof.

4. A method of restoring function and integrity of a tissue in a subject having an IgA-mediated disease, comprising administering sparsentan to the subject.

5. A method of healing IgA-related nephropathic damage, comprising administering sparsentan to a subject in need thereof.

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

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

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

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

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

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

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

13. The method of any one of claims 1-12, wherein normal function and integrity of a tissue is restored.

14. The method of any one of claims 1-13, wherein further deposition of IgA in the kidney is prevented.

15. The method of any one of claims 1-14, wherein adminstering comprises providing a daily dose of sparsentan over a period of at least 6 months, and wherein the subject returns to a normal diet following the 6-month period.

16. The method of any one of claims 1-15, wherein administering comprises first providing sparsentan at a daily dose of from 200 mg to 400 mg over a period of 6 months, and then providing sparsentan at a daily dose of 200 mg or less.

17. The method of any one of claims 1-15, wherein administering comprises first providing sparsentan at 400 mg per day over a period of 1 year, and then providing sparsentan at a daily dose of 200 mg or less.

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

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

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

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

22. Use of sparsentan in the manufacture of a medicament for use in the method according to any one of claims 1-18.

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