WO2022246200A1

WO2022246200A1 - Methods of treating kidney diseases or disorders

Info

Publication number: WO2022246200A1
Application number: PCT/US2022/030257
Authority: WO
Inventors: Rosanna COPPO; Ping He; Michelle RHEAULT; Moin SALEEM; Howard Trachtman; Radko KOMERS
Original assignee: Travere Therapeutics, Inc.
Priority date: 2021-05-21
Filing date: 2022-05-20
Publication date: 2022-11-24

Abstract

Methods of treating proteinuric glomerular diseases are provided, including methods comprising administering a compound having structure (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the subject is a pediatric patient.

Description

METHODS OF TREATING KIDNEY DISEASES OR DISORDERS

BACKGROUND

The present disclosure relates to the use of sparsentan, a dual angiotensin and endothelin receptor antagonist, in the treatment of kidney diseases or disorders, such as focal segmental glomerulosclerosis (FSGS).

FSGS is a rare disease that affects the kidneys. Patients with FSGS exhibit scarring of the glomeruli of the kidney. Glomeruli filter the blood and remove water and some toxins, producing urine and leaving proteins behind in the blood. The scarring of the glomeruli in patients with FSGS is associated with leakage of protein into the urine (instead of remaining in the blood), a condition called proteinuria. Proteinuria causes fluid to build up in the body. Additionally, protracted proteinuria may itself result in damage to the kidneys and kidney dysfunction. FSGS is categorized as primary (or "idiopathic"), secondary, or genetic. Primary FSGS has no known etiology. Secondary FSGS may be caused by reduction in renal mass, including that which may be associated with low birth weight; vesicoureteral reflux; obesity; medications; infections, including HIV infection; or systemic illnesses, such as diabetes, sickle cell anemia, and lupus. If FSGS goes untreated, it can lead to end-stage renal disease (ESRD) over five to ten years.

Angiotensin II (Angll) and endothelin-I (ET-1) are two of the most potent endogenous vasoactive peptides currently known and are believed to play a role in controlling both vascular tone and pathological tissue remodeling associated with a variety of diseases including diabetic nephropathy, heart failure, and chronic or persistently elevated blood pressure. Angiotensin receptor blockers (ARBs), which block the activity of Angll, have been used as a treatment for diabetic nephropathy, heart failure, chronic, or persistently elevated blood pressure. There is also a growing body of data that demonstrates the potential therapeutic benefits of ET receptor antagonists (ERAs) in blocking ET-1 activity. Additionally, Angll 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 Angll at its receptor, but also limit the production of ET-1. Similarly, ERAs block ET-1 activity and inhibit the production of Angll. Consequently, simultaneously blocking Angll and ET-1 activities may offer better efficacy than blocking either substance alone. Reduction in proteinuria is associated with lower risk of end-stage renal disease (ESRD) in FSGS patients (Troost et ah, Clin J Am Soc Nephrol 13:414-421, 2018; International Patent Application Publication No. WO2018/071784 Al). In a Phase 2 study, sparsentan was shown to reduce proteinuria in patients with FSGS (International Patent Application Publication No. WO2018/071784 Al). However, there is currently no approved treatment for FSGS, including in pediatric patients. There remains a need for treatments for proteinuric glomerular diseases, such as

FSGS, minimal change disease (MCD), immunoglobulin A nephropathy (IgAN), immunoglobulin A-associated vasculitis (IgAV), and Alport syndrome, including in pediatric patients.

BRIEF SUMMARY The present disclosure provides, in some embodiments, methods of treating proteinuric glomerular diseases, wherein the method comprises administering a compound having structure (I),

or a pharmaceutically acceptable salt thereof, to a subject ( e.g . , a human patient) in need thereof. In some embodiments, the subject is a pediatric patient. These and other aspects of the present invention will become apparent upon reference to the following detailed description.

DETAILED DESCRIPTION

The present disclosure generally relates to the use of biphenyl sulfonamide compounds that have dual angiotensin and endothelin receptor antagonist activity, such as sparsentan, in the treatment of kidney diseases or disorders. Accordingly, in some embodiments, the present disclosure relates to the use of such compounds in treating proteinuric glomerular diseases, including focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), immunoglobulin A nephropathy (IgAN), immunoglobulin A-associated vasculitis (IgAV), and Alport syndrome. In some further embodiments, such compounds are used to treat proteinuric glomerular diseases in pediatric subjects.

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

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

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

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

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

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

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

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

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

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

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

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

Prodrugs and solvates of the compound having structure (I) are also contemplated. The term "prodrug" denotes a compound that, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound having structure (I), or a salt or solvate thereof. Solvates of the compound having structure (I) may be hydrates. Any tautomers are also contemplated.

Crystallizations may produce a solvate of the compound having structure (I), or a salt thereof. As used herein, the term "solvate" refers to an aggregate that comprises one or more molecules of a compound as disclosed herein with one or more molecules of solvent. In some embodiments, the solvent is water, in which case the solvate is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Thus, the compounds of the present disclosure may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. In some embodiments, the compounds disclosed herein may be a true solvate, while in other cases, the compounds disclosed herein merely retain adventitious water or are mixtures of water plus some adventitious solvent.

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

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

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

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

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

"Treatment" or "treating" includes (1) inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease ( e.g ., arresting further development of the pathology or symptomatology); or (2) ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease ( e.g ., reversing the pathology or symptomatology); or (3) effecting any measurable decrease in a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease. "Preventing" in the context of preventing a subject (e.g. _, a patient) from experiencing or displaying the pathology or symptomology of a disease includes the failure to develop a disease, disorder, or condition, or the reduction in the development of a sign or symptom associated with such a disease, disorder, or condition (e.g, by a clinically relevant amount), or the exhibition of delayed signs or symptoms delayed (e.g, by days, weeks, months, or years).

Additional definitions are set forth throughout this disclosure.

Sparsentan

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

Sparsentan is a selective dual-acting receptor antagonist with affinity for endothelin (A type) receptors ("ET_A" receptors) and angiotensin II receptors (Type 1) ("ATi" receptors) (Kowala et al., JPET 309: 275-284, 2004). The compound of structure (I) may be prepared by methods such as those described in International Patent Application Publication No. WO2018/071784 Al. Additionally, the compound of structure (I) may be prepared by the methods recited in U.S. Patent Application Publication No. US 2015/0164865 Al and U.S. Patent No. US 6,638,937 B2.

Pharmaceutical Compositions and Methods of Use

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

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

Additionally, methods of treating a proteinuric glomerular disease comprising administering a compound of structure (I), or pharmaceutically acceptable salt thereof, e.g, sparsentan, are within the scope of the present disclosure. In some embodiments, methods of treating a proteinuric glomerular disease comprising administering a pharmaceutical composition comprising a compound of structure (I), or pharmaceutically acceptable salt thereof, e.g. , sparsentan, and a pharmaceutically acceptable excipient, are provided. In some embodiments, the proteinuric glomerular disease is FSGS, MCD, IgAN, IgAV, or Alport syndrome. In some embodiments, the subject is a pediatric subject less than 18 years of age (e.g, 1 year of age up to 17 years of age; 2 years of age up to 17 years of age; 8 years of age up to 17 years of age; 3 years of age up to 7 years of age; 5 years of age up to 7 years of age; 2 years of age up to 4 years of age; 1 year of age up to 2 years of age). In one aspect, a compound of structure (I) or pharmaceutically acceptable salt thereof, e.g, sparsentan, is useful in the treatment of proteinuric glomerular diseases. Accordingly, in some embodiments, a method of treating a proteinuric glomerular disease is provided, comprising administering to a subject in need thereof a compound of structure (I), or pharmaceutically acceptable salt thereof. In some embodiments, the method of treating a proteinuric glomerular disease comprises administering to a subject in need thereof an effective amount of a compound of structure (I), or pharmaceutically acceptable salt thereof. In some embodiments, the method of treating a proteinuric glomerular disease comprises administering to a subject in need thereof a pharmaceutical composition comprising a compound of structure (I), or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In still further embodiments, the pharmaceutical composition comprises a compound of structure (I), or pharmaceutically acceptable salt thereof, in an effective amount for treating a proteinuric glomerular disease, and a pharmaceutically acceptable excipient. In some embodiments, the proteinuric glomerular disease is FSGS, MCD, IgAN, IgAV, or Alport syndrome. In some embodiments, the subject is a pediatric subject less than 18 years of age (e.g, 1 year of age up to 17 years of age; 2 years of age up to 17 years of age; 8 years of age up to 17 years of age; 3 years of age up to 7 years of age; 5 years of age up to 7 years of age; 2 years of age up to 4 years of age; 1 year of age up to 2 years of age). In some further embodiments, the compound of structure (I), or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of structure (I), or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, are useful in the treatment of a proteinuric glomerular disease. In some embodiments, the proteinuric glomerular disease is FSGS, MCD, IgAN, IgAV, or Alport syndrome. In some embodiments, the subject is a pediatric subject less than 18 years of age ( e.g ., 1 year of age up to 17 years of age; 2 years of age up to 17 years of age; 8 years of age up to 17 years of age; 3 years of age up to 7 years of age; 5 years of age up to 7 years of age; 2 years of age up to 4 years of age; 1 year of age up to 2 years of age).

In still further embodiments, the compound of structure (I), or pharmaceutically acceptable salt thereof, is useful in the reduction of general morbidity or mortality as a result of the above utilities.

In some embodiments, the compound of structure (I), or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of structure (I), or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, are useful in prolonging the time to end stage renal disease or reducing a risk of end stage renal disease in a patient diagnosed with a proteinuric glomerular disease, such as FSGS, MCD, IgAN, IgAV, and Alport syndrome. In some embodiments, the subject is a pediatric subject less than 18 years of age (e.g., 1 year of age up to 17 years of age; 2 years of age up to 17 years of age; 8 years of age up to 17 years of age; 3 years of age up to 7 years of age; 5 years of age up to 7 years of age; 2 years of age up to 4 years of age; 1 year of age up to 2 years of age).

In some embodiments, the compound of structure (I), or pharmaceutically acceptable salt thereof, is useful in reducing proteinuria. As used herein, "proteinuria" refers to a condition in which the urine contains an abnormal amount of protein (i.e., urine protein excretion of greater than 300 mg per day). A urine protein to creatinine ("UP/C") ratio provides a measurement of total urine protein relative to the amount of creatinine in a urine sample (e.g, 1 g of protein in urine (dl) divided by 1 g of creatinine in urine (dl) = a UP/C ratio of 1). As used herein, a UP/C ratio of more than 0.3 g/g indicates proteinuria. In some embodiments, the compound of structure (I), or pharmaceutically acceptable salt thereof, is useful in reducing proteinuria to levels to less than or equal to 1.5 g/g. In some embodiments, the compound of structure (I), or pharmaceutically acceptable salt thereof, is useful in reducing proteinuria to levels to less than or equal to 1.0 g/g.

In some embodiments, a method of treating FSGS in a pediatric subject in need thereof is provided, the method comprising administering to the pediatric subject a pharmaceutical composition comprising a compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount sufficient to achieve a UP/C ratio of less than or equal to 1.5 g/g. In some embodiments, a method of treating FSGS in a pediatric subject in need thereof is provided, the method comprising administering to the pediatric subject a pharmaceutical composition comprising a compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount sufficient to achieve or maintain a UP/C ratio of less than or equal to 1.5 g/g. In some embodiments, a method of treating FSGS in a pediatric subject in need thereof is provided, the method comprising administering to the pediatric subject a pharmaceutical composition comprising a compound having structure (I), or pharmaceutically acceptable salt thereof, at a dosing regimen sufficient to achieve or maintain a UP/C ratio of less than or equal to 1.5 g/g. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 25 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 50 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 100 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 200 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 300 mg/day.

In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 400 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 600 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 800 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 200 mg/day for 8 weeks, 26 weeks, 36 weeks, 8 months, or 108 weeks. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 400 mg/day for 8 weeks, 26 weeks, 36 weeks, 8 months, or 108 weeks. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 800 mg/day for 8 weeks, 26 weeks, 36 weeks, 8 months, or 108 weeks.

In some embodiments, a method of treating IgAN in a pediatric subject in need thereof is provided, the method comprising administering to the pediatric subject a pharmaceutical composition comprising a compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount sufficient to achieve a UP/C ratio of less than or equal to 1.0 g/g. In some embodiments, a method of treating IgAN in a pediatric subject in need thereof is provided, the method comprising administering to the pediatric subject a pharmaceutical composition comprising a compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount sufficient to achieve or maintain a UP/C ratio of less than or equal to 1.0 g/g. In some embodiments, a method of treating IgAN in a pediatric subject in need thereof is provided, the method comprising administering to the pediatric subject a pharmaceutical composition comprising a compound having structure (I), or pharmaceutically acceptable salt thereof, at a dosing regimen sufficient to achieve or maintain a UP/C ratio of less than or equal to 1.0 g/g. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 50 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 100 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 150 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 200 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 300 mg/day.

In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 400 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 800 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 200 mg/day for 8 weeks, 26 weeks, 36 weeks, 8 months, or 108 weeks. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 400 mg/day for 8 weeks, 26 weeks, 36 weeks, 8 months, or 108 weeks. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 800 mg/day for 8 weeks, 26 weeks, 36 weeks, 8 months, or 108 weeks.

In some embodiments, if the subject's weight is from 20 kg to 50 kg, the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is 200 mg/day for the first 2 weeks and thereafter is 400 mg/day. In some embodiments, if the subject's weight is greater than 50 kg, the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is 400 mg/day for the first 2 weeks and thereafter is 800 mg/day.

In some embodiments, the subject is 2 years of age or older (>2 years), and the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is 50% of a target dose for the first 2 weeks and is administered to the subject at 100% of the target dose thereafter. In some embodiments, the target dose is 100 mg/day, 200 mg/day, 300 mg/day, 400 mg/day,

600 mg/day, or 800 mg/day. In some embodiments, the subject weighs 40 kg or more (>40 kg) and the target dose is 800 mg/day. In some embodiments, the subject weighs 40 kg or more (>40 kg) and the target dose is 400 mg/day. In some embodiments, the subject weighs from 30 to 39 kg (>30 kg to <40 kg) and the target dose is 600 mg/day. In some embodiments, the subject weighs from 30 to 39 kg (>30 kg to <40 kg) and the target dose is 300 mg/day. In some embodiments, the subject weighs from 20 to 29 kg (>20 kg to <30 kg) and the target dose is 400 mg/day. In some embodiments, the subject weighs from 20 to 29 kg (>20 kg to <30 kg) and the target dose is 200 mg/day. In some embodiments, the subject weighs less than 20 kg (<20 kg) and the target dose is 200 mg/day. In some embodiments, the subject weighs less than 20 kg (<20 kg) and the target dose is 100 mg/day.

In some embodiments, the subject is less than 2 years of age (<2 years), and the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is 25% of a target dose for the first 2 weeks, 50% of the target dose for the following 2 weeks, and 100% of the target dose thereafter. In some embodiments, the target dose is 100 mg/day or 200 mg/day. In some embodiments, the subject weighs from 10 kg to 19 kg (> 10 kg to <20 kg) and the target dose is 200 mg/day. In some embodiments, the subject weighs from 7 kg to 9 kg (>7 kg to <10 kg) and the target dose is 100 mg/day.

In some embodiments, a method of treating FSGS in a pediatric subject in need thereof is provided, the method comprising administering to the pediatric subject, over an administration period, a pharmaceutical composition comprising a compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount sufficient to achieve or maintain a UP/C ratio of less than or equal to 1.5 g/g for at least a portion of the administration period. "Administration period" refers to the time period during which the pharmaceutical composition is administered to the subject as least daily. In some embodiments, the administration period is 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 8 months.

In some embodiments, a method of maintaining a UP/C ratio at less than or equal to 1.5 g/g in a pediatric subject in need thereof is provided, the method comprising administering to the pediatric subject a pharmaceutical composition comprising a compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount sufficient to maintain a UP/C ratio of less than or equal to 1.5 g/g.

In some embodiments, a method of reducing a UP/C ratio to less than or equal to 1.5 g/g in a pediatric subject in need thereof is provided, comprising administering to the subject a pharmaceutical composition comprising a compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount sufficient to reduce said pediatric subject's UP/C ratio to less than or equal to 1.5 g/g. In some embodiments, the pediatric subject has, or has had, a UP/C ratio greater than 1.5 g/g prior to administration of the pharmaceutical composition.

In some embodiments, a method of treating IgAN in a pediatric subject in need thereof is provided, the method comprising administering to the pediatric subject, over an administration period, a pharmaceutical composition comprising a compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount sufficient to achieve or maintain a UP/C ratio of less than or equal to 1.0 g/g for at least a portion of the administration period. 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 8 months.

In some embodiments, a method of maintaining a UP/C ratio at less than or equal to 1.0 g/g in a pediatric subject in need thereof is provided, the method comprising administering to the pediatric subject a pharmaceutical composition comprising a compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount sufficient to maintain a UP/C ratio of less than or equal to 1.0 g/g. In some embodiments, a method of reducing a UP/C ratio to less than or equal to 1.0 g/g in a pediatric subject in need thereof is provided, comprising administering to the subject a pharmaceutical composition comprising a compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount sufficient to reduce said pediatric subject's UP/C ratio to less than or equal to 1.0 g/g. In some embodiments, the pediatric subject has, or has had, a UP/C ratio greater than 1.0 g/g prior to administration of the pharmaceutical composition.

In any of the aforementioned embodiments, the method may achieve a reduction in the subject’s UP/C ratio of at least 40% relative to the subject's baseline UP/C ratio. As used herein, a subject's "baseline UP/C ratio" refers to the subject's most recently calculated UP/C ratio prior to onset of treatment ( e.g ., treatment with the compound having structure (I), or pharmaceutically acceptable salt thereof, or pharmaceutical composition comprising the same).

In any of the aforementioned embodiments, the amount or dosing regimen may be sufficient to achieve a reduction in the subject's UP/C ratio of at least 40% relative to the subject's baseline UP/C ratio.

In any of the aforementioned embodiments, a UP/C ratio of less than or equal to 1.5 g/g may be achieved within 8 weeks of administering the pharmaceutical composition. In any of the aforementioned embodiments, a UP/C ratio of less than or equal to 1.5 g/g may be achieved within 26 weeks of administering the pharmaceutical composition. In any of the aforementioned embodiments, a UP/C ratio of less than or equal to 1.5 g/g may be achieved within 36 weeks of administering the pharmaceutical composition. In any of the aforementioned embodiments, a UP/C ratio of less than or equal to 1.5 g/g may be achieved within 8 months of administering the pharmaceutical composition. In any of the aforementioned embodiments, a UP/C ratio of less than or equal to 1.5 g/g may be achieved within 108 weeks of administering the pharmaceutical composition.

In some embodiments, a UP/C of less than or equal to 1.5 g/g and a reduction in UP/C of more than 40% from the baseline UP/C is achieved following 36 weeks of treatment with the compound of structure (I), or pharmaceutically acceptable salt thereof, or pharmaceutical composition comprising the same.

In some embodiments, the compound of structure (I), or pharmaceutically acceptable salt thereof, is useful in maintaining glomerular filtration rate. As used herein, "glomerular filtration rate" ("GFR") is a measure of kidney function and refers to the amount of fluid filtered through the glomeruli of the kidney per unit of time.

GFR may be estimated by measuring serum creatinine levels and using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation. As used herein, "estimated glomerular filtration rate" ("eGFR") refers to an estimate of GFR obtained from using the CKD-EPI creatinine equation. In some embodiments, the compound of structure (I), or pharmaceutically acceptable salt thereof, is useful in maintaining eGFR levels ( e.g ., preventing a reduction in GFR associated with FSGS).

In some embodiments, administering the compound of structure (I), or pharmaceutically acceptable salt thereof, to a subject results in eGFR being maintained at or above eGFR levels immediately prior to (e.g., within a month prior to) administration of said compound of structure (I), or pharmaceutically acceptable salt thereof, or pharmaceutical composition comprising the same. In some embodiments, administering the compound of structure (I), or pharmaceutically acceptable salt thereof, to a subject results in eGFR being maintained at or above baseline eGFR level, where "baseline eGFR level" refers to their most recently calculated eGFR level prior to onset of treatment. As used herein, "maintenance of eGFR" refers to no clinically meaningful reduction in baseline eGFR levels. Thus, as used herein, in reference to treatment of a patient having FSGS, the phrase “maintain eGFR constant” means treatment that maintains the subject's eGFR at a level that is clinically equivalent to or better than their baseline eGFR (i.e., most recently calculated eGFR level prior to onset of treatment). In some embodiments, the eGFR is maintained for months or years after administration. The period of time during which the subject's eGFR level is maintained constant typically is at least 12 months.

In some embodiments, any of the aforementioned uses or methods of treatment may comprise administering the compound of structure (I), or pharmaceutically acceptable salt thereof, or pharmaceutical composition comprising the same, in combination with one or more other active ingredients, such as other therapeutic or diagnostic agents. For example, in some embodiments, one or more other therapeutic agents may be administered prior to, simultaneously with, or following the administration of the pharmaceutical composition comprising an effective amount of a compound of structure (I), or pharmaceutically acceptable salt thereof. If formulated as a fixed dose, such combination products may employ the compound of structure (I), or pharmaceutically acceptable salt thereof, within the dosage range described below, and the other active ingredient within its approved dosage range.

In some embodiments, the compound of structure (I), or pharmaceutically acceptable salt thereof, is used in conjunction with hemodialysis.

In some embodiments of the aforementioned uses and methods of treatment, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 25 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 50 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 75 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 100 mg/day.

In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 150 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 200 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 300 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 400 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 500 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 600 mg/day.

In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 700 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 800 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 900 mg/day. In some embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 1000 mg/day.

In some embodiments of the aforementioned uses and methods of treatment, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 200 mg/day for 8 weeks, 26 weeks, 36 weeks, 8 months, or 108 weeks. In still further embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 400 mg/day for 8 weeks, 26 weeks, 36 weeks, 8 months, or 108 weeks. In still further embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 800 mg/day for 8 weeks, 26 weeks, 36 weeks, 8 months, or 108 weeks.

In any of the aforementioned embodiments, the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject may be from about 50 mg/day to about 1000 mg/day. For example, in some embodiments, the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is from about 200 mg/day to about 800 mg/day. In some other embodiments, the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is about 25 mg/day. In other embodiments, the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is about 50 mg/day. In other embodiments, the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is about 100 mg/day. In other embodiments, the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is about 150 mg/day. In other embodiments, the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is about 200 mg/day. In other embodiments, the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is about 300 mg/day. In other embodiments, the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is about 400 mg/day. In other embodiments, the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is about 500 mg/day. In other embodiments, the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is about 600 mg/day. In other embodiments, the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is about 700 mg/day. In other embodiments, the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is about 800 mg/day. In other embodiments, the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is about 900 mg/day. In other embodiments, the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is about 1000 mg/day. In any of the aforementioned embodiments, the method may further comprise administering to said subject one or more additional therapeutic agents.

In any of the aforementioned embodiments, the subject may be greater than or equal to 18 years old or younger than 18 years of age. In some embodiments, the subject is less than 18 years old. In some embodiments, the subject is from 1 year of age to 17 years of age (>1 year of age to <18 years of age). In some embodiments, the subject is from 2 years of age to 17 years of age (>2 year of age to <18 years of age). In some embodiments, the subject is from 8 to 17 years of age (>8 years to <18 years of age). In some embodiments, the subject is from 5 to 7 years of age (>5 years to <8 years of age). In some embodiments, the subject is from 3 to 7 years of age (>3 year to <8 years of age). In some embodiments, the subject is from 2 to 4 years of age (>2 years to <5 years of age). In some embodiments, the subject is from 1 to 2 years of age (>1 year to <3 years of age). In some embodiments, the subject is from 5 to 10 years of age. In some embodiments, the subject is from 6 to 12 years of age. In some embodiments, the subject is from 2 to 6 years of age. In some embodiments, the subject is 8 years of age or older.

In some embodiments of the aforementioned uses and methods of treatment, the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is from 1 mg/kg to 15 mg/kg per day. In some embodiments, the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is from 3 mg/kg to 12 mg/kg per day. In some embodiments, the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is from 3 mg/kg to 6 mg/kg per day. In some of these embodiments, the subject is a child less than 18 years of age; from 2 to 6 years of age; from 5 to 10 years of age; or from 6 to 12 years of age. In some of these embodiments, the subject is from 1 year of age to 17 years of age (>1 year of age to <18 years of age), from 2 years of age to 17 years of age (>2 year of age to <18 years of age), from 8 to 17 years of age (>8 years to <18 years of age), from 5 to 7 years of age (>5 years to <8 years of age), from 3 to 7 years of age (>3 year to <8 years of age), from 2 to 4 years of age (>2 years to <5 years of age), or from 1 to 2 years of age (>1 year to <3 years of age).

In any of the aforementioned methods, the FSGS may be primary FSGS. For subjects having primary FSGS, the FSGS is not secondary to other causes such as reduction in renal mass, including that which may be associated with low birth weight; vesicoureteral reflux; obesity; medications; infections, including HIV infection; and systemic illnesses, such as diabetes, sickle cell anemia, and lupus. In any of the aforementioned methods wherein the proteinuric glomerular disease is FSGS, the subject may have FSGS lesions or a genetic mutation in a podocyte protein associated with FSGS.

In any of the aforementioned methods wherein the proteinuric glomerular disease is MCD, the subject may have MCD histological patterns or a genetic mutation in a podocyte protein associated with MCD.

In any of the aforementioned methods wherein the proteinuric glomerular disease is IgAN or IgAV, the subject may have biopsy-confirmed IgAN or IgAV. In any of the aforementioned methods wherein the proteinuric glomerular disease is Alport syndrome, the subject may have a pathogenic X-linked COL4A5 mutation, autosomal- recessive mutations in both alleles of COL4A3 and/or COL4A4, or autosomal- dominant COL4A3 and/or COL4A4 and digenic mutations. In any of the aforementioned methods wherein the proteinuric glomerular disease is Alport syndrome, the subject may have pathogenic mutations in genes coding for collagen 4 alpha 3, alpha 4, or alpha 5 chains.

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

In some embodiments of the aforementioned methods, the subject does not have a significant hepatic condition, severe hepatic impairment, or severe renal impairment. In some embodiments, the subject does not have G5 renal impairment (7.t\, GFR <15 mL/min/1.73 m²). In some embodiments, the subject does not have severe hepatic impairment ( i.e . .Child-Pugh class C).

In some embodiments of the aforementioned methods, the subject does not have a significant cardiovascular condition. In some embodiments of the aforementioned methods, the subject is not coadministered one or more of: aliskiren, an angiotensin converting enzyme (ACE) inhibitor, a mineralocorticoid receptor antagonist, a strong CYP3A4/5 inhibitor, a strong CYP3 A4/5 inducer, a renin-angiotensin-aldosterone system (RAAS) inhibitor, and an endothelin system inhibitor.

In some embodiments of the aforementioned methods, the subject has not been administered a RAAS inhibitor for at least two weeks prior to administration of the pharmaceutical composition comprising the compound having structure (I), or pharmaceutically acceptable salt thereof.

In any of the aforementioned methods, the subject may have a baseline eGFR greater than or equal to 30 mL/min/1.73 m² and a baseline urinary protein to creatinine ratio (UP/C) greater than or equal to 1.5 g/g or greater than or equal to 1.0 g/g. In some embodiments, the subject has a baseline eGFR greater than or equal to 30 mL/min/1.73 m². In some embodiments, the subject has a baseline eGFR of less than 60 mL/min/1.73 m². In some embodiments, the subject has a baseline eGFR of greater than 60 mL/min/1.73 m². In some embodiments, the subject has a baseline UP/C of greater than or equal to 1.0 g/g. In some embodiments, the subject has a baseline UP/C of greater than 1.0 g/g. In some embodiments, the subject has a baseline UP/C of greater than or equal to 1.5 g/g. In some embodiments, the subject has a baseline UP/C of greater than 1.5 g/g. In some embodiments, the subject has a baseline UP/C of less than or equal to 2 g/g. In some embodiments, the subject has a baseline UP/C of greater than 3.5 g/g.

In some embodiments, the subject has FSGS, a baseline eGFR greater than or equal to 30 mL/min/1.73 m², and a baseline urinary protein to creatinine ratio (UP/C) greater than or equal to 1.5 g/g. In some embodiments, the subject having FSGS has biopsy-proven FSGS and clinical presentation consistent with primary FSGS despite history or ongoing treatment with corticosteroids and/or other immunosuppressive disease-modifying agents; documentation of a genetic mutation in a podocyte protein associated with FSGS; or biopsy-proven FSGS histological pattern with medical history and clinical presentation consistent with maladaptive cause of the lesion. In some embodiments, the subject has IgAN, a baseline eGFR greater than or equal to 30 mL/min/1.73 m², and a baseline urinary protein to creatinine ratio (UP/C) greater than or equal to 1.0 g/g. In some embodiments, the subject having IgAN has biopsy-confirmed IgAN.

In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having structure (I), or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient for use in any of the aforementioned methods.

In some embodiments, the present disclosure provides for the use of a pharmaceutical composition comprising a compound having structure (I), or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in any of the aforementioned therapeutic methods.

Pharmaceutical Formulations

In one aspect, the present disclosure relates to the administration of a pharmaceutical composition comprising the compound of structure (I), or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient. Techniques for formulation and administration of the compound of structure (I), or pharmaceutically acceptable salt thereof, may be found, for example, in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990, which is incorporated herein by reference for teachings relevant to such techniques. In some embodiments, the pharmaceutical composition is formulated as described below.

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

Acceptable excipients include, for example, microcrystalline cellulose, lactose, sucrose, starch powder, maize starch or derivatives thereof, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinyl-pyrrolidone, polyvinyl alcohol, saline, dextrose, mannitol, lactose monohydrate, lecithin, albumin, sodium glutamate, cysteine hydrochloride, croscarmellose sodium, sodium starch glycolate, hydroxypropyl cellulose, poloxamer (e.g., poloxamers 101, 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, 403, and 407, and poloxamer 105 benzoate, poloxamer 182 dibenzoate 407, and the like), sodium lauryl sulfate, colloidal silicon dioxide, and the like. Examples of suitable excipients for tablets and capsules include microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, sodium starch, hydroxypropyl cellulose, poloxamer 188, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. Examples of suitable excipients for soft gelatin capsules include vegetable oils, waxes, fats, and semisolid and liquid polyols. Suitable excipients for the preparation of solutions and syrups include, for example, water, polyols, sucrose, invert sugar, and glucose. The compound can also be made in microencapsulated form. If desired, absorption enhancing preparations (for example, liposomes), can be utilized. Acceptable excipients for therapeutic use are well known in the pharmaceutical art, and are described, for example, in "Handbook of Pharmaceutical Excipients," 5th edition (Raymond C Rowe, Paul J Sheskey and Sian C Owen, eds. 2005), and "Remington: The Science and Practice of Pharmacy," 21st edition (Lippincott Williams & Wilkins, 2005), which are incorporated herein by reference for teachings relevant to such excipients. In some embodiments, surfactants are used. Use of surfactants as wetting agents in oral drug forms or to improve the permeation and bioavailability of pharmaceutical active compounds is described in the literature, for example in H. Sucker, P. Fuchs, P. Speiser, Pharmazeutische Technologie_s 2nd edition, Thieme 1989, page 260, and Advanced Drug Delivery Reviews (1997), 23, pages 163-183, which are incorporated herein by reference for such teachings. Examples of surfactants include anionic surfactants, non-ionic surfactants, zwitterionic surfactants, and a mixture thereof. In some embodiments, the surfactant is selected from the group consisting of poly(oxyethylene) sorbitan fatty acid ester, poly(oxyethylene) stearate, poly(oxyethylene) alkyl ether, polyglycolated glyceride, poly(oxy ethylene) castor oil, sorbitan fatty acid ester, poloxamer, fatty acid salt, bile salt, alkyl sulfate, lecithin, mixed micelle of bile salt and lecithin, glucose ester vitamin E TPGS (D-a-tocopheryl polyethylene glycol 1000 succinate), sodium lauryl sulfate, and the like, and a mixture thereof.

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

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

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

In some embodiments, a lubricant is employed in the manufacture of certain dosage forms. For example, a lubricant may be employed when producing tablets. In some embodiments, a lubricant can be added just before the tableting step, and can be mixed with the other ingredients for a minimum period of time to obtain good dispersal. In some embodiments, one or more lubricants may be used. Examples of suitable lubricants include magnesium stearate, calcium stearate, zinc stearate, stearic acid, talc, glyceryl behenate, polyethylene glycol, polyethylene oxide polymers (for example, available under the registered trademarks of Carbowax® for polyethylene glycol and Polyox® for polyethylene oxide from Dow Chemical Company, Midland, Mich.), sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silica, and others as known in the art. Typical lubricants are magnesium stearate, calcium stearate, zinc stearate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants may comprise from about 0.25% to about 50% of the tablet weight, typically from about 1% to about 40%, more typically from about 5% to about 30%, and most typically from 20% to 30%. In some embodiments, magnesium stearate can be added as a lubricant, for example, to improve powder flow, prevent the blend from adhering to tableting equipment and punch surfaces, and provide lubrication to allow tablets to be cleanly ejected from tablet dies. In some embodiments, magnesium stearate may be added to pharmaceutical formulations at concentrations ranging from about 0.1% to about 5.0% w/w, or from about 0.25% to about 4% w/w, or from about 0.5% w/w to about 3% w/w, or from about 0.75% to about 2% w/w, or from about 0.8% to about 1.5% w/w, or from about 0.85% to about 1.25% w/w, or from about 0.9% to about 1.20% w/w, or from about 0.85% to about 1.15% w/w, or from about 0.90% to about 1.1.% w/w, or from about 0.95% to about 1.05% w/w, or from about 0.95% to about 1% w/w. The above ranges are examples of typical ranges. One of ordinary skill in the art would recognize additional lubricants and/or amounts that can be used in the formulations described herein. As would be recognized by one of ordinary skill in the art, when incorporated into the pharmaceutical compositions disclosed herein, the amounts of the major filler(s) and/or other excipients may be reduced accordingly to accommodate the amount of lubricant(s) added in order to keep the overall unit weight of the dosage form unchanged.

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

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

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

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

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

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

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

In some embodiments, one or more of, or any combination of, the listed excipients can be specifically included or excluded from the pharmaceutical compositions or methods disclosed herein. Any of the foregoing formulations may be appropriate in treatments and therapies in accordance with the disclosure herein, provided that the one or more active ingredient in the pharmaceutical composition is not inactivated by the formulation and the formulation is physiologically compatible and tolerable with the route of administration ( see also Baldrick P., Regul. Toxicol. Pharmacol. 32(2):210-218, 2000; Charman W.N., J. Pharm. Sci. 89(8):967-78, 2000, and the citations therein; which references are incorporated herein by reference for teachings relevant to formulations, excipients, and carriers well known to pharmaceutical chemists).

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

As will be appreciated by those of skill in the art, the amounts of excipients will be determined by drug dosage and dosage form size. In some embodiments disclosed herein, the dosage form size is about 200 mg to 800 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 500 mg. In some embodiments disclosed herein, the dosage form size is about 800 mg. One skilled in the art will realize that a range of weights may be made and are encompassed by this disclosure.

The pharmaceutical compositions of the present disclosure may be manufactured in a manner that is itself known, e.g, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or tableting processes. The pharmaceutical compositions of the present disclosure may provide low- dose formulations of the compound of structure (I), or pharmaceutically acceptable salt thereof, in tablets, film coated tablets, capsules, caplets, pills, gel caps, pellets, beads, or dragee dosage forms. The formulations disclosed herein can provide favorable drug processing qualities, including, for example, rapid tablet press speeds, reduced compression force, reduced ejection forces, blend uniformity, content uniformity, uniform dispersal of color, accelerated disintegration time, rapid dissolution, low friability (preferable for downstream processing such as packaging, shipping, pick-and- pack, etc.) and dosage form physical characteristics ( e.g ., weight, hardness, thickness, friability) with little variation.

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

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

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

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

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

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

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

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

Further disclosed herein are various pharmaceutical compositions well known in the pharmaceutical art for uses that include intraocular, intranasal, and intraauricular delivery. Suitable penetrants for these uses are generally known in the art. Pharmaceutical compositions for intraocular delivery include aqueous ophthalmic solutions of the active compounds in water-soluble form, such as eye drops, or in gellan gum (Shedden et ah, Clin. Ther. 23(3):440-50, 2001) or hydrogels (Mayer et ah, Ophthalmologica 210(2): 101-3, 1996); ophthalmic ointments; ophthalmic suspensions, such as microparticulates, drug-containing small polymeric particles that are suspended in a liquid carrier medium (Joshi, J. Ocul. Pharmacol. 10(l):29-45, 1994), lipid-soluble formulations (Aim et al., Prog. Clin. Biol. Res. 312:447-58, 1989), and microspheres (Mordenti, Toxicol. Sci. 52(1): 101-6, 1999); and ocular inserts (which references are incorporated herein by reference for teachings relevant to such compositions). Such suitable pharmaceutical formulations may be formulated to be sterile, isotonic, and buffered for stability and comfort. Pharmaceutical compositions for intranasal delivery may also include drops and sprays often prepared to simulate in many respects nasal secretions, to ensure maintenance of normal ciliary action. As disclosed in "Remington's Pharmaceutical Sciences," 18th Ed., Mack Publishing Co., Easton, PA (1990) (incorporated herein by reference for teachings relevant to such formulations), and well known to those skilled in the art, suitable formulations are most often and preferably isotonic, slightly buffered to maintain a pH of 5.5 to 6.5, and most often and preferably include antimicrobial preservatives and appropriate drug stabilizers. Pharmaceutical formulations for intraauricular delivery include suspensions and ointments for topical application in the ear. Common solvents for such aural formulations include glycerin and water.

The compound of structure (I), or pharmaceutically acceptable salt thereof may also be formulated in rectal compositions such as suppositories or retention enemas, e.g ., those containing conventional suppository bases such as cocoa butter or other glycerides.

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

For hydrophobic compounds, a suitable pharmaceutical carrier may be a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. A common cosolvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low- toxicity nonpolar surfactants may be used instead of Polysorbate 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. , polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well-known examples of delivery vehicles or carriers for hydrophobic drugs. In some embodiments, certain organic solvents such as dimethylsulfoxide also may be employed. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

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

In some embodiments, a solid dosage unit form comprising the compound of structure (I), or pharmaceutically acceptable salt thereof, is provided for use in the compositions and methods described herein. In some embodiments, the solid dosage unit form includes the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 200 mg; about 200 mg; 400 mg; about 400 mg; 500 mg; about 500 mg; 800 mg; or about 800 mg. In some embodiments, the solid dosage unit form includes the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 400 mg; about 400 mg; 800 mg; or about 800 mg.

In some embodiments, a liquid formulation of the compound of structure (I), or pharmaceutically acceptable salt thereof, is provided for use in the compositions and methods described herein. In some embodiments, the liquid formulation comprises sparsentan and a diluent or vehicle, such as water. In some embodiments, the liquid formulation further comprises (a) a preservative, such as potassium sorbate or sodium benzoate; (b) a sweetener, such as sucralose or sodium saccharin; (c) a flavoring agent; (d) a viscosity modifier such as xanthan gum, microcrystalline cellulose/sodium carboxymethylcellulose composite, methyl cellulose, or hydroxyethyl cellulose; or (e) a pH modifier, such as citric acid, tartaric acid, or sodium citrate; or combinations thereof. For example, in some embodiments, a liquid formulation of sparsentan is provided, which comprises sparsentan, water as a diluent or vehicle, sodium benzoate, sucralose, a flavoring agent, xanthan gum, and citric acid. In some embodiments, the liquid formulation comprises the compound of structure (I) at 80 mg/mL. For example, in some embodiments, the liquid formulation comprising the components as in Table 1 at the provided relative weights (% w/w).

Table 1. Exemplary liquid formulation.

^a Suspension weight equivalent to 40,000 L, based on a product density of 0.99 g/cm3.

In some embodiments, the liquid formulation is administered orally to a subject who is 18 years of age or older, 8 years of age or older, less than 18 years old, 12 years old or younger, from 6 to 12 years of age, or from 2 to 6 years of age. In some particular embodiments, the liquid formulation is administered to a subject who is from 1 year of age to 17 years of age (>1 year of age to <18 years of age), from 2 years of age to 17 years of age (>2 year of age to <18 years of age), from 8 to 17 years of age (>8 years to <18 years of age), from 5 to 7 years of age (>5 years to <8 years of age), from 3 to 7 years of age (>3 year to <8 years of age), from 2 to 4 years of age (>2 years to <5 years of age), or from 1 to 2 years of age (>1 year to <3 years of age). In some embodiments, the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, in the liquid formulation administered to the subject is adjusted to the subject's body weight. In some embodiments, the subject weighs 40 kg or more (>40 kg) and the target dose is 800 mg/day. In some embodiments, the subject weighs 40 kg or more (>40 kg) and the target dose is 400 mg/day. In some embodiments, the subject weighs from 30 to 39 kg (>30 kg to <40 kg) and the target dose is 600 mg/day. In some embodiments, the subject weighs from 30 to 39 kg (>30 kg to <40 kg) and the target dose is 300 mg/day. In some embodiments, the subject weighs from 20 to 29 kg (>20 kg to <30 kg) and the target dose is 400 mg/day. In some embodiments, the subject weighs from 20 to 29 kg (>20 kg to <30 kg) and the target dose is 200 mg/day. In some embodiments, the subject weighs less than 20 kg (<20 kg) and the target dose is 200 mg/day. In some embodiments, the subject weighs less than 20 kg (<20 kg) and the target dose is 100 mg/day. In some embodiments, the subject weighs from 10 kg to 19 kg (>10 kg to <20 kg) and the target dose is 200 mg/day. In some embodiments, the subject weighs from 7 kg to 9 kg (>7 kg to <10 kg) and the target dose is 100 mg/day.

Methods of Administration

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

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

Depending on the severity and responsiveness of the condition to be treated, dosing can also be a single administration of a slow-release composition, with course of treatment lasting from several days to several weeks or until cure is effected or diminution of the disease state is achieved. The amount of a composition to be administered will be dependent on many factors including the subject being treated, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician. In some embodiments, the compound of structure (I), or pharmaceutically acceptable salt thereof may be administered orally or via injection at a dose from 0.001 mg/kg to 2500 mg/kg of the patient's body weight per day. In some further embodiments, the dose range for adult humans is from 0.01 mg to 10 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of the compound of structure (I), or pharmaceutically acceptable salt thereof, that is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 1000 mg, usually from about 100 mg to about 800 mg. The dose employed will depend on a number of factors, including the age and sex of the patient, the precise disease or disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity. In cases wherein a salt is administered, dosages may be calculated as the dose of the free base.

In some embodiments, the dose range of the pharmaceutical composition administered to the patient is from about 0.01 mg/kg to about 1000 mg/kg of the patient's body weight. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient.

In some embodiments, the daily dosage regimen for an adult human patient is an oral dose of each active ingredient of between 0.1 mg and 2000 mg, or between 1 mg and 1500 mg, or between 5 mg to 1000 mg. In some other embodiments, an oral dose of each active ingredient of between 1 mg and 1000 mg, between 50 mg and 900 mg, and between 100 mg to 800 mg is administered. In some embodiments, the oral dose is administered 1 to 4 times per day. In some embodiments, compositions of the compound of structure (I), or pharmaceutically acceptable salt thereof, may be administered by continuous intravenous infusion, at a dose of each active ingredient up to 1000 mg per day. In some embodiments, the compound of structure (I), or pharmaceutically acceptable salt thereof, will be administered for a period of continuous therapy, for example for a week or more, or for months or years.

In some embodiments, the dosing regimen of the compound of structure (I), or pharmaceutically acceptable salt thereof, is administered for a period of time, which time period can be, for example, from at least about 4 weeks to at least about 8 weeks, from at least about 4 weeks to at least about 12 weeks, from at least about 4 weeks to at least about 16 weeks, or longer. In some embodiments, the dosing regimen of the compound of structure (I), or pharmaceutically acceptable salt thereof, is administered for 36 weeks or longer. In some embodiments, the dosing regimen of the compound of structure (I), or pharmaceutically acceptable salt thereof, is administered for 36 weeks. In some embodiments, the dosing regimen of the compound of structure (I), or pharmaceutically acceptable salt thereof, is administered for 108 weeks. The dosing regimen of the compound of structure (I), or pharmaceutically acceptable salt thereof can be administered three times a day, twice a day, daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously, or continuously.

In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration. The amount of composition administered may be dependent on the subject being treated, on the subject's weight, the severity of the affliction, and the manner of administration.

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

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

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

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

In some embodiments, the present disclosure provides a method of using the compound of structure (I), or pharmaceutically acceptable salt thereof, in the treatment of FSGS in a patient comprising administering to the patient a dosage containing an amount of about 800 mg of drug per dose, orally, at a frequency of three times per month, once monthly, once weekly, once every three days, once every two days, once per day, twice per day, or three times per day, for the desired duration of treatment.

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

In some embodiments of the aforementioned pharmaceutical compositions and methods, the pharmaceutical composition is a solid dosage unit form. In some embodiments, the solid dosage unit form includes the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 200 mg, 400 mg, or 800 mg, or about 200 mg, about 400 mg, or about 800 mg. In some embodiments, the solid dosage unit form includes the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 400 mg or 800 mg, or about 400 mg or about 800 mg. In some embodiments, the solid dosage unit form is administered once daily.

In some embodiments, the solid dosage unit form is administered orally.

In some embodiments of the aforementioned pharmaceutical compositions and methods, the pharmaceutical composition is a liquid formulation for oral administration. In some particular embodiments, the liquid formulation is administered to a subject who is 18 years old or younger, 12 years old or younger, from 6 to 12 years of age, or from 2 to 6 years of age. In some particular embodiments, the liquid formulation is administered to a subject who is from 1 year of age to 17 years of age (>1 year of age to <18 years of age), from 2 years of age to 17 years of age (>2 year of age to <18 years of age), from 8 to 17 years of age (>8 years to <18 years of age), from 5 to 7 years of age (>5 years to <8 years of age), from 3 to 7 years of age (>3 year to <8 years of age), from 2 to 4 years of age (>2 years to <5 years of age), or from 1 to 2 years of age (>1 year to <3 years of age). In some embodiments, the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, in the liquid formulation administered to the subject is adjusted to the subject's body weight. In some embodiments, the liquid formulation includes the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of about 80 mg/mL or 80 mg/mL, 400 mg or 800 mg, or about 400 mg or about 800 mg. In some embodiments, the liquid formulation is administered once daily. In some embodiments, the liquid formulation is administered orally.

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

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

Exemplary Embodiments

The present disclosure also provides in further embodiments:

1. A method of treating a proteinuric kidney disease or disorder in a patient in need thereof, the method comprising administering to said patient a pharmaceutical composition comprising a compound having structure (I),

or a pharmaceutically acceptable salt thereof.

2. A method of prolonging the time to end stage renal disease in a patient diagnosed with a proteinuric kidney disease or disorder, the method comprising administering to said patient a pharmaceutical composition comprising a compound having structure (I),

or a pharmaceutically acceptable salt thereof.

3. A method for reducing a risk of end stage renal disease in a patient diagnosed with a proteinuric kidney disease or disorder, the method comprising administering to said patient a pharmaceutical composition comprising a compound having structure (I),

or a pharmaceutically acceptable salt thereof.

4. The method according to any one of embodiments 1-3, wherein said proteinuric kidney disease or disorder is focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), immunoglobulin A nephropathy (IgAN), immunoglobulin A-associated vasculitis (IgAV), or Alport syndrome.

5. The method according to any one of embodiments 1-4, wherein said patient is a pediatric patient less than 18 years of age.

6. The method according to any one of embodiments 1-5, wherein said proteinuric kidney disease or disorder is FSGS or MCD.

7. The method according to embodiment 6, wherein said patient (i) has a baseline estimated glomerular filtration rate (eGFR) greater than or equal to 30 mL/min/1.73 m² and (ii) has a baseline urinary protein to creatinine ratio (UP/C) greater than or equal to 1.5 g/g.

8. The method according to embodiment 6 or embodiment 7, wherein said patient is a pediatric patient from 1 to 17 years of age (>1 year to <18 years of age).

9. The method according to embodiment 6 or embodiment 7, wherein said patient is a pediatric patient from 8 to 17 years of age (>8 year to <18 years of age).

10. The method according to embodiment 6 or embodiment 7, wherein said patient is a pediatric patient from 3 to 7 years of age (>3 year to <8 years of age).

11. The method according to embodiment 6 or embodiment 7, wherein said patient is a pediatric patient from 1 to 2 years of age (>1 year to <3 years of age).

12. The method according to any one of embodiments 6-11, wherein said proteinuric kidney disease or disorder is FSGS.

13. The method according to embodiment 12, wherein said FSGS is primary

FSGS.

14. The method according to embodiment 12 or embodiment 13, wherein said patient has FSGS lesions or a genetic mutation in a podocyte protein associated with FSGS.

15. The method according to any one of embodiments 6-11, wherein said proteinuric kidney disease or disorder is MCD.

16. The method according to embodiment 15, wherein said patient has MCD histological patterns or a genetic mutation in a podocyte protein associated with MCD. 17. The method according to any one of embodiments 1-5, wherein said proteinuric kidney disease or disorder is IgAN, IgAV, or Alport syndrome.

18. The method according to embodiment 17, wherein said patient (i) has a baseline estimated glomerular filtration rate (eGFR) greater than or equal to 30 mL/min/1.73 m² and (ii) has a baseline urinary protein to creatinine ratio (UP/C) greater than or equal to 1.0 g/g.

19. The method according to embodiment 17 or embodiment 18, wherein said patient is a pediatric patient from 2 to 17 years of age (>2 years to <18 years of age).

20. The method according to embodiment 17 or embodiment 18, wherein said patient is a pediatric patient from 8 to 17 years of age (>8 years to <18 years of age).

21. The method according to embodiment 17 or embodiment 18, wherein said patient is a pediatric patient from 5 to 7 years of age (>5 years to <8 years of age).

22. The method according to embodiment 17 or embodiment 18, wherein said patient is a pediatric patient from 2 to 4 years of age (>2 years to <5 years of age).

23. The method according to any one of embodiments 17-22, wherein said proteinuric kidney disease or disorder is IgAN or IgAV.

24. The method according to embodiment 23, wherein said patient has biopsy-confirmed IgAN or IgAV.

25. The method according to any one of embodiments 17-22, wherein said proteinuric kidney disease or disorder is IgAN.

26. The method according to embodiment 25, wherein said patient has biopsy-confirmed IgAN.

27. The method according to any one of embodiments 17-22, wherein said proteinuric kidney disease or disorder is Alport syndrome.

28. The method according to embodiment 27, wherein said patient has a pathogenic X-linked COL4A5 mutation, autosomal-recessive mutations in both alleles of COL4A3 and/or COL4A4, or autosomal -dominant COL4A3 and/or COL4A4 and digenic mutations. 29. The method according to any one of embodiments 1-28, wherein said patient has a baseline eGFR of less than 60 mL/min/1.73 m².

30. The method according to any one of embodiments 1-28, wherein said patient has a baseline eGFR of greater than 60 mL/min/1.73 m².

31. The method according to any one of embodiments 1-30, wherein said patient has a baseline UP/C of less than or equal to 2 g/g.

32. The method according to any one of embodiments 1-30, wherein said patient has a baseline UP/C of less than or equal to 3.5 g/g.

33. The method according to any one of embodiments 1-30, wherein said patient has a baseline UP/C of greater than 3.5 g/g.

34. The method according to any one of embodiments 1-33, wherein (a) if said patient's weight is from 20 kg to 50 kg, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 200 mg/day for the first 2 weeks and thereafter 400 mg/day, and (b) if said patient's weight is greater than 50 kg, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 400 mg/day for the first 2 weeks and thereafter 800 mg/day.

35. The method according to any one of embodiments 1-33, wherein if said patient is 2 years of age or older (>2 years), the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 50% of a target dose for the first 2 weeks and is 100% of said target dose thereafter.

36. The method according to embodiment 35, wherein said target dose is 100 mg/day, 200 mg/day, 300 mg/day, 400 mg/day, 600 mg/day, or 800 mg/day.

37. The method according to embodiment 35, wherein said target dose is 100 mg/day, 200 mg/day, 300 mg/day, 400 mg/day, 500 mg/day, 600 mg/day, or 800 mg/day.

38. The method according to embodiment 35, wherein said patient weighs 40 kg or more (>40 kg) and said target dose is 800 mg/day.

39. The method according to embodiment 35, wherein said patient weighs 40 kg or more (>40 kg) and said target dose is 400 mg/day. 40. The method according to embodiment 35, wherein said patient weighs from 30 to 39 kg (>30 kg to <40 kg) and said target dose is 600 mg/day.

41. The method according to embodiment 35, wherein said patient weighs from 30 to 39 kg (>30 kg to <40 kg) and said target dose is 300 mg/day.

42. The method according to embodiment 35, wherein said patient weighs from 20 to 29 kg (>20 kg to <30 kg) and said target dose is 400 mg/day.

43. The method according to embodiment 35, wherein said patient weighs from 20 to 29 kg (>20 kg to <30 kg) and said target dose is 200 mg/day.

44. The method according to embodiment 35, wherein said patient weighs less than 20 kg (<20 kg) and said target dose is 200 mg/day.

45. The method according to embodiment 35, wherein said patient weighs less than 20 kg (<20 kg) and said target dose is 100 mg/day.

46. The method according to any one of embodiments 1-33, wherein if said patient is less than 2 years of age (<2 years), the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 25% of a target dose for the first 2 weeks, 50% of said target dose for the following 2 weeks, and 100% of said target dose thereafter.

47. The method according to embodiment 46, wherein said target dose is 100 mg/day or 200 mg/day.

48. The method according to embodiment 46, wherein said patient weighs from 10 kg to 19 kg (>10 kg to <20 kg) and said target dose is 200 mg/day.

49. The method according to embodiment 46, wherein said patient weighs from 7 kg to 9 kg (>7 kg to <10 kg) and said target dose is 100 mg/day.

50. The method according to any one of embodiments 1-33, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 25 mg/day, 50 mg/day, 75 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 175 mg/day, 200 mg/day, 250 mg/day, 300 mg/day, 350 mg/day, 400 mg/day, 500 mg/day, 600 mg/day, 700 mg/day, or 800 mg/day. 51. The method according to any one of embodiments 1-33, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 100 mg/day.

52. The method according to any one of embodiments 1-33, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 200 mg/day.

53. The method according to any one of embodiments 1-33, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 300 mg/day.

54. The method according to any one of embodiments 1-33, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 400 mg/day.

55. The method according to any one of embodiments 1-33, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 500 mg/day.

56. The method according to any one of embodiments 1-33, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 600 mg/day.

57. The method according to any one of embodiments 1-33, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 800 mg/day.

58. The method according to any one of embodiments 1-57, wherein said pharmaceutical composition is a solid dosage unit form.

59. The method according to any one of embodiments 1-57, wherein said pharmaceutical composition is a liquid.

60. The method according to embodiment 59, wherein the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is adjusted to said patient's body weight.

61. The method according to any one of embodiments 1-60, wherein said pharmaceutical composition is administered to said patient once daily. 62. The method according to any one of embodiments 1-61, wherein said pharmaceutical composition is administered to said patient orally.

63. The method according to embodiment 62, wherein said pharmaceutical composition is administered to said patient with or without food.

64. The method according to any one of embodiments 1-63, wherein said patient is not a pregnant or breastfeeding female.

65. The method according to any one of embodiments 1-64, wherein if said patient is a female of childbearing potential, the method further comprises administering to said patient monthly pregnancy tests and if a pregnancy test indicates that said patient is pregnant, discontinuing administration of said pharmaceutical composition.

66. The method according to any one of embodiments 1-65, wherein if said patient is a female of childbearing potential, the method further comprises administering to said patient an oral contraceptive, an implanted contraceptive, an injected contraceptive, or an intrauterine device.

67. The method according to any one of embodiments 1-66, wherein said patient does not have a significant hepatic condition or severe hepatic impairment.

68. The method according to any one of embodiments 1-67, wherein said patient does not have severe renal impairment.

69. The method according to any one of embodiments 1-68, wherein said patient does not have a significant cardiovascular condition.

70. The method according to any one of embodiments 1-69, wherein said patient is not coadministered aliskiren.

71. The method according to any one of embodiments 1-70, wherein said patient is not coadministered an ACE inhibitor and a mineralocorticoid receptor antagonist.

72. The method according to any one of embodiments 1-71, wherein said patient is not coadministered a strong CYP3A4/5 inhibitor.

73. The method according to any one of embodiments 1-72, wherein said patient is not coadministered a strong CYP3 A4/5 inducer. 74. The method according to any one of embodiments 1-73, wherein said patient is not coadministered a renin-angiotensin-aldosterone system (RAAS) inhibitor or endothelin system inhibitor.

75. The method according to any one of embodiments 1-74, wherein said patient has not been administered a RAAS inhibitor for at least two weeks prior to administration of the pharmaceutical composition.

76. The method according to any one of embodiments 1-75, wherein said patient has a UP/C of less than or equal to 1.5 g/g following 108 weeks of treatment with said pharmaceutical composition. 77. The method according to any one of embodiments 1-76, wherein said patient has a UP/C of less than or equal to 1.0 g/g following 108 weeks of treatment with said pharmaceutical composition.

78. The method according to any one of embodiments 1-77, wherein said patient's UP/C is reduced by more than 40% from the baseline UP/C following 108 weeks of treatment with said pharmaceutical composition.

79. The method according to any one of embodiments 1-78, wherein said patient is administered one or more additional therapeutic agents.

80. A pharmaceutical composition comprising a compound having structure

(I),

or a pharmaceutically acceptable salt thereof, for use in the method according to any one of embodiments 1-79.

81. Use of a pharmaceutical composition comprising a compound having structure (I),

or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the method according to any one of embodiments 1-79.

EXAMPLES

EXAMPLE 1

TREATMENT OF PROTEINURIC GLOMERULAR DISEASES IN PEDIATRIC PATIENTS WITH SPARSENTAN

The safety, efficacy, tolerability, and pharmacokinetics (PK) of treatment with sparsentan in pediatric subjects having proteinuric glomerular diseases is evaluated in a Phase 2, global, open-label, single-arm cohort study. Subjects receive sparsentan oral suspension once daily for 108 weeks, after which changes in proteinuria are assessed. The study is a multicenter, open-label study in approximately 57 pediatric subjects with selected proteinuric glomerular diseases. PK is evaluated on Day 1 (baseline), Day 2, and Week 12.

Subjects are divided into 2 populations:

Population 1: Subjects with selected proteinuric glomerular diseases associated with Focal Segmental Glomerulosclerosis (FSGS) and Minimal Change Disease (MCD) histological patterns (approximately 30 subjects); or

Population 2: Subjects with biopsy-confirmed immunoglobulin A nephropathy (IgAN), immunoglobulin A vasculitis (IgAV), or subjects with Alport syndrome (AS) (approximately 27 subjects). Subjects in Population 1 receive 800 mg sparsentan once daily (800 mg/day); subjects in Population 2 receive 400 mg sparsentan once daily (400 mg/day). Alternatively, sparsentan is administered once daily in a liquid formulation at a dose adjusted to body weight ( e.g ., a sparsentan 80 mg/mL oral suspension). The once-daily dose is taken with or within 30 minutes of starting the first meal of the day. The doses of sparsentan are titrated from an initial lower dose administered at initiation of treatment. For patients >2 years old, sparsentan is taken at 50% of the target dose through Week 2; if tolerated, sparsentan is increased to the target dose. For patients <2 years old, sparsentan is taken at 25% of the target dose through Week 2; if tolerated, sparsentan is increased to 50% of the target dose through Week 4 and if tolerated at the end of Week 4, the dose is increased to the target dose. Allowed doses are 25%, 50%, and 100% of the target dose. Dose reductions are permitted at any time for safety and tolerability reasons. Target doses are shown in Table 2.

Table 2 Sparsentan Dosages.

^a Based on the World Health Organization child growth chart

(https://www.who.int/childgrowth/standards/en/), the 3rd to 97th percentiles of the body weight for a 2-year-old child are 9.8 to 15.1 kg and 9.2 to 14.6 kg for boys and girls, respectively. ^b Based on the World Health Organization child growth chart

(https://www.who.int/childgrowth/standards/en/), the 3rd percentile of the body weight for a 1-year-old child is 7.8 and 7.1 kg for boys and girls, respectively.

Note: Bold indicates starting doses. Clinic visits occur at Day 1 (baseline), Day 2 (PK sampling), and Weeks 2, 4, 6

(cohort 3 patients only), 8, 12, 24, 36, 48, 60, 72, 84, 96, and 108 (end of treatment).

PK assessments occur at Day 1 (baseline), Day 2 (Visit 3), and Week 12 (Visit 9).

Primary outcome measures include: incidence of treatment-emergent adverse events (TEAEs); serious adverse events (SAEs); adverse events (AEs) leading to treatment discontinuation; adverse events of interest (AEOIs); urine protein/creatinine ratio (UP/C) at week 108; and change in baseline in UP/C over the 108 week period. Secondary outcome measures include: observed plasma PK concentrations at scheduled timepoints and visits; steady-state PK parameters (area under the plasma concentration-time curve during a dosing interval [AUCr], maximum steady-state plasma drug concentration during a dosage interval [Cmax ss], and minimum steady- state plasma drug concentration [Cmin ss]) derived from population PK analysis at week 108; change from baseline in urine albumin/creatinine ratio (UA/C) over the 108- week treatment period; change from baseline in eGFR over the 108-week treatment period; and the proportion of subjects with FSGS and/or MCD histological patterns achieving partial remission defined as UP/C <1.5 g/g and >40% reduction in UP/C over the 108-week treatment period. UP/C and UA/C quantitative urinalysis measures use first morning void or Pediatric Urine Collector for patients using diapers.

Other safety endpoints include AEs, vital signs, peripheral edema, and clinical laboratory parameters.

Exploratory Endpoints include: patients undergoing initiation/intensification in immunosuppressive medication; patients undergoing reduction in immunosuppressive medication; and palatability and acceptability of sparsentan oral suspension.

Inclusion criteria for both Populations include: the subject has an eGFR >30 mL/min/1.73 m² at screening; and the subject has a mean seated blood pressure between the 5th and 95th percentile for age, sex, and height.

Inclusion criteria for Population 1 include: the subject is male or female >1 year to <18 years of age at screening; and the subject has a UP/C >1.5 g/g at screening AND one of the following:

• Biopsy-proven FSGS or MCD histological patterns and clinical presentation consistent with primary FSGS or MCD and qualifying proteinuria at screening despite history or ongoing treatment with corticosteroids and/or other immunosuppressive disease-modifying agents.

• Documentation of a genetic mutation in a podocyte protein associated with FSGS or MCD. Subjects with a documented podocytic mutation do not require kidney biopsy. • Biopsy-proven FSGS histological pattern with medical history and clinical presentation consistent with maladaptive cause of the lesion. Note: The biopsy may have been performed at any time in the past but must include light microscopy and electron microscopy characteristics and/or immunofluorescence findings consistent with FSGS or MCD.

Population 1 includes three age-based cohorts: (i) >8 years to <18 years of age; (ii) >3 years to <8 years of age; and (iii) >1 years to <3 years of age (Table 2).

Table 2 Population 1 Cohorts.

Inclusion criteria for Population 2 include: the subject is male or female >2 years to <18 years of age at screening; and the subject has a UP/C >1.0 g/g at screening AND one of the following diagnoses:

• Biopsy-confirmed IgAN or IgAV · AS (pathogenic X-linked COL4A5 mutation OR autosomal -recessive mutations in both alleles of COL4A3 and/or COL4A4 OR autosomal -dominant COL4A3 and/or COL4A4 and digenic mutations [i.e., simultaneous mutations in 2 of the COL4A3, COL4A4, and COL4A5 genes]).

Population 2 includes three age-based cohorts: (i) >8 years to <18 years of age; (ii) >5 years to <8 years of age; and (iii) >2 years to <5 years of age (Table 3).

Table 3 Population 2 Cohorts.

Following initial screening, subjects undergo a 2-week washout period prior to initiation of sparsentan administration, during which they do not receive any renin- angiotensin-aldosterone system (RAAS) inhibitors.

Antihypertensive agents, except RAAS inhibitors or endothelin inhibitors, are allowed to maintain blood pressure control in patients with hypertension.

Exclusion criteria for both Populations include: the subject weighs <7.3 kg at screening; the subject has FSGS or MCD histological pattern secondary to viral infections, drug toxicities, or malignancies; the subject has immunoglobulin A (IgA) glomerular deposits not in the context of primary IgAN or IgAV (i.e., secondary to another condition; e.g ., systemic lupus erythematosus and liver cirrhosis); the subject has had an acute onset or presentation of glomerular disease or a diagnostic biopsy or a relapse of glomerular disease requiring new or different class of immunosuppressive treatment (including, but not limited to, systemic corticosteroids, calcineurin inhibitors and mycophenolate mofetil, abatacept, cyclophosphamide, rituximab, ofatumumab, and ocrelizumab) within 6 months before screening; new immunosuppressive therapy within 6 months of screening or subjects taking chronic immunosuppressive medications (including systemic steroids) must be on a stable dose for >1 month before screening; the subject requires any of the prohibited concomitant medications as defined in the study protocol; the subject has undergone any organ transplantation, with the exception of corneal transplants; the subject has a documented history of congenital or acquired heart failure (modified Ross heart failure classification for children Class II to Class IV) and/or previous hospitalization for heart failure or unexplained dyspnea, orthopnea, paroxysmal nocturnal dyspnea, ascites, and/or peripheral edema; the subject has hemodynamically significant cardiac valvular disease; the subject has clinically significant congenital vascular disease; the subject has jaundice, hepatitis, or known hepatobiliary disease, or alanine aminotransferase and/or aspartate aminotransferase >2 times the upper limit of the normal range at screening; the subject has a history of malignancy within the past 2 years; the subject has a screening hematocrit <27% or a hemoglobin value <9 g/dL; the subject has a screening potassium value >5.5 mEq/L; the subject has any abnormal clinical laboratory screening values that are considered by the Investigator to be clinically significant; the subject has a history of allergic response to any angiotensin II antagonist or endothelin receptor antagonist, including sparsentan, or has a hypersensitivity to any of the excipients in the investigational product; the subject has participated in a study of another investigational product within 28 days before screening or plans to participate in such a study during the course of this study; and the subject has had prior exposure to sparsentan.

Additionally, for subjects in both Populations, female subjects of childbearing potential, beginning at menarche, who do not agree to use 1 highly reliable (i.e., can achieve a failure rate of <1% per year) method of contraception from 7 days before the first dose of the investigational product until 90 days after the last dose of investigational product are excluded. Examples of highly reliable contraception methods include stable oral, implanted, transdermal, or injected contraceptive hormones associated with the inhibition of ovulation or an intrauterine device in place for at least 3 months. One additional barrier method must also be used during sexual activity, such as a diaphragm, diaphragm with spermicide (preferred), or male partner’s use of male condom or male condom with spermicide (preferred), from Day 1 /Randomization until 90 days after the last dose of investigational product. Female subjects of childbearing potential are defined as those who are fertile after menarche, unless permanently sterile; permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. All female subjects of childbearing potential must have a negative serum pregnancy test result at screening (Visit 1) and a negative urine pregnancy test result, with positive results confirmed by serum, at every study visit from Day 1 (Visit 3) and after. Note: Before menarche, pregnancy testing and contraceptive use are not required. However, subjects and their parents/legal guardians must be advised that, immediately upon menarche, subjects will be required to begin pregnancy testing and initiate contraceptive use.

EXAMPLE 2

METHOD OF PREPARING LIQUID FORMULATION

The formulation of Table 1 can be prepared by the following steps. First, a Krieger 50 L Liquid Mixing Vessel is set up with a vacuum draw system. ~80 % (31,680 g), of the theoretical weight of the water for irrigation (injection in bulk) is dispensed into a suitable sized container(s) and transferred into the Krieger 50 L Liquid Mixing Vessel. The inner and outer blade mixing speed is set to either 1 or 2, depending on the speed necessary to achieve a suitable mixing pattern (/. ., one which achieves rapid circulation of material without deposition on the side of the vessel).

Dispensed sodium benzoate is transferred into the Krieger 50 L Liquid Mixing Vessel. If necessary, the impeller speed may be adjusted to achieve a suitable vortex. The solution will be mixed for a minimum of 5 minutes, after which it is visually inspected to confirm full dissolution. If the material has not fully dissolved, mixing can continue until full dissolution is achieved.

Next, dispensed citric acid anhydrous powder is transferred into the Krieger 50 L Liquid Mixing Vessel. If necessary, the impeller speed may be adjusted to achieve a suitable vortex. The solution is mixed for a minimum of 5 minutes, after which it is visually inspected to confirm full dissolution. If the material has not fully dissolved, mixing can continue until full dissolution is achieved.

Next, dispensed sucralose powder is transferred into the Krieger 50 L Liquid Mixing Vessel. If necessary, the impeller speed may be adjusted to achieve a suitable vortex. The solution is mixed for a minimum of 5 minutes, after which it is visually inspected to confirm full dissolution. If the material has not fully dissolved, mixing can continue until full dissolution is achieved.

Next, dispensed flavoring agent is transferred into the Krieger 50 L Liquid Mixing Vessel. If necessary, the impeller speed may be adjusted to achieve a suitable vortex. The solution is mixed for a minimum of 5 minutes, after which it is visually inspected to confirm full dissolution. If the material has not fully dissolved, mixing can continue until full dissolution is achieved. The mixture should be a clear colorless solution.

Next, the xanthan gum is added slowly into the vortex and mixed for a minimum of 30 minutes. The homogeniser and impeller are switched on. If necessary, the impeller/homogeniser speed may be adjusted to achieve a suitable vortex. At the 15 minute timepoint, the impeller and homogeniser are stopped and any unhydrated material are removed from the homogeniser head and rinsed with 100 mL of water.

After 30 minutes, a visual check is performed on the dispersion. If there are flocculent particles present, mixing/homogenisation should be resumed until a suitable dispersion is achieved. The mixture should be a white/off-white suspension, with no visual flocculent particles. The acceptable pH range for the mixture at this stage is 2.5 - 4.0.

If there are flocculent particles present, homogenisation should be resumed until a suitable dispersion is achieved.

Next, the homogeniser and impeller are switched on, and if necessary, the impeller/homogeniser speed may be adjusted to achieve a suitable vortex. Sparsentan is added slowly into the vortex and mixed for a minimum of 60 minutes. At the 30 minute timepoint, the homogeniser is stopped and the homogeniser head is rinsed with 100 mL water. A visual check is performed on the dispersion, noting the amount and severity of foaming. There should be no visual flocculent particles present. If there are flocculent particles present, homogenisation should be resumed until a suitable dispersion is achieved. The appearance should be a white/off-white suspension at this stage, with no visual flocculent particles. The pH of the mixture is determined.

Finally, the solution will be made to a final volume of 40,000 mL using water for irrigation (injection in bulk). The quantity required is based off the difference in weight between the target batch size (39,600 g) and the total weight of excipients dispensed prior to this stage. The homogeniser and impeller is switched on. If necessary, the impeller/homogeniser speed is adjusted to achieve a suitable vortex. Mixing/homogenisation is performed for a minimum of 15 minutes. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications referred to in this specification or listed in the Application Data Sheet, including U.S. Provisional Patent Application Nos. 63/191,801 filed May 21, 2021, 63/210,594 filed June 15, 2021, and 63/254,361 filed October 11, 2021 are incorporated herein by reference, in their entirety, unless otherwise stated.

The various embodiments described above can be combined to provide further embodiments. Aspects of the embodiments can be modified, if necessary, to employ concepts of the various patents, applications, and publications to provide yet further embodiments. These and other changes can be made to the embodiments in light of the above-detailed description.

In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

CLAIMS What is claimed is:

1. A pharmaceutical composition comprising a compound having structure

(I),

or a pharmaceutically acceptable salt thereof, for use in a method of treating a proteinuric kidney disease or disorder in a patient in need thereof, wherein:

(a) said patient is a pediatric patient 2 years of age or older (>2 years), and the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 50% of a target dose for the first 2 weeks and is 100% of said target dose thereafter;

(b) said patient is a pediatric patient less than 2 years of age (<2 years), and the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 25% of a target dose for the first 2 weeks, 50% of said target dose for the following 2 weeks, and 100% of said target dose thereafter;

(c) if said patient's weight is from 20 kg to 50 kg, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 200 mg/day for the first 2 weeks and thereafter 400 mg/day, and if said patient's weight is greater than 50 kg, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 400 mg/day for the first 2 weeks and thereafter 800 mg/day; or (d) said proteinuric kidney disease or disorder is minimal change disease (MCD) or immunoglobulin A-associated vasculitis (IgAV).

2 A pharmaceutical composition comprising a compound having structure

or a pharmaceutically acceptable salt thereof, for use in a method of prolonging the time to end stage renal disease in a patient diagnosed with a proteinuric kidney disease or disorder, wherein:

(c) if said patient's weight is from 20 kg to 50 kg, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 200 mg/day for the first 2 weeks and thereafter 400 mg/day, and if said patient's weight is greater than 50 kg, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 400 mg/day for the first 2 weeks and thereafter 800 mg/day; or

(d) said proteinuric kidney disease or disorder is minimal change disease (MCD) or immunoglobulin A-associated vasculitis (IgAV).

3. A pharmaceutical composition comprising a compound having structure

or a pharmaceutically acceptable salt thereof, for use in a method for reducing a risk of end stage renal disease in a patient diagnosed with a proteinuric kidney disease or disorder, wherein:

(a) said patient is a pediatric patient 2 years of age or older (>2 years), and the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 50% of a target dose for the first 2 weeks and is 100% of said target dose thereafter; (b) said patient is a pediatric patient less than 2 years of age (<2 years), and the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 25% of a target dose for the first 2 weeks, 50% of said target dose for the following 2 weeks, and 100% of said target dose thereafter;

4. A method of treating a proteinuric kidney disease or disorder in a patient in need thereof, the method comprising administering to said patient a pharmaceutical composition comprising a compound having structure (I),

or a pharmaceutically acceptable salt thereof, wherein: (a) said patient is a pediatric patient 2 years of age or older (>2 years), and the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 50% of a target dose for the first 2 weeks and is 100% of said target dose thereafter;

5. A method of prolonging the time to end stage renal disease in a patient diagnosed with a proteinuric kidney disease or disorder, the method comprising administering to said patient a pharmaceutical composition comprising a compound having structure (I),

or a pharmaceutically acceptable salt thereof, wherein:

6. A method for reducing a risk of end stage renal disease in a patient diagnosed with a proteinuric kidney disease or disorder, the method comprising administering to said patient a pharmaceutical composition comprising a compound having structure (I),

or a pharmaceutically acceptable salt thereof, wherein:

7. Use of a pharmaceutical composition comprising a compound having structure (I),

or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a proteinuric kidney disease or disorder, wherein:

(b) said patient is a pediatric patient less than 2 years of age (<2 years), and the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 25% of a target dose for the first 2 weeks, 50% of said target dose for the following 2 weeks, and 100% of said target dose thereafter; (c) if said patient's weight is from 20 kg to 50 kg, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 200 mg/day for the first 2 weeks and thereafter 400 mg/day, and if said patient's weight is greater than 50 kg, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 400 mg/day for the first 2 weeks and thereafter 800 mg/day; or

8. Use of a pharmaceutical composition comprising a compound having structure (I),

or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for prolonging the time to end stage renal disease in a patient diagnosed with a proteinuric kidney disease or disorder, wherein:

9. Use of a pharmaceutical composition comprising a compound having structure (I),

or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for reducing a risk of end stage renal disease in a patient diagnosed with a proteinuric kidney disease or disorder, wherein: (a) said patient is a pediatric patient 2 years of age or older (>2 years), and the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 50% of a target dose for the first 2 weeks and is 100% of said target dose thereafter;

10. The pharmaceutical composition for use, method, or use according to any one of claims 1-9, wherein said proteinuric kidney disease or disorder is focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), immunoglobulin A nephropathy (IgAN), immunoglobulin A-associated vasculitis (IgAV), or Alport syndrome.

11. The pharmaceutical composition for use, method, or use according to any one of claims 1-10, wherein said patient is a pediatric patient less than 18 years of age.

12. The pharmaceutical composition for use, method, or use according to any one of claims 1-11, wherein said proteinuric kidney disease or disorder is FSGS or MCD.

13. The pharmaceutical composition for use, method, or use according to claim 12, wherein said patient (i) has a baseline estimated glomerular filtration rate (eGFR) greater than or equal to 30 mL/min/1.73 m² and (ii) has a baseline urinary protein to creatinine ratio (UP/C) greater than or equal to 1.5 g/g.

14. The pharmaceutical composition for use, method, or use according to claim 12 or claim 13, wherein said patient is a pediatric patient from 1 to 17 years of age (>1 year to <18 years of age).

15. The pharmaceutical composition for use, method, or use according to claim 12 or claim 13, wherein said patient is a pediatric patient from 8 to 17 years of age (>8 year to <18 years of age).

16. The pharmaceutical composition for use, method, or use according to claim 12 or claim 13, wherein said patient is a pediatric patient from 3 to 7 years of age (>3 year to <8 years of age).

17. The pharmaceutical composition for use, method, or use according to claim 12 or claim 13, wherein said patient is a pediatric patient from 1 to 2 years of age (>1 year to <3 years of age).

18. The pharmaceutical composition for use, method, or use according to any one of claims 12-17, wherein said proteinuric kidney disease or disorder is FSGS.

19. The pharmaceutical composition for use, method, or use according to claim 18, wherein said FSGS is primary FSGS.

20. The pharmaceutical composition for use, method, or use according to claim 18 or claim 19, wherein said patient has FSGS lesions or a genetic mutation in a podocyte protein associated with FSGS.

21. The pharmaceutical composition for use, method, or use according to any one of claims 12-17, wherein said proteinuric kidney disease or disorder is MCD.

22. The pharmaceutical composition for use, method, or use according to claim 21, wherein said patient has MCD histological patterns or a genetic mutation in a podocyte protein associated with MCD.

23. The pharmaceutical composition for use, method, or use according to any one of claims 1-11, wherein said proteinuric kidney disease or disorder is IgAN, IgAV, or Alport syndrome.

24. The pharmaceutical composition for use, method, or use according to claim 23, wherein said patient (i) has a baseline estimated glomerular filtration rate (eGFR) greater than or equal to 30 mL/min/1.73 m² and (ii) has a baseline urinary protein to creatinine ratio (UP/C) greater than or equal to 1.0 g/g.

25. The pharmaceutical composition for use, method, or use according to claim 23 or claim 24, wherein said patient is a pediatric patient from 2 to 17 years of age (>2 years to <18 years of age).

26. The pharmaceutical composition for use, method, or use according to claim 23 or claim 24, wherein said patient is a pediatric patient from 8 to 17 years of age (>8 years to <18 years of age).

27. The pharmaceutical composition for use, method, or use according to claim 23 or claim 24, wherein said patient is a pediatric patient from 5 to 7 years of age (>5 years to <8 years of age).

28. The pharmaceutical composition for use, method, or use according to claim 23 or claim 24, wherein said patient is a pediatric patient from 2 to 4 years of age (>2 years to <5 years of age).

29. The pharmaceutical composition for use, method, or use according to any one of claims 23-28, wherein said proteinuric kidney disease or disorder is IgAN or IgAV.

30. The pharmaceutical composition for use, method, or use according to claim 29, wherein said patient has biopsy-confirmed IgAN or IgAV.

31. The pharmaceutical composition for use, method, or use according to any one of claims 23-28, wherein said proteinuric kidney disease or disorder is IgAN.

32. The pharmaceutical composition for use, method, or use according to claim 31, wherein said patient has biopsy-confirmed IgAN.

33. The pharmaceutical composition for use, method, or use according to any one of claims 23-28, wherein said proteinuric kidney disease or disorder is Alport syndrome.

34. The pharmaceutical composition for use, method, or use according to claim 33, wherein said patient has a pathogenic X-linked COL4A5 mutation, autosomal-recessive mutations in both alleles of COL4A3 and/or COL4A4, or autosomal-dominant COL4A3 and/or COL4A4 and digenic mutations.

35. The pharmaceutical composition for use, method, or use according to any one of claims 1-34, wherein said patient has a baseline eGFR of less than 60 mL/min/1.73 m².

36. The pharmaceutical composition for use, method, or use according to any one of claims 1-34, wherein said patient has a baseline eGFR of greater than 60 mL/min/1.73 m².

37. The pharmaceutical composition for use, method, or use according to any one of claims 1-36, wherein said patient has a baseline UP/C of less than or equal to 2 g/g-

38. The pharmaceutical composition for use, method, or use according to any one of claims 1-36, wherein said patient has a baseline UP/C of less than or equal to 3-5 g/g.

39. The pharmaceutical composition for use, method, or use according to any one of claims 1-36, wherein said patient has a baseline UP/C of greater than 3.5 g/g·

40. The pharmaceutical composition for use, method, or use according to any one of claims 1-39, wherein (a) if said patient's weight is from 20 kg to 50 kg, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 200 mg/day for the first 2 weeks and thereafter 400 mg/day, and (b) if said patient's weight is greater than 50 kg, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 400 mg/day for the first 2 weeks and thereafter 800 mg/day.

41. The pharmaceutical composition for use, method, or use according to any one of claims 1-39, wherein if said patient is 2 years of age or older (>2 years), the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 50% of a target dose for the first 2 weeks and is 100% of said target dose thereafter.

42. The pharmaceutical composition for use, method, or use according to claim 41, wherein said target dose is 100 mg/day, 200 mg/day, 300 mg/day, 400 mg/day, 600 mg/day, or 800 mg/day.

43. The pharmaceutical composition for use, method, or use according to claim 41, wherein said patient weighs 40 kg or more (>40 kg) and said target dose is 800 mg/day.

44. The pharmaceutical composition for use, method, or use according to claim 41, wherein said patient weighs 40 kg or more (>40 kg) and said target dose is 400 mg/day.

45. The pharmaceutical composition for use, method, or use according to claim 41, wherein said patient weighs from 30 to 39 kg (>30 kg to <40 kg) and said target dose is 600 mg/day.

46. The pharmaceutical composition for use, method, or use according to claim 41, wherein said patient weighs from 30 to 39 kg (>30 kg to <40 kg) and said target dose is 300 mg/day.

47. The pharmaceutical composition for use, method, or use according to claim 41, wherein said patient weighs from 20 to 29 kg (>20 kg to <30 kg) and said target dose is 400 mg/day.

48. The pharmaceutical composition for use, method, or use according to claim 41, wherein said patient weighs from 20 to 29 kg (>20 kg to <30 kg) and said target dose is 200 mg/day.

49. The pharmaceutical composition for use, method, or use according to claim 41, wherein said patient weighs less than 20 kg (<20 kg) and said target dose is 200 mg/day.

50. The pharmaceutical composition for use, method, or use according to claim 41, wherein said patient weighs less than 20 kg (<20 kg) and said target dose is 100 mg/day.

51. The pharmaceutical composition for use, method, or use according to any one of claims 1-39, wherein if said patient is less than 2 years of age (<2 years), the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 25% of a target dose for the first 2 weeks, 50% of said target dose for the following 2 weeks, and 100% of said target dose thereafter.

52. The pharmaceutical composition for use, method, or use according to claim 51, wherein said target dose is 100 mg/day or 200 mg/day.

53. The pharmaceutical composition for use, method, or use according to claim 51, wherein said patient weighs from 10 kg to 19 kg (> 10 kg to <20 kg) and said target dose is 200 mg/day.

54. The pharmaceutical composition for use, method, or use according to claim 51, wherein said patient weighs from 7 kg to 9 kg (>7 kg to <10 kg) and said target dose is 100 mg/day.

55. The pharmaceutical composition for use, method, or use according to any one of claims 1-39, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 25 mg/day, 50 mg/day, 75 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 175 mg/day, 200 mg/day, 250 mg/day, 300 mg/day, 350 mg/day, 400 mg/day, 500 mg/day, 600 mg/day, 700 mg/day, or 800 mg/day.

56. The pharmaceutical composition for use, method, or use according to any one of claims 1-39, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 100 mg/day.

57. The pharmaceutical composition for use, method, or use according to any one of claims 1-39, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 200 mg/day.

58. The pharmaceutical composition for use, method, or use according to any one of claims 1-39, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 300 mg/day.

59. The pharmaceutical composition for use, method, or use according to any one of claims 1-39, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 400 mg/day.

60. The pharmaceutical composition for use, method, or use according to any one of claims 1-39, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 600 mg/day.

61. The pharmaceutical composition for use, method, or use according to any one of claims 1-39, the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is 800 mg/day.

62. The pharmaceutical composition for use, method, or use according to any one of claims 1-61, wherein said pharmaceutical composition is a solid dosage unit form.

63. The pharmaceutical composition for use, method, or use according to any one of claims 1-61, wherein said pharmaceutical composition is a liquid.

64. The pharmaceutical composition for use, method, or use according to claim 63, wherein the amount of said compound having structure (I), or pharmaceutically acceptable salt thereof, administered to said patient is adjusted to said patient's body weight.

65. The pharmaceutical composition for use, method, or use according to any one of claims 1-64, wherein said pharmaceutical composition is administered to said patient once daily.

66. The pharmaceutical composition for use, method, or use according to any one of claims 1-65, wherein said pharmaceutical composition is administered to said patient orally.

67. The pharmaceutical composition for use, method, or use according to claim 66, wherein said pharmaceutical composition is administered to said patient with or without food.

68. The pharmaceutical composition for use, method, or use according to any one of claims 1-67, wherein said patient is not a pregnant or breastfeeding female.

69. The pharmaceutical composition for use, method, or use according to any one of claims 1-68, wherein if said patient is a female of childbearing potential, the method further comprises administering to said patient monthly pregnancy tests and if a pregnancy test indicates that said patient is pregnant, discontinuing administration of said pharmaceutical composition.

70. The pharmaceutical composition for use, method, or use according to any one of claims 1-69, wherein if said patient is a female of childbearing potential, the method further comprises administering to said patient an oral contraceptive, an implanted contraceptive, an injected contraceptive, or an intrauterine device.

71. The pharmaceutical composition for use, method, or use according to any one of claims 1-70, wherein said patient does not have a significant hepatic condition or severe hepatic impairment.

72. The pharmaceutical composition for use, method, or use according to any one of claims 1-71, wherein said patient does not have severe renal impairment.

73. The pharmaceutical composition for use, method, or use according to any one of claims 1-72, wherein said patient does not have a significant cardiovascular condition.

74. The pharmaceutical composition for use, method, or use according to any one of claims 1-73, wherein said patient is not coadministered aliskiren.

75. The pharmaceutical composition for use, method, or use according to any one of claims 1-74, wherein said patient is not coadministered an ACE inhibitor and a mineralocorticoid receptor antagonist.

76. The pharmaceutical composition for use, method, or use according to any one of claims 1-75, wherein said patient is not coadministered a strong CYP3A4/5 inhibitor.

77. The pharmaceutical composition for use, method, or use according to any one of claims 1-76, wherein said patient is not coadministered a strong CYP3A4/5 inducer.

78. The pharmaceutical composition for use, method, or use according to any one of claims 1-77, wherein said patient is not coadministered a renin-angiotensin- aldosterone system (RAAS) inhibitor or endothelin system inhibitor.

79. The pharmaceutical composition for use, method, or use according to any one of claims 1-78, wherein said patient has not been administered a RAAS inhibitor for at least two weeks prior to administration of the pharmaceutical composition.

80. The pharmaceutical composition for use, method, or use according to any one of claims 1-79, wherein said patient has a UP/C of less than or equal to 1.5 g/g following 108 weeks of treatment with said pharmaceutical composition.

81. The pharmaceutical composition for use, method, or use according to any one of claims 1-80, wherein said patient has a UP/C of less than or equal to 1.0 g/g following 108 weeks of treatment with said pharmaceutical composition.

82. The pharmaceutical composition for use, method, or use according to any one of claims 1-81, wherein said patient's UP/C is reduced by more than 40% from the baseline UP/C following 108 weeks of treatment with said pharmaceutical composition.

83. The pharmaceutical composition for use, method, or use according to any one of claims 1-82, wherein said patient is administered one or more additional therapeutic agents.