Sparsentan for the treatment of immunoglobulin A nephropathy (IgAN)

Abstract

The present invention provides a method for treating immunoglobulin A nephropathy, comprising a method of administering to a subject in need a compound having structure (I), also known as sparsentan, or a pharmaceutically acceptable salt thereof.

Description

Background Technology

[0001] This disclosure relates to the use of sparsentan, a dual angiotensin and endothelin receptor antagonist, in the treatment of immunoglobulin A nephropathy (IgAN).

[0002] IgAN, also known as Berger's disease, is caused by the accumulation of immunoglobulin A (IgA) in the kidneys. The presence of IgA in the kidneys can lead to inflammation, glomerular damage, and impaired kidney function, including proteinuria. In some cases, patients with IgA nephropathy may develop end-stage renal disease (ESRD).

[0003] Angiotensin II (AngII) and endothelin-1 (ET-1) are the two most potent known endogenous vasoactive peptides and are believed to play a role in controlling vascular tension and pathological tissue remodeling associated with a variety of diseases, including diabetic nephropathy, heart failure, and chronic or persistent hypertension. Angiotensin receptor blockers (ARBs) that block AngII activity have been used to treat diabetic nephropathy, heart failure, and chronic or persistent hypertension. Increasing data also demonstrate the potential therapeutic benefits of ET receptor antagonists (ERAs) that block ET-1 activity. Furthermore, AngII and ET-1 are believed to work together in blood pressure control and pathological tissue remodeling. For example, ARBs not only block the action of AngII on its receptors but also limit ET-1 production. Similarly, ERAs block ET-1 activity and inhibit AngII production. Therefore, simultaneously blocking the activity of AngII and ET-1 can provide better efficacy compared to blocking either one alone. For patients with another proteinuric glomerular disease, focal segmental glomerulosclerosis (FSGS), a reduction in proteinuria is associated with a lower risk of end-stage renal disease (ESRD) (Troost et al., Clin J Am Soc Nephrol 13:414-421, 2018; International Patent Application Publication No. WO2018 / 071784 A1. In a phase 2 study, sparsentan showed a reduction in proteinuria in patients with FSGS (International Patent Application Publication No. WO2018 / 071784 A1). However, there are currently no approved treatments for various proteinuric glomerular diseases, including IgAN. Summary of the Invention

[0004] In some embodiments, this disclosure provides a method for treating immunoglobulin A nephropathy, wherein the method includes administering a compound having structure (I) to a subject in need (e.g., a patient). , Or its pharmaceutically acceptable salt.

[0005] These and other aspects of the invention will become apparent from the following detailed description. Attached Figure Description

[0006] This patent or application document contains at least one color-drawn drawing. After requesting and paying the necessary fees, The Patent Office will provide a copy of the publication of this patent or patent application with one or more color drawings.

[0007] Figure 1 The changes in estimated glomerular filtration rate (eGFR) at each visit compared to baseline are shown.

[0008] Figure 2 This study illustrates the projected effect of sparsentan on the time to progression to end-stage renal disease. ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; eGFR, estimated glomerular filtration rate; RASI, renin-angiotensin system inhibitors; SOC, standard of care. Baseline (0 years) eGFR is based on the mean eGFR of the sparsentan group in the PROTECT study at the interim analysis (Heerspink HJL et al., Lancet. 2023;401(10388):1584-1594). a Based on the average observed slope of maximizing ACEi / ARB reported in 5 clinical trials (Lafayette R et al., Lancet 2023, 402(10405):859-870; Lv J et al., JAMA 2022, 327(19):1888-1898; Wheeler DC et al., Kidney Int. 2021, 100:215-225; Manno C et al., Nephrol Dial Transplant. 2009,24(12):3694-3701; Li PK-T et al., Am J Kidney Dis. 2006, 47(5):751-760).

[0009] Figure 3 The percentage change in the urine protein to creatinine ratio (UP / C) at each visit compared to the baseline UP / C is shown. Detailed Implementation

[0010] This disclosure generally relates to the use of biphenylsulfonamide compounds (e.g., sparsentan) having dual angiotensin and endothelin receptor antagonist activity in the treatment of immunoglobulin A nephropathy (IgAN).

[0011] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the invention. However, those skilled in the art will understand that the invention can be practiced without these details.

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. As used herein, certain terms may have the following limited meanings.

[0013] Unless the context otherwise requires, throughout this specification and claims, the word “comprise” and its variations, such as “comprises” and “comprising”, shall be understood in an open, inclusive sense, that is, as “including but not limited to”.

[0014] As used in the specification and claims, the word “including” and its variations, such as “include” and “includes”, shall be understood in an open, inclusive sense; that is, it is equivalent to “including but not limited to”. As used herein, the terms “including” and “having” are used synonymously, and the terms and their variations are intended to be understood as non-limiting.

[0015] As used in this article, the phrase “as” refers to a non-restrictive instance.

[0016] Throughout this specification, references to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the invention. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing in different places throughout this specification do not necessarily refer to the same embodiment. Furthermore, specific features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0017] As used herein and in the claims, unless the context clearly specifies otherwise, the singular forms “a,” “an,” and “the” include plural references. For example, the term “cell” includes a variety of cells, including mixtures thereof. Similarly, unless the context clearly specifies otherwise, “a compound” as used herein for therapeutic or pharmaceutical preparation covers the use of one or more compounds of the present invention for said therapeutic or pharmaceutical preparation.

[0018] The use of alternatives (e.g., "or") should be understood to mean one, two, or any combination of alternatives.

[0019] "Optional" or "optionally" means that the event or situation described below may or may not occur, and the description includes examples of the event or situation occurring and examples of it not occurring.

[0020] As used herein, “about” and “approximately” generally refer to the acceptable degree of error in a measured quantity, depending on the nature or precision of the measurement. Typical illustrative 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 a value within an order of magnitude, possibly within 5 times or 2 times a given value. When not explicitly stated, the terms “about” and “approximately” mean equal to a value, or within 20% of said value.

[0021] As used in this article, the numerical values ​​are accurate to the extent reflected by the number of significant digits reported. For example, a value of 0.1 should be understood to mean 0.05 to 0.14. As another example, the range of values ​​from 0.1 to 0.2 includes the range of 0.05 to 0.24.

[0022] Compounds having structure (I) can form salts, which are also within the scope of this disclosure. Unless otherwise specified, references to compounds having structure (I) herein should generally be understood to include references to their salts. As used herein, the term "salt" means an acidic or basic salt formed from an inorganic or organic acid and a base. Furthermore, because compounds having structure (I) contain both a basic and an acidic moiety, they may form zwitterions ("internal salts") and these are included in the term "salt" as used herein. Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, but other salts may be useful, for example, in separation or purification steps that may be employed during preparation. Salts of compounds having structure (I) can be formed, for example, by reacting the compound having structure (I) with a certain amount of an acid or base (e.g., an equal amount) in a medium (e.g., a medium in which the salt precipitates) or in an aqueous medium, followed by lyophilization.

[0023] The term "pharmaceutically acceptable salt" includes both acid addition salts and base addition salts.

[0024] It also covers prodrugs and solvates of compounds having structure (I). The term "prodrug" refers to a compound that, upon administration to a target, undergoes a chemical transformation through metabolism or a chemical process to yield a compound having structure (I) or a salt or solvate thereof. Solvates of compounds having structure (I) may be hydrates. Any tautomers are also covered.

[0025] Crystallization can produce solvates of compounds having structure (I) or salts thereof. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of a compound as disclosed herein and one or more molecules of a solvent. In some embodiments, the solvent is water, in which case the solvate is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Thus, the compounds of this disclosure can exist in hydrated form, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., and corresponding solvated forms. In some embodiments, the compounds disclosed herein can be true solvates, while in others, the compounds disclosed herein retain only adventitious water, or a mixture of water and some adventitious solvent.

[0026] The present invention disclosed herein also intends to cover in vivo metabolites of the disclosed compounds. These products can be generated by, for example, oxidation, reduction, hydrolysis, amidation, esterification, etc., of the applied compound, primarily due to enzymatic processes. Therefore, the present invention includes compounds produced by a process comprising administering the compound of the present invention to a mammal for a period sufficient to produce its metabolites. Such products are typically identified by administering a radiolabeled compound of the present invention at a detectable dose to an animal (e.g., rat, mouse, guinea pig, monkey, or human), allowing sufficient time for metabolism, and isolating its metabolites from its urine, blood, or other biological samples.

[0027] "Stable compound" and "stable structure" are intended to indicate a compound that is robust enough to withstand separation from the reaction mixture to obtain a suitable purity and to be formulated into an effective therapeutic agent.

[0028] The term "object" refers to a mammal, such as a domestic pet (like a dog or cat) or a human. Preferably, the object is a person. In some embodiments, the object is a patient who has been diagnosed with a disease or condition (such as IgAN).

[0029] The phrase "effective amount" refers to the amount sufficient to achieve the treatment of a disease when administered to a subject or patient.

[0030] The term "unit dosage form" (or "dosage unit form") refers to the form of a pharmaceutical product, including but not limited to the form in which the pharmaceutical product is marketed. Examples include pills, tablets, capsules, and liquid solutions and suspensions.

[0031] "Treatment" or "treating" includes (1) suppressing the disease of a subject or patient experiencing or presenting a lesion or symptom of the disease (e.g., preventing further development of the lesion or symptom); or (2) improving the disease of a subject or patient experiencing or presenting a lesion or symptom of the disease (e.g., reversing the lesion or symptom); or (3) achieving any measurable reduction in the disease of a subject or patient experiencing or presenting a lesion or symptom of the disease.

[0032] In cases where the subject of prevention (e.g., a patient) experiences or presents with lesions or symptoms of a disease, "prevention" includes preventing the development of a disease, condition, or symptom, or reducing the development of signs or symptoms associated with such a disease, condition, or symptom (e.g., reducing the clinically relevant amount), or delaying the onset of signs or symptoms (e.g., delaying by days, weeks, months, or years).

[0033] Other definitions are presented throughout this publication.

[0034] Spasentan Sparsentan (CAS 254740-64-2, 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-2-(ethoxymethyl)phenyl]-N-(4,5-dimethyl-1,2-oxazol-3-yl)benzenesulfonamide) is a biphenylsulfonamide compound with structure (I). .

[0035] Sparsentan is an inhibitor of endothelin (type A) receptors (ET). A Selective dual-acting receptor antagonists with affinity for both the AT1 receptor and angiotensin II receptor (type 1) ("AT1" receptor) (Kowala et al., JPET 309: 275-284, 2004).

[0036] Compounds of structure (I) can be prepared by, for example, those methods described in International Patent Application Publication No. WO2018 / 071784 A1. Alternatively, compounds of structure (I) can be prepared by the methods described in U.S. Patent Application Publication No. US 2015 / 0164865A1 and U.S. Patent No. US 6,638,937 B2.

[0037] Pharmaceutical Compositions and Methods of Use In some embodiments, this disclosure relates to the administration of pharmaceutical compositions comprising a compound containing structure (I) or a pharmaceutically acceptable salt thereof. As used herein, the term "pharmaceutical composition" refers to a composition comprising an active ingredient and a pharmaceutically acceptable excipient. Pharmaceutical compositions can be used to facilitate the administration of the active ingredient to a living organism. Various techniques exist in the art for administering compounds, such as oral, injectable, aerosol, parenteral, and topical administration. Pharmaceutical compositions can be obtained, for example, by reacting the compound with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. As used herein, the terms "physiologically acceptable excipient" or "pharmaceutically acceptable excipient" refer to physiologically and pharmaceutically suitable, non-toxic and inactive materials or ingredients that do not interfere with the activity of the active ingredient, including any adjuvants, carriers, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the U.S. Food and Drug Administration as acceptable materials for human or animal use.

[0038] In some embodiments, the pharmaceutical composition may be formulated as described below.

[0039] Additionally, methods for treating IgAN comprising an administration of a compound of structure (I) or a pharmaceutically acceptable salt thereof (e.g., sparsentan) are within the scope of this disclosure. In some embodiments, methods for treating IgAN are provided, the methods comprising administering a pharmaceutical composition comprising a compound of structure (I) or a pharmaceutically acceptable salt thereof, such as sparsentan, and a pharmaceutically acceptable excipient.

[0040] In one aspect, a compound of structure (I) or a pharmaceutically acceptable salt thereof, such as sparsentan, can be used to treat IgAN. Therefore, in some embodiments, a method of treating IgAN is provided, comprising administering to a subject in need a compound of structure (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating IgAN comprises administering to a subject in need an effective amount of a compound of structure (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating IgAN comprises administering to a subject in need a pharmaceutical composition comprising a compound of structure (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In other embodiments, the pharmaceutical composition comprises an effective amount of a compound having structure (I) or a pharmaceutically acceptable salt thereof for treating IgAN, and a pharmaceutically acceptable excipient.

[0041] In some other embodiments, a compound of structure (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of structure (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, may be used to treat IgAN.

[0042] In other embodiments, the compound of structure (I) or its pharmaceutically acceptable salt may be used to reduce overall morbidity or mortality due to the above-mentioned effects.

[0043] In some embodiments, a compound of structure (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of structure (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, may be used to prolong the time it takes for a patient diagnosed with IgAN to develop end-stage renal disease or to reduce their risk of developing end-stage renal disease.

[0044] In some embodiments, the compound of structure (I) or a pharmaceutically acceptable salt thereof may be used to reduce proteinuria. As used herein, “proteinuria” refers to a condition in which urine contains an abnormal amount of protein (i.e., urinary protein excretion greater than 300 mg per day). The protein-to-creatinine (“UP / C”) ratio provides a measure of the amount of total urinary protein relative to creatinine in a urine sample (e.g., a UP / C ratio of 1 g protein (dl) in urine divided by 1 g creatinine (dl) in urine = 1). As used herein, a UP / C ratio greater than 0.3 g / g indicates proteinuria. In some embodiments, the compound of structure (I) or a pharmaceutically acceptable salt thereof may be used to reduce proteinuria to less than or equal to 1.0 g / g. In some embodiments, the compound of structure (I) or a pharmaceutically acceptable salt thereof may be used to reduce proteinuria to less than or equal to 0.5 g / g. In some embodiments, the compound of structure (I) or a pharmaceutically acceptable salt thereof may be used to reduce proteinuria to less than or equal to 0.3 g / g (i.e., complete remission of proteinuria). Therefore, this disclosure also provides a method for inducing complete remission in a subject suffering from IgAN by administering a compound of structure (I) or a pharmaceutically acceptable salt thereof to the subject.

[0045] In some embodiments, a method is provided for treating IgAN in a subject of need, the method comprising administering to the subject a pharmaceutical composition comprising a compound having structure (I) 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 is provided for treating IgAN in a subject of need, the method comprising administering to the subject a pharmaceutical composition comprising a compound having structure (I) 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 is provided for treating IgAN in a subject of need, the method comprising administering to the subject a pharmaceutical composition comprising a compound having structure (I) or a pharmaceutically acceptable salt thereof, the 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 (i.e., sparsentan treatment induces complete remission of proteinuria). In some embodiments, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose of 100 mg / day. In some embodiments, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose of 200 mg / day. In some embodiments, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose of 400 mg / day. In some embodiments, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose of 800 mg / day. In some embodiments, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose of 200 mg / day for 8 weeks, 26 weeks, 36 weeks, 8 months, or 108 weeks. In some embodiments, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose of 400 mg / day for 8 weeks, 26 weeks, 36 weeks, 8 months, or 108 weeks. In some embodiments, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose of 800 mg / day for 8 weeks, 26 weeks, 36 weeks, 8 months, or 108 weeks. In some embodiments, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose of 200 mg / day for 6 weeks, 36 weeks, 58 weeks, or 110 weeks. In some embodiments, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose of 400 mg / day for 6 weeks, 36 weeks, 58 weeks, or 110 weeks.

[0046] In some embodiments, if the subject's weight is between 20 kg and 50 kg, the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof administered to the subject is 200 mg / day for the first two weeks and 400 mg / day thereafter. In some embodiments, if the subject's weight is greater than 50 kg, the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof administered to the subject is 400 mg / day for the first two weeks and 800 mg / day thereafter.

[0047] In some embodiments, a method is provided for treating IgAN in a subject of need, the method comprising administering to the subject a pharmaceutical composition comprising a compound having structure (I) or a pharmaceutically acceptable salt thereof during an administration period, the amount administered being 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 at least daily. In some embodiments, the administration period is 6 weeks. In some embodiments, the administration period is 8 weeks. In some embodiments, the administration period is 26 weeks. In some embodiments, the administration period is 36 weeks. In some embodiments, the administration period is 108 weeks. In some embodiments, the administration period is 110 weeks. In some embodiments, the administration period is 8 months.

[0048] In some embodiments, a method is provided for maintaining a UP / C ratio of less than or equal to 1.0 g / g in a desired object, the method comprising administering to the object a pharmaceutical composition comprising a compound having structure (I) 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.

[0049] In some embodiments, a method is provided for reducing the UP / C ratio to less than or equal to 1.0 g / g in a desired object, the method comprising administering to the object a pharmaceutical composition comprising a compound having structure (I) or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce the UP / C ratio of the object to less than or equal to 1.0 g / g. In some embodiments, the object has, or previously had, a UP / C ratio greater than 1.0 g / g prior to the administration of the pharmaceutical composition.

[0050] In some embodiments, the compound of structure (I) or a pharmaceutically acceptable salt thereof may be used to maintain 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 time. GFR can be estimated by measuring serum creatinine levels and using the Chronic Kidney Disease Epidemiology Collaboration Group (CKD-EPI) creatinine equation. As used herein, “estimated glomerular filtration rate” (“eGFR”) refers to an estimate of GFR obtained using the CKD-EPI creatinine equation. In some embodiments, the compound of structure (I) or a pharmaceutically acceptable salt thereof may be used to maintain eGFR levels (e.g., to prevent a decrease in eGFR associated with IgAN or to reduce the rate of eGFR decline in patients with IgAN). In some embodiments, administration of the compound of structure (I) or a pharmaceutically acceptable salt thereof to a subject results in eGFR being maintained at or above the eGFR level prior to (e.g., within the previous month) the administration of the compound having structure (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing thereof. In some embodiments, administration of the compound of structure (I) or a pharmaceutically acceptable salt thereof to the subject results in the maintenance of eGFR at or above a baseline eGFR level, where “baseline eGFR level” refers to the most recently calculated eGFR level prior to the initiation of treatment. As used herein, “maintenance of eGFR” means that there is no clinically significant decrease in the baseline eGFR level. Therefore, as used herein, regarding the treatment of patients with IgAN, the phrase “maintaining constant eGFR” means treatment that maintains the subject’s eGFR at a clinically equal to or better than their baseline eGFR level (i.e., the most recently calculated eGFR level prior to the initiation of treatment). In some embodiments, eGFR is maintained for months or years after administration. The period during which the subject’s eGFR level remains constant is typically at least 12 months.

[0051] In some embodiments, any of the foregoing uses or treatment methods may comprise the administration of a compound of structure (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, in combination with one or more other active ingredients (e.g., other therapeutic agents or diagnostic agents). For example, in some embodiments, one or more other therapeutic agents may be administered before, simultaneously with, or after administration of a pharmaceutical composition comprising an effective amount of a compound of structure (I) or a pharmaceutically acceptable salt thereof. If formulated as a fixed dose, the combination product may comprise a compound of structure (I) or a pharmaceutically acceptable salt thereof within the dose range described below, and other active ingredients within its approved dose range.

[0052] In some embodiments, the compound of structure (I) or its pharmaceutically acceptable salt is used in combination with hemodialysis.

[0053] In some embodiments of the foregoing uses and treatment methods, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose of 50 mg / day. In some embodiments, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose of 100 mg / day. In some embodiments, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose of 200 mg / day. In some embodiments, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose of 300 mg / day. In some embodiments, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose of 400 mg / day. In some embodiments, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose of 500 mg / day. In some embodiments, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose of 600 mg / day. In some embodiments, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose of 700 mg / day. In some embodiments, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose of 800 mg / day. In some embodiments, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose of 900 mg / day. In some embodiments, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose of 1000 mg / day.

[0054] In some embodiments of the foregoing uses and treatment methods, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose 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 foregoing uses and treatment methods, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose 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 foregoing uses and treatment methods, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose of 400 mg / day for 6 weeks, 8 weeks, 26 weeks, 36 weeks, 8 months, 108 weeks, or 110 weeks. In other embodiments, the dosing regimen comprises administering a compound having structure (I) or a pharmaceutically acceptable salt thereof at a dose of 800 mg / day for 6 weeks, 8 weeks, 26 weeks, 36 weeks, 8 months, 108 weeks, or 110 weeks.

[0055] In any of the foregoing embodiments, the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof applied to the subject may be from about 50 mg / day to about 1000 mg / day. For example, in some embodiments, the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof applied to the subject is from about 200 mg / day to about 800 mg / day. In other embodiments, the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof applied to the subject is about 50 mg / day. In other embodiments, the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof applied to the subject is about 100 mg / day. In other embodiments, the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof applied to the subject is about 200 mg / day. In other embodiments, the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof applied to the subject is about 300 mg / day. In other embodiments, the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof applied to the subject is about 400 mg / day. In other embodiments, the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof applied to the subject is about 500 mg / day. In other embodiments, the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof applied to the subject is about 600 mg / day. In other embodiments, the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof applied to the subject is about 700 mg / day. In other embodiments, the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof applied to the subject is about 800 mg / day. In other embodiments, the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof applied to the subject is about 900 mg / day. In other embodiments, the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof applied to the subject is about 1000 mg / day.

[0056] In any of the foregoing embodiments, the method may further include administering one or more additional therapeutic agents to the subject.

[0057] In any of the foregoing embodiments, the subject can be an adult or a child under 18 years of age. In some embodiments, the subject is under 18 years of age. In some embodiments, the subject is 5 to 10 years of age. In some embodiments, the subject is 6 to 12 years of age. In some embodiments, the subject is 2 to 6 years of age. In some embodiments of the foregoing method, the subject is 8 years of age or older.

[0058] In some implementations, the subjects are pediatric subjects aged 2 to 4 years; 5 to 7 years; or 8 to 17 years.

[0059] In some embodiments of the foregoing uses and treatment methods, the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof administered to the subject is from 1 mg / kg to 15 mg / kg daily. In some embodiments, the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof administered to the subject is from 3 mg / kg to 12 mg / kg daily. In some embodiments, the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof administered to the subject is from 3 mg / kg to 6 mg / kg daily. In some of these embodiments, the subject is a child (e.g., under 18 years of age; 2 to 6 years of age; 5 to 10 years of age; 6 to 12 years of age).

[0060] In any of the aforementioned methods, the subject may have primary IgAN confirmed by biopsy or verified by biopsy.

[0061] In any of the aforementioned methods, the subject may have IgAN that is not secondary to another condition.

[0062] In any of the foregoing methods, the subject may currently receive a stable dose of ACEI and / or ARB therapy, for example, continuous use for at least 12 weeks prior to treatment with sparsentan. In some embodiments, the subject may receive the maximum tolerated dose of ACEI and / or ARB and at least half of the maximum labeled dose of ACEI and / or ARB.

[0063] In any of the aforementioned methods, prior to treatment with sparsentan, the subject may have a systolic blood pressure of ≤150 mmHg and a diastolic blood pressure of ≤100 mmHg.

[0064] In some embodiments of the foregoing method, the subject is not a pregnant or breastfeeding woman. In some embodiments, if the subject is of fertility potential, a monthly pregnancy test is also administered to the subject, and if the pregnancy test indicates that the subject is pregnant, the administration of the compound of structure (I) or a pharmaceutically acceptable salt thereof is discontinued. In some embodiments, if the subject is of fertility potential, an oral contraceptive, implantable contraceptive, injectable contraceptive, or intrauterine device is also administered to the subject.

[0065] In some implementations of the aforementioned method, for example, within 6 months of starting treatment with sparsentan, the subject did not exhibit cellular glomerular crescents in >25% of the glomeruli at the time of renal biopsy.

[0066] In some implementations of the aforementioned method, the subject does not suffer from chronic kidney disease (CKD) other than IgAN.

[0067] In some implementations of the aforementioned method, the subject has no history of organ transplantation other than corneal transplantation.

[0068] In some embodiments of the aforementioned method, the subjects did not receive more than 2 weeks of systemic immunosuppressive drugs (including corticosteroids) within 3 months of starting sparsentan treatment.

[0069] In some embodiments of the aforementioned method, the subject has no history of heart failure or previous hospitalization for heart failure or unexplained dyspnea, orthopnea, paroxysmal nocturnal dyspnea, ascites and / or peripheral edema.

[0070] In some implementations of the aforementioned method, the subjects did not have clinically significant cerebrovascular disease or coronary artery disease within 6 months of starting treatment with sparsentan.

[0071] In some embodiments of the aforementioned method, the subject did not have significant liver disease or severe liver injury. In some embodiments, the subject did not have severe liver injury (i.e., Child-Pugh C). In some embodiments, prior to starting sparsentan treatment, the subject did not have jaundice, hepatitis, or known hepatobiliary disease, or elevated transaminase (ALT / AST) levels not exceeding twice the upper limit of normal.

[0072] In some implementations of the aforementioned method, the subject does not have a history of malignancy other than adequately treated basal or squamous cell skin cancer or cervical cancer within the past two years prior to starting treatment with sparsentan.

[0073] In some embodiments of the aforementioned method, prior to initiating treatment with sparsentan, the subject did not have a hematocrit value of <27% (0.27 V / V), a hemoglobin value of <9 g / dL (90 g / L), and / or a potassium level of >5.5 mEq / L (5.5 mmol / L).

[0074] In any of the aforementioned methods, the object may have a flow rate greater than or equal to 30 mL / min / 1.73 m 2 The baseline eGFR and the baseline protein-to-creatinine ratio (UP / C) greater than or equal to 1.0 g / g.

[0075] In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound having structure (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, used in any of the foregoing methods.

[0076] In some embodiments, this disclosure provides the use of a pharmaceutical composition in the preparation of a medicament for any of the foregoing treatment methods, said pharmaceutical composition comprising a compound having structure (I) or a pharmaceutically acceptable salt thereof.

[0077] pharmaceutical preparations In one aspect, this disclosure relates to administering a pharmaceutical composition comprising a compound of structure (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Techniques for formulating and administering a compound of structure (I) or a pharmaceutically acceptable salt thereof can be found, for example, in “Remington’s Pharmaceutical Sciences”, Mack Publishing Co., Easton, PA, 18th edition, 1990, the teachings of which relating to such techniques are incorporated herein by reference. In some embodiments, the pharmaceutical composition is formulated as described below.

[0078] In some embodiments, excipients include any substance that is not itself a therapeutic agent, which serves as a carrier, diluent, adjuvant, or mediator to deliver a therapeutic agent to a subject or to be added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate the formation of dosage units of the composition into discrete articles, such as capsules, tablets, film-coated tablets, gel caps, pills, granules, beads, etc., suitable for oral administration. For example, excipients may be surface active agents (or "surfactants"), carriers, diluents, disintegrants, binders, wetting agents, polymers, lubricants, flow aids, coating or coating auxiliaries, film-forming substances, sweeteners, solubilizers, smoothers, suspending agents, substances added to mask or counteract unpleasant tastes or odors, flavoring agents, coloring agents, fragrances, or substances added to improve the appearance of the composition, or combinations thereof.

[0079] Acceptable excipients include, for example, microcrystalline cellulose, lactose, sucrose, starch powder, corn starch or its derivatives, cellulose esters of alkanonic acids, alkyl cellulose esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, polyvinyl alcohol, physiological saline, dextrose, mannitol, lactose monohydrate, lecithin, albumin, monosodium glutamate, cysteine ​​hydrochloride, croscarmellose sodium, sodium glycolate starch, hydroxypropyl cellulose, and poloxamer. (e.g., poloxamer 101, 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, 403 and 407 and poloxamer 105 benzoate, poloxamer 182 dibenzoate 407, etc.), sodium lauryl sulfate, colloidal silica, etc. 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 silica, and magnesium stearate. Examples of suitable excipients for soft gelatin capsules include vegetable oils, waxes, fats, and semi-solid and liquid polyols. Suitable excipients for preparing solutions and syrups include, for example, water, polyols, sucrose, invert sugar, and glucose. Compounds may also be manufactured in microencapsulated form. Where necessary, absorption-enhancing formulations (e.g., liposomes) may be utilized. Acceptable excipients for therapeutic purposes are well known in the pharmaceutical field and are described, for example, in “Handbook of Pharmaceutical Excipients,” 5th edition (edited by Raymond C. Rowe, Paul J. Sheskey, and Siân C. Owen, 2005), and “Remington: The Science and Practice of Pharmacy,” 21st edition (Lippincott Williams & Wilkins, 2005), the teachings of which relating to such excipients are incorporated herein by reference.

[0080] In some embodiments, surfactants are used. The use of surfactants in oral pharmaceutical forms as wetting agents or for improving the penetration and bioavailability of the active pharmaceutical compound is described in the literature, for example, by H. Sucker, P. Fuchs, P. Speiser, Pharmazeutische Technologie , 2nd edition, Thieme 1989, page 260, and Advanced Drug Delivery Reviews(1997), 23, pp. 163-183, the referenced document is incorporated herein by reference for the purposes of such teaching. Examples of surfactants include anionic surfactants, nonionic surfactants, amphoteric surfactants, and mixtures thereof. In some embodiments, the surfactant is selected from the group consisting of: poly(oxyethylene) sorbitan fatty acid esters, poly(oxyethylene) stearates, poly(oxyethylene) alkyl ethers, polyethylene glycol-modified glycerol esters, poly(oxyethylene) castor oil, sorbitan fatty acid esters, poloxamer, fatty acid salts, bile salts, alkyl sulfates, lecithin, mixed micelles of bile salts and lecithin, glucose ester vitamin E TPGS (D-α-tocopherol polyethylene glycol 1000 succinate), sodium lauryl sulfate, and mixtures thereof.

[0081] As used herein, the term "carrier" is defined as a compound that facilitates the incorporation of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier because it facilitates the absorption of many organic compounds into the cells or tissues of an organism. As used herein, the term "diluent" is defined as a compound diluted in water, which dissolves the target compound and stabilizes the biologically active form of the compound. In this field, salts dissolved in buffer solutions are commonly used as diluents. A commonly used buffer solution is phosphate-buffered saline because it mimics the salt profile of human blood. Because buffer salts can control the pH of the solution at low concentrations, buffered diluents rarely alter the biological activity of the compound. In some embodiments, a diluent selected from one or more of the following compounds is used: sucrose, fructose, glucose, galactose, lactose, maltose, invert sugar, calcium carbonate, lactose, starch, microcrystalline cellulose, lactose monohydrate, dicalcium phosphate, anhydrous dicalcium phosphate, pharmaceutically acceptable polyols (such as xylitol, sorbitol, maltitol, mannitol, isomaltitol, and glycerol), polydextrose, starch, etc., or any mixture thereof. Acceptable carriers or diluents for therapeutic purposes are well known in the pharmaceutical field and are described, for example, in "Remington's Pharmaceutical Sciences," 18th edition, Mack Publishing Co., Easton, PA (1990), which is incorporated herein by reference as teaching material in relation to such carriers or diluents.

[0082] In some embodiments, disintegrants such as starch, clay, cellulose, alginate, gum, or cross-linked polymers are used to, for example, promote tablet disintegration after administration. Suitable disintegrants include, for example, croscarmellose (PVP-XL), sodium glycolate starch, alginate, DYB methacrylate, microcrystalline cellulose, croscarmellose, potassium polacriline, sodium glycolate starch, starch, pregelatinized starch, sodium croscarmellose carboxymethyl cellulose, etc. In some embodiments, the formulation may also contain small amounts of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, etc.; for example, sodium acetate, sorbitan monolaurate, sodium triethanolamine acetate, sodium triethanolamine oleate, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, polyoxyethylene sorbitan fatty acid esters, etc.

[0083] In some embodiments, an adhesive is used, for example, to impart cohesiveness to the formulation and thus ensure that the resulting dosage form remains intact after compression. Suitable adhesive 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, cellulose polymers (including, for example, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), methylcellulose, hydroxyethyl cellulose, etc.). Therefore, in some embodiments, the formulations disclosed herein include at least one adhesive to enhance the compressibility of one or more major excipients. For example, the formulation may include at least one of the following binders from the following range: about 2% to about 6% w / w hydroxypropyl cellulose (Klucel); about 2% to about 5% w / w polyvinylpyrrolidone (PVP); about 1% to about 5% w / w methylcellulose; about 2% to about 5% hydroxypropyl methylcellulose; about 1% to about 5% w / w ethylcellulose; about 1% to about 5% w / w sodium carboxymethyl cellulose; and so on. Those skilled in the art will recognize additional binders and / or amounts that may be used in the formulations described herein. As those skilled in the art will recognize, when incorporated into the formulations disclosed herein, the amount of one or more major fillers and / or other excipients may be reduced accordingly to accommodate the amount of binder added in order to maintain a constant total unit weight of the dosage form. In some embodiments, the binder is sprayed as a solution, for example, by wet granulation, to increase adhesive activity.

[0084] In some embodiments, lubricants are used to prepare certain dosage forms. For example, lubricants may be used when manufacturing tablets. In some embodiments, the lubricant may be added just before the tableting step and may be mixed with other components for a minimal time period to achieve good dispersion. In some embodiments, one or more lubricants may be used. Examples of suitable lubricants include magnesium stearate, calcium stearate, zinc stearate, stearic acid, talc, glyceryl behenate, polyethylene glycol, polyethylene oxide polymers (e.g., the registered trademarks of Dow Chemical Company of Midland, Michigan, polyethylene glycol Carbowax® and polyethylene oxide Polyox® may be used), sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silica, and other lubricants as known in the art. Typical lubricants are magnesium stearate, calcium stearate, zinc stearate, and mixtures of magnesium stearate and sodium lauryl sulfate. The lubricant may comprise about 0.25% to about 50% of the tablet weight, typically about 1% to about 40%, more typically about 5% to about 30%, and most typically 20% to 30%. In some embodiments, magnesium stearate may be added as a lubricant, for example, to improve powder flow, prevent admixtures from adhering to tableting equipment and stamping surfaces, and provide lubrication to allow the tablets to eject smoothly from the tablet die. In some embodiments, magnesium stearate may be added to the pharmaceutical formulation at concentrations ranging from about 0.1% to about 5.0% w / w, or about 0.25% to about 4% w / w, or about 0.5% w / w to about 3% w / w, or about 0.75% to about 2% w / w, or about 0.8% to about 1.5% w / w, or about 0.85% to about 1.25% w / w, or about 0.9% to about 1.20% w / w, or about 0.85% to about 1.15% w / w, or about 0.90% to about 1.1% w / w, or about 0.95% to about 1.05% w / w, or about 0.95% to about 1% w / w. These ranges are examples of typical ranges. Those skilled in the art will recognize additional lubricants and / or amounts that may be used in the formulations described herein. As will be appreciated by one of ordinary skill in the art, when incorporated into the pharmaceutical compositions disclosed herein, the amount of one or more major fillers and / or other excipients may be reduced accordingly to accommodate the amount of one or more lubricants added in order to maintain the total unit weight of the dosage form.

[0085] In some embodiments, one or more flow aids are used. Examples of flow aids include colloidal silica, magnesium trisilicate, powdered cellulose, starch, talc, and calcium phosphate, and mixtures thereof.

[0086] In some embodiments, the formulation may include a coating, such as a film coating. In cases involving film coating, the coating formulation may include, for example, a film-forming polymer, a plasticizer, etc. Furthermore, the coating may include pigments or opacifiers. Examples of film-forming polymers include hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, and starch. Examples of plasticizers include polyethylene glycol, tributyl citrate, dibutyl sebate, castor oil, and acetylated monoglycerides. Furthermore, examples of pigments and opacifiers include iron oxides of various colors, lake dyes of many colors, titanium dioxide, etc.

[0087] In some embodiments, one or more color additives are included. The colorant may be used in an amount sufficient to differentiate dosage form strength. In some embodiments, color additives approved for use in pharmaceuticals (see 21 CFR pt. 74) are added to commercial formulations to differentiate tablet strength. This disclosure also covers the use of other pharmaceutically acceptable colorants and combinations thereof.

[0088] The pharmaceutical compositions disclosed herein may include any other agents that provide improved transfer, delivery, tolerability, etc. These compositions may include, for example, powders, pastes, gels, waxes, oils, lipids, vesicle-containing lipids (cationic or anionic) (such as Lipofectin®), DNA conjugates, anhydrous absorbent pastes, oil-in-water and water-in-oil emulsions, carbowax (polyethylene glycol of various molecular weights) emulsions, semi-solid gels, and semi-solid mixtures containing carbowax.

[0089] In various embodiments, alcohols, esters, sulfated aliphatic alcohols, etc., can be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicates, magnesium aluminate, magnesium aluminum metasilicate, synthetic aluminum silicate, calcium carbonate, sodium bicarbonate, calcium hydrogen phosphate, calcium carboxymethyl cellulose, etc., can be used as excipients; magnesium stearate, talc, hardened oil, etc., can be used as smoothing agents; coconut oil, olive oil, sesame oil, peanut oil, and soybean oil can be used as suspending agents or lubricants; cellulose acetate phthalate, as a derivative of carbohydrates such as cellulose or sugar, methyl methacrylate copolymer as a polyethylene derivative, or plasticizers such as phthalates can be used as suspending agents.

[0090] In some embodiments, the pharmaceutical compositions disclosed herein may further comprise one or more of preservatives, stabilizers, dyes, sweeteners, flavorings, and tasters. 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.

[0091] In addition to being used as monotherapy, the compounds and pharmaceutical compositions disclosed herein can also be used in combination therapy. Effective combination therapy can be achieved with a single pharmaceutical composition comprising multiple active ingredients or with two or more different pharmaceutical compositions. Alternatively, each therapy can be administered before or after other therapies at intervals ranging from minutes to months.

[0092] In some embodiments, the pharmaceutical compositions or methods disclosed herein may specifically include or exclude one or more of the listed excipients or any combination thereof.

[0093] Any of the foregoing formulations may be used in the treatments and therapies disclosed herein, provided that one or more active ingredients in the pharmaceutical composition are not inactivated by the formulation and that the formulation is physiologically compatible and tolerable to the route of administration (see also Baldrick P., Regul. Toxicol. Pharmacol . 32(2):210-218, 2000; Charman WN, J. Pharm. Sci 89(8):967-78, 2000 and the references cited therein; the references and teachings relating to formulations, excipients and carriers familiar to medicinal chemists are incorporated herein by reference.

[0094] In some embodiments, the above excipients may be present in an amount of up to about 95%, or up to about 85%, or up to about 75%, or up to about 65%, or up to about 55%, or up to about 45%, or up to about 43%, or up to about 40%, or up to about 35%, or up to about 30%, or up to about 25%, or up to about 20%, or up to about 15%, or up to about 10% or less of the total composition weight.

[0095] As those skilled in the art will understand, the amount of excipient will be determined by the drug dosage and dosage form size. In some embodiments disclosed herein, the dosage form size is from 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. Those skilled in the art will recognize that a range of weights can be manufactured, and these weights are all included in this disclosure.

[0096] The pharmaceutical compositions disclosed herein can be manufactured in ways known per se, such as by means of conventional mixing, dissolving, granulation, sugar-coated pill manufacturing, water milling, emulsification, encapsulation, coating or tableting processes.

[0097] The pharmaceutical compositions disclosed herein can provide low-dose formulations of a compound of structure (I) or a pharmaceutically acceptable salt thereof in dosage forms such as tablets, film-coated tablets, capsules, capsule tablets, pills, sac-shaped tablets, granules, beads, or sugar-coated pills. The formulations disclosed herein can provide advantageous pharmaceutical processing qualities, including, for example, rapid tablet compression speed, reduced compression force, reduced ejection force, uniform blending, uniform content, uniform color dispersion, accelerated disintegration time, rapid dissolution, low friability (preferably for downstream processing such as packaging, shipping, pick-and-pack, etc.), and dosage form physical characteristics with minimal variation (e.g., weight, hardness, thickness, friability).

[0098] Appropriate formulations depend on the chosen route of administration. Suitable routes of administration for the compound of structure (I) or its pharmaceutically acceptable salts or pharmaceutical compositions comprising it may include, for example, oral, rectal, mucosal, topical or enteral administration; and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary, intrathecal, direct intraventricular, intraperitoneal, intranasal or intraocular injection. The compound of structure (I) or its pharmaceutically acceptable salts may also be administered in sustained or controlled-release formulations, including accumulation injections, osmotic pumps, pills, transdermal (including electromigration) patches, etc., for prolonged or timed, pulsed administration at a predetermined rate.

[0099] Injectable formulations can be prepared in conventional forms (as liquid solutions or suspensions), solid forms suitable for dissolving or suspending in a liquid prior to injection, or emulsions. Suitable excipients may include, for example, water, physiological saline, dextran, mannitol, lactose, lecithin, albumin, monosodium glutamate, cysteine ​​hydrochloride, etc. Additionally, if desired, injectable pharmaceutical compositions may contain small amounts of non-toxic adjuvants, such as wetting agents, pH buffers, etc. Physiologically compatible buffers include Hanks' solution, Ringer's solution, or physiological saline buffer. If necessary, absorption-enhancing agents (e.g., liposomes) may be used.

[0100] For transmural application, a penetrant suitable for the target barrier can be used in the formulation.

[0101] Pharmaceutical formulations intended for parenteral administration (e.g., by bolus or continuous infusion) include aqueous solutions of the active compound in a water-soluble form. Alternatively, suspensions of the active compound can be prepared as suitable oily injectable suspensions. Suitable lipophilic solvents or mediators include fatty oils, such as sesame oil, or other organic oils, such as soybean oil, grapeseed oil, or almond oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injectable suspensions may contain 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 compound to allow for the preparation of high-concentration solutions. Injectable formulations may be present in unit dosage forms, such as in ampoules or multi-dose containers, and may contain preservatives. Compositions may take the form of suspensions, solutions, or emulsions in oily or aqueous mediators, and may contain formulations such as suspending agents, stabilizers, or dispersants. Alternatively, the active ingredient can be in powder form so that it can be prepared together with a suitable medium (e.g., sterile, pyrogen-free water) before use.

[0102] For oral administration, the compound of structure (I) or a pharmaceutically acceptable salt thereof can be formulated by combining the active compound with a pharmaceutically acceptable carrier known in the art. The carrier enables the compound to be formulated as tablets, film-coated tablets, pills, sugar-coated pills, capsules, liquids, gels, capsule-shaped tablets, granules, beads, syrups, liquids, suspensions, etc., for oral ingestion by a patient to be treated.

[0103] Pharmaceutical formulations for oral use can be obtained by combining an active compound with a solid excipient, optionally grinding the resulting mixture, and processing the granular mixture (if necessary) after adding appropriate excipients to obtain tablets or sugar-coated cores. Specifically, suitable excipients are fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, astragalus gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrants such as croscarmellose, agar, or alginate or its salts, such as sodium alginate, can be added. Sugar-coated cores with suitable coatings are also within the scope of this disclosure. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the coating of tablets or sugar-coated pills to facilitate the identification or characterization of different combinations of active compound agents. For this purpose, concentrated sugar solutions may be used, optionally containing gum arabic, talc, polyvinylpyrrolidone, carbomer gel, polyethylene glycol, titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the coating of tablets or sugar-coated pills to facilitate the identification or characterization of different combinations of active compound agents. Additionally, stabilizers may be added. In some embodiments, formulations for oral administration are in doses suitable for such administration. In some embodiments, formulations of compounds of structure (I) or pharmaceutically acceptable salts thereof have acceptable immediate-release dissolution properties and robust, scalable manufacturing methods.

[0104] Orally administered pharmaceutical formulations include push-fit capsules made of gelatin and soft-seal capsules made of gelatin and plasticizers such as glycerin or sorbitol. Push-fit capsules may contain an active ingredient mixed with a filler (such as lactose), a binder (such as starch), or a lubricant (such as talc or magnesium stearate), and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added.

[0105] For buccal administration, the composition may be in the form of tablets or lozenges formulated in a conventional manner.

[0106] For administration by inhalation, compounds of structure (I) or pharmaceutically acceptable salts thereof can be conveniently delivered from a pressurized package or nebulizer in the form of an aerosol spray using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of pressurized aerosols, the dosage unit can be determined by providing a valve to deliver the measured amount. Capsules and cartridges (e.g., made of gelatin) for inhalers or blowpipes can be formulated as a powder mixture containing the compound and a suitable powder matrix (e.g., lactose or starch).

[0107] This article further discloses various pharmaceutical compositions well-known in the pharmaceutical field for use in intraocular, intranasal, and intraauricular delivery. Suitable penetrants for these uses are known in the art. Pharmaceutical compositions for intraocular delivery include aqueous ophthalmic solutions of the active compound in a water-soluble form, such as eye drops, or gellan gum (Shedden et al., Clin. Ther . 23(3):440-50, 2001) or hydrogel (Mayer et al., Ophthalmologica 210(2):101-3, 1996); ophthalmic ointments; ophthalmic suspensions, such as microparticles, drug-containing small polymer particles suspended in a liquid carrier medium (Joshi, J. Ocul. Pharmacol . 10(1):29-45, 1994), lipid-soluble preparations (Alm et al., Prog. Clin. Biol. Res . 312:447-58, 1989) and microspheres (Mordenti, Toxicol. Sci . 52(1):101-6, 1999); and ocular inserts (the teachings relating to such compositions are incorporated herein by reference). Suitable pharmaceutical formulations may be formulated as sterile, isotonic, and buffered to achieve stability and comfort. Pharmaceutical compositions for intranasal delivery may also include drops and sprays, which are generally prepared to mimic nasal secretions in many respects to ensure maintenance of normal ciliary function. As disclosed in “Remington's Pharmaceutical Sciences,” 18th edition, Mack Publishing Co., Easton, PA (1990) (the teachings relating to such formulations are incorporated herein by reference) and well known to those skilled in the art, suitable formulations are most generally and preferably isotonic, slightly buffered to maintain a pH of 5.5 to 6.5, and most generally and preferably include antimicrobial preservatives and suitable pharmaceutical stabilizers. Pharmaceutical formulations for intraocular delivery include suspensions and ointments for topical application in the ear. Common solvents for such otomedicines include glycerin and water.

[0108] Compounds of structure (I) or pharmaceutically acceptable salts thereof may also be formulated into rectal compositions such as suppositories or retention enemas, for example, compositions containing a conventional suppository base such as cocoa butter or other glycerides.

[0109] In addition to the formulations described above, compounds of structure (I) or pharmaceutically acceptable salts thereof may also be formulated as long-acting formulations. Such long-acting formulations may be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Thus, for example, compounds of structure (I) or pharmaceutically acceptable salts thereof may be formulated with suitable polymeric or hydrophobic materials (e.g., in the form of emulsions in acceptable oils) or ion exchange resins, or as slightly soluble derivatives, such as in the form of slightly soluble salts.

[0110] For hydrophobic compounds, suitable drug carriers can be co-solvent systems comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. A commonly used co-solvent system is the VPD co-solvent system, which consists of 3% w / v benzyl alcohol and 8% w / v nonpolar surfactant Polysorbate 80. TM A solution containing 65% w / v polyethylene glycol 300, with the remaining volume in pure ethanol. The proportions of the cosolvent system can be significantly varied without compromising its solubility and toxicity characteristics. Furthermore, the identity of the cosolvent component can be changed: for example, other low-toxicity, non-polar surfactants can be used instead of Polysorbate 80. TM It can change the size of polyethylene glycol; other biocompatible polymers can replace polyethylene glycol, such as polyvinylpyrrolidone; and other sugars or polysaccharides can replace dextrose.

[0111] Alternatively, other delivery systems for hydrophobic drug compounds may be used. Liposomes and emulsions are well-known examples of delivery carriers or loads for hydrophobic drugs. In some embodiments, certain organic solvents, such as dimethyl sulfoxide, may also be used.

[0112] Alternatively, sustained-release systems, such as semi-permeable matrices containing solid hydrophobic polymers of therapeutic agents, can be used to deliver compounds. Various sustained-release materials have been developed and are known to those skilled in the art. Sustained-release capsules can release the compound for weeks to over 100 days, depending on their chemical properties. Further protein stabilization strategies can be employed depending on the chemical properties and biological stability of the therapeutic agent.

[0113] Drugs intended for intracellular administration can be administered using techniques well known to those skilled in the art. For example, such drugs can be encapsulated in liposomes. Molecules present in an aqueous solution during liposome formation are incorporated into the aqueous interior. The contents of the liposome are protected from the external microenvironment and, because the liposome fuses with the cell membrane, can be efficiently delivered into the cytoplasm. Liposomes can be coated with tissue-specific antibodies. The liposomes will target the desired organ and be selectively absorbed by it. Alternatively, small hydrophobic organic molecules can be administered directly intracellularly.

[0114] In some embodiments, a solid unit dosage form comprising a compound having structure (I) or a pharmaceutically acceptable salt thereof is provided for use in the compositions and methods described herein. In some embodiments, the solid unit dosage form comprises a compound having structure (I) 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 unit dosage form comprises a compound having structure (I) or a pharmaceutically acceptable salt thereof in an amount of 400 mg; or about 400 mg.

[0115] In some embodiments, a liquid formulation of a compound of structure (I) 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 mediator, 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, a microcrystalline cellulose / sodium carboxymethyl cellulose complex, methylcellulose, or hydroxyethyl cellulose; or (e) a pH adjuster, such as citric acid, tartaric acid, or sodium citrate; or combinations thereof. For example, in some embodiments, a liquid formulation of sparsentan is provided, comprising sparsentan, water as a diluent or mediator, sodium benzoate, sucralose, a flavoring agent, xanthan gum, and citric acid. In some embodiments, the liquid formulation is administered orally to subjects aged 18 years or younger, 12 years or younger, 6 to 12 years, or 2 to 6 years.

[0116] Application method The compound of structure (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, may be administered to a subject (e.g., a human patient) by any suitable manner. Examples of administration methods include (a) administration via the oral route, including administration in capsules, tablets, granules, sprays, syrups, and other such forms; (b) administration via non-oral routes, such as rectal, vaginal, urethral, ​​intraocular, intranasal, and intraauricular routes, including administration in aqueous suspensions, oily preparations, etc., in the form of drops, sprays, suppositories, ointments, creams, etc.; (c) administration by injection, subcutaneous, intraperitoneal, intravenous, intramuscular, intradermal, intraorbital, intracapsularly, intraspinal, intrasternal, etc., including delivery by infusion pump; (d) local administration, such as direct injection into the renal or cardiac region via accumulation implantation; and (e) topical administration; and, where appropriate as a person skilled in the art deems it suitable, contact between the compound of structure (I) or a pharmaceutically acceptable salt thereof and living tissue.

[0117] Suitable pharmaceutical compositions include those containing a compound of structure (I) or a pharmaceutically acceptable salt thereof in an amount sufficient to effectively achieve its intended purpose. Dosage may be adjusted to achieve the desired effect, but will depend on factors such as weight, diet, concurrent medication, and other factors that a person skilled in the medical field will recognize.

[0118] In some embodiments, the compound of structure (I) or a pharmaceutically acceptable salt thereof will be administered as a continuous therapy for a period of time, such as a week or longer, or for months or years. In some embodiments, the compound of structure (I) or a pharmaceutically acceptable salt thereof will be administered once daily, provided that eGFR > 20 ml / min / 1.73 m 2 Or the patient may develop end-stage renal disease (ESRD) requiring renal replacement therapy (RRT).

[0119] In some embodiments, the compound of structure (I) or a pharmaceutically acceptable salt thereof is administered for a period of time, such period being, for example, at least about 4 weeks to at least about 8 weeks, at least about 4 weeks to at least about 12 weeks, at least about 4 weeks to at least about 16 weeks or longer. In some embodiments, the administration of the compound of structure (I) or a pharmaceutically acceptable salt thereof lasts for 36 weeks or longer. In some embodiments, the administration of the compound of structure (I) or a pharmaceutically acceptable salt thereof lasts for 36 weeks. In some embodiments, the administration of the compound of structure (I) or a pharmaceutically acceptable salt thereof lasts for 108 weeks. In some embodiments, the administration of the compound of structure (I) or a pharmaceutically acceptable salt thereof lasts for 110 weeks. The administration of the compound of structure (I) or a pharmaceutically acceptable salt thereof may be administered three times a day, twice a day, once a day, every other day, three times a week, every other week, three times a month, once a month, generally continuously or continuously.

[0120] In cases of topical application or selective uptake, the effective local concentration of the drug may be independent of plasma concentration. The amount of composition applied may depend on the subject being treated, the subject's weight, the severity of the ailment, and the method of administration.

[0121] In some embodiments, this disclosure relates to a method of treating IgAN using a compound of structure (I) or a pharmaceutically acceptable salt thereof, comprising orally administering to a patient a dose of a compound of structure (I) or a pharmaceutically acceptable salt thereof at a generally continuous or continuous frequency for the duration required for treatment, said dose containing an amount of the drug from about 10 mg to about 1000 mg per dose.

[0122] In some embodiments, this disclosure provides a method of treating a patient with IgAN using a compound of structure (I) or a pharmaceutically acceptable salt thereof, comprising orally administering to the patient a dose containing about 100 mg to about 1000 mg of the drug at a frequency of three times a month, once a month, once a week, once every three days, once every two days, once a day, twice a day, or three times a day, for the desired duration of treatment.

[0123] In some other embodiments, this disclosure provides a method of treating a patient with IgAN using a compound of structure (I) or a pharmaceutically acceptable salt thereof, comprising orally administering to the patient a dose containing about 200 mg of the drug at a frequency of three times a month, once a month, once a week, once every three days, once every two days, once a day, twice a day, or three times a day, for the desired duration of treatment.

[0124] In some embodiments, this disclosure provides a method of treating a patient with IgAN using a compound of structure (I) or a pharmaceutically acceptable salt thereof, comprising orally administering to the patient a dose containing about 400 mg of the drug at a frequency of three times a month, once a month, once a week, once every three days, once every two days, once a day, twice a day, or three times a day, for the desired duration of treatment.

[0125] In some embodiments, this disclosure provides a method of treating a patient with IgAN using a compound of structure (I) or a pharmaceutically acceptable salt thereof, comprising orally administering to the patient a dose containing about 800 mg of the drug at a frequency of three times a month, once a month, once a week, once every three days, once every two days, once a day, twice a day, or three times a day, for the desired duration of treatment.

[0126] In some embodiments, this disclosure provides a method of treating a patient with IgAN using a compound of structure (I) or a pharmaceutically acceptable salt thereof, comprising administering to the patient daily in a dose of about 0.1 mg / kg to about 100 mg / kg, or about 0.2 mg / kg to about 50 mg / kg, or about 0.5 mg / kg to about 25 mg / kg body weight (or about 1 mg to about 2500 mg, or about 100 mg to about 800 mg), which may be administered in a single dose or in separate fractionated doses, for example, 1 to 4 times daily. In some embodiments, the amount of the compound of structure (I) or a pharmaceutically acceptable salt thereof administered to the patient is about 1 mg / kg to about 15 mg / kg, about 3 mg / kg to about 12 mg / kg, or about 3 mg / kg to about 6 mg / kg daily, which may be administered in a single dose or in separate fractionated doses, for example, 1 to 4 times daily.

[0127] In some embodiments of the foregoing pharmaceutical compositions and methods, the pharmaceutical composition is a solid unit dosage form. In some embodiments, the solid unit dosage form comprises a compound having structure (I) 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 unit dosage form comprises a compound having structure (I) or a pharmaceutically acceptable salt thereof, in an amount of 400 mg or about 400 mg. In some embodiments, the solid unit dosage form is administered once daily. In some embodiments, the solid unit dosage form is administered orally.

[0128] In some embodiments of the foregoing pharmaceutical compositions and methods, the pharmaceutical composition is a liquid formulation for oral administration. In some specific embodiments, the liquid formulation is administered to subjects under the age of 18 (e.g., 2 to 6 years old).

[0129] In some embodiments of the foregoing pharmaceutical compositions and methods, the pharmaceutical composition is formulated for oral administration and may or may not be administered with food.

[0130] Where necessary, the composition may be presented in a package or dispenser device that may contain one or more unit dosage forms containing the active ingredient. The package may, for example, contain a metal or plastic film, such as blister packs. The package or dispenser may be accompanied by instructions for use. The package or dispenser may also be accompanied by precautions associated with the container, in the form prescribed by the government agency regulating the manufacture, use, or sale of the drug, reflecting the agency's approval for the drug form to be used in human or veterinary administration. For example, such precautions may be a prescription drug label approved by the U.S. Food and Drug Administration or an approved product information label. Compositions of compounds containing structure (I) or pharmaceutically acceptable salts thereof, formulated in a compatible drug carrier, placed in a suitable container, and labeled for the treatment of a specified condition may also be prepared.

[0131] Exemplary Implementation In another embodiment, this disclosure also provides: 1. A method for treating immunoglobulin A nephropathy (IgAN) in a patient in need, the method comprising administering a pharmaceutical composition to the patient, the pharmaceutical composition comprising a compound having structure (I), , Or its pharmaceutically acceptable salt, wherein the patient (i) has a concentration greater than or equal to 30 mL / min / 1.73 m 2 (ii) having a baseline estimated glomerular filtration rate (eGFR) and a baseline proteinuria to creatinine ratio (UP / C) greater than or equal to 1.0 g / g.

[0132] 2. A method for prolonging the time it takes for a patient diagnosed with IgAN to develop end-stage renal disease, the method comprising administering a pharmaceutical composition to the patient, the pharmaceutical composition comprising a compound having structure (I), , Or its pharmaceutically acceptable salt, wherein the patient (i) has a concentration greater than or equal to 30 mL / min / 1.73 m 2 (ii) having a baseline eGFR and (ii) having a baseline proteinuria to creatinine ratio (UP / C) greater than 1.0 g / g.

[0133] 3. A method for reducing the risk of end-stage renal disease in a patient diagnosed with IgAN, the method comprising administering a pharmaceutical composition to the patient, the pharmaceutical composition comprising a compound having structure (I), , Or its pharmaceutically acceptable salt, wherein the patient (i) has a concentration greater than or equal to 30 mL / min / 1.73 m 2 (ii) having a baseline eGFR and a baseline proteinuria to creatinine ratio (UP / C) greater than or equal to 1.0 g / g.

[0134] 4. A method for inducing complete remission in a patient with immunoglobulin A nephropathy (IgAN), the method comprising administering a pharmaceutical composition to the patient, the pharmaceutical composition comprising a compound having structure (I), , Or its pharmaceutically acceptable salt, wherein the patient (i) has a concentration greater than or equal to 30 mL / min / 1.73 m 2 (ii) having a baseline estimated glomerular filtration rate (eGFR) and a baseline proteinuria to creatinine ratio (UP / C) greater than or equal to 1.0 g / g.

[0135] 5. The method according to embodiment 4, wherein after administration of the pharmaceutical composition, the UP / C decreases to less than or equal to 0.3 g / g.

[0136] 6. A method for reducing the rate of decline in estimated glomerular filtration rate (eGFR) in a patient with immunoglobulin A nephropathy (IgAN), the method comprising administering a pharmaceutical composition to the patient, the pharmaceutical composition comprising a compound having structure (I), , Or its pharmaceutically acceptable salt, wherein the patient (i) has a concentration greater than or equal to 30 mL / min / 1.73 m 2 (ii) having a baseline estimated glomerular filtration rate (eGFR) and a baseline proteinuria to creatinine ratio (UP / C) greater than or equal to 1.0 g / g.

[0137] 7. The method according to any one of embodiments 1 to 6, wherein the subject suffers from primary IgAN confirmed by biopsy.

[0138] 8. The method according to any one of embodiments 1 to 7, wherein the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof administered to the patient is 100 mg / day.

[0139] 9. The method according to any one of embodiments 1 to 7, wherein the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof administered to the patient is 200 mg / day.

[0140] 10. The method according to any one of embodiments 1 to 7, wherein the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof administered to the patient is 400 mg / day.

[0141] 11. The method according to any one of embodiments 1 to 7, wherein the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof administered to the patient is 200 mg / day for the first 2 weeks and thereafter 400 mg / day.

[0142] 12. The method according to any one of embodiments 1 to 7, wherein (a) if the patient's weight is 20 kg to 50 kg, the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof administered to the patient is 100 mg / day for the first 2 weeks and thereafter 200 mg / day.

[0143] 13. The method according to any one of embodiments 1 to 12, wherein the pharmaceutical composition is administered orally.

[0144] 14. The method according to embodiment 13, wherein the pharmaceutical composition is administered with or without food.

[0145] 15. The method according to any one of embodiments 1 to 14, wherein the patient is not a pregnant or lactating woman.

[0146] 16. The method according to any one of embodiments 1 to 15, wherein if the patient is a woman of fertility potential, the method further includes administering a monthly pregnancy test to the patient, and if the pregnancy test indicates that the patient is pregnant, discontinuing the administration of the compound of structure (I) or a pharmaceutically acceptable salt thereof.

[0147] 17. The method according to any one of embodiments 1 to 16, wherein if the patient is a woman of fertility potential, the method further includes administering an oral contraceptive, an implantable contraceptive, an injectable contraceptive, or an intrauterine device to the patient.

[0148] 18. The method according to any one of embodiments 1 to 17, wherein the patient does not suffer from severe liver damage.

[0149] 19. The method according to any one of embodiments 1 to 18, wherein the patient does not suffer from severe kidney damage.

[0150] 20. The method according to any one of embodiments 1 to 19, wherein the patient has a UP / C of less than or equal to 1.0 g / g after 36 weeks of treatment.

[0151] 21. The method according to any one of embodiments 1 to 20, wherein one or more additional therapeutic agents are administered to the patient.

[0152] 22. A pharmaceutical composition comprising a compound having structure (I), , Or a pharmaceutically acceptable salt thereof, used in the method according to any one of embodiments 1 to 21.

[0153] 23. Use of a pharmaceutical composition in the preparation of a medicament according to any one of embodiments 1 to 21, said pharmaceutical composition comprising a compound having structure (I), , Or its pharmaceutically acceptable salt.

[0154] Example Example 1 Treatment of immunoglobulin A nephropathy (IgAN) with sparsentan The long-term renal protective potential of sparsentan has been evaluated in PROTECT, a 114-week, randomized, global, multicenter, double-blind, parallel-group, active-controlled phase 3 study in patients with IgAN who had persistent, significant proteinuria and remained at high risk of disease progression despite receiving a stable dose (or multiple doses) of angiotensin-converting enzyme inhibitors (ACEIs) and / or angiotensin receptor blockers (ARBs) at a dose that was the maximum tolerated dose, i.e., at least half of the maximum labeled dose (MLD) (according to the approved prescribing information). The aim of the study was to assess the potential benefit of sparsentan for renal function by analyzing changes in proteinuria (protein in urine) and estimated glomerular filtration rate (eGFR) compared to current standard of care.

[0155] The study has an open-label extension period of up to 156 weeks, with a total duration of up to 270 weeks.

[0156] The study recruited 404 patients aged 18 years or older worldwide.

[0157] Patients recruited were at high risk of progressing to renal failure. The trial recruited patients with eGFR ≥30 mL / min / 1.73 m at screening. 2Patients with a proteinuria-to-creatinine ratio (UP / C) ≥1.0 g / g.

[0158] Inclusion criteria included: age 18 years or older at screening; biopsy-confirmed primary IgAN; proteinuria (UP / C) ≥1 g / day at screening; and eGFR ≥30 mL / min / 1.73 m³ at screening. 2 Currently receiving a stable dose of ACEI and / or ARB therapy and continuing to use it for at least 12 weeks prior to screening (at least half of the maximum tolerated dose and the maximum labeled dose); systolic blood pressure ≤150 mmHg and diastolic blood pressure ≤100 mmHg at screening; willing to switch ACEI and / or ARB and antihypertensive medication; and agree to use contraception.

[0159] Exclusion criteria during the double-blind period included: IgAN secondary to another condition; presence of cellular glomerular crescents in >25% of glomeruli at the time of renal biopsy (if biopsy could be performed within 6 months of screening); chronic kidney disease (CKD) other than IgAN; history of organ transplantation, excluding corneal transplantation; use of any contraindicated medications; treatment with systemic immunosuppressive drugs (including corticosteroids) for >2 weeks within 3 months of screening; history of heart failure or previous respiratory failure of unknown cause. History of hospitalization for dyspnea, orthopnea, paroxysmal nocturnal dyspnea, ascites, and / or peripheral edema; clinically significant cerebrovascular disease or coronary artery disease within the past 6 months; jaundice, hepatitis, or known hepatobiliary disease at screening time, or elevated ALT / AST levels >2 times the upper limit of normal; history of malignancy other than well-treated basal cell or squamous cell skin cancer or cervical cancer within the past 2 years; hematocrit <27% (0.27%) at screening time. V / V) or hemoglobin level <9 g / dL (90 g / L); potassium >5.5 mEq / L (5.5 mmol / L) at screening; history of alcohol or illicit drug use disorder; history of serious adverse reactions or allergic reactions to any angiotensin II antagonist or endothelin receptor antagonist (including sparsentan or irbesartan), or allergy to any excipient of the investigational drug; female patients who are pregnant, planning to become pregnant during the study, or are breastfeeding; and patients who have participated in other investigational products within 28 days prior to screening.

[0160] Exclusion criteria for the open-label extension period, determined based on assessments at weeks 110 and 114, included: progression to end-stage renal disease (ESRD) requiring renal replacement therapy (RRT); any criteria for discontinuation of the study drug or withdrawal from the study occurring between weeks 110 and 114; inability to initiate RAAS inhibitor therapy or the presence of contraindications to RAAS inhibitor therapy between weeks 110 and 114; and eGFR ≤20 mL / min / 1.73 m at week 110. 2 And female patients who are pregnant or breastfeeding.

[0161] All patients were randomized 1:1 to receive either a single oral morning dose of sparsentan or an active control irbesartan (an angiotensin receptor blocker). Sparsentan was administered orally at a dose of 200 mg once daily for 2 weeks, followed by a dose adjustment to 400 mg once daily based on tolerability. Irbesartan was administered orally at a dose of 150 mg once daily for 2 weeks, followed by a dose adjustment to 300 mg once daily based on tolerability.

[0162] Sparsentan is available in tablet form, with each tablet containing 200 mg or 400 mg of sparsentan. Inactive ingredients include silicified microcrystalline cellulose, anhydrous lactose, sodium glycolate starch, colloidal silica, and magnesium stearate.

[0163] The change in proteinuria (UP / C) at week 36 compared to baseline (day 1) was assessed in patients treated with sparsentan and those treated with ibesartan. UP / C at week 36 was measured based on 24-hour urine samples. Secondary outcome measures included eGFR at week 52 and week 104 following the initial acute effect of randomization. The initial acute effect of randomization was defined as the first 6 weeks of randomization with the study drug; therefore, analyses were performed from week 6 to week 58 after randomization (1-year chronic eGFR slope) or week 110 (2-year chronic eGFR slope), respectively. eGFR was also assessed at weeks 58 and 110 (approximately 2 years) after randomization (analyses were performed from week 1 to week 58 or from week 1 to week 110 after randomization, i.e., the 2-year total eGFR slope).

[0164] The study provides an analysis of preliminary results at week 36 after the first 280 patients completed 36 weeks of treatment. At week 36, patients treated with irbesartan showed a mean reduction of 15.1% in proteinuria from baseline, compared to a mean reduction of 49.8% in patients receiving sparsentan (p<0.0001), meaning the sparsentan group showed more than a three-fold reduction in proteinuria compared to the irbesartan group. The geometric mean ratio was 0.59. The relative reduction rate was 41%. Preliminary results from the interim analysis indicate that sparsentan is generally well-tolerated in the studies to date and is consistent with the safety profile observed to date. Preliminary eGFR data available at the interim analysis suggest a potentially clinically meaningful treatment effect after two years of treatment.

[0165] At the end of the study, clinically significant treatment-related differences in eGFR slope were observed. The chronic eGFR slope over 2 years was 1.1 (0.07, 2.12) mL / min / 1.73 m 2 / year (two-sided p-value = 0.037), and the total slope of eGFR over 2 years was 1.0 (-0.03, 1.94) mL / min / 1.73 m 2 / year (two-sided p = 0.058). In patients treated with sparsentan for two years, the average annual rate of renal function decline was one of the slowest observed in clinical trials (-2.7 to -2.9 ml / min / 1.73 m). 2 ( / year). In all clinical trials conducted to date, sparsentan has been well tolerated and has a consistent safety profile with irbesartan, supporting long-term use.

[0166] Figure 1-3 Tables 1-3 show additional results from the final analysis set (FAS).

[0167] Table 1. Changes in eGFR from baseline at each visit - FAS a MMRM analysis, including treatment-period data up to week 110. b A single-slope random coefficient analysis was used to include eGFR data during the available treatment period from week 6 to week 110, after multiple imputation; mL / min / 1.73 m 2 / Year c A single-slope randomized coefficient analysis was used, including multiple-imputation eGFR data during the available treatment period up to week 110; mL / min / 1.73 m 2 / Year FAS - Final Analysis Set CFB - Change relative to baseline LSM - Least Squares Mean Table 2. Other Secondary Endpoints - FAS a MMRM analysis, including data during treatment with multiple intercalation up to week 110. b MMRM analysis, including treatment-period data up to week 110. c Relative risk is estimated using the Poisson regression model. FAS - Final Analysis Set The results are the LS mean and 95% confidence interval. Table 3. UP / C g / g Results - FAS FAS - Final Analysis Set MMRM analysis, including data during treatment with multiple intercalation up to week 110. GLS - Geometric Least Squares GMR - Geometric Mean Ratio Unless otherwise stated, all U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications mentioned in this specification or listed in the application data sheets are incorporated herein by reference, including U.S. Provisional Patent Application No. 63 / 584,125, filed September 20, 2023, which is incorporated herein by reference.

[0168] The various embodiments described above can be combined to provide other embodiments. Where necessary, aspects of the embodiments can be modified to employ various patented, applied, and disclosed concepts to provide other embodiments. Based on the detailed description above, these and other changes can be made to these embodiments.

[0169] Generally, the terminology used in the following claims should not be construed as limiting the claims to the specific embodiments disclosed in this specification and claims, but should be interpreted to include all possible embodiments and the full scope of equivalents entitled to be obtained by these claims. Accordingly, the claims are not limited by this disclosure.

Claims

1. A method for treating immunoglobulin A nephropathy (IgAN) in a patient in need, the method comprising administering a pharmaceutical composition to the patient, the pharmaceutical composition comprising a compound having structure (I), ， Or its pharmaceutically acceptable salt, wherein the patient (i) has a concentration greater than or equal to 30 mL / min / 1.73 m 2 (ii) having a baseline estimated glomerular filtration rate (eGFR) and a baseline proteinuria to creatinine ratio (UP / C) greater than or equal to 1.0 g / g.

2. A method for prolonging the time it takes for a patient diagnosed with IgAN to develop end-stage renal disease, the method comprising administering a pharmaceutical composition to the patient, the pharmaceutical composition comprising a compound having structure (I), ， Or its pharmaceutically acceptable salt, wherein the patient (i) has a concentration greater than or equal to 30 mL / min / 1.73 m 2 (ii) having a baseline eGFR and (ii) having a baseline proteinuria to creatinine ratio (UP / C) greater than 1.0 g / g.

3. A method for reducing the risk of end-stage renal disease in a patient diagnosed with IgAN, the method comprising administering a pharmaceutical composition to the patient, the pharmaceutical composition comprising a compound having structure (I), ， Or its pharmaceutically acceptable salt, wherein the patient (i) has a concentration greater than or equal to 30 mL / min / 1.73 m 2 (ii) having a baseline eGFR and a baseline proteinuria to creatinine ratio (UP / C) greater than or equal to 1.0 g / g.

4. A method for inducing complete remission in a patient with immunoglobulin A nephropathy (IgAN), the method comprising administering a pharmaceutical composition to the patient, the pharmaceutical composition comprising a compound having structure (I), ， Or its pharmaceutically acceptable salt, wherein the patient (i) has a concentration greater than or equal to 30 mL / min / 1.73 m 2 (ii) having a baseline estimated glomerular filtration rate (eGFR) and a baseline proteinuria to creatinine ratio (UP / C) greater than or equal to 1.0 g / g.

5. The method according to claim 4, wherein after administration of the pharmaceutical composition, the UP / C decreases to less than or equal to 0.3 g / g.

6. A method for reducing the rate of decline in estimated glomerular filtration rate (eGFR) in a patient with immunoglobulin A nephropathy (IgAN), the method comprising administering a pharmaceutical composition to the patient, the pharmaceutical composition comprising a compound having structure (I), ， Or its pharmaceutically acceptable salt, wherein the patient (i) has a concentration greater than or equal to 30 mL / min / 1.73 m 2 (ii) having a baseline estimated glomerular filtration rate (eGFR) and a baseline proteinuria to creatinine ratio (UP / C) greater than or equal to 1.0 g / g.

7. The method according to any one of claims 1 to 6, wherein the subject suffers from biopsy-confirmed primary IgAN.

8. The method according to any one of claims 1 to 7, wherein the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof administered to the patient is 100 mg / day.

9. The method according to any one of claims 1 to 7, wherein the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof administered to the patient is 200 mg / day.

10. The method according to any one of claims 1 to 7, wherein the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof administered to the patient is 400 mg / day.

11. The method according to any one of claims 1 to 7, wherein the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof administered to the patient is 200 mg / day for the first 2 weeks and thereafter 400 mg / day.

12. The method according to any one of claims 1 to 7, wherein (a) if the patient's weight is 20 kg to 50 kg, the amount of the compound having structure (I) or a pharmaceutically acceptable salt thereof administered to the patient is 100 mg / day for the first 2 weeks and thereafter 200 mg / day.

13. The method according to any one of claims 1 to 12, wherein the pharmaceutical composition is administered orally.

14. The method of claim 13, wherein the pharmaceutical composition is administered with or without food.

15. The method according to any one of claims 1 to 14, wherein the patient is not a pregnant or lactating woman.

16. The method according to any one of claims 1 to 15, wherein if the patient is a woman of fertility potential, the method further comprises administering a monthly pregnancy test to the patient, and if the pregnancy test indicates that the patient is pregnant, discontinuing the administration of the compound of structure (I) or a pharmaceutically acceptable salt thereof.

17. The method according to any one of claims 1 to 16, wherein if the patient is a woman of fertility potential, the method further comprises administering an oral contraceptive, an implantable contraceptive, an injectable contraceptive, or an intrauterine device to the patient.

18. The method according to any one of claims 1 to 17, wherein the patient does not suffer from severe liver damage.

19. The method according to any one of claims 1 to 18, wherein the patient does not suffer from severe kidney damage.

20. The method according to any one of claims 1 to 19, wherein the patient has a UP / C of less than or equal to 1.0 g / g after 36 weeks of treatment.

21. The method according to any one of claims 1 to 20, wherein one or more additional therapeutic agents are administered to the patient.

22. A pharmaceutical composition comprising a compound having structure (I), ， Or a pharmaceutically acceptable salt thereof, used in the method according to any one of claims 1 to 21.

23. Use of a pharmaceutical composition in the preparation of a medicament for use in any one of claims 1 to 21, said pharmaceutical composition comprising a compound having structure (I), ， Or its pharmaceutically acceptable salt.

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