WO2024073672A1 - Polythérapie avec du sparsentan et un inhibiteur de sglt2 pour le traitement de maladies ou de troubles rénaux - Google Patents

Polythérapie avec du sparsentan et un inhibiteur de sglt2 pour le traitement de maladies ou de troubles rénaux Download PDF

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WO2024073672A1
WO2024073672A1 PCT/US2023/075525 US2023075525W WO2024073672A1 WO 2024073672 A1 WO2024073672 A1 WO 2024073672A1 US 2023075525 W US2023075525 W US 2023075525W WO 2024073672 A1 WO2024073672 A1 WO 2024073672A1
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subject
sparsentan
composition
sglt2 inhibitor
administered
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PCT/US2023/075525
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Radko KOMERS
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Travere Therapeutics, Inc.
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Publication of WO2024073672A1 publication Critical patent/WO2024073672A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys

Definitions

  • the present disclosure relates to the use of sparsentan, a dual angiotensin and endothelin receptor antagonist, and a sodium-glucose cotransporter-2 (SGLT2) inhibitor in the treatment of kidney diseases or disorders, such as focal segmental glomerulosclerosis (FSGS) and immunoglobulin A nephropathy (IgAN).
  • FSGS focal segmental glomerulosclerosis
  • IgAN immunoglobulin A nephropathy
  • 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, and 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.
  • ESRD end-stage renal disease
  • IgAN also known as Berger's disease
  • IgA immunoglobulin A
  • ESRD end-stage renal disease
  • 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.
  • ET receptor antagonists ERAs
  • 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.
  • 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.
  • SGLT2 inhibitors are a class of molecules that are FDA-approved for the treatment of type 2 diabetes (http://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and- providers/sodium-glucose-cotransporter-2-sglt2-inhibitors). They include canagliflozin, dapagliflozin (e.g., FARXIGA®), and empagliflozin (e.g., JARDIANCE®), among others. SGLT2 inhibitors have been suggested as a therapeutic option for slowing disease progression in patients with diabetic and nondiabetic chronic kidney disease (Mende, Adv Ther (2022) 39:148- 164). Use of a SGLT2 inhibitor and a selective endothelin A receptor antagonist in a combination therapy for treating IgAN has been described (International Patent Application Publication No. WO2021126977A1).
  • kidney diseases or disorders including those associated with elevated proteinuria.
  • the present disclosure provides, in some embodiments, methods of treating a kidney disease or disorder, wherein the method comprises administering a compound having structure (I),
  • the kidney disease or disorder is a proteinuric disease, such as focal segmental glomerulosclerosis (FSGS) or immunoglobulin A nephropathy (IgAN).
  • FSGS focal segmental glomerulosclerosis
  • IgAN immunoglobulin A nephropathy
  • 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 combination with a SGLT2 inhibitor, in the treatment of kidney diseases or disorders, e.g., proteinuric diseases, including focal segmental glomerulosclerosis (FSGS) and immunoglobulin A nephropathy (IgAN).
  • FSGS focal segmental glomerulosclerosis
  • IgAN immunoglobulin A nephropathy
  • a cell includes a plurality of cells, including mixtures thereof.
  • 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.
  • “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.
  • zwitterions inner salts
  • Pharmaceutically 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.
  • 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.
  • 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.
  • the solvent is water, in which case the solvate is a hydrate.
  • the solvent is an organic solvent.
  • 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.
  • 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.
  • an animal such as rat, mouse, guinea pig, monkey, or to human
  • Solid 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.
  • subject refers to a mammal, such as a domestic pet (for example, a dog or cat), or human.
  • a domestic pet for example, a dog or cat
  • the subject is a human.
  • the subject is a patient that has been diagnosed as having a disease or disorder (e.g., IgAN or FSGS).
  • a disease or disorder e.g., IgAN or FSGS.
  • phrases "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.
  • unit dosage 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 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).
  • Sparsentan (CAS 254740-64-2, 2-[4-[(2-butyl-4-oxo-I,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 ("ETA” receptors) and angiotensin II receptors (Type 1) ("ATi” receptors) (Kowala et al., JPET 309:275-284, 2004).
  • a type endothelin
  • Type 1 angiotensin II receptors
  • the compound of structure (I) may be prepared by methods such as those described in International Patent Application Publication No. WO2018/071784 Al and U.S. Patent Application Publication No. US 2019/0262317 Al, which references are incorporated herein by reference in their entireties. 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, which references are incorporated herein by reference in their entireties.
  • SGLT2 inhibitors are a class of molecules that have been shown to result in significant improvement in kidney function in diabetic patients suffering from diabetic nephropathy, as well as protection of kidneys in patients with chronic kidney disease who do not have diabetes (https://www.kidney.org/atoz/content/sglt2-inhibitors, accessed September 26, 2022; Mende, Adv Ther 39: 148-164, 2022).
  • SGLT2 inhibitors have been approved by the United States Food and Drug Administration for the treatment of type 2 diabetes (http://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/sodium- glucose-cotransporter-2-sglt2 -inhibitors, accessed September 26, 2022).
  • SGLT2 inhibitor refers to a substance (e.g., a compound or molecule) that inhibits activity or expression of SGLT2.
  • SGLT2 inhibitors include compounds that inhibit SGLT2 activity, for example, gliflozins, such as canagliflozin (e.g., INV0KANA®, TA-7284), dapagliflozin (e.g., FARXIGA®), empagliflozin (e.g., JARDIANCE®, BI 10773), ertugliflozin (e.g., STEGLAGTRO®), ipragliflozin (e.g., SUGLAT®, ASP- 1941), tofogliflozin or tofogliflozin hydrate (e.g., DEBERZA®, APLEWAY®, R-7201), luseogliflozin (e.g., LUSEFI®, TS-071),
  • SGLT2 inhibitors also include molecules that modulate SGLT2 activity by inhibiting expression of SGLT2 proteins, for example, siRNA molecules; and antisense molecules, such as ISIS-SGLT2Rx. See, e.g., Oku et al., Diabetes 48(9): 1794-1800, 1999; Isaji et al., Kidney Ini 'll (Suppl 120): S14-S19, 2011; Nomura et al., ACSMed Chem Lett. 5(1):51- 55, 2013; Haas et al., Nutr & Diabetes 4:el43, 2014; Hsia et al., Curr Opin Endocrinol Diabetes Obes. 24(l):73-79, 2017; Bhatt et al., N Engl J Med 384: 117-128, 2021; Dobbins et al., BMC Pharmacol Toxicol 22:34, 2021.
  • siRNA molecules molecules that modulate
  • the present disclosure relates to the administration of (i) a pharmaceutical composition comprising a compound of structure (I), or pharmaceutically acceptable salt thereof, and (ii) a pharmaceutical composition comprising a SGLT2 inhibitor.
  • a pharmaceutical composition comprising a compound of structure (I), or pharmaceutically acceptable salt thereof, and the SGLT2 inhibitor.
  • the compound of structure (I), or pharmaceutically acceptable salt thereof, and the SGLT2 inhibitor are formulated together in the same pharmaceutical composition.
  • compositions 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.
  • 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.
  • the pharmaceutical composition may be formulated as described in further detail below.
  • kits including components of a combination therapy.
  • the kit comprises: a pharmaceutical composition comprising sparsentan; and a pharmaceutical composition comprising a SGLT2 inhibitor.
  • the kit is for use in any one of the methods described herein.
  • a kidney disease or disorder comprising administering a combination therapy
  • the combination therapy comprises administering (i) a compound of structure (I), or pharmaceutically acceptable salt thereof, e.g., sparsentan, and (ii) a SGLT2 inhibitor, to a subject in need thereof.
  • the present disclosure provides methods of treating a kidney disease or disorder comprising administering a combination therapy, wherein the combination therapy comprises administering (i) a pharmaceutical composition comprising a compound of structure (I), or pharmaceutically acceptable salt thereof, e.g., sparsentan, and a pharmaceutically acceptable excipient, and (ii) a pharmaceutical composition comprising a SGLT2 inhibitor, and a pharmaceutically acceptable excipient, to a subject in need thereof.
  • a pharmaceutical composition comprising a compound of structure (I), or pharmaceutically acceptable salt thereof, e.g., sparsentan, and a pharmaceutically acceptable excipient
  • a pharmaceutical composition comprising a SGLT2 inhibitor, and a pharmaceutically acceptable excipient
  • a combination therapy as described above is useful in the treatment of a kidney disease or disorder. In some embodiments, a combination therapy as described above is useful in the treatment of a proteinuric disease. In some embodiments, a combination therapy as described above is useful in the reduction of general morbidity or mortality as a result of such utilities.
  • a combination therapy as described above is useful in prolonging the time to end stage renal disease or reducing a risk of end stage renal disease in a subject, e.g., a patient diagnosed with FSGS or IgAN.
  • a combination therapy as described above is useful in reducing proteinuria.
  • proteinuria refers to a condition in which the urine contains an abnormal amount of protein (z.e., urine protein excretion of greater than 300 mg per day).
  • a UP/C ratio of more than 0.3 g/g indicates proteinuria.
  • the combination therapy is useful in reducing proteinuria to less than or equal to 1.5 g/g. In some embodiments, the combination therapy is useful in reducing proteinuria to less than or equal to 1.0 g/g. In some embodiments, the combination therapy is useful in reducing proteinuria to less than or equal to 0.5 g/g. In some embodiments, the combination therapy is useful in reducing proteinuria to less than or equal to 0.3 g/g (i.e., complete remission of proteinuria). Accordingly, the present disclosure also provides methods of inducing complete remission in a subject having a kidney disease or disorder, e.g., FSGS or IgAN, by administering the combination therapy to the subject.
  • a kidney disease or disorder e.g., FSGS or IgAN
  • 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.
  • baseline UP/C ratio refers to the subject's most recently calculated UP/C ratio prior to onset of treatment.
  • 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 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.
  • 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.
  • the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 200 mg/day for 6 weeks, 36 weeks, 58 weeks, or 110 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 6 weeks, 36 weeks, 58 weeks, or 110 weeks.
  • 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.
  • a method of treating a kidney disease or disorder in a subject in need thereof comprising administering to the subject, over an administration period, the combination therapy 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.
  • a method of treating a kidney disease or disorder in a subject in need thereof is provided, the method comprising administering to the subject, over an administration period, the combination therapy in an amount sufficient to achieve or maintain a UP/C ratio of less than or equal to 1.0 g/g for at least a portion of the administration period.
  • Administration period refers to the time period during which the pharmaceutical composition is administered to the subject as least daily.
  • the administration period is 6 weeks. In some embodiments, the administration period is 8 weeks. In some embodiments, the administration period is 26 weeks. In some embodiments, the administration period is 36 weeks. In some embodiments, the administration period is 108 weeks. In some embodiments, the administration period is 110 weeks. In some embodiments, the administration period is 8 months. In some embodiments, a method of maintaining a UP/C ratio at less than or equal to 1.5 g/g in a subject in need thereof is provided, the method comprising administering to the subject the combination therapy in an amount sufficient to maintain a UP/C ratio of less than or equal to 1-5 g/g.
  • a method of maintaining a UP/C ratio at less than or equal to 1.0 g/g in a subject in need thereof comprising administering to the subject the combination therapy in an amount sufficient to maintain a UP/C ratio of less than or equal to 1.0 g/g.
  • a method of reducing a UP/C ratio to less than or equal to 1.5 g/g in a subject in need thereof comprising administering to the subject the combination therapy in an amount sufficient to reduce said subject's UP/C ratio to less than or equal to 1.5 g/g.
  • the subject has, or has had, a UP/C ratio greater than 1.5 g/g prior to administration of the combination therapy.
  • a method of reducing a UP/C ratio to less than or equal to 1.0 g/g in a subject in need thereof comprising administering to the subject the combination therapy in an amount sufficient to reduce said subject's UP/C ratio to less than or equal to 1.0 g/g.
  • the subject has, or has had, a UP/C ratio greater than 1.0 g/g prior to administration of the combination therapy.
  • the combination therapy is useful in maintaining glomerular filtration rate.
  • GFR glomerular filtration rate
  • eGFR estimated glomerular filtration rate
  • the combination therapy is useful in maintaining eGFR levels (e.g., preventing a reduction in eGFR associated with a kidney disease or disorder, such as FSGS or IgAN, or reducing the rate of decline in eGFR in a subject having a kidney disease or disorder, such as FSGS or IgAN).
  • administering the combination therapy 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 the combination therapy.
  • administering the combination therapy 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.
  • baseline eGFR level refers to their most recently calculated eGFR level prior to onset of treatment.
  • maintenance of eGFR refers to no clinically meaningful reduction in baseline eGFR levels.
  • 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).
  • 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.
  • treatment with the combination therapy is more effective than treatment with the compound of structure (I), or pharmaceutically acceptable salt thereof, e.g., sparsentan, or the SGLT2 inhibitor alone.
  • the combination therapy prolongs the time to end stage renal disease or reduces a risk of end stage renal disease in a subject, e.g., a patient diagnosed with FSGS or IgAN, relative to treatment with the compound of structure (I), or pharmaceutically acceptable salt thereof, e.g., sparsentan, or the SGLT2 inhibitor alone.
  • the combination therapy provides a greater reduction in proteinuria in a subject, e.g., a patient diagnosed with FSGS or IgAN, relative to treatment with the compound of structure (I), or pharmaceutically acceptable salt thereof, e.g., sparsentan, or the SGLT2 inhibitor alone.
  • the combination therapy results in complete remission of proteinuria (reduced proteinuria to less than or equal to 0.3 g/g) in a subject, e.g., a patient diagnosed with FSGS or IgAN, more than treatment with the compound of structure (I), or pharmaceutically acceptable salt thereof, e.g., sparsentan, or the SGLT2 inhibitor alone.
  • the combination therapy achieves a reduction in the subject’s UP/C ratio of at least 40% relative to the subject's baseline UP/C ratio in a subject, e.g., a patient diagnosed with FSGS or IgAN, more than treatment with the compound of structure (I), or pharmaceutically acceptable salt thereof, e.g., sparsentan, or the SGLT2 inhibitor alone.
  • the combination maintains eGFR levels in a subject, e.g., a patient diagnosed with FSGS or IgAN, more than treatment with the compound of structure (I), or pharmaceutically acceptable salt thereof, e.g., sparsentan, or the SGLT2 inhibitor alone.
  • the use or method comprises administering the combination therapy as a fixed dose combination formulation.
  • any of the aforementioned uses or methods of treatment may comprise administering the combination therapy in combination with one or more other active ingredients, such as other therapeutic or diagnostic agents.
  • one or more other therapeutic agents may be administered prior to, simultaneously with, or following the administration of the combination therapy. If formulated as a fixed dose, such combination products may employ the combination therapy, within the dosage ranges described herein, and the other active ingredient within its approved dosage range.
  • the combination therapy is used in conjunction with hemodialysis.
  • 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.
  • 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.
  • the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 100 mg/day for 6 weeks, 8 weeks, 26 weeks, 36 weeks, 8 months, 108 weeks, or 110 weeks. In some embodiments of the aforementioned uses and methods of treatment, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 200 mg/day for 6 weeks, 8 weeks, 26 weeks, 36 weeks, 8 months, 108 weeks, or 110 weeks.
  • the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 400 mg/day for 6 weeks, 8 weeks, 26 weeks, 36 weeks, 8 months, 108 weeks, or 110 weeks. In still further embodiments, the dosing regimen comprises administering the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 800 mg/day for 6 week, 8 weeks, 26 weeks, 36 weeks, 8 months, 108 weeks, or 110 weeks.
  • 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.
  • 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.
  • the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is about 50 mg/day.
  • the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is about 100 mg/day.
  • the amount of the compound having structure (I), or pharmaceutically acceptable salt thereof, administered to the subject is about 200 mg/day.
  • 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.
  • 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.
  • the subject may be an adult or may be a child of less than 18 years of age. In some embodiments, the subject is younger than 18 years of age. In some embodiments, the subject is from 5 to 10 years of age. In some embodiments, the subject is from 6 to 12 years of age. In some embodiments, the subject is from 2 to 6 years of age. In some embodiments of the aforementioned methods, the subject is 8 years old or older.
  • the subject is a pediatric subject who is from 2 years of age up to
  • 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 (e.g., less than 18 years of age; from 2 to 6 years of age; from 5 to 10 years of age; from 6 to 12 years of age).
  • the amount of the SGLT2 inhibitor administered to the subject may be from about 1 mg/day to about 1000 mg/day.
  • the amount of the SGLT2 inhibitor administered to the subject is from about
  • the amount of the SGLT2 inhibitor administered to the subject is from about 5 mg/day to about 50 mg/day. In some embodiments, the amount of the SGLT2 inhibitor administered to the subject is 5 mg/day to 50 mg/day. In some embodiments, the amount of the SGLT2 inhibitor administered to the subject is 5 mg/day, 10 mg/day, 12.5 mg/day, or 25 mg/day.
  • the compound having structure (I), or pharmaceutically acceptable salt thereof, and the SGLT2 inhibitor may be administered on the same day or on different days.
  • the compound having structure (I), or pharmaceutically acceptable salt thereof, and the SGLT2 inhibitor are administered on the same day.
  • the compound of structure (I), or pharmaceutically acceptable salt thereof, and the SGLT2 inhibitor are formulated together in the same pharmaceutical composition for simultaneous administration.
  • the subject is administered the compound having structure (I), or pharmaceutically acceptable salt thereof, and begins treatment with the SGLT2 inhibitor days or weeks after.
  • the compound having structure (I), or pharmaceutically acceptable salt thereof, and the SGLT2 inhibitor may be administered together in a fixed dose combination formulation.
  • the dose of one or both of the compound having structure (I), or pharmaceutically acceptable salt thereof, and the SGLT2 inhibitor may be lower than when administered without the other.
  • the dose of the compound having structure (I), or pharmaceutically acceptable salt thereof is less than 800 mg/day, less than 400 mg/day, or less than 200 mg/day.
  • the dose of the SGLT2 inhibitor is less than 5 mg/day, 10 mg/day, 12.5 mg/day, or 25 mg/day.
  • the kidney disease or disorder may be a proteinuric disease, such as focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), immunoglobulin A nephropathy (IgAN), immunoglobulin A-associated vasculitis (IgAV), or Alport syndrome.
  • FSGS focal segmental glomerulosclerosis
  • MCD minimal change disease
  • IgAN immunoglobulin A nephropathy
  • IgAV immunoglobulin A-associated vasculitis
  • Alport syndrome such as focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), immunoglobulin A nephropathy (IgAN), immunoglobulin A-associated vasculitis (IgAV), or Alport syndrome.
  • the present disclosure provides a combination therapy as described herein for use in any of the aforementioned methods.
  • the present disclosure provides a combination therapy as described herein for use in the manufacture of a medicament for use in any of the aforementioned therapeutic methods.
  • a combination therapy as described herein (such as in any of the aforementioned embodiments) is used to treat a subject having FSGS.
  • a method of treating FSGS in a subject in need thereof comprising administering to the subject, over an administration period, the combination therapy 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.
  • the FSGS may be 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.
  • the subject may have FSGS lesions or a genetic mutation in a podocyte protein associated with FSGS.
  • the subject is not a pregnant or breastfeeding female.
  • 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.
  • the subject is also administered an oral contraceptive, an implanted contraceptive, an injected contraceptive, or an intrauterine device.
  • the subject does not have severe hepatic impairment or severe renal impairment. In some embodiments, the subject does not have G5 renal impairment (i.e., GFR ⁇ 15 mL/min/1.73 m 2 ). In some embodiments, the subject does not have severe hepatic impairment (i.e., Child-Pugh class C).
  • 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 CYP3A4/5 inducer, a renin angiotensin aldosterone system (RAAS) inhibitor, and an endothelin system inhibitor.
  • ACE angiotensin converting enzyme
  • a mineralocorticoid receptor antagonist a strong CYP3A4/5 inhibitor
  • RAAS renin angiotensin aldosterone system
  • endothelin system inhibitor an endothelin system inhibitor.
  • the subject may have a baseline eGFR greater than or equal to 30 mL/min/1.73 m 2 and a baseline urinary protein to creatinine ratio (UP/C) greater than 1.5 g/g.
  • the subject has a baseline eGFR greater than or equal to 30 mL/min/1.73 m 2 .
  • the subject has a baseline eGFR of less than 60 mL/min/1.73 m 2 .
  • the subject has a baseline eGFR of greater than 60 mL/min/1.73 m 2 .
  • the subject has a baseline UP/C of less than or equal to 2 g/g.
  • the subject has a baseline UP/C of greater than 3.5 g/g.
  • a combination therapy as described herein (such as in any of the aforementioned embodiments) is used to treat a subject having IgAN.
  • a method of treating IgAN in a subject in need thereof comprising administering to the subject, over an administration period, the combination therapy 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.
  • the subject has biopsy-confirmed or biopsy-proven primary IgAN.
  • the subject may have IgAN that is not secondary to another condition.
  • the subject may be currently on a stable dose of ACEI and/or ARB therapy, e.g., for at least 12 weeks prior to treatment with sparsentan.
  • the subject may be receiving an ACEI and/or ARB at the maximum tolerated dose and at least one-half of the maximum labeled dose.
  • the subject may have a systolic BP ⁇ 150 mmHg and diastolic BP ⁇ 100 mmHg prior to treatment with sparsentan.
  • the subject is not a pregnant or breastfeeding female.
  • 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.
  • the subject is also administered an oral contraceptive, an implanted contraceptive, an injected contraceptive, or an intrauterine device.
  • the subject does not exhibit cellular glomerular crescents in >25% of glomeruli on renal biopsy, e.g., within 6 months of beginning treatment with sparsentan.
  • the subject does not have chronic kidney disease (CKD) in addition to IgAN.
  • CKD chronic kidney disease
  • the subject does not have a history of organ transplantation, with the exception of corneal transplants.
  • the subject is not treated with systemic immunosuppressive medications (including corticosteroids) for >2 weeks within 3 months of beginning treatment with sparsentan.
  • systemic immunosuppressive medications including corticosteroids
  • the subject does not have a history of heart failure or previous hospitalization for heart failure or unexplained dyspnea, orthopnea, paroxysmal nocturnal dyspnea, ascites, and/or peripheral edema.
  • the subject does not have clinically significant cerebrovascular disease or coronary artery disease within 6 months of beginning treatment with sparsentan. In some embodiments, the subject does not have a significant hepatic condition or severe hepatic impairment. In some embodiments, the subject does not have severe hepatic impairment (i.e., Child-Pugh class C). In some embodiments, the subject does not have jaundice, hepatitis, or known hepatobiliary disease or elevations of transaminases (ALT/AST) >2 times upper limit of normal prior to beginning treatment with sparsentan.
  • ALT/AST transaminases
  • the subject does not have a history of malignancy other than adequately treated basal cell or squamous cell skin cancer or cervical carcinoma within the past 2 years prior to beginning treatment with sparsentan.
  • the subject does not have a hematocrit value ⁇ 27% (0.27 V/V), a hemoglobin value ⁇ 9 g/dL (90 g/L), and/or potassium >5.5 mEq/L (5.5 mmol/L) prior to beginning treatment with sparsentan.
  • the subject may have a baseline eGFR greater than or equal to 30 mL/min/1.73 m 2 and a baseline urinary protein to creatinine ratio (UP/C) greater than or equal to 1.0 g/g.
  • a baseline eGFR greater than or equal to 30 mL/min/1.73 m 2
  • a baseline urinary protein to creatinine ratio (UP/C) greater than or equal to 1.0 g/g.
  • the present disclosure relates to the administration of (i) a pharmaceutical composition comprising the compound of structure (I), or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient, and (ii) a pharmaceutical composition comprising an SGLT2 inhibitor.
  • the compound of structure (I), or pharmaceutically acceptable salt thereof, and the SGLT2 inhibitor are formulated together in the same pharmaceutical composition, such as in a fixed dose combination unit dose form.
  • Techniques for formulation and administration of the compound of structure (I), or pharmaceutically acceptable salt thereof, and/or the SGLT2 inhibitor 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.
  • the pharmaceutical composition is formulated as described below.
  • 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.
  • 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.
  • surfactant surface active agent
  • 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, pol oxamer (e.g., poloxamers 101, 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217, 231, 234, 235, 237,
  • 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.
  • 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.
  • 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. Suiter, Pharmazeutician Technologic 2nd edition, Thieme 1989, page 260, and Advanced Drug De livery Reviews (1997), 23, pages 163-183, which are incorporated herein by reference for such teachings.
  • surfactants include anionic surfactants, non-ionic surfactants, zwitterionic surfactants, and a mixture thereof.
  • the surfactant is selected from the group consisting of poly(oxyethylene) sorbitan fatty acid ester, poly(oxyethylene) stearate, poly(oxyethylene) alkyl ether, polyglycolated glyceride, poly(oxyethylene) castor oil, sorbitan fatty acid ester, pol oxamer, 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.
  • poly(oxyethylene) sorbitan fatty acid ester poly(oxyethylene) stearate, poly(oxyethylene) alkyl ether, polyglycolated glyceride, poly(oxyethylene) castor oil, sorbitan fatty acid ester, pol oxamer, fatty acid salt, bile salt,
  • carrier defines a chemical compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • 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.
  • a buffered diluent rarely modifies the biological activity of a compound.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • HPC hydroxypropyl cellulose
  • HPMC hydroxypropyl methylcellulose
  • a formulations disclosed herein includes at least one binder to enhance the compressibility of the major excipient(s).
  • 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.
  • binders in the following ranges: from about 2% to about 6% w/w hydroxypropyl cellulose (Klucel); from about 2% to about 5% w/w/w polyvinylpyrrolidone (PVP); from about 1% to about 5% w/w methylcellulose; from about
  • binders and/or amounts that can be used in the formulations described herein.
  • the amounts of the major fdler(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.
  • a binder is sprayed on from solution, e.g., wet granulation, to increase binding activity.
  • a lubricant is employed in the manufacture of certain dosage forms.
  • a lubricant may be employed when producing tablets.
  • 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.
  • one or more lubricants may be used.
  • 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%.
  • 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.
  • 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.
  • one or more glidants are used.
  • glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and calcium phosphate, and the like, and mixtures thereof.
  • the formulations can include a coating, for example, a film coating.
  • coating preparations may include, for example, a film-forming polymer, a plasticizer, or the like.
  • the coatings may include pigments or opacifiers.
  • film-forming polymers include hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinyl pyrrolidine, and starches.
  • plasticizers include polyethylene glycol, tributyl citrate, dibutyl sebecate, castor oil, and acetylated monoglyceride.
  • pigments and opacifiers include iron oxides of various colors, lake dyes of many colors, titanium dioxide, and the like.
  • one or more color additives are included.
  • the colorants can be used in amounts sufficient to distinguish dosage form strengths.
  • color additives approved for use in drugs 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.
  • compositions may include, for example, powders, pastes, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as Lipofectin®), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions of Carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semisolid mixtures containing Carbowax.
  • vesicles such as Lipofectin®
  • alcohols, esters, sulfated aliphatic alcohols, and the like may be used as surface active agents; sucrose, glucose, lactose, starch, crystallized cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium methasilicate aluminate, synthetic aluminum silicate, calcium carbonate, sodium acid carbonate, calcium hydrogen phosphate, calcium carboxymethyl cellulose, and the like may be used as excipients; magnesium stearate, talc, hardened oil, and the like may be used as smoothing agents; coconut oil, olive oil, sesame oil, peanut oil, and soya may be used as suspension agents or lubricants; cellulose acetate phthalate as a derivative of a carbohydrate such as cellulose or sugar, methyl acetatemethacrylate copolymer as a derivative of polyvinyl, or plasticizers such as ester phthalate may be used as suspension agents.
  • a pharmaceutical composition as disclosed herein further comprises one or more of preservatives, stabilizers, dyes, sweeteners, fragrances, flavoring agents, and the like.
  • preservatives 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.
  • 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.
  • 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).
  • 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.
  • the amounts of excipients will be determined by drug dosage and dosage form size.
  • the dosage form size for providing the compound of structure (I), or a pharmaceutically acceptable salt thereof is about 100 mg to 800 mg. In some embodiments disclosed herein, the dosage form size is about 100 mg. In some embodiments disclosed herein, the dosage form size is about 200 mg. In some embodiments disclosed herein, the dosage form size is about 400 mg. In some embodiments disclosed herein, the dosage form size is about 800 mg.
  • the dosage form size for providing the compound of structure (I), or a pharmaceutically acceptable salt thereof is about 100 mg to 800 mg. In some embodiments disclosed herein, the dosage form size is about 100 mg. In some embodiments disclosed herein, the dosage form size is about 200 mg. In some embodiments disclosed herein, the dosage form size is about 400 mg. In some embodiments disclosed herein, the dosage form size is about 800 mg.
  • 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.
  • compositions of the present disclosure may provide low-dose formulations of the compound of structure (I), or pharmaceutically acceptable salt thereof, or the SGLT2 inhibitor, 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.
  • Suitable routes for administering the compound of structure (I), or pharmaceutically acceptable salt thereof, or the SGLT2 inhibitor, 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, or the SGLT2 inhibitor 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.
  • 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.
  • penetrants appropriate to the barrier to be permeated may be used in the formulation.
  • compositions for parenteral administration 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.
  • 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.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the compound of structure (I), or pharmaceutically acceptable salt thereof, or the SGLT2 inhibitor 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 subject (e.g., a patient) to be treated.
  • compositions 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).
  • PVP polyvinylpyrrolidone
  • 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.
  • 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.
  • 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.
  • stabilizers can be added.
  • formulations for oral administration are in dosages suitable for such administration.
  • formulations of the compound of structure (I), or pharmaceutically acceptable salt thereof, or the SGLT2 inhibitor have an acceptable immediate release dissolution profile and a robust, scalable method of manufacture.
  • compositions 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.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • compositions may take the form of tablets or lozenges formulated in a conventional manner.
  • the compound of structure (I), or pharmaceutically acceptable salt thereof, or the SGLT2 inhibitor 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.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • 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.
  • compositions for intraocular delivery include aqueous ophthalmic solutions of the active compounds in water- soluble form, such as eye drops, or in gellan gum (Shedden et al., Clin. Ther. 23(3):440-50, 2001) or hydrogels (Mayer et al., 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.
  • lipid-soluble formulations (Alm 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).
  • 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.
  • 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, or the SGLT2 inhibitor 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.
  • the compound of structure (I), or pharmaceutically acceptable salt thereof, or the SGLT2 inhibitor 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.
  • the compound of structure (I), or pharmaceutically acceptable salt thereof, or the SGLT2 inhibitor 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.
  • 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 80TM, 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.
  • co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of Polysorbate 80TM; 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.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are well-known examples of delivery vehicles or carriers for hydrophobic drugs.
  • certain organic solvents such as dimethylsulfoxide also may be employed.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • 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.
  • 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.
  • 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.
  • small hydrophobic organic molecules may be directly administered intracellularly.
  • a solid unit dosage form comprising the compound of structure (I), or pharmaceutically acceptable salt thereof, is provided for use in the compositions and methods described herein.
  • the solid unit dosage form includes the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 100 mg; about 100 mg; 200 mg; about 200 mg; 400 mg; or about 400 mg.
  • the solid unit dosage form includes the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 400 mg; or about 400 mg.
  • 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.
  • the liquid formulation comprises sparsentan and a diluent or vehicle, such as water.
  • 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.
  • a preservative such as potassium sorbate or sodium benzoate
  • a sweetener such as sucralose or sodium saccharin
  • a flavoring agent such as a viscosity modifier such as xanthan gum, microcrystalline cellulose/sodium carboxymethylcellulose composite, methyl cellulose, or hydroxyethyl cellulose
  • a pH modifier such as citric acid, tartaric acid, or sodium citrate; or combinations thereof.
  • a liquid formulation of sparsentan which comprises sparsentan, water as a diluent or vehicle, sodium benzoate, sucralose, a flavoring agent, xanthan gum, and citric acid.
  • the liquid formulation is administered orally to a subject who is 18 years old or younger, 12 years old or younger, from 6 to 12 years of age, or from 2 to 6 years of age.
  • the combination therapies described herein may be administered to the subject (e.g., a human patient) by any suitable means.
  • 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
  • compositions suitable for administration include compositions where the compound of structure (I), or pharmaceutically acceptable salt thereof, or the SGLT2 inhibitor 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.
  • the combination therapy will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
  • the compound of structure (I), or pharmaceutically acceptable salt thereof will be administered once daily as long as eGFR is >20 ml/min/1.73 m 2 or the subject develops endstage renal disease (ESRD) requiring renal replacement therapy (RRT).
  • ESRD endstage renal disease
  • RRT renal replacement therapy
  • 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.
  • the dosing regimen of the compound of structure (I), or pharmaceutically acceptable salt thereof is administered for 36 weeks or longer.
  • the dosing regimen of the compound of structure (I), or pharmaceutically acceptable salt thereof is administered for 36 weeks.
  • 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 is administered for 110 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.
  • the dosing regimen of the SGLT2 inhibitor 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, for 36 weeks, for 108 weeks, for 110 weeks, or longer.
  • the dosing regimen of the SGLT2 inhibitor 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.
  • the compound of structure (I), or pharmaceutically acceptable salt thereof, and the SGLT2 inhibitor are administered daily on a continuous or ongoing basis, e.g., for treating a chronic disease or disorder.
  • 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.
  • the present disclosure relates combination therapies that include administering to the subject 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.
  • the present disclosure provides a method of using the compound of structure (I), or pharmaceutically acceptable salt thereof, in the treatment of FSGS or IgAN in a subject comprising administering to the subject 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.
  • the present disclosure provides a method of using the compound of structure (I), or pharmaceutically acceptable salt thereof, in the treatment of FSGS or IgAN in a subject comprising administering to the subject 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.
  • the present disclosure provides a method of using the compound of structure (I), or pharmaceutically acceptable salt thereof, in the treatment of FSGS or IgAN in a subject comprising administering to the subject 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.
  • the present disclosure provides a method of using the compound of structure (I), or pharmaceutically acceptable salt thereof, in the treatment of FSGS or IgAN in a subject comprising administering to the subject 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.
  • the present disclosure provides a method of using the compound of structure (I), or pharmaceutically acceptable salt thereof, in the treatment of FSGS or IgAN in a subject comprising administering to the subject 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.
  • the amount of the compound of structure (I), or pharmaceutically acceptable salt thereof, administered to the subject 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.
  • the pharmaceutical composition is a solid unit dosage form.
  • the solid unit dosage form includes the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 100 mg, 200 mg, or 400 mg, or about 100 mg, about 200 mg, or about 400 mg.
  • the solid unit dosage form includes the compound having structure (I), or pharmaceutically acceptable salt thereof, in an amount of 400 mg, or about 400 mg.
  • the solid unit dosage form is administered once daily. In some embodiments, the solid unit dosage form is administered orally.
  • the pharmaceutical composition is a liquid formulation for oral administration.
  • the liquid formulation is administered to a subject who is less than 18 years of age (e.g., from 2 to 6 years of age).
  • the pharmaceutical composition is formulated for oral administration and is administered with or without food.
  • 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 United States 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.
  • a method of treating a kidney disease or disorder in a subject in need thereof comprising administering to said subject (i) sparsentan, and (ii) a SGLT2 inhibitor.
  • a method of treating a proteinuric disease in a subject in need thereof comprising administering to said subject (i) sparsentan, and (ii) a SGLT2 inhibitor.
  • a method of reducing proteinuria in a subject in need thereof comprising administering to said subject (i) sparsentan, and (ii) a SGLT2 inhibitor.
  • a method of prolonging the time to end stage renal disease in a subject having a kidney disease or disorder comprising administering to said subject (i) sparsentan, and (ii) a SGLT2 inhibitor.
  • a method for reducing a risk of end stage renal disease in a subject having a kidney disease or disorder comprising administering to said subject (i) sparsentan, and (ii) a SGLT2 inhibitor.
  • a method of inducing complete remission in a subject having a kidney disease or disorder comprising administering to said subject (i) sparsentan, and (ii) a SGLT2 inhibitor.
  • a method of reducing the rate of decline in estimated glomerular filtration rate (eGFR) in a subject having a kidney disease or disorder comprising administering to said subject (i) sparsentan, and (ii) a SGLT2 inhibitor.
  • the rate of decline in eGFR is reduced following administration of sparsentan and the SGLT2 inhibitor, and the reduction is greater relative to that of a subject who is not administered the SGLT2 inhibitor.
  • said SGLT2 inhibitor is dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, ipragliflozin, tofogliflozin, or luseogliflozin, or a pharmaceutically acceptable salt, solvate, complex, or salt of solvates thereof.
  • kidney disease or disorder or proteinuric disease is focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), immunoglobulin A nephropathy (IgAN), immunoglobulin A-associated vasculitis (IgAV), or Alport syndrome.
  • FSGS focal segmental glomerulosclerosis
  • MCD minimal change disease
  • IgAN immunoglobulin A nephropathy
  • IgAV immunoglobulin A-associated vasculitis
  • kidney disease or disorder is immunoglobulin A nephropathy (IgAN).
  • renin angiotensin aldosterone system RAAS
  • endothelin system inhibitor a renin angiotensin aldosterone system (RAAS) inhibitor or endothelin system inhibitor.
  • RAAS renin angiotensin aldosterone system
  • kidney disease or disorder is Alport syndrome.
  • kits for use in the method according to any one of embodiments 1-71 comprising: a pharmaceutical composition comprising sparsentan; and a pharmaceutical composition comprising a SGLT2 inhibitor.
  • the long-term nephroprotective potential of treatment with sparsentan was evaluated in PROTECT, a 114-week, randomized, global, multicenter, double-blind, parallel-group, activecontrol Phase 3 clinical study in patients with IgAN who have persistent overt proteinuria and remain at high risk of disease progression despite being on a stable dose (or doses) of an angiotensin-converting enzyme inhibitor (ACEI) and/or angiotensin receptor blocker (ARB) that is (are) a maximum tolerated dose that is at least one half of the maximum labeled dose (MLD) (according to approved labeling).
  • ACEI angiotensin-converting enzyme inhibitor
  • ARB angiotensin receptor blocker
  • the purpose of the study is to evaluate the potential benefit of sparsentan on kidney function by analyzing change in proteinuria (protein in urine) and estimated glomerular filtration rate (eGFR) as compared to current standard treatment.
  • the study has an open-label extension period of up to 156 weeks, for a total duration of up to 270 weeks.
  • the trial enrolled patients with eGFR>30 mL/min/1.73 m 2 and urinary protein to creatinine ratio (UP/C) >1.0g/g at screening.
  • UP/C urinary protein to creatinine ratio
  • Inclusion criteria included: age 18 years or older at screening; biopsy-proven primary IgAN; proteinuria (UP/C) of >1 g/day at screening; eGFR >30 mL/min/1.73 m 2 at screening; currently on stable dose of ACEI and/or ARB therapy, for at least 12 weeks prior to screening (maximum tolerated dose and at least one-half of the maximum labeled dose); systolic BP ⁇ 150 mmHg and diastolic BP ⁇ 100 mmHg at screening; willing to undergo change in ACEI and/or ARB and anti-hypertensive medications; and agree to contraception.
  • Exclusion criteria for the double-blind period included: IgAN secondary to another condition; presence of cellular glomerular crescents in >25% of glomeruli on renal biopsy (if biopsy available within 6 months of screening); chronic kidney disease (CKD) in addition to IgAN; history of organ transplantation, with exception of corneal transplants; require any prohibited medications; treatment of systemic immunosuppressive medications (including corticosteroids) for >2 weeks within 3 months of screening; history of heart failure or previous hospitalization for heart failure or unexplained dyspnea, orthopnea, paroxysmal nocturnal dyspnea, ascites, and/or peripheral edema; clinically significant cerebrovascular disease or coronary artery disease within 6 months of screening; jaundice, hepatitis, or known hepatobiliary disease or elevations of transaminases (ALT/AST) >2 times upper limit of normal at screening; history of malignancy other than adequately treated basal cell or squamous cell skin cancer or cervical
  • ESRD end-stage renal disease
  • RRT renal replacement therapy
  • irbesartan an angiotensin receptor blocker
  • Sparsentan was administered at a dose of 200 mg once daily by mouth for 2 weeks and then titrated to 400 mg once daily as tolerated.
  • Irbesartan was administered at a dose of 150 mg once daily by mouth for 2 weeks and then titrated to 300 mg once daily as tolerated.
  • Sparsentan was provided as a tablet, comprising 200 mg or 400 mg of sparsentan.
  • Inactive ingredients included silicified microcrystalline cellulose, lactose anhydrous, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate.
  • UP/C Change in proteinuria
  • Day 1 Change in proteinuria (UP/C) from baseline (Day 1) at Week 36 in sparsentan-treated patients as compared to irbesartan-treated patients was assessed.
  • the Week 36 UP/C was based on a 24-hour urine sample.
  • Secondary outcome measures included eGFR over a 52-week period and a 104-week period following the initial acute effect of randomized therapy.
  • the initial acute effect of randomized therapy is defined as the first 6 weeks of randomized treatment with study medication; thus, the analysis is from 6 weeks postrandomization to 58 weeks (eGFR chronic slope at 1 year) or 110 weeks (eGFR chronic slope at 2 years) postrandomization, respectively.
  • eGFR over a 58-week and a 110-week (approximately 2-year) period following the initiation of randomized therapy (the analysis is from Day 1 to 58 weeks postrandomization or from Day 1 to 110 weeks postrandomization, eGFR total slope at 2 years).
  • 3 patients were administered 400 mg of sparsentan and 10 mg, 12.5 mg, or 25 mg of empagliflozin/JARDIANCE® per day, after completing the double-blind portion of the trial.
  • Randomization was stratified based on eGFR (>30 to ⁇ 60 mL/min/1.73 m2 versus eGFR >60 mL/min/1.73 m 2 ) and UP/C values ( ⁇ 3.5 g/g versus >3.5 g/g for patients >18 years of age, or ⁇ 2 g/g versus >2 g/g for patients ⁇ 18 years of age). Randomized Trial with Administration of Spar sentan
  • irbesartan Sparsentan was administered at a dose of 400 mg once daily by mouth for 2 weeks and then titrated to 800 mg once daily as tolerated. Irbesartan was administered at a dose of 150 mg once daily by mouth for 2 weeks and then titrated to 300 mg once daily as tolerated In patients weighing 50 kg or less, dosing was halved in both treatment arms (e.g., sparsentan administered at a dose of 200 mg once daily by mouth for 2 weeks and then titrated to 400 mg once daily as tolerated).
  • Sparsentan was provided as a tablet, comprising 200 mg or 400 mg of sparsentan.
  • Inactive ingredients included silicified microcrystalline cellulose, lactose anhydrous, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate.
  • a total of 371 patients were randomized 1 : 1 to receive either sparsentan or irbesartan, the active control.
  • UP/C urine protein-to-creatinine ratio
  • DAI drug-drug interactions
  • the open-label DDI study included Period 1 (Days 1-5; single dose of 10 mg dapagliflozin (“DAPA”) on Day 1, PK sampling pre-dose and up to 96 hours post-dose) and Period 2 (Days 5-14; 800 mg sparsentan (“SPAR”) once daily for 10 days with single 10 mg dose DAPA co-administered on Day 11, DAPA PK sampling pre-dose and up to 96 hours after Day 11 dosing).
  • DAPA dapagliflozin
  • SPAR sparsentan
  • the trial is a 28-week, open-label, multi center, single-group Phase 2 exploratory study to determine the safety and effect of sparsentan in participants with IgAN who are at risk of disease progression to kidney failure despite being on both stable renin-angiotensin-aldosterone system inhibitor (RAASi) and sodium glucose cotransporter-2 (SGLT2) inhibitor treatment for at least 12 weeks prior to study entry.
  • RAASi stable renin-angiotensin-aldosterone system inhibitor
  • SGLT2 sodium glucose cotransporter-2
  • This study includes 3 periods: a screening period (up to 42 days), a treatment period (24 weeks) and a follow-up period (4 weeks). All participants are required to be on a stable dose(s) of angiotensin converting enzyme inhibitor (ACEI) and/or angiotensin receptor blocker (ARB) therapy and on a stable dose of a SGLT2 inhibitor at screening and will continue their stable treatments through the screening period. Eligible participants entering the study will remain on the stable dose of the SGLT2 inhibitor for the duration of the study, however, they will discontinue ACEI and/or ARB therapy before the Day 1 visit. The final dose of an ACEI and/or ARB therapy should be taken on the day before the Day 1 visit. Baseline evaluations will be taken on Day 1 prior to administration of the first dose of the study intervention with sparsentan.
  • ACEI angiotensin converting enzyme inhibitor
  • ARB angiotensin receptor blocker
  • the full daily dose of study intervention (sparsentan) is preferred to be taken prior to the morning meal, with the exception of the day of a study visit. Allowed doses of sparsentan during the treatment period are 200 mg and 400 mg. The goal is to titrate from the initial dose of 200 mg (Day 1) to the target dose of 400 mg at Week 2.
  • Planned maximum duration for each participant in this study is 34 weeks.
  • Study visits will be conducted at weeks 2-, 4-, 12-, and 24- following Day 1. Following the 24-week treatment period, study intervention will be discontinued for 4 weeks followed by a return to standard of care. Participants will return to the site for a visit at Week 28 for the safety follow-up visit.
  • Urine albumin-to-creatinine ratio (UA/C) and urine protein-to-creatinine ratio (UP/C) will be determined using first morning void (FMV) samples and will be calculated as the average of 2 FMV samples collected within 3 days prior to each visit. If 1 of the samples is missing, UA/C and UP/C from the single sample will be used.
  • FMV first morning void
  • the total duration of participation from the screening visit to the safety follow-up visit (Week 28) will be a maximum of 34 weeks.
  • Sparsentan will be administered daily as a 200-mg or 400-mg oral tablet.
  • the starting dose will be 200 mg per day.
  • the goal is to titrate from the initial dose of 200 mg (Day 1) to the target dose of 400 mg starting at Week 3.
  • TEAEs treatment-emergent AEs
  • SAEs serious adverse events
  • AEs adverse events leading to treatment discontinuation
  • AEOIs adverse event of interest
  • the change from baseline (Day 1) in UA/C at Week 24 will be determined to evaluate the effect of sparsentan on albuminuria in participants on chronic stable treatment with an SGLT2 inhibitor.
  • Inclusion criteria will include:
  • Participant has biopsy-proven IgAN.
  • the biopsy may have been performed at any time in the past.
  • Participant has a UA/C >0.3 g/g at screening.
  • Participant has an eGFR value of >25 mL/min/1.73m2 at screening.
  • the participant has been on a stable dose of an SGLT2 inhibitor for at least 12 weeks prior to screening.
  • Participant has been on a stable dose of ACEI and/or ARB therapy for at least 12 weeks prior to screening that is: the participant’s maximum tolerated dose (MTD), and at least one half of the maximum labeled dose (MLD).
  • MTD maximum tolerated dose
  • MLD maximum labeled dose
  • Exclusion criteria will include:
  • Participant has IgAN secondary to another condition or immunoglobulin A (IgA) vasculitis.
  • IgA immunoglobulin A

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Abstract

La présente invention concerne des méthodes de traitement d'une maladie ou d'un trouble rénal, y compris des méthodes consistant à administrer du sparsentan et un inhibiteur de SGLT2 à un sujet en ayant besoin.
PCT/US2023/075525 2022-09-30 2023-09-29 Polythérapie avec du sparsentan et un inhibiteur de sglt2 pour le traitement de maladies ou de troubles rénaux WO2024073672A1 (fr)

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