Urinary biomarker analysis reveals rapid intra-renal Anti-inflammatory and Anti-fibrotic effects of sparsentan in IGA nephropathy (IGAN)

Abstract

Use of sparsentan to reduce inflammation or fibrosis in patients with IgAN, wherein inflammation production and fibrosis production are measured by urinalysis.

Description

URINARY BIOMARKER ANALYSIS REVEALS RAPID INTRA-RENAL ANTIINFLAMMATORY AND ANTI-FIBROTIC EFFECTS OF SPARSENTAN IN IGA NEPHROPATHY (IGAN)BACKGROUND

[0001] SPARTAN (NCT04663204) is an experimental medicine study designed to study the effects of a novel therapy on pathogenic pathways in IgAN. The study incorporates a biomarker focused approach to the evaluation of sparsentan (SPAR), a dual endothelin and angiotensin receptor antagonist, in adults newly diagnosed with IgAN, and includes a repeat kidney biopsy. It was previously reported that SPAR treatment resulted in rapid and sustained reductions in proteinuria by -70% over 24 weeks. Here, we present findings on urinary biomarkers.

[0002] Dual endothelin and angiotensin receptor antagonism modulates key intra-renal pathways promoting inflammation and fibrosis as well as B cell and complement activation pathways. This enhances the scope of SPAR mode of action to cellular effects well beyond haemodynamic actions. SPAR may offer the possibility of limiting the consequences of IgA immune complex deposition both within the glomerulus and tubule.BRIEF SUMMARY

[0003] In one embodiment is provided use of sparsentan to reduce inflammation in patients with IgAN.

[0004] In another embodiment, the use of sparsentan to reduce inflammation is provided, wherein inflammation production is measured by urinalysis.BRIEF DESCRIPTION OF THE DRAWINGS

[0005] Figure 1 shows the by visit changes in urine biomarkers sCD163, IL-6, BAFF and sC5b-9 over 24 weeks of SPAR treatment as changes from baseline.DETAILED DESCRIPTION

[0006] 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.

[0007] 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.1#11479294.1

[0008] 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."

[0009] 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.

[0010] As used in herein, the phrase "such as" refers to non-limiting examples.

[0011] 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.

[0012] 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.

[0013] The use of the alternative (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives.

[0014] "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.

[0015] 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.

[0016] 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 2#11479294.10.05 to 0.14. As another example, the interval of values 0.1 to 0.2 includes the range from 0.05 to 0.24.

[0017] The compound having structure (I) may form salts, which are also within the scope of this disclosure. Reference to a compound having structure (I) herein is generally understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)," as employed herein, denotes acidic or basic salts formed with inorganic or organic acids and bases. In addition, as the compound having structure (I) contains both a basic moiety and an acidic moiety, zwitterions ("inner salts") may be formed and are included within the term "salt(s)," as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts may be useful, e.g., in isolation or purification steps which may be employed during preparation. Salts of the compound having structure (I) may be formed, for example, by reacting the compound having structure (I) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0018] The term "pharmaceutically acceptable salt" includes both acid and base addition salts.

[0019] 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.

[0020] 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.

[0021] 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 3#11479294.1by 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.

[0022] 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.

[0023] 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).

[0024] 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.

[0025] 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.

[0026] Treatment" or "treating" includes (1) inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease (e.g., arresting further development of the pathology or symptomatology); or (2) ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease (e.g., reversing the pathology or symptomatology); or (3) effecting any measurable decrease in a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease.

[0027] "Preventing" in the context of preventing a subject (e.g., a patient) from experiencing or displaying the pathology or symptomology of a disease includes the failure to develop a disease, disorder, or condition, or the reduction in the development of a sign or symptom associated with such a disease, disorder, or condition (e.g., by a clinically relevant amount), or the exhibition of delayed signs or symptoms delayed (e.g., by days, weeks, months, or years). Additional definitions are set forth throughout this disclosure.Sparsentan and its formulation and pharmaceutically acceptable compositions.

[0028] 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 dualacting 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).4#11479294.1

[0029] 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.

[0030] 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.Method of Treatment or Risk Reduction

[0031] The method of treatment or reduction of inflammation in a patient with IgAN described herein can be informed by certain urinary biomarkers associated with inflammation.

[0032] In one embodiment is provided a method of treating or reducing inflammation in a patient with IgAN, the method comprising administering a therapeutically effective amount of sparsentan.

[0033] In one embodiment, the method of treating or reducing inflammation in a patient with IgAN comprises:i) orally administering an initial dose of 200 mg of sparsentan to the subject once a day for a period of 14 days; andii) after the initial 14 day period, orally administering a subsequent dose of 400 mg of sparsentan to the subject once a day.

[0034] The method of treatment or reduction of fibrosis in a patient with IgAN described herein can be informed by certain urinary biomarkers associated with inflammation.

[0035] In one embodiment is provided a method of treating or reducing fibrosis in a patient with IgAN, the method comprising administering a therapeutically effective amount of sparsentan.

[0036] In one embodiment, the method of treating or reducing fibrosis in a patient with IgAN comprises:i) orally administering an initial dose of 200 mg of sparsentan to the subject once a day for a period of 14 days; andii) after the initial 14 day period, orally administering a subsequent dose of 400 mg of sparsentan to the subject once a day.

[0037] For any of the above dosing regimens, patients who do not tolerate the target dose should have their dose reduced back to 200 or 100 mg / day; patients should be maintained on the maximum allowed dose of sparsentan they can tolerate. When reducing sparsentan due to tolerability issues or when resuming treatment with sparsentan after an interruption, a patient 5#11479294.1may continue or initiate treatment with sparsentan at 50% of the recommended dose and titrate to the recommended dose after 14 days.

[0038] In one embodiment, the subject has a baseline level of expression of one or more urine biomarker that is high compared to a healthy subject, and wherein administering a therapeutically effective amount of the dual endothelin angiotensin receptor antagonist reduces the level of expression of the one or more urine biomarker in the subject from the baseline level. In one embodiment, the one or more urine biomarker comprises alpha-2 macroglobulin, B cell activating factor (BAFF), chitinase-3 -like protein- 1 (CHI3L1; YKL-40), clusterin, C-X-C motif chemokine ligand- 10 (CXCL10), C-X-C motif chemokine ligand- 16 (CXCL16), Growth differentiation factor- 15 (GDF-15), Interleukin-6 (IL-6), monocyte chemoattractant protein-q (MCP-1), plasminogen, soluble C5b-9, or soluble CD163 (sCD163).

[0039] In one embodiment, the one or more urine biomarker comprises alpha-2 macroglobulin, wherein administering a therapeutically effective amount of sparsentan reduces the level of alpha-2 macroglobulin by at least about 80% from baseline within the first 24 weeks of treatment.

[0040] In one embodiment, the one or more urine biomarker comprises BAFF, wherein administering a therapeutically effective amount of sparsentan reduces the level of BAFF by at least about 70% from baseline within the first 24 weeks of treatment.

[0041] In one embodiment, the one or more urine biomarker comprises CHI3L1, wherein administering a therapeutically effective amount of sparsentan reduces the level of CHI3L1 by at least about 70% from baseline within the first 24 weeks of treatment.

[0042] In one embodiment, the one or more urine biomarker comprises clusterin, wherein administering a therapeutically effective amount of sparsentan reduces the level of clusterin by at least about 45% from baseline within the first 24 weeks of treatment.

[0043] In one embodiment, the one or more urine biomarker comprises CXCL10, wherein administering a therapeutically effective amount of sparsentan reduces the level of CXCL10 by at least about 50% from baseline within the first 24 weeks of treatment.

[0044] In one embodiment, the one or more urine biomarker comprises CXCL16, wherein administering a therapeutically effective amount of sparsentan reduces the level of CXCL16 by at least about 15% from baseline within the first 24 weeks of treatment.

[0045] In one embodiment, the one or more urine biomarker comprises GDF-15, wherein administering a therapeutically effective amount of sparsentan reduces the level of GDF-15 by at least about 45% from baseline within the first 24 weeks of treatment.6#11479294.1

[0046] In one embodiment, the one or more urine biomarker comprises IL-6, wherein administering a therapeutically effective amount of sparsentan reduces the level of IL-6 by at least about 15% from baseline within the first 24 weeks of treatment.

[0047] In one embodiment, the one or more urine biomarker comprises MCP-1, wherein administering a therapeutically effective amount of sparsentan reduces the level of MCP-1 by at least about 20% from baseline within the first 24 weeks of treatment.

[0048] In one embodiment, the one or more urine biomarker comprises plasminogen, wherein administering a therapeutically effective amount of sparsentan reduces the level of plasminogen by at least about 80% from baseline within the first 24 weeks of treatment.

[0049] In one embodiment, the one or more urine biomarker comprises soluble C5b-9, wherein administering a therapeutically effective amount of sparsentan reduces the level of soluble C5b-9 by at least about 55% from baseline within the first 24 weeks of treatment.

[0050] In one embodiment, the one or more urine biomarker comprises sCD163, wherein administering a therapeutically effective amount of sparsentan reduces the level of sCD163 by at least about 65% from baseline within the first 24 weeks of treatment.

[0051] In one embodiment is provided use of sparsentan to reduce inflammation in patients with IgAN.

[0052] In another embodiment, the use of sparsentan to reduce inflammation is provided, wherein inflammation production is measured by urinalysis.

[0053] In one embodiment is provided use of sparsentan to reduce fibrosis in patients with IgAN.

[0054] In another embodiment, the use of sparsentan to reduce fibrosis is provided, wherein inflammation production is measured by urinalysis.Methods of Administration

[0055] 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.EXAMPLE

[0056] Twelve adults with biopsy-proven IgAN within 6 months, proteinuria >0.5 g / day, eGFR >30 mL / min / 1.73 m2, and no prior ACEi or ARB treatment within the past 12 months were enrolled. SPAR treatment is for 110 weeks. One participant discontinued treatment before 24 weeks due to hypotension. Changes in urinary biomarkers measured by ELISA, normalized to urine creatinine concentration, were analysed in the remaining 11 patients at baseline, 6, 12 and 24 weeks.7#11479294.1

[0057] Table 1 shows tabulation of the changes in key urinary biomarkers at 12 weeks expressed as percent reduction from baseline. This shows rapid and sustained reductions in urinary biomarkers of inflammation and fibrosis were observed within 12 weeks of starting SPAR.TABLE 1Change from baseline at Week 12 n* % (SEM)Alpha-2 macroglobulin 11 -83 (8)B cell activating factor (BAFF) 9 -71 (7)Chitinase-3 -like protein- 1 (CHI3L1; YKL-40) 7 -71 (H) Clusterin 11 -47 (12)C-X-C motif chemokine ligand- 10 (CXCL10) 6 -51 (15)C-X-C motif chemokine ligand- 16 (CXCL16) 11 -18 (9)Growth differentiation factor- 15 (GDF-15) 11 -46 (7) Interleukin-6 (IL-6) 7 -16 (16) Monocyte chemoattractant protein-q (MCP-1) 11 -23 (9) Plasminogen 11 -85 (5)Soluble C5b-9 9 -57 (18)Soluble CD 163 (sCD163) 11 -66 (6)*Patients excluded from analysis if baseline biomarker concentration was lower than the second lowest calibration point on standard curve.

[0058] Protein-protein interaction network mapping (https: / / string-db.org / ) reveals a close relationship between all affected biomarkers, suggesting a coordinated effect of SPAR on modulation of intra-renal inflammatory and fibrotic pathways within multiple segments of the nephron. Reductions in B AFF and C5b9 are shown indicative of actions on B cell and complement activation. Figure 1 shows data over 24 weeks illustrating substantial, rapid, and sustained reductions in urinary sCD163, IL6, BAFF and C5b9.

[0059] The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and / or listed in the Application Data Sheet are incorporated herein by reference, in their entirety, including U.S. Provisional Patent Application No. 63 / 777,585, filed March 25, 2025, unless otherwise stated. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments.

[0060] These and other changes can be made to the embodiments in light of the abovedetailed description. In general, in the following claims, the terms used should not be construed 8#11479294.1to 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.9#11479294.1

Claims

CLAIMS1. A method of treating or reducing inflammation or fibrosis in a patient with IgAN, the method comprising administering a therapeutically effective amount of sparsentan.

2. The method of claim 1 of treating or reducing inflammation in a patient with IgAN, the method comprising administering a therapeutically effective amount of sparsentan.

3. The method of claim 2, wherein the method comprises:i) orally administering an initial dose of 200 mg of sparsentan to the subject once a day for a period of 14 days; andii) after the initial 14 day period, orally administering a subsequent dose of 400 mg of sparsentan to the subject once a day.

4. The method of any one of claims 1-3, wherein the subject has a baseline level of expression of one or more urine biomarker that is high compared to a healthy subject, and wherein administering a therapeutically effective amount of the dual endothelin angiotensin receptor antagonist reduces the level of expression of the one or more urine biomarker in the subject from the baseline level.

5. The method of claim 4, wherein the one or more urine biomarker comprises alpha-2 macroglobulin, B cell activating factor (BAFF), chitinase-3 -like protein- 1 (CHI3L1; YKL-40), clusterin, C-X-C motif chemokine ligand- 10 (CXCL10), C-X-C motif chemokine ligand- 16 (CXCL16), Growth differentiation factor- 15 (GDF-15), Interleukin-6 (IL-6), monocyte chemoattractant protein-q (MCP-1), plasminogen, soluble C5b-9, or soluble CD163 (sCD163).

6. The method of claim 4 or 5, wherein the one or more urine biomarker comprises alpha-2 macroglobulin, and wherein administering a therapeutically effective amount of sparsentan reduces the level of alpha-2 macroglobulin by at least about 80% from baseline within the first 24 weeks of treatment.

7. The method of any one of claims 4-6, wherein the one or more urine biomarker comprises BAFF, and wherein administering a therapeutically effective amount of sparsentan reduces the level of BAFF by at least about 70% from baseline within the first 24 weeks of treatment.10#11479294.

18. The method of any one of claims 4-7, wherein the one or more urine biomarker comprises CHI3L1, and wherein administering a therapeutically effective amount of sparsentan reduces the level of CHI3L1 by at least about 70% from baseline within the first 24 weeks of treatment.

9. The method of any one of claims 4-8, wherein the one or more urine biomarker comprises clusterin, and wherein administering a therapeutically effective amount of sparsentan reduces the level of clusterin by at least about 45% from baseline within the first 24 weeks of treatment.

10. The method of any one of claims 4-9, wherein the one or more urine biomarker comprises CXCL10, and wherein administering a therapeutically effective amount of sparsentan reduces the level of CXCL10 by at least about 50% from baseline within the first 24 weeks of treatment.

11. The method of any one of claims 4-10, wherein the one or more urine biomarker comprises CXCL16, and wherein administering a therapeutically effective amount of sparsentan reduces the level of CXCL16 by at least about 15% from baseline within the first 24 weeks of treatment.

12. The method of any one of claims 4-11, wherein the one or more urine biomarker comprises GDF-15, and wherein administering a therapeutically effective amount of sparsentan reduces the level of GDF-15 by at least about 45% from baseline within the first 24 weeks of treatment.

13. The method of any one of claims 4-12, wherein the one or more urine biomarker comprises IL-6, and wherein administering a therapeutically effective amount of sparsentan reduces the level of IL-6 by at least about 15% from baseline within the first 24 weeks of treatment.

14. The method of any one of claims 4-13, wherein the one or more urine biomarker comprises MCP-1, and wherein administering a therapeutically effective amount of sparsentan reduces the level of MCP-1 by at least about 20% from baseline within the first 24 weeks of treatment.11#11479294.

115. The method of any one of claims 4-14, wherein the one or more urine biomarker comprises plasminogen, and wherein administering a therapeutically effective amount of sparsentan reduces the level of plasminogen by at least about 80% from baseline within the first 24 weeks of treatment.

16. The method of any one of claims 4-15, wherein the one or more urine biomarker comprises soluble C5b-9, and wherein administering a therapeutically effective amount of sparsentan reduces the level of soluble C5b-9 by at least about 55% from baseline within the first 24 weeks of treatment.

17. The method of any one of claims 4-16, wherein the one or more urine biomarker comprises sCD163, and wherein administering a therapeutically effective amount of sparsentan reduces the level of sCD163 by at least about 65% from baseline within the first 24 weeks of treatment.

18. The method of claim 1 of treating or reducing fibrosis in a patient with IgAN, the method comprising administering a therapeutically effective amount of sparsentan.

19. The method of claim 18, wherein the method comprises:i) orally administering an initial dose of 200 mg of sparsentan to the subject once a day for a period of 14 days; andii) after the initial 14 day period, orally administering a subsequent dose of 400 mg of sparsentan to the subject once a day.

20. The method of claim 18 or 19, wherein the subject has a baseline level of expression of one or more urine biomarker that is high compared to a healthy subject, and wherein administering a therapeutically effective amount of the dual endothelin angiotensin receptor antagonist reduces the level of expression of the one or more urine biomarker in the subject from the baseline level.

21. The method of claim 20, wherein the one or more urine biomarker comprises alpha-2 macroglobulin, B cell activating factor (BAFF), chitinase-3 -like protein- 1 (CHI3L1; YKL-40), clusterin, C-X-C motif chemokine ligand- 10 (CXCL10), C-X-C motif chemokine ligand- 16 (CXCL16), Growth differentiation factor- 15 (GDF-15), Interleukin-6 (IL-6), monocyte chemoattractant protein-q (MCP-1), plasminogen, soluble C5b-9, or soluble CD163 (sCD163).12#11479294.

122. The method of claim 20 or 21, wherein the one or more urine biomarker comprises alpha-2 macroglobulin, and wherein administering a therapeutically effective amount of sparsentan reduces the level of alpha-2 macroglobulin by at least about 80% from baseline within the first 24 weeks of treatment.

23. The method of any one of claims 20-22, wherein the one or more urine biomarker comprises BAFF, and wherein administering a therapeutically effective amount of sparsentan reduces the level of BAFF by at least about 70% from baseline within the first 24 weeks of treatment.

24. The method of any one of claims 20-23, wherein the one or more urine biomarker comprises CHI3L1, and wherein administering a therapeutically effective amount of sparsentan reduces the level of CHI3L1 by at least about 70% from baseline within the first 24 weeks of treatment.

25. The method of any one of claims 20-24, wherein the one or more urine biomarker comprises clusterin, and wherein administering a therapeutically effective amount of sparsentan reduces the level of clusterin by at least about 45% from baseline within the first 24 weeks of treatment.

26. The method of any one of claims 20-25, wherein the one or more urine biomarker comprises CXCL10, and wherein administering a therapeutically effective amount of sparsentan reduces the level of CXCL10 by at least about 50% from baseline within the first 24 weeks of treatment.

27. The method of any one of claims 20-26, wherein the one or more urine biomarker comprises CXCL16, and wherein administering a therapeutically effective amount of sparsentan reduces the level of CXCL16 by at least about 15% from baseline within the first 24 weeks of treatment.

28. The method of any one of claims 20-27, wherein the one or more urine biomarker comprises GDF-15, and wherein administering a therapeutically effective amount of sparsentan reduces the level of GDF-15 by at least about 45% from baseline within the first 24 weeks of treatment.13#11479294.

129. The method of any one of claims 20-28, wherein the one or more urine biomarker comprises IL-6, and wherein administering a therapeutically effective amount of sparsentan reduces the level of IL-6 by at least about 15% from baseline within the first 24 weeks of treatment.

30. The method of any one of claims 20-29, wherein the one or more urine biomarker comprises MCP-1, and wherein administering a therapeutically effective amount of sparsentan reduces the level of MCP-1 by at least about 20% from baseline within the first 24 weeks of treatment.

31. The method of any one of claims 20-30, wherein the one or more urine biomarker comprises plasminogen, and wherein administering a therapeutically effective amount of sparsentan reduces the level of plasminogen by at least about 80% from baseline within the first 24 weeks of treatment.

32. The method of any one of claims 20-31, wherein the one or more urine biomarker comprises soluble C5b-9, and wherein administering a therapeutically effective amount of sparsentan reduces the level of soluble C5b-9 by at least about 55% from baseline within the first 24 weeks of treatment.

33. The method of any one of claims 20-32, wherein the one or more urine biomarker comprises sCD163, and wherein administering a therapeutically effective amount of sparsentan reduces the level of sCD163 by at least about 65% from baseline within the first 24 weeks of treatment.

34. Use of sparsentan to reduce inflammation in a patient with IgAN.

35. The use of claim 34, wherein inflammation production is measured by urinalysis.

36. Use of sparsentan to reduce fibrosis in a patient with IgAN.

37. The use of claim 36, wherein fibrosis production is measured by urinalysis.14#11479294.1

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