Sparsentan for the treatment of patients post kidney transplantation with proteinuric IGA nephropathy or fsgs

Abstract

Methods of treating a kidney transplant patient are provided, including methods comprising administering sparsentan to a subject in need thereof. Additionally, compositions for use in such methods are provided.

Description

[0001] SPARSENTAN FOR THE TREATMENT OF PATIENTS POST KIDNEY TRANSPLANTATION WITH PROTEINURIC IGA NEPHROPATHY OR FSGS BACKGROUND

[0002] The present disclosure relates to the use of sparsentan, a dual angiotensin and endothelin receptor antagonist in the treatment of subjects who have received a kidney transplant, and may be subject to kidney diseases or disorders, such as focal segmental glomerulosclerosis (FSGS) and immunoglobulin A nephropathy (IgAN).

[0003] 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 genetic, undetermined cause, or secondary. Primary FSGS has no known etiology. Secondary FSGS may be caused by reduction in functional 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.

[0004] IgAN, also known as Berger's disease, is caused by the buildup of immunoglobulin A (IgA) containing immune complexes in the kidney. The presence of IgA in the kidneys may lead to inflammation, damage to the glomeruli of the kidney, and impaired kidney function, including proteinuria. In many cases, patients with IgA nephropathy progress to end-stage renal disease (ESRD).

[0005] Generally, patients with IgAN or FSGS are treated, put on diets and behavioral regimens to prevent ESRD. However, not all patients are able to live out a normal lifespan without further interventions alone, and some face the eventuality of ESRD.

[0006] Dialysis is a life-saving intervention that is used when kidney function is only 10-15% of normal, as measured by estimated glomerular filtration rate (eGFR). Often this low level is defined as end-stage renal disease (ESRD). Dialysis uses medical technology (an “artificial kidney” membrane) in place of kidney function: Dialysis removes waste and extra fluid from the blood, helps control blood pressure, restores electrolyte levels, removes salt, and keeps mineral and vitamin levels safe. While dialysis can occur at home or in a clinic, it can also lead to complications. Often, people waiting for kidney transplantation are on dialysis.A kidney transplant places a healthy kidney into a person whose kidneys no longer function properly. To be eligible for a kidney transplant, a patient must meet a number of criteria such as kidney failure or dialysis, generally with an eGFR of <20 mL / min, but otherwise should be healthy enough to withstand the burden of the procedure and long-term immunosuppression.

[0007] Often by the time a person receives a transplant; they already have very serious loss of kidney function. Often the addition of a “new” and working kidney restores function, but the patient will be using immunosuppressant drugs to prevent rejection of the transplant, and often the patient’s transplanted kidney is stressed, and subject over time to the same maladies that created the need for transplantation to begin with.

[0008] As a result it is necessary to treat such patients prophylactically in an effort to prevent deterioration of the transplanted kidney by the same maladies that precipitated the need for the transplant. There is also a need to treat such disease recurrence in the transplant when it is diagnosed. Thus, there remains a need for treatments of patients with kidney transplants as described above.

[0009] Kidney transplantation has enjoyed great success and has (in the last 25 years) seen improvements in one year graft survival and rejection rates. However, in the US alone, there is a huge unmet need for post-transplant patients who eventually experience poor long term outcomes and poorly tolerated therapies post-transplant. Annual rates of graft loss after year 1 and death with functional graft are regarded as unacceptable and as not improving, and patient perceptions of post-transplant quality of life are poor.

[0010] BRIEF SUMMARY OF THE INVENTION

[0011] The present disclosure provides, in some embodiments, methods of treating kidney transplant patients, wherein the method comprises administering a compound having structure (I)

[0012]

[0013] or a pharmaceutically acceptable salt thereof, to a subject (e.g., a patient) in need thereof. In some embodiments, the treatment is either to treat and / or provide prophylaxis for kidney transplant patients against kidney disease or disorder, generally a proteinuric disease, such as focal segmental glomerulosclerosis (FSGS) or immunoglobulin A nephropathy (IgAN). These and other aspects of the present invention will become apparent upon reference to the following detailed description.

[0014] BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0015] Figure 1 shows the clinical trial schedule of Example 1.

[0016] DETAILED DESCRIPTION

[0017] The present detailed description provides, in some embodiments, methods of treating kidney transplant patients, wherein the method comprises administering a compound having structure (I), or a pharmaceutically acceptable salt thereof.

[0018] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the invention. However, one skilled in the art will understand that the invention may be practiced without these details.

[0019] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. As used herein, certain terms may have the following defined meanings.

[0020] Unless the context requires otherwise, throughout the present specification and claims, the word "comprise" and variations thereof, such as "comprises" and "comprising," are to be construed in an open, inclusive sense, that is, as "including, but not limited to."

[0021] As used in the specification and claims, "including" and variants thereof, such as "include" and "includes," are to be construed in an open, inclusive sense; i.e., it is equivalent to "including, but not limited to." As used herein, the terms "include" and "have" are used synonymously, which terms and variants thereof are intended to be construed as non-limiting.

[0022] As used herein, the phrase "such as" refers to non-limiting examples.

[0023] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.As used in the specification and claims, the singular for "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a cell" includes a plurality of cells, including mixtures thereof. Similarly, use of "a compound" for treatment of preparation of medicaments as described herein contemplates using one or more compounds of the invention for such treatment or preparation unless the context clearly dictates otherwise.

[0024] The use of the alternative (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives.

[0025] "Optional" or "optionally" means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not occur.

[0026] As used herein, "about" and "approximately" generally refer to an acceptable degree of error for the quantity measured, given the nature or precision of the measurements. Typical, exemplary degrees of error may be within 20%, 10%, or 5% of a given value or range of values. Alternatively, and particularly in biological systems, the terms "about" and "approximately" may mean values that are within an order of magnitude, potentially within 5-fold or 2-fold of a given value. When not explicitly stated, the terms "about" and "approximately" mean equal to a value, or within 20% of that value.

[0027] 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.

[0028] The compound having structure (I) may form salts, which are also within the scope of this disclosure. Reference to a compound having structure (I) herein is generally understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)," as employed herein, denotes acidic or basic salts formed with inorganic or organic acids and bases. In addition, as the compound having structure (I) contains both a basic moiety and an acidic moiety, zwitterions ("inner salts") may be formed and are included within the term "salt(s)," as used herein. Pharmaceutically acceptable ( / .< ., non-toxic, physiologically acceptable) salts are preferred, although other salts may be useful, e.g., in isolation or purification steps which may be employed during preparation. Salts of the compound having structure (I) may be formed, for example, by reacting the compound having structure (I) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0029] The term "pharmaceutically acceptable salt" includes both acid and base addition salts. Prodrugs and solvates of the compound having structure (I) are also contemplated. The term "prodrug" denotes a compound that, upon administration to a subject, undergoes chemicalconversion 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.

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

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

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

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

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

[0035] The term “unit dosage form" (or "unit dose 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.

[0036] "Treatment" or "treating" includes (1) inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease (e.g., arrestingfurther 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.

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

[0038] Sparsentan and its formulation and pharmaceutically acceptable compositions.

[0039] Sparsentan (CAS 254740-64-2, 2-[4-[(2-butyl-4-oxo-l,3-diazaspiro[4.4]non-l-en-3-yl)methyl]-2-(ethoxymethyl)phenyl]-N-(4,5-dimethyl-l,2-oxazol-3-yl)benzene sulfonamide) is a biphenyl sulfonamide compound having structure (I) above. 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).

[0040] The compound of structure (I) may be prepared by methods such as those described in International Patent Application Publication No. WO2018 / 071784 Al. Additionally, the compound of structure (I) may be prepared by the methods recited in U.S. Patent Application Publication No. US 2015 / 0164865 Al and U.S. Patent No. US 6,638,937 B2.

[0041] Pharmaceutical compositions are described in PCT Publication WO 2018 / 071784 Al, incorporated herein by reference. Multiple techniques of administering such pharmaceutical compositions, physiologically or pharmaceutically acceptable excipient, and their formulation are described in the above references.

[0042] Methods of Treatment and Other Uses

[0043] Additionally, methods of treatment comprising administering the invention are within the scope of the present disclosure.

[0044] In some embodiments, 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 previously diagnosed with FSGS or IgAN or who has received a kidney transplant.

[0045] In some embodiments, therapy as described above is also useful in treatment of patients who have previously presented with IgAN, FSGS, or other kidney disease as evidenced byimprovements seen histologically in the kidney, reduction in complement deposition in the kidney, and in various functional measures, such as podocyte specific measures, and other measures of remission of kidney disease. In this embodiment, clinical trial data or a patient’s own history may illustrate the usefulness of this treatment.

[0046] In some embodiments, therapy as described above is also useful in treatment of patients who have previously had a kidney transplant, as evidenced by improvements seen histologically in the kidney, reduction in complement deposition in the kidney, and in various functional measures, such as podocyte specific measures, and other measures of remission of kidney disease. In this embodiment, clinical trial data or a patient’s own history may illustrate the usefulness of this treatment.

[0047] In some embodiments, therapy as described above is useful in reducing proteinuria. As used herein, "proteinuria" refers to a condition in which the urine contains an abnormal amount of protein (z.e., urine protein excretion of greater than 300 mg per day). A urinary protein to creatinine (UP / C) ratio provides a measurement of total urine protein relative to the amount of creatinine in a urine sample (e.g., 1 g of protein in urine (dl) divided by 1 g of creatinine in urine (dl) = a UP / C ratio of 1 g / g). While the skilled artisan, using methods known in the art may be very able to treat a subject with FSGS or IgAN, and may understand the needs of the kidney transplant patient, it is essential that the skilled artisan review and understand the uniqueness of the patient post-transplant.

[0048] In another embodiment, the therapy as described above is useful in treating patients who are using immunosuppression to prevent graft rejection or organ rejection. In many cases, immunosuppressants used in transplantation are nephrotoxic, and the treatment of the invention may improve the longevity of the transplant, may improve quality of life for the patient, and may reduce complications seen in large numbers of patients.

[0049] Methods of Administration

[0050] The combination therapies described herein may be administered to the subject (e.g., a human patient) by any suitable means. Examples of methods of administration are found in PCT publication WO2018 / 071784 Al, incorporated herein by reference.

[0051] Exemplary Embodiments

[0052] The present disclosure also provides in further embodiments:

[0053] 1. A method of treating a kidney transplant in a subject in need thereof, the method comprising administering to said subject sparsentan.2. A method of treating a proteinuric disease in a kidney transplant subject in need thereof, the method comprising administering to said subject sparsentan.

[0054] 3. A method of reducing proteinuria in a kidney transplant subject in need thereof, the method comprising administering to said subject sparsentan.

[0055] 4. A method of prolonging the time to end stage renal disease in a kidney transplant subject, the method comprising administering to said subject sparsentan.

[0056] 5. A method for reducing a risk of end stage renal disease in a subject having a kidney transplant, the method comprising administering to said subject sparsentan.

[0057] 6. A method of inducing remission of proteinuria in a subject having a kidney transplant, the method comprising administering to said subject sparsentan.

[0058] 7. The method of claim 6, wherein urinary protein to creatinine ratio (UP / C) is reduced to less than or equal to 0.3 g / g following administration.

[0059] 8. A method of reducing the rate of decline in estimated glomerular filtration rate (eGFR) in a subject having a kidney disease or disorder, the method comprising administering to said subject sparsentan.

[0060] 9. The method according to any one of claims 1-8, wherein the amount of sparsentan administered to said subject is from 100 mg / day to 800 mg / day.

[0061] 10. The method according to any one of claims 1-8, wherein the amount of sparsentan administered to said subject is 200 mg / day.

[0062] 11. The method according to any one of claims 1-8, wherein the amount of sparsentan administered to said subject is 400 mg / day.

[0063] 12. The method according to any one of claims 1-8, wherein the amount of sparsentan administered to said subject is 800 mg / day.

[0064] 13. The method according to any one of claims 1-8, wherein the amount of sparsentan administered to said subject is 200 mg / day for the first 2 weeks and thereafter 400 mg / day.

[0065] 14. The method according to any one of claims 1-8, wherein if said subject's weight is from 20 kg to 50 kg, the amount of sparsentan administered to said subject is 100 mg / day for the first 2 weeks and thereafter 200 mg / day.

[0066] 15. The method according to any one of claims 1-8, wherein the amount of sparsentan administered to said subject is 400 mg / day for the first 2 weeks and thereafter 800 mg / day.

[0067] 16. The method according to any one of claims 1-15, wherein said sparsentan is administered orally.17. The method according to claim 16, wherein said sparsentan is administered with or without food.

[0068] 18. The method according to any one of claims 1-17, wherein said kidney transplant subject has immunoglobulin A nephropathy (IgAN).

[0069] 19. The method according to claim 18, wherein said subject (i) has a baseline eGFR greater than or equal to 30 mL / min / 1.73 m2and (ii) has a baseline UP / C greater than 1.0 g / g- 20. The method according to claim 18-19, wherein said subject has biopsy-proven primary IgAN.

[0070] 21. The method according to any preceding claim, wherein said kidney transplant subject has focal segmental glomerulosclerosis (FSGS).

[0071] 22. The method according to claim 21, wherein said subject is 8 years of age or older.

[0072] 23. The method according to any one of claims 21-22, wherein said subject has FSGS lesions.

[0073] 24. The method according to any one of claims 21-23, wherein said subject's UP / C is reduced by more than 40% from the baseline UP / C with treatment.

[0074] 25. Sparsentan for use in the method according to any one preceding claim.

[0075] 26. Use of sparsentan in the manufacture of a medicament for use in the method according to any preceding claim.

[0076] 27. Use of sparsentan in preventing kidney disease in transplanted kidneys according to any preceding claim.

[0077] 28. Use of sparsentan in maintaining kidney function of patents having transplanted kidneys according to any preceding claim.

[0078] 29. A method of treating a kidney transplant patient, the method comprising administering to said subject sparsentan according to any preceding claim..

[0079] EXAMPLES EXAMPLE 1

[0080] MULTI-CENTER, OPEN-LABEL, SINGLE GROUP CLINICAL TRIAL A minimum of 20 kidney transplant patients (within this group a minimum of 4 patients with biopsy-proven IgAN and 4 patients with FSGS histological pattern in the graft) are enrolled in a roughly 36 week study to evaluate the safety of sparsentan treatment, as well as the response to sparsentan treatment, based on proteinuria, albuminuria and estimated GFR. One 200 mgtablet administered orally once daily for 2 weeks, then one 400 mg tablet administered orally once daily through Week 24 to explore sparsentan treatment in kidney transplant patients with IgAN or 400 mg followed by 800 mg / day in FSGS with regard to, pharmacokinetics, plasma, serum, and urine biomarkers.

[0081] Eligible patients with a kidney transplant receiving stable standard of care therapy, including standard immunosuppressive therapy to prevent graft rejection, will be enrolled to receive sparsentan treatment for 24 weeks. Patients will remain on immunosuppressive therapy for the duration of the study and will stop renin-angiotensin system inhibitors (RASi) prior to initiating sparsentan treatment. All patients will complete a 4 week off-SPAR (off-sparsentan) treatment follow-up period, during which time treatment will be at the discretion of the investigator.

[0082] Inclusion Criteria:

[0083] Subjects may be male or female aged >18 years, with a kidney transplant with biopsy-proven IgAN or FSGS histological pattern in the graft. There must be a period of >12 months since kidney transplantation.

[0084] Patients must have a urine protein-creatinine ratio (UP / C) > 0.5 g / g and estimated glomerular filtration rate (eGFR) value > 25 mL / min / 1.73 m2, systolic BP < 160 mmHg and > 100 mmHg, and diastolic blood pressure < 100 mmHg and > 60 mmHg at screening. UP / C and urinary albumin to creatinine ratio (UA / 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.

[0085] For patients on an ACEi and / or ARB, and / or SGLT2 inhibitor the dosing regimen(s) is stable for at least 12 weeks prior to screening.

[0086] Female patients not of childbearing potential, or of childbearing potential and agreeing to use the contraceptive methods

[0087] Exclusion Criteria:

[0088] Patient has multiorgan transplants (with the exception of pancreas and corneal transplants)

[0089] Immunosuppressive therapy (1ST) regimen for kidney transplant that is not stable for >3 months prior to Day 1. Exceptions include routine protocol tapering and for CNIs, changes in dose to meet target level.

[0090] More than 3 months after antirejection treatment and active rejection.Active bacterial, fungal or viral infection and / or active treatment of infection including BKV, CMV, HIV, Hepatitis B and C <3 months prior to and during the screening period.

[0091] Current treatment for surgical complications.

[0092] History of heart failure (NYHA Class II-IV), clinically significant cerebrovascular disease, or coronary artery disease, Jaundice, hepatitis, or known hepatobiliary disease.

[0093] Malignancy within the past 2 years with the exception of adequately treated basal cell carcinoma or non-metastatic squamous cell carcinoma of the skin, with no evidence or recurrence.

[0094] Haematocrit <27%, haemoglobin <90 g / L (9 g / dL), or potassium >5.5 mmol / L (5.5 mEq / L).

[0095] History of alcohol or illicit drug use disorder (as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition).

[0096] History of serious side effects or allergic response to any angiotensin II antagonist or endothelin receptor antagonist (ERA).

[0097] The female patient is pregnant, plans to become pregnant during the course of the study, or is breastfeeding.

[0098] The patient has participated in a study of any investigational product within 28 days prior to screening, or plans to participate in such a study during the course of this study.

[0099] The patient, in the opinion of the clinical investigator, is unable to adhere to the requirements of the study, including the ability to swallow the IMP whole.

[0100] The patient, in the opinion of the Investigator, has a medical condition or abnormal clinically significant laboratory screening value not listed above that may interfere with the evaluation of sparsentan safety or activity.

[0101] Outcomes measured

[0102] Proportion of patients with adverse events (AEs), serious AEs, AEs leading to discontinuation, AEs leading to death.

[0103] Proportion of patients with abnormalities in clinical laboratory assessments and vital signs at each visit.

[0104] Change from baseline in proteinuria (urinary protein / creatinine ratio [UP / C] and albuminuria (urinary albumin / creatinine ratio [UA / C]) at Weeks 12, 24 assessed on the log scale.

[0105] Achievement of UP / C <0.3 g / g at Weeks 12 and 24.

[0106] Change from baseline in glomerular filtration rate (GFR) at each visit based on eGFR (applying creatinine and cystatin C based formulae).

[0107] Mean change from baseline in systolic and diastolic blood pressure at each visitMean change from baseline in hematuria at each visit (IgAN only).

[0108] Estimation of sparsentan pharmacokinetic (PK) profile in plasma based on trough levels at each visit.

[0109] Change from baseline in biomarkers in plasma, serum, and urine at each visit Monitoring for change in CNI or mTORi levels at each visit (for patients receiving CNIs or mTORi treatment).

[0110] The clinical trial’s schedule is illustrated in Figure 1.

[0111] Schedule of Assessments within the clinical trial

[0112]

[0113] Full physical examinations will be performed at screening; a symptom-directed targeted physical examination will be performed at all other visits. Peripheral edema assessment guidance is provided.

[0114] Vital signs will always be measured prior to having blood drawn for laboratory evaluations. Blood pressure will be measured after patients have been sitting comfortably in a chair for at least 5 minutes prior to obtaining 3 readings, using the same arm for each reading; the mean of the last 2 readings will then be recorded. Heart rate, temperature, respiration rate, weight, and height (height measured only at screening) will also be recorded.

[0115] UP / C and UA / C will be determined using FMV samples and will be calculated as the average of measurements from 2 FMV samples collected within 3 days of at screening and within 3 days prior to other study visit. If one of the samples is missing, the measurement of UP / C and UA / C from the single FMV sample will be used. Participants will be provided with adequate urine collection containers in advance of collection time points. For screening, patients will be given supplies for FMV sample collections at Visit 1 (Screening Visit), and will return with the collected samples within the visit window (i.e., within 28 days prior to Day 1).

[0116] Patients will be instructed to take their CNI or mTORi at the clinic on the day of office visits. Visit 3 (Day 5) is included for measurement and evaluation of CNI or mTORi levels. At the discretion on the investigator, CNI or mTORi levels may be measured for evaluation at any time during the study.

[0117] Serum pregnancy tests will be performed at screening. Urine pregnancy tests will be performed at all other visits and monthly between visits. A positive urine pregnancy test will be confirmed by a serum test. Urine pregnancy tests will be dispensed to conduct pregnancy testing at home between trial visits. Site will provide the patient enough tests to conduct pregnancy testing once per month until the next scheduled trial visit, and will contact these patients monthly to confirm that the pregnancy test has been performed and the results are negative. A positive urine pregnancy test will be confirmed by a serum test.

[0118] At Visit 2 (Day 1), the first dose will be administered in clinic. Patients will be instructed to take their sparsentan at the clinic on the day of office visits. All other days, sparsentan should be taken prior to the morning meal. Patients will be instructed to avoid drinking or eating anything that contains grapefruit, Seville oranges (bitter oranges often used as marmalade), or starfruit (carambola) throughout the trial. The patient will be instructed to bring all remaining sparsentan and their original containers to the next clinic visit.EXAMPLE 2

[0119] A clinical trial measuring proteinuria, a key indicator of kidney function is conducted on patients with recurrent IgAN:

[0120] Inclusion Criteria for enrollment

[0121] 1. Male and female aged >18 years

[0122] 2. Diagnosis of IgAN based on histological analysis of a native kidney biopsy 3. Diagnosis of recurrent IgAN based on histological analysis of a transplanted kidney biopsied <6 months

[0123] 4. A time period of >12 months since kidney transplantation

[0124] 5. UP / C > 50 mg / mmol (0.44 g / g) and eGFR value > 25 mL / min / 1.73 m2

[0125] 6. For patients on an ACEi and / or ARB, and / or an SGLT2 inhibitor, the dosing regimen is stable for > 12 weeks prior to and during the screening period

[0126] 7. SBP < 150 mmHg and > 100 mmHg, and DBP < 100 mmHg and > 60 mmHg at screening.

[0127] 8. Tacrolimus treatment as part of standard of care immunosuppression following kidney transplantation

[0128] 9. Female patients not of childbearing potential, or of childbearing potential and agreeing to use the contraceptive methods

[0129] Exclusion criteria

[0130] 1. Patient has multi organ transplants (with the exception of pancreas or corneal transplants)

[0131] 2. 1ST regimen for kidney transplant or other chronic ISTs (including enteric budesonide) that is not stable for 6 weeks prior to Day 1. Exceptions include routine changes in the dose of CNIs to meet target level.

[0132] 3. < 3 months after antirejection treatment and active rejection.

[0133] 4. The patient has recurrent IgAN secondary to another condition or cause (eg, SLE, liver cirrhosis)

[0134] 5. Evidence of alternative pathology on the kidney transplant biopsy as the main cause for proteinuria (e.g. diabetic nephropathy, chronic transplant glomerulopathy, mTORi treatment)

[0135] 6. 1ST regimen for kidney transplant or other chronic ISTs, including enteric budesonide, that is not stable for > 6 weeks prior to Day 1. Exceptions include routine protocol tapering and for tacrolimus, changes in dose to meet target level7. < 3 months after anti -rejection treatment or active rejection

[0136] 8. Uncontrolled diabetes mellitus (defined by HbAlC > 8%)

[0137] Measures

[0138] <

[0139]

[0140] <

[0141] EXAMPLE 3

[0142] Study endpoints and pharmacokinetic monitoring in kidney transplant subjects receiving sparsentan

[0143] In some embodiments, a clinical study in kidney transplant subjects receiving sparsentan includes assessment of safety, efficacy, and pharmacokinetics. In some embodiments, endpoints and assessments include one or more of (a) the proportion of subjects with treatment-emergent AEs, severe AEs, and / or AEs leading to discontinuation; (b) weight, vital signs, and laboratory parameters; (c) change from baseline in UP / C at one or more time points (e.g., up to Week 36); (d) change from baseline in UP / C, UA / C, eGFR, and / or systolic and diastolic blood pressure at one or more time points; (e) achievement of UP / C <0.3 g / g at one or more time points (e.g., Weeks 12, 24, and / or 36); (f) a proportion of subjects achieving a specified reduction in albumin to creatinine ratio (ACR) (e.g., a reduction of at least 30% and / or at least 50%); and (g) trough plasma PK concentrations for sparsentan and / or co-administered immunosuppressive agents (e.g., a CNI and / or an mTOR inhibitor) at one or more study visits.EXAMPLE 4

[0144] Kidney Transplant Registry of Sparsentan (KTRS)

[0145] In some embodiments, a retrospective chart review (e.g., a kidney transplant registry study) is conducted to evaluate outcomes in kidney transplant recipients with proteinuria who receive sparsentan in routine clinical practice. In some embodiments, the chart review includes about 30 proteinuric kidney transplant recipients treated with sparsentan. In some embodiments, subjects are age >18 years and have received a kidney transplant. In some embodiments, multiorgan transplant recipients are excluded (with optional exceptions such as pancreas or corneal transplants). In some embodiments, subjects have proteinuria (e.g., >1 g / day) and are treated with sparsentan. In some embodiments, subjects have at least three UP / C measurements prior to initiation of sparsentan. In some embodiments, efficacy outcomes include one or more of complete remission, partial remission, and / or clinical remission, and safety outcomes include adverse events and changes in kidney function, including maintenance of renal function.

[0146] EXAMPLE 5

[0147] Case series of sparsentan treatment in kidney transplant recipients with proteinuria In some embodiments, sparsentan is administered to kidney transplant recipients with proteinuria in a clinical setting. In one report, a case series (e.g., presented at a transplant congress) included nine kidney transplant recipients treated with sparsentan and followed for changes in proteinuria and kidney function. In some embodiments, seven subjects were treated over approximately a six-week period and two subjects were treated over approximately twelve months. In some embodiments, subjects were selected based on proteinuria (e.g., UP / C >1 g / g) and included cases of recurrent IgAN, recurrent membranous nephropathy (PMN), diabetic glomerulopathy, recurrent FSGS, and / or de novo FSGS. In some embodiments, urine protein to creatinine ratio (UP / C) decreases (e.g., by about 40% to about 80%) in a majority of subjects. In some embodiments, estimated glomerular filtration rate (eGFR) is stable after an initial decline. In some embodiments, donor-derived cell-free DNA (dd-cfDNA) does not increase during sparsentan treatment. In some embodiments, sparsentan is generally well tolerated, and blood pressure is managed with dose adjustment in some subjects.

[0148] All of the above U.S. patents, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification, are incorporated hereinby reference in their entirety, including U.S. Provisional Patent Application No. 63 / 752,181 filed January 31, 2025, unless otherwise stated.

[0149] The various embodiments described above can be combined to provide further embodiments. Aspects of the embodiments can be modified, if necessary, to employ concepts of the various patents, applications, and publications to provide yet further embodiments. These and other changes can be made to the embodiments in light of the above-detailed description.

[0150] In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

CLAIMSWhat is claimed is:

1. A method of treating a kidney transplant subject in need thereof, the method comprising administering to said subject sparsentan.

2. A method of treating a proteinuric disease in a kidney transplant subject in need thereof, the method comprising administering to said subject sparsentan.

3. A method of reducing proteinuria in a kidney transplant subject in need thereof, the method comprising administering to said subject sparsentan.

4. A method of prolonging the time to end stage renal disease in a kidney transplant subject, the method comprising administering to said subject sparsentan.

5. A method for reducing a risk of end stage renal disease in a subject having a kidney transplant, the method comprising administering to said subject sparsentan.

6. A method of inducing remission of proteinuria in a subject having a kidney transplant, the method comprising administering to said subject sparsentan.

7. The method of claim 6, wherein urinary protein to creatinine ratio (UP / C) is reduced to less than or equal to 0.3 g / g following administration.

8. A method of reducing the rate of decline in estimated glomerular filtration rate (eGFR) in a subject having a kidney disease or disorder, the method comprising administering to said subject sparsentan.

9. The method according to any one of claims 1-8, wherein the amount of sparsentan administered to said subject is from 100 mg / day to 800 mg / day.

10. The method according to any one of claims 1-8, wherein the amount of sparsentan administered to said subject is 200 mg / day.

11. The method according to any one of claims 1-8, wherein the amount of sparsentan administered to said subject is 400 mg / day.

12. The method according to any one of claims 1-8, wherein the amount of sparsentan administered to said subject is 800 mg / day.

13. The method according to any one of claims 1-8, wherein the amount of sparsentan administered to said subject is 200 mg / day for the first 2 weeks and thereafter 400 mg / day.

14. The method according to any one of claims 1-8, wherein if said subject's weight is from 20 kg to 50 kg, the amount of sparsentan administered to said subject is 100 mg / day for the first 2 weeks and thereafter 200 mg / day.

15. The method according to any one of claims 1-8, wherein the amount of sparsentan administered to said subject is 400 mg / day for the first 2 weeks and thereafter 800 mg / day.

16. The method according to any one of claims 1-15, wherein said sparsentan is administered orally.

17. The method according to claim 16, wherein said sparsentan is administered with or without food.

18. The method according to any one of claims 1-17, wherein said kidney transplant subject has immunoglobulin A nephropathy (IgAN).

19. The method according to claim 18, wherein said subject (i) has a baseline eGFR greater than or equal to 30 mL / min / 1.73 m2and (ii) has a baseline UP / C greater than 1.0 g / g.

20. The method according to claim 18-19, wherein said subject has biopsy-proven primary IgAN.

21. The method according to any preceding claim, wherein said kidney transplant subject has focal segmental glomerulosclerosis (FSGS).

22. The method according to claim 21, wherein said subject is 8 years of age or older.

23. The method according to any one of claims 21-22, wherein said subject has FSGS lesions.

24. The method according to any one of claims 21-23, wherein said subject's UP / C is reduced by more than 40% from the baseline UP / C with treatment.

25. Sparsentan for use in the method according to any one preceding claim.

26. Use of sparsentan in the manufacture of a medicament for use in the method according to any preceding claim.

27. Use of sparsentan in preventing kidney disease in transplanted kidneys according to any preceding claim.

28. Use of sparsentan in maintaining kidney function of a patient having a transplanted kidney according to any preceding claim.

29. A method of treating a kidney transplant patient, the method comprising administering to said patient sparsentan according to any preceding claim.

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