How to treat IGA nephropathy with atrasentan

Abstract

Provided herein is a method for treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof. Also provided herein is a method for reducing renal inflammation and / or fibrosis, reducing the occurrence of hematuria, stabilizing eGFR, reducing the number of disease flares associated with IgA nephropathy, delaying the onset of ESRD, reducing proteinuria, and reducing fatigue in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the subject has not previously been diagnosed with one or more of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, prostate cancer, or acute renal failure.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 949,115, filed December 17, 2019, U.S. Provisional Application No. 63 / 005,003, filed April 3, 2020, U.S. Provisional Application No. 63 / 072,699, filed August 31, 2020, U.S. Provisional Application No. 63 / 084,739, filed September 29, 2020, and U.S. Provisional Application No. 63 / 125,205, filed December 14, 2020, which are incorporated by reference in their entireties. [Background technology]

[0002] IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Aberrant glycosylation of IgA1 results in increased serum levels of galactose-deficient IgA1 (Gd-IgA1), which is recognized by glycan-specific IgA and IgG autoantibodies. Immune complex aggregates form in situ and / or are deposited in the glomerular mesangium. This promotes mesangial cell proliferation, increased synthesis of extracellular matrix proteins, cytokines, and chemokines, and infiltration of immune cells into the surrounding tissue. Thus, disease progression involves (1) production of Gd-IgA1, (2) its recognition by anti-glycan autoantibodies, (3) formation of immune complexes in the kidney, and (4) activation of mesangial cells. See, for example, Penfold et al., Int. J. Nephrol. and Renovascular Dis. 11, pp. 137-148 (2017). Unlike other progressive renal diseases such as diabetic nephropathy, IgAN occurs primarily in healthy subjects in their 20s and 30s. Patients present with a variety of symptoms, typically including micro- or macrohematuria and increased excretion of protein in the urine. Patients may also present with hypertension as a result of persistent renal damage. Current therapeutic approaches only provide supportive care, including administration of maximally tolerated doses of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, or administration of immunosuppressants, whose benefits are greatly outweighed by side effects. Ultimately, 30-40% of patients will develop end-stage renal disease (ESRD) within 20-30 years of the diagnosis of IgAN. In the meantime, patients experience many symptoms that significantly reduce their quality of life, in addition to declining renal function. IgAN patients often exhibit significantly increased expression of endothelin-1 (ET-1) and ET-RA in the kidney. Increased expression of endothelin positively correlates with proteinuria, one of the hallmark symptoms of IgAN. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Penfold et al.,Int.J.Nephrol.and Renovascular Dis.11,pp.137-148(2017) Summary of the Invention [Means for solving the problem]

[0004] Atrasentan is a selective endothelin A (ETA) receptor antagonist (ETA Ki approx. 34 pM, ETB Ki approx. 63 nM, ETA selectivity approx. 1800x). See, e.g., Wu-Wong et al., Clin. Sci. (Lond.), 103(48), pp. 107s-111s (2002). Selective ETA receptor antagonists block ETA function while minimizing effects on the ETB receptor, resulting in beneficial effects on the kidney such as vasodilation and reduced inflammation, while allowing clearance of ET-1. See, e.g., Jandellet-Dahm and Watson, Curr. Opin. Nephrol. Hypertens., 21(1), pp. 66-71 (2012); see also Nakamura, et al., Nephron, Vol. 72, pp. 454-460 (1996). ETA receptor antagonists increase sodium and water retention by the kidney, which is usually clinically manageable. See, e.g., Saleh, et al., J. Pharm. Exp. Ther., 338(1), pp. 263-270 (2011). Atrasentan has been shown to significantly reduce the risk of renal events, defined as a doubling of serum creatinine or end-stage renal disease, in patients with diabetic kidney disease (DKD). See, e.g., Heerspink, et al., The Lancet, 393, pp 1937-1947 (2019). DKD is referred to as secondary glomerular disease, where kidney disease develops secondary to an identified systemic cause, and in the case of DKD, it develops as a microvascular complication of long-standing diabetes. See, e.g., Dattani and McAdoo, Medicine, 47(10), pp. 644-648 (2019). The pathogenesis of DKD is multifactorial and complex. Chronically elevated blood glucose levels due to diabetes, which cause glucose toxicity in renal cells, especially renal endothelial cells, and systemic and renal hemodynamic factors associated with hypertension, which transmits shear stress to resident glomerular cells, are major drivers of DKD. See, for example, Thomas et al., Nat. Rev. Disease Primers. 1, pp. 15018-15026 (2015).Multiple dysregulated factors in the diabetic milieu, including metabolic components such as hyperglycemia, dyslipidemia, and oxidative stress, as well as hemodynamic factors such as vasoactive substances associated with hypertension, all stimulate renal ET-1 formation. In addition, DKD is commonly observed in older populations, as long-term diabetes is usually required before the development of DKD, and aging is also associated with increased ET-1 production in the kidney. See, for example, Kohan, Kidney Int., 86(5), pp. 896-904 (2014). Combined, all this provides a solid scientific rationale for the treatment of DKD with the ETA receptor blocker atrasentan. See, Dhaun, et al., Hypertension, Vol. 57, pp. 772-779 (2011).

[0005] In contrast to DKD, IgA nephropathy is considered a primary glomerular disease in which local or intrinsic renal lesions are present. The peak incidence of IgA nephropathy is seen in young individuals in the second or third decade of life, and unlike DKD, it is an autoimmune disease. IgA nephropathy results from the deposition of pathogenic IgA / immune complexes in the glomerular mesangium. See, for example, Lai, et al., Nature Reviews Disease Primers, 2, pp. 16001, 2016. Definitive diagnosis requires a renal biopsy with confirmation of mesangial IgA deposition by immunofluorescence microscopy. Recent advances in understanding the inciting events that cause IgA nephropathy have revealed that an abnormal mucosal immune response stimulates the production of galactose-deficient IgA1, which is recognized as an autoantigen by circulating anti-glycan autoantibodies. Immune recognition leads to the formation of nephritogenic immune complexes that are deposited in the kidney and activate mesangial cells. Activated mesangial cells proliferate and produce excessive amounts of extracellular matrix components, cytokines and chemokines. See, for example, Suzuki, et al., J. Am. Soc. Nephrol., Vol. 22, pp. 1795-1803 (2011). Up to 40% of patients with biopsy-proven IgA nephropathy progress to end-stage renal failure at some point during long-term follow-up. The role of ET-1 or ETA receptors in mesangial cell activation has not been reported previously, and atrasentan has not been tested previously in IgA nephropathy. As further described herein, atrasentan can be administered at an effective dose with acceptable toxicity and has suitable selectivity to treat the underlying IgAN and improve the quality of life of subjects while minimizing undesirable side effects. Some embodiments provide a method of inhibiting mesangial cell activation in a subject having IgA nephropathy, comprising administering to the subject a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof, wherein the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure.

[0006] Some embodiments provide a method of inhibiting PDGF (e.g., reducing the activity and / or expression of one or more of PIK3R1, PDGFRA, NFKBIA, PIK3CG, PLA2G4A, TIAM1, PDGFB, NFKB1, and MAP3K1) in mesangial cells in a subject with IgA nephropathy, comprising administering to the subject a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof, wherein the subject has not previously been diagnosed with one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure.

[0007] Some embodiments provide a method of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof to a subject in need thereof, wherein the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure.

[0008] Some embodiments provide a method of treating IgA nephropathy, comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof, wherein the subject does not have one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure.

[0009] Some embodiments provide a method of treating IgA nephropathy, comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof, wherein the subject is not afflicted with one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure.

[0010] Some embodiments provide a method of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof to a subject in need thereof, wherein the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, prostate cancer, or acute renal failure.

[0011] Some embodiments provide a method of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof to a subject in need thereof, wherein the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV-associated nephropathy, prostate cancer, or acute renal failure.

[0012] Some embodiments provide a method of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof to a subject in need thereof, wherein the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV-associated nephropathy, or acute renal failure.

[0013] Some embodiments provide a method of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof to a subject in need thereof, wherein the subject is not receiving treatment for one or more of diabetic nephropathy, HIV-associated nephropathy, or acute renal failure.

[0014] Some embodiments provide a method of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof to a subject in need thereof, wherein the subject has been determined to have a controlled serum glucose level, and wherein the subject has not been diagnosed with one or more of HIV-associated nephropathy or acute renal failure.

[0015] Some embodiments provide a method of reducing renal inflammation and / or fibrosis in a subject with IgA nephropathy, comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof.

[0016] Some embodiments provide a method of reducing the incidence of hematuria in a subject with IgA nephropathy, comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof.

[0017] Some embodiments provide a method of stabilizing eGFR in a subject with IgA nephropathy, comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof.

[0018] Some embodiments provide a method of reducing the number of IgA nephropathy associated disease flares in a subject with IgA nephropathy, comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof.

[0019] Some embodiments provide a method of delaying the onset of ESRD in a subject with IgA nephropathy, comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof.

[0020] Some embodiments provide a method of reducing proteinuria in a subject with IgA nephropathy, comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof.

[0021] Some embodiments provide a method of reducing fatigue in a subject with IgA nephropathy, comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof, wherein the subject has been determined to not be afflicted by one or more of diabetic nephropathy, HIV-associated nephropathy, prostate cancer, or acute renal failure.

[0022] Some embodiments provide a method of inhibiting mesangial cell activation, comprising contacting mesangial cells with an effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof.

[0023] Some embodiments provide a method of reducing activation of mesangial cells in contact with IgA immune complexes, comprising contacting mesangial cells with an effective amount of atrasentan, or a pharma- ceutical acceptable salt thereof.

[0024] Some embodiments provide a method of treating IgA nephropathy in a subject in need of such treatment, comprising: a) determining that the subject has an elevated serum Gd-IgA1 level; and b) administering to the subject a therapeutically effective amount of atrasentan or a pharma- ceutical acceptable salt thereof.

[0025] Some embodiments provide a method of treating IgA nephropathy in a subject in need thereof, comprising: a) determining that the subject has an elevated level of mesangial activation; and b) administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutical acceptable salt thereof.

[0026] Some embodiments provide a method of treating IgA nephropathy in a subject in need of such treatment, comprising: a) determining that the subject has elevated levels of IgA immune complexes in the kidney; and b) administering to the subject a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof. [Brief description of the drawings]

[0027] [Figure 1A] Treatment with atrasentan has been shown to reduce proliferation of primary human mesangial cells exposed to immune complexes from subjects with IgAN. [Figure 1B] The contents of galactose-deficient (Gd)-IgA and total IgA after purification of immune complexes from IgAN or healthy control serum are shown. [Figure 2A]FIG. 1 shows the reduction in endothelin-1 (ET-1) stimulated proliferation of primary human mesangial cells (after 48 hours) upon treatment with increasing concentrations of atrasentan, shown on a logarithmic scale, exhibiting an IC50 of approximately 5.1 nM. [Figure 2B] FIG. 1 shows the reduction in endothelin-1 (ET-1) stimulated proliferation of primary human mesangial cells (after 72 hours) upon treatment with increasing concentrations of atrasentan shown on a logarithmic scale, exhibiting an IC50 of approximately 50.8 nM. [Figure 3A] Figure 1 shows increased IL-6 production by primary human mesangial cells exposed to ET-1 for 48 hours (approximately 6-fold increase) and decreased IL-6 levels upon treatment with increasing concentrations of atrasentan, shown on a logarithmic scale, exhibiting an IC50 of approximately 1 nM. [Figure 3B] Figure 1 shows increased IL-6 production by primary human mesangial cells exposed to ET-1 for 72 hours (approximately 2.2-fold increase) and decreased IL-6 levels upon treatment with increasing concentrations of atrasentan, shown on a logarithmic scale, exhibiting an IC50 of approximately 1 nM. [Figure 4] Shown are UACR levels in g-ddY mice at baseline, before administration of atrasentan, and after treatment with atrasentan at 0 (control), 10, 20, or 30 mg / kg / day in drinking water for approximately 5 days (*P<0.05 compared to baseline levels, paired t-test). [Diagram 5] Changes in UACR levels (% of baseline) in g-ddY mice after administration of atrasentan at 0 (control), 10, 20, or 30 mg / kg / day in drinking water for approximately 5 days are shown. (*P<0.05 compared to control group (0 mg / kg / day), unpaired t-test). [Figure 6] Figure 1 shows the top 100 differentially expressed genes in kidney tissue following treatment of g-ddY mice with 0 (control), 10, 20, or 30 mg / kg / day atrasentan. The heatmap shows row-wise z-transformed counts per million (CPM) values ​​for each of the top 100 differentially expressed genes. [Figure 7A]1 shows differential gene expression in kidney tissue following treatment of g-ddY mice with 0 (control) and 10 mg / kg / day atrasentan. Black dots indicate genes that are not significantly differentially expressed. Grey dots above 0 log fold change indicate upregulated genes. Grey dots below 0 log fold change indicate downregulated genes. [Figure 7B] 1 shows differential gene expression in kidney tissue following treatment of g-ddY mice with 0 (control) and 20 mg / kg / day atrasentan. Black dots indicate genes that are not significantly differentially expressed. Grey dots above 0 log fold change indicate upregulated genes. Grey dots below 0 log fold change indicate downregulated genes. [Figure 7C] 1 shows differential gene expression in kidney tissue following treatment of g-ddY mice with 0 (control) and 30 mg / kg / day atrasentan. Black dots indicate genes that are not significantly differentially expressed. Grey dots above 0 log fold change indicate upregulated genes. Grey dots below 0 log fold change indicate downregulated genes. [Figure 8A] 1 shows differentially expressed genes in kidney tissue of a subset of genes associated with the ET1 gene signature following treatment of g-ddY mice with 0 (control) and 10 mg / kg / day atrasentan. [Figure 8B] 1 shows differentially expressed genes in kidney tissue of a subset of genes associated with the ET1 gene signature following treatment of g-ddY mice with 0 (control) and 20 mg / kg / day atrasentan. [Figure 8C] 1 shows differentially expressed genes in kidney tissue of a subset of genes associated with the ET1 gene signature following treatment of g-ddY mice with 0 (control) and 30 mg / kg / day atrasentan. [Figure 9A]Figure 1 shows significantly enriched (FDR<0.05) signature gene sets following treatment of g-ddY mice with 10 mg / kg / day atrasentan compared to 0 mg / kg / day (control) atrasentan treatment. A negative normalized enrichment score (NES) indicates under-expression and a positive NES indicates over-expression. [Figure 9B] Figure 1 shows significantly enriched (FDR<0.05) signature gene sets following treatment of g-ddY mice with 20 mg / kg / day atrasentan compared to 0 mg / kg / day (control) atrasentan treatment. A negative normalized enrichment score (NES) indicates under-expression and a positive NES indicates over-expression. [Figure 9C] Figure 1 shows significantly enriched (FDR<0.05) signature gene sets following treatment of g-ddY mice with 30 mg / kg / day atrasentan compared to 0 mg / kg / day (control) atrasentan treatment. A negative normalized enrichment score (NES) indicates under-expression and a positive NES indicates over-expression. [Figure 10] Showing significantly enriched (FDR<0.05) signature gene set pathway concordance following treatment of ET-1 stimulated HRMCs with 1 nM and 25 nM atrasentan, as well as treatment of ET-1 stimulated HRMCs compared to untreated HRMCs (control), and treatment of g-ddY mice with 10, 20, or 30 mg / kg / day atrasentan compared to 0 (control). [Figure 11A]Gene signature overlap is shown between the published human mesangial single cell signature (Lake et al., A single-nucleus RNA-sequencing pipeline to decipher the molecular anatomy and pathophysiology of human kidneys. Nat. Comm., 10(1), 1-15(2018); labeled as Mesangial), differentially expressed genes following treatment of g-ddY mice with 30 mg / kg / day atrasentan (labeled as g-ddY), and differentially expressed genes following treatment of HRMC with 25 nM atrasentan in the presence of ET1 (labeled as HRMC). [Figure 11B] Figure 1 shows expression levels (log2 counts per million of row-type z-transformed values) of 44 genes that overlap between the human mesangial single-cell signature and differentially expressed genes after treatment of g-ddY mice with 30 mg / kg / day atrasentan. [Figure 12A] A comparison between human and mouse based potential biomarkers is shown, with an "x" indicating translatability and indicating whether the potential biomarker is in plasma / serum and / or urine. Notably, each of the relevant markers is found in both humans and mice (e.g., g-ddY mice). [Figure 12B] Shown are the log2 (CPM) of each potential biomarker following treatment of g-ddY mice with 0 (control), 10, 20, or 30 mg / kg / day atrasentan. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] Table 1. Top 40 DEGs (25 upregulated and 15 downregulated) upon treatment of g-ddY mice with 10 mg / kg / day atrasentan compared with 0 mg / kg / day (control).

[0029] Table 2. Top 50 DEGs (25 upregulated and 25 downregulated) upon treatment of g-ddY mice with 20 mg / kg / day atrasentan compared with 0 mg / kg / day (control).

[0030] Table 3. Top 50 DEGs (25 upregulated and 25 downregulated) upon treatment of g-ddY mice with 30 mg / kg / day atrasentan compared with 0 mg / kg / day (control).

[0031] Table 4. Enriched signaling pathways following treatment of g-ddY mice with 10, 20, or 30 mg / kg / day atrasentan compared to 0 mg / kg / day (control). Z-score values ​​indicate the magnitude of effect seen at each dosage.

[0032] Table 5. Gene set enrichment analysis showing enrichment of signature gene sets following treatment of g-ddY mice with 10, 20, or 30 mg / kg / day atrasentan compared to 0 mg / kg / day (control). NES is a normalized enrichment score that indicates the representation of DEGs within a gene set and takes into account the size of the gene set. NES of <-1.5 or >1.5 are considered biologically significant. Adj p-value is the estimated probability that the calculated NES of a given enriched gene set is a false positive result.

[0033] Table 6. List of upstream regulators categorized by cytokine and growth factor molecule type. P-values ​​of overlap indicate the significance of enrichment based on the number of overlapping genes between the dataset and IPKB gene targets. p-values ​​for activation z-score thresholds of <-2 or >2 and overlap threshold of <0.05 were considered significant.

[0034] Table 7. List of upstream regulators categorized by molecule type: transmembrane receptors, G protein-coupled receptors, and protein complexes. The overlap P-value indicates the significance of enrichment based on the number of overlapping genes between the dataset and IPKB gene targets. An activation z-score threshold of <-2 or >2 and an overlap threshold of <0.05 p-value were considered significant.

[0035] Table 8. List of upstream regulators categorized by transcriptional regulator and ligand-dependent nuclear receptor molecule type. P-values ​​for overlap indicate the significance of enrichment based on the number of genes overlapping between the dataset and IPKB gene targets. p-values ​​for activation z-score thresholds of <-2 or >2 and overlap threshold of <0.05 were considered significant.

[0036] Table 9. Gene expression of components of the NF-kB signaling pathway following treatment of g-ddY mice with 10, 20, or 30 mg / kg / day atrasentan compared to 0 mg / kg / day (control).

[0037] Table 10. Gene expression of components of the IL6 signaling pathway following treatment of g-ddY mice with 10, 20, or 30 mg / kg / day atrasentan compared to 0 mg / kg / day (control).

[0038] Table 11 Gene expression of components of the PDGF signaling pathway following treatment of g-ddY mice with 10, 20, or 30 mg / kg / day atrasentan compared to 0 mg / kg / day (control).

[0039] Table 12. Gene expression of components of cell proliferation signaling pathways (mitotic spindle and G2M cell cycle checkpoint) following treatment of g-ddY mice with 10, 20, or 30 mg / kg / day atrasentan compared to 0 mg / kg / day (control).

[0040] Table 13. Gene expression of components of the inflammatory response signaling pathway following treatment of g-ddY mice with 10, 20, or 30 mg / kg / day atrasentan compared to 0 mg / kg / day (control).

[0041] Table 14. Gene expression of 44 genes associated with mesangial cell signature following treatment of g-ddY mice with 10, 20, or 30 mg / kg / day atrasentan compared to 0 mg / kg / day (control). [Mode for carrying out the invention]

[0042] A.Definition In order that this disclosure may be more readily understood, certain terms are first defined. As used in this application, unless otherwise expressly defined herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout the application.

[0043] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press, The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press, and Oxford Dictionary Of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press provide those skilled in the art with a general dictionary of many terms used in this disclosure.For the purposes of this disclosure, the following terms are defined.

[0044] Units, prefixes, and symbols are indicated in the format accepted by the Systeme International de Unites (SI). Numerical ranges include the numerical values ​​defining the range. The headings provided herein do not limit the various aspects of the disclosure that can be had by reference to the entire specification. Thus, the terms defined immediately below are more fully defined by reference to the entire specification.

[0045] As used herein, the terms "a," "an," or "the" include not only embodiments having one member, but also embodiments having two or more members. As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "cell" includes a plurality of such cells, reference to an "agent" includes reference to one or more agents known to those of skill in the art, and so forth.

[0046] As used herein, the term "or" should generally be interpreted non-exclusively. For example, a claim to "a composition comprising A or B" would typically present an embodiment having a composition that includes both A and B. However, "or" should be interpreted to exclude presented embodiments that cannot be combined without contradiction (e.g., a composition pH of 9-10 or 7-8).

[0047] The group "A or B" is typically equivalent to the group "selected from the group consisting of A and B."

[0048] As used herein, the term "and / or" should be interpreted as a specific disclosure of each of two specific features or components, with or without the other. Thus, when used in phrases such as "A and / or B" herein, the term "and / or" is intended to include "A and B," "A or B," "A" (only), and "B" (only). Similarly, when used in phrases such as "A, B, and / or C," the term "and / or" is intended to include each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (only); B (only); and C (only).

[0049] As used herein, the terms "about" and "approximately" generally refer to an acceptable degree of error for a measured quantity, given the nature or precision of the measurement. Typical exemplary degrees of error are within 20 percent (%), within 10%, within 5% of a given value or range of values. Reference to "about X" specifically denotes at least the values ​​X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, "about X" is intended to provide a written explanatory complement to a claim limitation of, for example, "0.98X". The terms "about" and "approximately" encompass and describe the given quantity itself, particularly with respect to the given quantity.

[0050] When "about" is applied to the beginning of a numerical range, it applies to both ends of the range. Thus, "about 5 to 20%" is equivalent to "about 5% to about 20%." When "about" is applied to the first value in a set of values, it applies to every value in that set. Thus, "about 0.5, 0.75, or 1.0 mg" is equivalent to "about 0.5, about 0.75, or about 1.0 mg."

[0051] As used herein, the term "about," when preceding a series of peak positions (e.g., 2θ values) in X-ray powder diffraction, means that all peaks in the preceding series are reported with respect to angular positions with a variation of ±0.1°. Thus, for example, the phrase about 8.3°, 9.7°, 10.0°, 13.0°, 15.6°, 17.2°, or 19.5° means 8.3°±0.1°, 9.7°±0.1°, 10.0°±0.1°, 13.0°±0.1°, 15.6°±0.1°, 17.2°±0.1°, or 19.5°+0.1°.

[0052] "Treatment" or "therapy" of a subject refers to any type of intervention or process performed on a subject, or the administration of an active agent to a subject, for the purpose of reversing, ameliorating, ameliorating, inhibiting, or slowing the onset, progression, development, severity, or recurrence of a symptom, complication, condition, or biochemical manifestation associated with a disease.

[0053] "Administering" or "administration" refers to the physical introduction of a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. Routes of administration can include oral, intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration, such as injection or infusion (e.g., intravenous infusion). Administration can also be performed, for example, once, multiple times, and / or over one or more extended periods of time.

[0054] The terms "prophylactic" or "prophylactically" refer to any type of intervention or process performed on a subject, or administration of an active agent to a subject, for the purpose of preventing or preventing a disease or condition from developing, or at least not developing altogether (e.g., to reduce the symptoms or severity of the disease or condition), such as in the development of side effects.

[0055] A "subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In some embodiments, the subject is a human. The terms "subject" and "patient" and "individual" are used interchangeably herein.

[0056] An "effective amount" or "therapeutically effective amount" or "therapeutically effective dosage" of a drug or therapeutic agent is that amount of any drug that, when used alone or in combination with another therapeutic agent, delays the onset of a disease or promotes regression of a disease as evidenced by a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease-free periods, or an improvement in the functional or disabling effects of the disease. The ability of a therapeutic agent to promote regression of a disease can be evaluated using a variety of methods known to the skilled practitioner, for example, by evaluating the activity of the agent in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or in in vitro assays.

[0057] The phrase "pharmacologically acceptable" indicates that a substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation, and / or the mammal being treated therewith.

[0058] As used herein, "polymorph" refers to distinct solids that share the same molecular formula, but each polymorph may have distinct solid-state physical properties. A single compound may give rise to various polymorphic forms, each with different distinct solid-state physical properties, such as different solubility profiles, melting point temperatures, flow properties, dissolution rates, and / or different X-ray diffraction peaks. These actual physical characteristics are influenced by the conformation and orientation of the molecules within the unit cell that defines the particular polymorphic form of the substance. Polymorphic forms of a compound can be distinguished in the laboratory by X-ray diffraction spectroscopy, such as X-ray powder diffraction ("XRPD"), and other methods, such as infrared spectroscopy. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient may be administered by themselves or formulated as a pharmaceutical product (pharmaceutical composition), and are well known in the pharmaceutical arts to affect, for example, the solubility, stability, flow properties, ease of handling, and compressibility of the drug substance, as well as the safety and efficacy of the drug product. For further details see Hilfiker, Rolf (ed.), Polymorphism in the Pharmaceutical Industry. Weinheim, Germany: Wiley-VCH 2006.

[0059] As used herein, the term "amorphous" refers to a solid in a solid state that is in a non-crystalline state. Amorphous solids generally have short-range molecular ordering like crystals, but do not have the long-range ordered molecular packing seen in crystalline solids. The solid-state morphology of a solid can be determined by polarized light microscopy, X-ray powder diffraction ("XRPD"), differential scanning calorimetry ("DSC"), or other standard techniques known to those skilled in the art.

[0060] As used herein, the term "crystalline" refers to a solid in a solid state having a regularly repeating arrangement of molecules or external surfaces. The solid state form of a solid can be determined by polarized light microscopy, X-ray powder diffraction ("XRPD"), differential scanning calorimetry ("DSC"), or other standard techniques known to those skilled in the art. Thus, as used herein, the term "crystalline purity" refers to the percentage of a particular crystalline polymorph of atrasentan or a pharma- ceutically acceptable salt thereof, one or more additional crystalline polymorphs of atrasentan or a pharma- ceutically acceptable salt thereof, or a mixture thereof, in a sample that may contain amorphous atrasentan or a pharma- ceutically acceptable salt thereof. When a crystalline polymorph of atrasentan or a pharma- ceutically acceptable salt thereof is described as having "substantial crystalline purity," it means that the polymorph is substantially free (e.g., less than 10%, less than 5%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.05%) of other polymorphs (amorphous and / or crystalline).

[0061] The term "chemical purity" as used herein refers to the percentage of a particular compound (e.g., atrasentan or a pharma- ceutically acceptable salt thereof) in a sample. Thus, atrasentan or a pharma- ceutically acceptable salt thereof, and compositions comprising or made therefrom, may be used in any of the following solutions: water, ethyl acetate, ethanol, (2R,3R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid, (2R,3R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-((N-(n-butyl)-N-ethyl ... The atrasentan or pharmaceutically acceptable salt thereof may contain one or more impurities, including, but not limited to, (2R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid, (2R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylate, or ethyl (2R,3R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylate. When a sample of atrasentan or a pharmaceutically acceptable salt thereof is described as having "substantial purity," the sample is substantially free of impurities (e.g., contains less than 10%, less than 5%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.05%).

[0062] As used herein, the term "diastereomeric excess" refers to the amount of one diastereomer of a compound (e.g., atrasentan or a pharma- ceutically acceptable salt thereof) in a mixture that may have other diastereomers of the same compound in the mixture. As used herein, the term "substantial diastereomeric purity" refers to a diastereomeric excess of greater than about 90%, 95%, 99%, 99.5%, 99.9%, or 100%.

[0063] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance that aids in the administration of an active agent to a cell, organism, or subject. "Pharmaceutically acceptable carrier" refers to a carrier or excipient that can be included in the compositions of the present disclosure and does not cause significant adverse toxicological effects in a subject. Non-limiting examples of pharmaceutically acceptable carriers include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colorants, liposomes, dispersion media, microcapsules, cationic lipid carriers, isotonicity agents, and absorption delaying agents, and the like. Carriers can also be substances that provide stability, sterility, and isotonicity to the formulation (e.g., antimicrobial preservatives, antioxidants, chelating agents, and buffers), prevent the action of microorganisms (e.g., antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc.), or provide edible flavors, and the like, to the formulation. In some embodiments, the carrier is an agent that facilitates delivery of a small molecule drug or antibody to a target cell or tissue. Those of skill in the art will recognize that other pharmaceutical carriers are useful in the present disclosure.

[0064] As used herein, the term "expression" refers to the level of protein or mRNA in mammalian cells.

[0065] The term "activity" as used herein refers to one or more activities of a protein, such as binding or enzymatic activity (e.g., one or more of phosphorylation, dephosphorylation, transport into the nucleus, transcriptional activation, transcriptional repression, and / or binding activity to a substrate or binding partner).

[0066] As used herein, the term "IL-6 signaling" refers to the expression and / or activity of one or more proteins in a signaling pathway that begins with activation of the IL-6 receptor and ends with gene expression. Non-limiting examples of proteins in a signaling pathway that begins with activation of the IL-6 receptor and ends with gene expression include IL-6 receptor, JAK, STAT3, PI3K, Akt / PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, and ERK.

[0067] As used herein, the term "NF-kB signaling" refers to the expression and / or activity of one or more of IKKα, IKKβ, IkB, and NF-kB, and / or one or more genes that are upregulated by the activity of NF-kB (e.g., one or more of TNF-α, IL-1, CAM, COX-2, and iNOS).

[0068] As used herein, the term "PDGF signaling" refers to the signaling pathways involved in the regulation of PDGF receptor, PKC, PI3K, Src, Ras, ERK1 / 2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, and cPLA. 2 By "expression" is meant the expression and / or activity of one or more of the following:

[0069] The term "SGLT-2 inhibitor" as used herein refers to a compound that inhibits sodium glucose cotransporter-2 (SGLT-2). SGLT-2 inhibitors interfere with the reabsorption of glucose by the kidney, thus exerting a glucose-lowering effect. SGLT-2 inhibitors have been shown to treat type 2 diabetes and improve cardiovascular outcomes by enhancing glycosuria independent of insulin. See Wright, 2001, Am. J. Physiol. Renal Physiol. 280:F10 and Scheen, 2018, Circ. Res. 122:1439. In some embodiments, the term "SGLT-2 inhibitor" refers to a compound whose primary effect is the inhibition of SGLT-2, but is not limited to compounds that inhibit only SGLT-2, and thus includes compounds that have other activities in addition to SGLT-2 inhibition (e.g., SGLT-1 inhibition).

[0070] In some embodiments, the SGLT-2 inhibitor comprises a compound of the class of drugs known as gliflozin. In some embodiments, the SGLT-2 inhibitor comprises a compound approved as an SGLT-2 inhibitor by a regulatory agency such as the FDA or EMA. Non-limiting examples of SGLT-2 inhibitors include, but are not limited to, bexagliflozin, canagliflozin (INVOKANA®), dapagliflozin (FARXIGA®), empagliflozin (JARDIANCE®), ertugliflozin (STEGLATRO™), ipragliflozin (SUGLAT®), luseogliflozin (LUSEFI®), remogliflozin, sergliflozin, licogliflozin, sotagliflozin (ZYNQUISTA™), and tofogliflozin.

[0071] In some embodiments, the SGLT-2 inhibitors include dapagliflozin, canagliflozin, ipragliflozin, empaglifosin, bexagliflozin, licogliflozin, janagliflozin (XZP-5695), tofogliflozin, ertugliflozin, henagliflozin (SHR-3824), enavogliflozin (DWP-16001), TA-1887 (3-(4-cyclopropylbenzyl)-4-fluoro-1-(β-D-glucopyranosyl)-1H-indole), indole-N-glycoside 18 (3 -(4-ethylbenzyl)-1-(β-D-glucopyranosyl)-1H-indole), sotagliflozin, luseogliflozin, sergliflozin etabonate (ethyl carbonate), remogliflozin, remogliflozin etabonate, and T-1095 (((2R,3S,4S,5R,6S)-6-(2-(3-(benzofuran-5-yl)propanoyl)-3-hydroxy-5-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)etabonate).

[0072] In some embodiments, the SGLT-2 inhibitor comprises a C-glycoside, such as dapagliflozin, canagliflozin, ipragliflozin, empaglifosin, bexagliflozin, licogliflozin, janagliflozin (XZP-5695), tofogliflozin, ertugliflozin, henagliflozin (SHR-3824), enavogliflozin (DWP-16001), etc. In some embodiments, the SGLT-2 inhibitor comprises a C-glycoside with a bicyclic or spiropyran group, such as tofogliflozin, ertugliflozin, and henagliflozin (SHR-3824). In some embodiments, the SGLT-2 inhibitor comprises a C-glycoside that does not have a bicyclic or spiropyran group, such as dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, bexagliflozin, licogliflozin, janagliflozin (XZP-5695), and enavogliflozin (DWP-16001).

[0073] In some embodiments, the SGLT-2 inhibitor comprises an N-glycoside such as TA-1887 (3-(4-cyclopropylbenzyl)-4-fluoro-1-(β-D-glucopyranosyl)-1H-indole) and indole-N-glycoside 18 (3-(4-ethylbenzyl)-1-(β-D-glucopyranosyl)-1H-indole).

[0074] In some embodiments, the SGLT-2 inhibitor comprises a 2-methylthio-C-glycoside, such as sotagliflozin.

[0075] In some embodiments, the SGLT-2 inhibitor comprises a thiopyran-C-glycoside, such as luseogliflozin.

[0076] In some embodiments, SGLT-2 inhibitors include O-glycosides and O-glycoside prodrugs such as sergliflozin etabonate (ethyl carbonate), remogliflozin, remogliflozin etabonate, and T-1095 (((2R,3S,4S,5R,6S)-6-(2-(3-(benzofuran-5-yl)propanoyl)-3-hydroxy-5-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)etabonate).

[0077] In some embodiments, SGLT-2 inhibitors as defined herein include any compound that exhibits SGLT-2 inhibitory activity. In some embodiments, SGLT-2 inhibitors are selective for SGLT-2 over SGLT-1, for example by having greater activity against SGLT-2 than against SGLT-1 by about 2-fold, about 5-fold, about 10-fold, about 20-fold, about 50-fold, about 100-fold, about 200-fold, about 300-fold, about 400-fold, about 500-fold, about 750-fold, about 1,000-fold, about 1,250-fold, about 1,500-fold, about 1,750-fold, about 2,000-fold, about 2,500-fold, or any value therebetween. Exemplary SGLT-2 inhibitors have an inhibitory activity (IC) against SGLT-2 of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM, as measured in the assays described herein. 50 In some embodiments, the SGLT-2 inhibitor can exhibit an inhibitory activity (IC) against SGLT-2 of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM, as measured in the assays provided herein. 50 ) can be shown. An exemplary assay for determining SGLT-2 inhibitory activity is described in Ryan, et al., Kidney International, Vol. 45, pp. 48-57 (1994). Briefly, CHO cells are stably transfected with cDNA encoding human SGLT-2 (GenBank M95549). The cells are washed and then incubated with 10 μM [ 14 C] α-methylglucopyranoside (AMG) and 10 μM inhibitor. 14 The uptake of [C]AMG is quenched with cold buffer containing phlorizin and the cells are lysed. 14 Quantify [C]AMG uptake.

[0078] SGLT-2 inhibitors include pharma- ceutically acceptable salts, solvates, complexes, and salts of those solvates, e.g., "dapagliflozin" includes salts (such as the hydrochloride salt) and solvates (such as propylene glycol hydrate) of dapagliflozin, and similarly, "canagliflozin" includes solvates (such as canagliflozin hemihydrate) and salts of solvates (such as the hydrochloride salt of the hydrate). Similarly, henagliflozin (SHR-3824) and dapagliflozin include complexes (such as the complexes henagliflozin proline and dapagliflozin proline, respectively).

[0079] As used herein, when a subject is described as having a "controlled serum glucose level", it means that the subject has a serum glucose level within a normal or healthy range. In some embodiments, the subject has a fasting serum glucose level of about 70 mg / dL to about 130 mg / dL. For example, the subject has been determined to have a fasting serum glucose level of less than about 130 mg / dL, 125 mg / dL, 120 mg / dL, 115 mg / dL, 110 mg / dL, 105 mg / dL, 100 mg / dL, 95 mg / dL, 90 mg / dL, 85 mg / dL, 80 mg / dL, or 75 mg / dL.

[0080] As used in the methods herein, the term "reduce" refers to a reduction in a parameter as compared to a baseline measurement (or measurements) of the same parameter in a subject made before the start of administration of atrasentan or a pharmaceutically acceptable salt thereof, or a reduction in a parameter as compared to a baseline measurement (or measurements) of the same parameter in a healthy subject (e.g., a subject without IgA nephropathy). Similarly, the term "increase" as used herein refers to an increase in a parameter as compared to a baseline measurement (or measurements) of the same parameter in a subject made before the start of administration of atrasentan or a pharmaceutically acceptable salt thereof, or an increase in a parameter as compared to a baseline measurement (or measurements) of the same parameter in a healthy subject (e.g., a subject without IgA nephropathy).

[0081] The term "glomerular filtration rate (GFR)" is defined as the volume of fluid filtered from the renal (kidney) glomerular capillaries into Bowman's capsule per unit time. It indicates overall kidney function. Glomerular filtration rate (GFR) can be calculated by measuring any chemical that has a certain level in the blood and is freely filtered by the kidney and is neither reabsorbed nor secreted. The ratio measured is therefore the amount of substance in the urine that comes from the calculated amount of blood. GFR is generally recorded in units of volume per hour, e.g. milliliters / minute, and the following formula can be used: GFR = (urine concentration x urine volume) / plasma concentration. GFR can be measured by injecting inulin into the plasma. Since inulin is neither reabsorbed nor secreted by the kidney after glomerular filtration, its excretion rate is directly proportional to the filtration rate of water and solutes passing through the glomerular filter. Normal values ​​are GFR = 90-125 mL / min / 1.73 m 2 , especially GFR = 100-125 mL / min / 1.73 m 2Other principles for measuring GFR include measuring 51Cr-EDTA, [125I] iothalamate or iohexol. "Estimated glomerular filtration rate (eGFR)" is defined as derived by screening from serum creatinine value based on Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, Cockcroft-Gault formula, or Modification of Diet in Renal Disease (MDRD) formula, all of which are known in the art. As used herein, "stabilizing eGFR" means reducing the rate of decline of eGFR and / or attenuating the rate of decline of eGFR. In some embodiments, the rate of decline in a subject's eGFR may be attenuated by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%, or any value therebetween, following treatment with atrasentan or a pharma- ceutically acceptable salt thereof. This attenuation can be, for example, after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks of treatment, or any value therebetween. In some embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days. In some embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 6 months to about 1 year.

[0082] "ESRD" is an abbreviation for end stage renal disease. As used herein, the onset of ESRD is defined as when a subject has a renal failure rate of approximately 15 mL / min / 1.73 m 2A subject is defined as the time when the subject has an eGFR of less than 60 and / or when the subject begins chronic dialysis. If a subject is defined as being at "high risk of progressing to ESRD," the subject has more than 1 g / day protein in the urine and / or an eGFR of less than 60 for at least about 3 months prior to the first administration of atrasentan or a pharmacologic salt thereof.

[0083] As used herein, "IgA nephropathy-associated disease flare" refers to a disease flare associated with worsening hematuria, proteinuria, constitutional symptoms, and a decline in eGFR. Other symptoms associated with disease flares include increased edema, fatigue, increased hematuria, gross hematuria, and other symptoms that generally adversely affect disease progression.

[0084] As used herein, when a subject is described as "maintaining potassium levels within the normal physiological range," the subject has a blood potassium level of about 3.5 mEq / L to about 5.2 mEq / L.

[0085] As used herein, when a subject is described as "maintaining sodium levels within the normal physiological range," the subject has a blood sodium level of about 135 to about 145 mEq / L.

[0086] As used herein, the term "proteinuria" refers to the presence of protein in urine above normal levels. "Proteinuria" includes "albuminuria" and "microalbuminuria". Normal human protein levels are found in urine in the range of about 0-30 mg / L, but in any given urine sample, levels can reach about 80 mg / L. For a 24-hour urine collection, normal human urinary protein levels range from about 0-150 mg. Proteinuria can be indicated by a urinary total protein / creatinine ratio (UPCR) or by a ratio of a specific protein, such as a urinary albumin / creatinine ratio (ACR) of greater than about 30 mg / g. Typically, a urinary UACR value in mg / g is approximately equal to the amount of albumin excreted by a subject in mg / day. Proteinuria, including albuminuria and microalbuminuria, often causes or is indicative of disease, but is not limited to the occurrence of disease. Proteinuria is intended to encompass all forms of proteinuria, including but not limited to physiological proteinuria, functional proteinuria, and exercise proteinuria, which is related to a form of functional proteinuria after excessive muscle exertion.In addition, proteinuria encompasses benign proteinuria (also known as "essential" proteinuria), which refers to the type or proteinuria that is not the result of pathological changes in the kidney.Proteinuria also encompasses pathological proteinuria, for example, the level of protein in urine that is higher than normal physiological levels.

[0087] As used herein, the term "albuminuria" (also known as "macroalbuminuria") refers to the presence of albumin in urine above normal levels. Normal human urinary UACR levels range from about 0 to 30 mg / mmol, since urinary protein is primarily albumin. As used herein, the term "microalbuminuria" refers to the presence of albumin in urine, which is excreted in humans at a rate of about 20 to 200 μg / min or at a level of about 30 to 300 mg / L. When defined by urinary ACR, "microalbuminuria" refers to a urinary UACR of more than about 30 mg / g, or a urinary UACR of about 3.5 mg / mmol or more for women and about 2.5 mg / mmol or more for men. Microalbuminuria is often an early warning of kidney disease, but may manifest for other reasons.

[0088] As used herein, the term "hematuria" refers to the presence of blood in urine. It may appear as gross hematuria (visible traces of blood cells) or microscopic hematuria (microscopic traces of blood) in the urine. A confirmed sign of microscopic hematuria is defined as three or more red blood cells present per microscopic high power field (HPF) in at least three properly collected urine samples. Microscopic hematuria may also be detected by dipstick testing (colorimetric comparison estimate) in the clinic. Hematuria (either microscopic or gross) may be asymptomatic (no additional symptoms associated with hematuria) or symptomatic. Additional symptoms include dysuria (painful urination), sensation of incomplete bladder emptying, increased frequency or urination, or flank pain.

[0089] As used herein, "ALT" refers to alanine transaminase. As used herein, "AST" refers to aspartate transaminase.

[0090] The term "synergy" or "synergistic" is used herein to mean that the effect of the combination of two therapeutic agents is greater than the sum of the effects of each agent when administered alone. See, e.g., Chou and Talalay, Advances in Enzyme Regulation (1984), 22, 27-55. A "synergistically effective amount" is an amount of a combination of two or more therapeutic agents that results in a synergistic effect (as "synergistic" is defined herein). In some embodiments, a synergistically effective amount of a combination can be therapeutically effective even when one or more compounds in the combination are administered at a dose that would be sub-therapeutic when the compound is administered alone.

[0091] It will be understood that different concentrations of each compound can be used for various art-recognized factors, such as the height, weight, sex, age, and medical history of the patient.Exemplary synergistic effects include, but are not limited to, enhanced therapeutic effect, reduced dosage at equivalent or increased levels of efficacy, reduced or delayed development of drug resistance, and simultaneous enhanced or equivalent therapeutic action (e.g., the same therapeutic effect of at least one of the therapeutic agents) and reduced undesirable drug effect (e.g., side effects and adverse events) of at least one of the therapeutic agents.

[0092] In some embodiments, "synergistic effect" as used herein refers to a combination of atrasentan or a pharma- ceutically acceptable salt thereof and one or more additional therapeutic agents (e.g., an SGLT-2 inhibitor) that results in any of the beneficial or desired results, including the clinical results described herein, that are greater than the sum of the effects observed when atrasentan or a pharma- ceutically acceptable salt thereof and an SGLT-2 inhibitor are administered alone. Such clinical results include, but are not limited to, treating IgA nephropathy, reducing renal inflammation and / or fibrosis, reducing hematuria, reducing proteinuria (e.g., albuminuria), stabilizing eGFR, reducing the number of disease flares associated with IgA nephropathy, delaying the onset of ESRD, reducing fatigue, and reducing mesangial cell activation.

[0093] In some embodiments, "synergistic effect" as used herein refers to a combination of atrasentan, or a pharma- ceutically acceptable salt thereof, and an SGLT-2 inhibitor that results in a greater reduction in proteinuria, such as albuminuria, than the sum of the effects observed when atrasentan, or a pharma-ceutically acceptable salt thereof, and an SGLT-2 inhibitor are administered alone.

[0094] In some embodiments, "synergy" as used herein refers to a combination of atrasentan or a pharma- ceutically acceptable salt thereof and an SGLT-2 inhibitor that results in a desirable therapeutic effect and a reduction in the occurrence and / or severity of undesirable drug effects, side effects, or adverse events. In some embodiments, the undesirable drug effects, side effects, or adverse events are associated with or observed in monotherapy of atrasentan or a pharma- ceutically acceptable salt thereof and an SGLT-2 inhibitor. In some embodiments, the undesirable drug effects, side effects, or adverse events are one or more of fluid retention, anemia, nausea, constipation, thirst, bone fractures, increased urination, urinary tract infections, yeast infections, vaginal itching, increased LDL cholesterol levels, increased brain natriuretic peptide (BNP) levels, acute sodium retention, and a sudden increase in creatinine levels. In some embodiments, the fluid retention is associated with a weight gain of more than about 3 kg. In some embodiments, the increased BNP level is greater than about 300 pg / mL.

[0095] As described herein, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the recited range, and fractions thereof, where appropriate (such as tenths and hundredths of integers), unless otherwise indicated.

[0096] Unless otherwise specified, any reference to an amount of atrasentan in this disclosure is based on the free equivalent amount of atrasentan. For example, 0.75 mg of atrasentan refers to 0.75 mg of atrasentan in the free form or an equivalent amount of a salt form of atrasentan.

[0097] Various aspects of the disclosure are described in further detail in the following subsections.

[0098] B. Introduction Most subjects with IgAN first present with isolated or transient gross hematuria or after detection of microscopic hematuria and / or proteinuria during routine urinalysis. In some cases, subjects present with acute kidney injury such as crescentic IgAN or the result of gross hematuria causing tubular obstruction. Definitive diagnosis of IgAN is typically established by renal biopsy with immunofluorescence and / or immunoperoxidase studies of IgA deposits. Prominent globular deposits of less prominent IgA (sometimes with C3 and IgG) within the mesangium and along the glomerular capillary walls are characteristic of IgAN. Specific histopathological features that correlate with long-term outcome include mesangial proliferation, endocapillary proliferation, segmental scarring, and tubular atrophy.

[0099] C. Treatment Methods In normal healthy human kidneys, ET-1 and ET-RA expression is stronger in vascular tissues and less strong in glomerular structures. In contrast, subjects with IgAN show increased expression of ET-1 and ET-RA in the kidney. In that population, ET-1 expression is positively correlated with proteinuria and is at least partially ameliorated by administration of ACE inhibitors. Indeed, current treatments for IgAN optimize antihypertensive and antiproteinuric drugs (e.g., angiotensin-converting enzyme inhibitors and / or angiotensin II receptor blockers) along with courses of corticosteroids to inhibit disease progression. See, for example, Penfold et al., Int. J. Nephrol. and Renovascular Dis. 11, pp. 137-148 (2017). However, the combination of these drugs can exhibit significant dose-limiting side effects, such as hyperkalemia, and further immunosuppression may be required in more severe cases.

[0100] Clinically, IgAN is diagnosed by renal biopsy, showing the presence of mesangial cell proliferation and / or matrix expansion (or advanced focal segmental glomerulosclerosis) with a predominance of mesangial granular deposits of IgA (≥2+) on immunofluorescence. This condition differs from other progressive renal diseases such as diabetic nephropathy, which typically presents with diffuse capillary basement membrane thickening with peripheral hyaline PAS-positive nodules, advanced segmental or global glomerulosclerosis, and thickened arteries with hyaline deposits. See, e.g., Zanatta, et al., Renal Failure, 34(3), pp. 308-315 (2012).

[0101] Thus, in one aspect, provided herein is a method of treating IgA nephropathy, comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof.

[0102] In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject has not been previously diagnosed with any of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject has not been previously diagnosed with diabetic nephropathy. In some embodiments, the subject has not been previously diagnosed with HIV / AIDS. In some embodiments, the subject has not been previously diagnosed with HIV-associated nephropathy. In some embodiments, the subject has not been previously diagnosed with prostate cancer. In some embodiments, the subject has not been previously diagnosed with acute renal failure. In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, cancer, or acute renal failure. In some embodiments, the subject has not been previously diagnosed with diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject has been previously diagnosed with diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject has been previously diagnosed with diabetes and has not been previously diagnosed with diabetic nephropathy. In some embodiments, the subject has not been previously diagnosed with type 2 diabetes. In some embodiments, the subject has been previously diagnosed with type 2 diabetes. In some embodiments, the subject has been previously diagnosed with type 2 diabetes and has not been previously diagnosed with diabetic nephropathy.

[0103] In some embodiments, the subject has not currently been diagnosed with cancer. In some embodiments, the subject is not currently undergoing treatment for cancer. In some embodiments, the cancer is lung cancer or prostate cancer.

[0104] In some embodiments, the subject does not have one or more of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject does not have any of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject does not have diabetic nephropathy. In some embodiments, the subject does not have HIV / AIDS. In some embodiments, the subject does not have HIV-associated nephropathy. In some embodiments, the subject does not have cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the subject does not have acute renal failure. In some embodiments, the subject does not have one or more of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, cancer, or acute renal failure. In some embodiments, the cancer is lung cancer or prostate cancer. In some embodiments, the subject has diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject does not have diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject has diabetes and does not have diabetic nephropathy. In some embodiments, the subject has type 2 diabetes. In some embodiments, the subject does not have type 2 diabetes. In some embodiments, the subject has type 2 diabetes and does not have diabetic nephropathy.

[0105] In some embodiments, the subject does not suffer from one or more of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject does not suffer from any of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject does not suffer from diabetic nephropathy. In some embodiments, the subject does not suffer from HIV / AIDS. In some embodiments, the subject does not suffer from HIV-associated nephropathy. In some embodiments, the subject does not suffer from cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the subject does not suffer from acute renal failure. In some embodiments, the subject does not suffer from one or more of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, cancer, or acute renal failure. In some embodiments, the cancer is lung cancer or prostate cancer. In some embodiments, the subject does not suffer from diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject has diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject has diabetes, such as type 1 or type 2 diabetes, but does not have diabetic nephropathy. In some embodiments, the subject does not have type 2 diabetes. In some embodiments, the subject has type 2 diabetes. In some embodiments, the subject has type 2 diabetes, but does not have diabetic nephropathy.

[0106] In some embodiments, the subject is not being treated for one or more of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject is not being treated for any of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject is not being treated for diabetic nephropathy. In some embodiments, the subject is not being treated for HIV / AIDS. In some embodiments, the subject is not being treated for HIV-associated nephropathy. In some embodiments, the subject is not being treated for prostate cancer. In some embodiments, the subject is not being treated for acute renal failure. In some embodiments, the subject is not being treated for one or more of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, cancer, or acute renal failure. In some embodiments, the cancer is lung cancer or prostate cancer. In some embodiments, the subject is not being treated for diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject is being treated for diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject is being treated for diabetes, such as type 1 diabetes or type 2 diabetes, but is not being treated for diabetic nephropathy. In some embodiments, the subject is not being treated for type 2 diabetes. In some embodiments, the subject is being treated for type 2 diabetes. In some embodiments, the subject is being treated for type 2 diabetes, but is not being treated for diabetic nephropathy.

[0107] In certain embodiments, the subject has been determined to have a controlled serum glucose level. In some embodiments, the subject with the controlled serum glucose level is not being treated for diabetes. In some embodiments, the subject with the controlled serum glucose level is being treated for diabetes. In some embodiments, the subject with the controlled serum glucose level is not being treated for type 2 diabetes. In some embodiments, the subject with the controlled serum glucose level is being treated for type 2 diabetes. In some embodiments, the subject has been determined to have a controlled serum glucose level, and the subject has not been diagnosed with one or more of HIV-associated nephropathy or acute renal failure. For example, the subject is determined to have a fasting serum glucose level of less than about 130 mg / dL, about 125 mg / dL, about 120 mg / dL, about 115 mg / dL, about 110 mg / dL, about 105 mg / dL, about 100 mg / dL, about 95 mg / dL, about 90 mg / dL, about 85 mg / dL, about 80 mg / dL, or about 75 mg / dL, or any value therebetween. In certain embodiments, the subject has not been diagnosed with one or more of HIV-associated nephropathy or acute renal failure. In certain embodiments, the subject has been determined to have a controlled serum glucose level as described elsewhere herein, and the subject has not been diagnosed with one or more of HIV-associated nephropathy or acute renal failure. In certain embodiments, the subject has been determined to have a controlled serum glucose level, and the subject has not been diagnosed with one or more of HIV-associated nephropathy or acute renal failure.

[0108] In another aspect, provided herein is a method of reducing renal inflammation and / or fibrosis in a subject having IgA nephropathy, comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof.

[0109] In some embodiments, renal inflammation in a subject with IgA nephropathy is reduced by at least about 10% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In certain embodiments, renal inflammation in the subject is reduced by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%, or any value therebetween. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 to about 30 days.

[0110] In some embodiments, renal fibrosis in subjects with IgA nephropathy is reduced by at least about 10% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In certain embodiments, renal fibrosis in the subject is reduced by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%, or any value therebetween. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 to about 30 days.

[0111] In some embodiments, renal fibrosis in a subject with IgA nephropathy is reduced to less than about 50% of the cortical area of ​​the affected kidney after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween).In certain embodiments, renal fibrosis in a subject is reduced to less than about 40% of the cortical area. For example, in some embodiments, renal fibrosis in the subject is reduced to less than about 35%, about 30%, about 25%, about 20%, about 15%, or about 10% of the cortical area, or any value therebetween. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days.

[0112] In another aspect, provided herein is a method of reducing the incidence of hematuria in a subject with IgA nephropathy, comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof.

[0113] In some embodiments, the number of urinary red blood cells per high power (microscopic) field (rbc / hpf) in a subject with IgA nephropathy is reduced by at least about 10% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In certain embodiments, the urinary rbc / hpf in the subject is reduced by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%, or any value therebetween. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 to about 30 days.

[0114] In another aspect, provided herein is a method of stabilizing eGFR in a subject with IgA nephropathy, comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof.

[0115] In some embodiments, provided herein is a method of reducing the rate of decline of eGFR in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof to a subject in need thereof. In some embodiments, the rate of decline of the eGFR of the subject is reduced by at least about 10% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In some embodiments, the subject's eGFR decline is at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%, or any value therebetween. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 6 months to about 1 year.

[0116] In some embodiments, the rate of decline in eGFR in a subject with IgA nephropathy after treatment with atrasentan or a pharma- ceutical acceptable salt thereof is about 10 mL / min / 1.73 m 2The reduction is less than about 9 mL / min / 1.73 m after about 6 months to about 1 year of treatment with atrasentan or a pharmacologic acceptable salt thereof. For example, after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks of treatment, or any value therebetween). In certain embodiments, the reduction in the subject's eGFR is less than about 9 mL / min / 1.73 m after about 6 months to about 1 year of treatment with atrasentan or a pharmacologic acceptable salt thereof. 2 , approx. 8mL / min / 1.73m 2 , about 7mL / min / 1.73m 2 , approx. 6mL / min / 1.73m 2 , about 5mL / min / 1.73m 2 , approx. 4mL / min / 1.73m 2 , about 3mL / min / 1.73m 2 , about 2mL / min / 1.73m 2 , about 1mL / min / 1.73m 2 , or about 0.75 mL / min / 1.73 m 2 A typical decline in eGFR with age is, for example, about 1 mL / min / 1.73 m per year in subjects aged about 20 to about 30 years. 2 It is.

[0117] In another aspect, provided herein is a method of reducing the number of IgA nephropathy-related disease flares in a subject with IgA nephropathy, comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the method reduces disease flares associated with hematuria. In some embodiments, the method reduces disease flares associated with proteinuria. In some embodiments, the method reduces disease flares associated with IgA nephropathy associated with systemic symptoms. In some embodiments, the method reduces the decline in eGFR as described elsewhere herein. In some embodiments, the method reduces one or more of edema, fatigue, hematuria, or gross hematuria. In some embodiments, the method positively impacts disease progression.

[0118] In another aspect, provided herein is a method of delaying the onset of ESRD in a subject with IgA nephropathy, comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof.

[0119] In some embodiments, the method includes diagnosing IgA nephropathy in a subject and determining whether the subject's eGFR is 15 mL / min / 1.73 m 2 In certain embodiments, the method increases the time between a diagnosis of IgA nephropathy in a subject and the time the subject's eGFR falls below 15 mL / min / 1.73 m. 2 By at least about 10%. For example, in some embodiments, the method includes determining whether a subject has IgA nephropathy and whether the subject's eGFR is below 15 mL / min / 1.73 m. 2 by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, or about 500%, or any value therebetween.

[0120] In certain embodiments, the method includes a diagnosis of IgA nephropathy in a subject and a determination of whether the subject's eGFR is 15 mL / min / 1.73 m 2 For example, the method increases the time between when a subject's eGFR is below 15 mL / min / 1.73 m by at least about 1 year. 2 In some embodiments, the time below the end of the prostate cancer treatment may be delayed by at least about 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, 5 years, 5.5 years, 6 years, 6.5 years, 7 years, 7.5 years, 8 years, 8.5 years, 9 years, 9.5 years, 10 years, 11 years, 12 years, 13 years, 15 years, 15 years, 16 years, 17 years, 18 years, 19 years, or 20 years.

[0121] In another aspect, provided herein is a method of reducing proteinuria in a subject with IgA nephropathy, comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof.

[0122] In some embodiments, the amount of protein (e.g., albumin) in the urine of a subject with IgA nephropathy is reduced by at least about 10% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In some embodiments, the amount of protein in the subject's urine is reduced by at least about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%, or any value therebetween. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 to about 30 days.

[0123] In certain embodiments, the amount of protein (e.g., albumin) in the urine of a subject with IgA nephropathy is reduced by about 20% to about 80% about 2 days to about 30 days after treatment with atrasentan or a pharma- ceutically acceptable salt thereof. In certain embodiments, the amount of protein (e.g., albumin) in the urine of a subject with IgA nephropathy is reduced by about 20% to about 80% about 15 days to about 30 days after treatment with atrasentan or a pharma- ceutically acceptable salt thereof. In some of these embodiments, the amount of protein in the urine of the subject is reduced by about 25% to about 80%. In some of these embodiments, the amount of protein in the urine of the subject is reduced by about 30% to about 80%. In some of these embodiments, the amount of protein in the urine of the subject is reduced by about 35% to about 80%. In some of these embodiments, the amount of protein in the urine of the subject is reduced by about 40% to about 80%. In some of these embodiments, the amount of protein in the urine of the subject is reduced by about 45% to about 80%. In some of these embodiments, the amount of protein in the subject's urine is reduced by about 50% to about 80%. In the foregoing embodiments, the reduction in the amount of protein (e.g., albumin) in the urine of a subject with IgA nephropathy is relative to the amount of protein (e.g., albumin) in the urine prior to the initiation of treatment with atrasentan or a pharma- ceutically acceptable salt thereof.

[0124] In some embodiments, the amount of protein (e.g., albumin) in the urine of a subject with IgA nephropathy is reduced by about 100 mg / dL to about 3,000 mg / dL after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks of treatment, or any value therebetween). In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 2,500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 2,000 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 1,500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 1,000 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 400 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 300 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 200 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 2,500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 2,000 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 1,500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 1,000 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 900 mg / dL.In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 800 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 600 mg / dL to about 900 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 700 mg / dL to about 900 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 1,000 mg / dL to about 2,000 mg / dL. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days. In the foregoing embodiments, the reduction in the amount of protein (e.g., albumin) in the urine of the subject having IgA nephropathy is relative to the amount of protein (e.g., albumin) in the urine prior to the initiation of treatment with atrasentan or a pharma- ceutically acceptable salt thereof.

[0125] In certain embodiments, the amount of protein (e.g., albumin) in the urine of a subject with IgA nephropathy is reduced by about 100 mg / dL to about 500 mg / dL about 15 to about 30 days after treatment with atrasentan or a pharma- ceutically acceptable salt thereof. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 200 mg / dL to about 500 mg / dL about 15 to about 30 days after treatment with atrasentan or a pharma- ceutically acceptable salt thereof. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 300 mg / dL to about 500 mg / dL about 15 to about 30 days after treatment with atrasentan or a pharma- ceutically acceptable salt thereof. In the foregoing embodiments, the reduction in the amount of protein (e.g., albumin) in the urine of a subject with IgA nephropathy is relative to the amount of protein (e.g., albumin) in the urine before the initiation of treatment with atrasentan or a pharma- ceutically acceptable salt thereof.

[0126] In certain embodiments, the amount of protein (e.g., albumin) in the urine of a subject with IgA nephropathy is reduced by about 500 mg / dL to about 900 mg / dL about 15 to about 30 days after treatment with atrasentan or a pharma- ceutically acceptable salt thereof. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 600 mg / dL to about 900 mg / dL about 15 to about 30 days after treatment with atrasentan or a pharma- ceutically acceptable salt thereof. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 700 mg / dL to about 900 mg / dL about 15 to about 30 days after treatment with atrasentan or a pharma- ceutically acceptable salt thereof. In the foregoing embodiments, the reduction in the amount of protein (e.g., albumin) in the urine of a subject with IgA nephropathy is relative to the amount of protein (e.g., albumin) in the urine before the initiation of treatment with atrasentan or a pharma- ceutically acceptable salt thereof.

[0127] In some embodiments, a subject with IgA nephropathy has a reduced level of urinary protein (e.g., albumin) of less than about 1.0 gram / day after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, 50 weeks, 60 weeks, 70 weeks, 80 weeks, 90 weeks, 100 weeks, 110 weeks, 120 weeks, 130 weeks, 140 weeks, 150 weeks, 160 weeks, 170 weeks, 180 weeks, 190 weeks, or 200 weeks of treatment). In certain embodiments, the subject has a reduced level of urinary protein of less than about 0.9 gram / day. In certain embodiments, the subject has a reduced level of urinary protein of less than about 0.8 gram / day. In certain embodiments, the subject has a reduced level of protein in the urine of less than about 0.7 grams / day. In certain embodiments, the subject has a reduced level of protein in the urine of less than about 0.6 grams / day. In certain embodiments, the subject has a reduced level of protein in the urine of less than about 0.5 grams / day. In certain embodiments, the subject has a reduced level of protein in the urine of less than about 0.4 grams / day. In certain embodiments, the subject has a reduced level of protein in the urine of less than about 0.3 grams / day. In certain embodiments, the subject has a reduced level of protein in the urine of less than about 0.2 grams / day. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for about 15 to about 30 days. In the foregoing embodiments, the reduction in the amount of protein (e.g., albumin) in the urine of the subject with IgA nephropathy is related to the amount of protein (e.g., albumin) in the urine prior to the initiation of treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0128] In another aspect, provided herein is a method for reducing fatigue in a subject with IgA nephropathy, comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject is determined not to have one or more of diabetic nephropathy, HIV-associated nephropathy, prostate cancer, or acute renal failure. In certain embodiments, the subject is determined not to have diabetic nephropathy. In certain embodiments, the subject is determined not to have HIV-associated neuropathy. In certain embodiments, the subject is determined not to have prostate cancer. In certain embodiments, the subject is determined not to have acute renal failure.

[0129] In some embodiments, fatigue in a subject with IgA nephropathy is reduced by about 5% to about 80% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In certain embodiments, fatigue is reduced by about 10% to about 75%. In certain embodiments, fatigue is reduced by about 10% to about 70%. In certain embodiments, fatigue is reduced by about 10% to about 65%. In certain embodiments, fatigue is reduced by about 10% to about 60%. In certain embodiments, fatigue is reduced by about 10% to about 55%. In certain embodiments, fatigue is reduced by about 10% to about 50%. In certain embodiments, fatigue is reduced by about 10% to about 45%. In certain embodiments, fatigue is reduced by about 10% to about 40%. In certain embodiments, fatigue is reduced by about 10% to about 35%. In certain embodiments, fatigue is reduced by about 10% to about 30%. In certain embodiments, fatigue is reduced by about 10% to about 25%. In certain embodiments, fatigue is reduced by about 10% to about 20%. In certain embodiments, fatigue is reduced by about 10% to about 15%. In certain embodiments, fatigue is reduced by about 20% to about 75%. In certain embodiments, fatigue is reduced by about 20% to about 70%. In certain embodiments, fatigue is reduced by about 20% to about 65%. In certain embodiments, fatigue is reduced by about 20% to about 60%. In certain embodiments, fatigue is reduced by about 20% to about 55%. In certain embodiments, fatigue is reduced by about 20% to about 50%. In certain embodiments, fatigue is reduced by about 20% to about 45%. In certain embodiments, fatigue is reduced by about 20% to about 40%. In certain embodiments, fatigue is reduced by about 20% to about 35%.In certain embodiments, fatigue is reduced by about 20% to about 30%.In certain embodiments, fatigue is reduced by about 30% to about 75%. In certain embodiments, fatigue is reduced by about 30% to about 70%. In certain embodiments, fatigue is reduced by about 30% to about 65%. In certain embodiments, fatigue is reduced by about 30% to about 60%. In certain embodiments, fatigue is reduced by about 30% to about 55%. In certain embodiments, fatigue is reduced by about 30% to about 50%. In certain embodiments, fatigue is reduced by about 30% to about 45%. In certain embodiments, fatigue is reduced by about 30% to about 40%. In certain embodiments, fatigue is reduced by about 40% to about 75%. In certain embodiments, fatigue is reduced by about 40% to about 70%. In certain embodiments, fatigue is reduced by about 40% to about 65%. In certain embodiments, fatigue is reduced by about 40% to about 60%. In certain embodiments, fatigue is reduced by about 40% to about 55%. In certain embodiments, fatigue is reduced by about 40% to about 50%. In certain embodiments, fatigue is reduced by about 50% to about 75%. In certain embodiments, fatigue is reduced by about 50% to about 70%. In certain embodiments, fatigue is reduced by about 50% to about 65%. In certain embodiments, fatigue is reduced by about 50% to about 60%. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days. In certain embodiments, the reduction in fatigue comprises a reduction in one or more scores on the Fatigue Severity Scale, the Chalder Fatigue Scale, the FACIT Fatigue Scale, the Short Fatigue Inventory, the FACT-F subscale, overall energy and impact, the May and Kline adjective checklist, the Pearson-Byars fatigue emotion checklist, the Rhoten fatigue scale, the schedule for fatigue and anergy, a visual analog scale, or individual strengths of the checklist. In the above embodiments, the reduction in fatigue experienced by the subject with IgA nephropathy is related to the fatigue experienced by the subject before the start of treatment with atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the reduction in fatigue comprises a reduction in the score on the Short Fatigue Inventory.

[0130] Selecting a target Subjects with IgA nephropathy as described elsewhere herein can be diagnosed using one or more methods known in the art. Non-limiting examples include renal biopsy, detecting galactose-deficient IgA (e.g., Gd-IgA1), detecting anti-glycan antibodies, detecting deposition of IgA immune complexes in the kidney, or any combination of the foregoing. In some embodiments, the diagnosis of IgA nephropathy includes detecting deposition of IgA immune complexes in the kidney. In certain embodiments, the diagnosis of IgA nephropathy includes renal biopsy. In certain embodiments, the diagnosis of IgA nephropathy includes detecting galactose-deficient IgA. In certain embodiments, the diagnosis of IgA nephropathy includes detecting anti-glycan antibodies (e.g., KM55). In certain embodiments, the diagnosis of IgA nephropathy includes renal biopsy followed by detecting deposition of IgA immune complexes in the kidney (e.g., by light microscopy and / or immunofluorescence microscopy).

[0131] In some embodiments, the presence and / or level of a particular protein in the subject is determined prior to administration of atrasentan or a pharma- ceutically acceptable salt thereof. For example, serum levels of Gd-IgA1, serum levels of autoantibodies specific to Gd-IgA1, and / or serum and / or urinary levels of IgA1-containing immune complexes. See, for example, Knoppova, et al., Front. Immunol., Vol. 17, Art. 117 (2016), which is incorporated herein by reference in its entirety. In some embodiments, the subject has a Gd-IgA level equal to or greater than the 90th percentile prior to administration of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject has a Gd-IgA level equal to or greater than the 95th percentile prior to administration of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject's Gd-IgA level decreases to below the 90th percentile after about 6 months to 1 year of treatment with atrasentan or a pharma- ceutically acceptable salt thereof.

[0132] In certain embodiments, the subject has mesangial cellularity in about 50% or more (e.g., about 60% or more, about 70% or more, or about 80% or more) of the glomerulus, where mesangial cellularity is defined as more than four mesangial cells in any mesangial region of the glomerulus. In certain embodiments, endocapillary hypercellularity is present in the subject, where endocapillary hypercellularity is defined as cellularity with increased cell numbers within the lumen of the glomerular capillaries. In certain embodiments, segmental sclerosis is present in the subject, where segmental sclerosis is defined as adhesion or sclerosis (obstruction of the capillary lumen by matrix) in some but not all of the glomerular tuft. In certain embodiments, the subject has tubular atrophy / interstitial fibrosis in about 50% or more (e.g., about 60% or more, about 65% or more, about 70% or more, about 75% or more, or about 80% or more) of the cortical area, where tubular atrophy / interstitial fibrosis is defined as the estimated percentage of the cortical area that exhibits tubular atrophy or interstitial fibrosis. In certain embodiments, the subject has crescents present on glomeruli. In some of these embodiments, the subject has crescents present in less than about 25% (e.g., about 20%, about 15%, about 10%, or less than about 5%) of the glomeruli. In certain embodiments, the subject has a MEST-C score of M1, E1, S1, T1 or T2, and / or C0 or C1 under the Oxford MEST-C classification system. The Oxford MEST-C classification system is defined in Kidney International (2009) 76, 546-556 and Nature Reviews Nephrology (2017) 13, 385-386, each of which is incorporated by reference in its entirety. (See also Kidney Research and Clinical Practice (2016) 35, 197-203; and IgA Nephropathy in Medscape, accessed November 4, 2019, each of which is incorporated by reference in its entirety.)

[0133] In some embodiments, the subject is at high risk of progressing to ESRD. In some of these embodiments, the subject is excreting an average of about 1 gram or more of protein in the urine per day for at least about 3 months prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. In certain embodiments, the subject is excreting an average of about 60 mL / min / 1.73 m 2 protein in the urine for at least about 3 months prior to the first administration of atrasentan or a pharma-ceutically acceptable salt thereof. 2 In some of these embodiments, the subject has a mean eGFR of 30 mL / min / 1.73 m or less (e.g., about 55 or less, about 50 or less, about 45 or less, about 40 or less, about 35 or less) prior to the first administration of atrasentan or a pharmacologic acceptable salt thereof. 2 have an eGFR of >

[0134] In some embodiments, the subject is excreting an average of about 1 gram or more of protein in the urine per day for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years) prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. For example, a subject may excrete an average of about 1.1 grams, 1.2 grams, 1.3 grams, 1.4 grams, 1.5 grams, 1.6 grams, 1.7 grams, 1.8 grams, 1.9 grams, 2.0 grams, 2.1 grams, 2.2 grams, 2.3 grams, 2.4 grams, 2.5 grams, 2.6 grams, 2.7 grams, 2.8 grams, 2.9 grams, 3.0 grams, 3.1 grams, 3.2 grams, 3.3 grams, 3.4 grams, 3.5 grams, 5 grams, 7.5 grams, or 10 grams of protein in the urine per day, or any value therebetween, for at least about three months prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof.

[0135] In some embodiments, the subject excretes an average of about 0.3 grams to about 2 grams of protein in the urine per day for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years) prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. For example, the subject may excrete about 0.3 grams to 0.5 grams, 0.5 grams to 1 gram, about 0.5 grams to 1.5 grams, about 1 gram to 1.5 grams, or about 1.5 grams to 2 grams of protein in the urine per day for at least about 3 months.

[0136] In some embodiments, the subject excretes at least about 1 gram of protein in the urine per day on at least two of three consecutive measurements for one year prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. For example, the subject is excreting about 1.1 grams, 1.2 grams, 1.3 grams, 1.4 grams, 1.5 grams, 1.6 grams, 1.7 grams, 1.8 grams, 1.9 grams, 2.0 grams, 2.1 grams, 2.2 grams, 2.3 grams, 2.4 grams, 2.5 grams, 2.6 grams, 2.7 grams, 2.8 grams, 2.9 grams, 3.0 grams, 3.1 grams, 3.2 grams, 3.3 grams, 3.4 grams, 3.5 grams, 5 grams, 7.5 grams, or 10 grams of protein per day, or any value therebetween, in the urine for at least two of three consecutive measurements for a year prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof.

[0137] In some embodiments, the subject has a UACR value of at least about 300 mg / g, e.g., 300 mg / g to about 5,000 mg / g, for at least 3 months prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject has a UACR value of about 800 mg / g, e.g., 800 mg / g to about 5,000 mg / g, for at least 3 months prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject has a UACR value of at least about 500 mg / g, about 600 mg / g, about 700 mg / g, about 800 mg / g, about 900 mg / g, about 1,000 mg / g, about 1,500 mg / g, about 2,000 mg / g, about 2,500 mg / g, about 3,000 mg / g, about 3,500 mg / g, about 4,000 mg / g, about 4,500 mg / g, or about 5,000 mg / g, or any value therebetween, for at least about three months prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof.

[0138] In some embodiments, the subject has a reduction in UACR value of at least about 30% compared to the subject's average UACR value for at least 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, for example, a reduction of about 30% to about 100% compared to the subject's average UACR value for at least 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a reduction in UACR value of at least about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%, or any value therebetween, compared to the subject's average UACR value for at least 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject having a reduction in UACR value also does not experience significant sodium retention and / or significant fluid retention. In some embodiments, significant fluid retention can be from about 1 kg to about 4 kg, e.g., about 4 kg, about 3.5 kg, about 3 kg, about 2.5 kg, about 2 kg, about 1.5 kg, or about 1 kg, over a 6 week period, or any value over 6 weeks or more. In some embodiments, subjects with significant fluid retention exhibit clinical symptoms of edema.

[0139] In certain embodiments, the subject is administered about 20 to about 90 mL / min / 1.73 m for at least 3 months (e.g., about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 1.5 years, or about 2 years) prior to the first administration of atrasentan or a pharma- ceutical acceptable salt thereof. 2 For example, the patient has a mean eGFR of about 20 to about 50 mL / min / 1.73 m for at least 3 months prior to the first administration of atrasentan or a pharma- ceutical acceptable salt thereof. 2 , about 30~about 60mL / min / 1.73m 2 , about 40~70mL / min / 1.73m 2 , about 50~about 80mL / min / 1.73m 2 , or about 60 to about 90 mL / min / 1.73 m 2In some embodiments, the subject receives at least 60 mL / min / 1.73 m for at least about 3 months prior to the first administration of atrasentan or a pharma- ceutical acceptable salt thereof. 2 In certain embodiments, subjects have a mean eGFR of 55 mL / min / 1.73 m for at least about three months. 2 In certain embodiments, the subject has a mean eGFR of 50 mL / min / 1.73 m for at least about three months. 2 In certain embodiments, subjects have a mean eGFR of 45 mL / min / 1.73 m for at least about three months. 2 In certain embodiments, subjects have a mean eGFR of 40 mL / min / 1.73 m for at least about three months. 2 In certain embodiments, subjects have a mean eGFR of 35 mL / min / 1.73 m for at least about three months. 2 In certain embodiments, the subject has a mean eGFR of 25 mL / min / 1.73 m for at least about three months. 2 In certain embodiments, the subject has a mean eGFR of 20 mL / min / 1.73 m for at least about three months. 2 In some of the foregoing embodiments, the subject has a mean eGFR of about 30 mL / min / 1.73 m for at least 3 months prior to administration of atrasentan or a pharmacologic acceptable salt thereof. 2 ~Approx. 60mL / min / 1.73m 2 For example, subjects have an average eGFR of about 30 mL / min / 1.73 m 2 ~Approx. 55mL / min / 1.73m 2 , about 30mL / min / 1.73m 2 ~Approx. 50mL / min / 1.73m 2 , about 30mL / min / 1.73m 2 ~About 45mL / min / 1.73m 2 , or about 30 mL / min / 1.73 m 2 ~ approx. 40mL / min / 1.73m 2 The patient may have a mean eGFR of

[0140] In certain embodiments, the subject is administered about 30 mL / min / 1.73 m for at least 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years) prior to the first administration of atrasentan or a pharma- ceutical acceptable salt thereof. 2 ~About 45mL / min / 1.73m 2 , e.g., about 45 or less, about 40 or less, about 35 or less, or about 30 or less. In some embodiments, the subject has a mean eGFR of about 25 mL / min / 1.73 m for at least about 3 months prior to the first administration of atrasentan or a pharma- ceutical acceptable salt thereof. 2 ~Approx. 75mL / min / 1.73m 2 For example, the patient has a mean eGFR of about 25 mL / min / 1.73 m for at least 3 months prior to the first administration of atrasentan or a pharma- ceutical acceptable salt thereof. 2 , about 30mL / min / 1.73m 2 , about 35mL / min / 1.73m 2 , approx. 40mL / min / 1.73m 2 , about 45mL / min / 1.73m 2 , about 50mL / min / 1.73m 2 , about 55mL / min / 1.73m 2 , about 60mL / min / 1.73m 2 , about 65mL / min / 1.73m 2 , about 70mL / min / 1.73m 2 , about 75mL / min / 1.73m 2 , or any value in between.

[0141] In some embodiments, the subject has an average HbA1c of about 4% to about 6% for at least 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years) prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. For example, the subject may have an average HbA1c of about 4.2%, about 4.4%, about 4.6%, about 4.8%, about 5.0%, about 5.2%, about 5.4%, about 5.6%, about 5.8%, or about 6, or any value therebetween.

[0142] In some embodiments, the subject has an average fasting blood glucose level of about 125 mg / dL or less for at least 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years) prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. For example, the subject may have an average fasting blood glucose level of about 120 mg / dL, about 115 mg / dL, about 110 mg / dL, about 105 mg / dL, about 100 mg / dL, about 95 mg / dL, about 90 mg / dL, about 85 mg / dL, about 80 mg / dL, or about 75 mg / dL, or any value therebetween.

[0143] In some embodiments, the subject maintains potassium levels within the normal physiological range. In certain embodiments, the subject maintains potassium levels within the normal physiological range for at least 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years) prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. In certain embodiments, the subject maintains potassium levels within 3.5-5.2 mEq / L. For example, the subject maintains an average potassium level of about 3.5mEq / L, about 3.6mEq / L, about 3.7mEq / L, about 3.8mEq / L, about 3.9, about mEq / L, about 4.0mEq / L, about 4.1mEq / L, about 4.2mEq / L, about 4.3mEq / L, about 4.4mEq / L, about 4.5mEq / L, about 4.6mEq / L, about 4.7mEq / L, about 4.8mEq / L, about 4.9mEq / L, about 5.0mEq / L, about 5.1mEq / L, or about 5.2mEq / L, or any value therebetween.

[0144] In some embodiments, the subject maintains sodium levels within the normal physiological range. In certain embodiments, the subject maintains potassium levels within the normal physiological range for at least 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years) prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. In certain embodiments, the subject maintains sodium levels within 135-145 mEq / L. For example, the subject maintains an average sodium level of about 135mEq / L, about 136mEq / L, about 137mEq / L, about 138mEq / L, about 139mEq / L, about 140mEq / L, about 141mEq / L, about 142mEq / L, about 143mEq / L, about 144mEq / L, about or 145mEq / L, or any value therebetween.

[0145] In some embodiments, the subject has ALT / AST levels during administration of atrasentan or a pharmaceutically acceptable salt thereof that are about the same as the ALT / AST levels prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the subject has ALT / AST levels during administration of atrasentan or a pharmaceutically acceptable salt thereof that are within about 25%, about 20%, about 15%, about 10%, about 5%, about or 2.5%, or any value therebetween, of the levels prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, the subject has a bilirubin level during administration of atrasentan or a pharmaceutically acceptable salt thereof that is about the same as the bilirubin level prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the subject has a bilirubin level during administration of atrasentan or a pharmaceutically acceptable salt thereof that is about 25%, about 20%, about 15%, about 10%, about 5%, or about 2.5%, or any value therebetween, of the level prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments, fluid retention in a subject can be managed with a diuretic (e.g., during treatment with atrasentan or a pharma- ceutically acceptable salt thereof and / or before the first administration of atrasentan or a pharma- ceutically acceptable salt thereof). For example, fluid retention can be less than about 3 kilograms (kg) of weight gain over 6 weeks. In some embodiments, fluid retention is less than about 4 kg, about 3.5 kg, about 3 kg, about 2.5 kg, about 2 kg, about 1.5 kg, or about 1 kg, or any value therebetween, over 6 weeks or more.

[0148] In some embodiments, the subject undergoes surgery and / or other regimens prior to, substantially simultaneously with, or following administration of atrasentan or a pharmaceutically acceptable salt thereof as disclosed herein. In some embodiments, the subject is administered other chemical and / or biological therapeutic agents prior to, substantially simultaneously with, or following administration of atrasentan or a pharmaceutically acceptable salt thereof as disclosed herein.

[0149] In some embodiments, the subject has been receiving one or more inhibitors of the renin-angiotensin system for at least about 60 weeks prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. For example, in some embodiments, the subject has been receiving one or more inhibitors of the renin-angiotensin system for at least about 12 weeks, about 24 weeks, about 48 weeks, or about 60 weeks, or any value therebetween, prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof.

[0150] In some embodiments, the subject is receiving a maximum tolerated stable dose of one or more renin-angiotensin system inhibitors.For example, the subject may be receiving a maximum tolerated stable dose of one or more renin-angiotensin system inhibitors for at least about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 25 weeks, about 30 weeks, about 35 weeks, about 40 weeks, about 45 weeks, or about 50 weeks, or any value therebetween, before the first administration of atrasentan or its pharma-ceutically acceptable salt.In some embodiments, the one or more inhibitors of the renin-angiotensin system are selected from the group consisting of angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), renin inhibitors, and aldosterone antagonists.For example, the one or more inhibitors of the renin-angiotensin system may be ACE inhibitors, ARBs, or combinations thereof, and the ACE inhibitors or ARBs may be described elsewhere herein. For example, the ACE inhibitor can be selected from quinapril, fosinopril perindopril, captopril, enalapril, enalaprilat, ramipril, cilazapril, delapril, fosenopril, zofenopril, indolapril, benazepril, lisinopril, spirapril, trandolapril, perindep, pentopril, moexipril, rescinnamine, and pivopril.For example, the ARB can be selected from candesartan, candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan, olmesartan medoxomil, telmisartan, valsartan, azilsartan medoxomil, and BRA-657.

[0151] In some embodiments, the subject is also administered one or more additional agents. In some embodiments, the one or more additional agents are selected from calcineurin inhibitors, proteasome inhibitors, aminoquinolines, complement inhibitors, B cell inhibitors, cytotoxic agents, mTOR inhibitors, and steroids. In some embodiments, the dosage of the one or more additional agents is decreased about 15 to about 30 days after treatment with atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the one or more additional agents are immunosuppressants.

[0152] In some embodiments, the subject is not currently receiving one or more additional medications. In certain embodiments, the subject has not used one or more additional medications for more than two weeks within six months prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof.

[0153] In some embodiments, the one or more additional agents are selected from a calcineurin inhibitor, a proteasome inhibitor, an aminoquinoline, a complement inhibitor, a B cell inhibitor, a cytotoxic agent, an mTOR inhibitor, and a steroid.

[0154] In certain embodiments, the one or more additional agents are steroids. For example, the one or more additional agents can be selected from the group consisting of prednisone, dexamethasone, hydrocortisone, cyclosporine, and any combination of the foregoing.

[0155] In certain embodiments, the one or more additional agents is an aminoquinoline. For example, the one or more additional agents can be hydroxychloroquine.

[0156] In some embodiments, the subject is receiving one or more additional agents during treatment with atrasentan. In certain embodiments, the dosage of the one or more additional agents is decreased after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, 50 weeks, 60 weeks, 70 weeks, 80 weeks, 90 weeks, 100 weeks, 110 weeks, 120 weeks, 130 weeks, 140 weeks, 150 weeks, 160 weeks, 170 weeks, 180 weeks, 190 weeks, or 200 weeks of treatment). In some of these embodiments, the dosage of the one or more additional agents is decreased about 15 days to about 30 days after treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some of the foregoing embodiments, the dosage of the additional agent is decreased by about 10% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 15% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 20% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 25% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 30% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 35% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 40% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 45% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 50% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 55% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 60% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 65% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 70% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 75% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 80% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 85% to about 100%.In certain embodiments, the dosage of the additional agent is reduced by about 90% to about 100%. In some of the foregoing embodiments, the dosage of the one or more additional agents is reduced after about 15 to about 30 days (e.g., about 15 days, about 20 days, about 25 days, or about 30 days) of treatment with atrasentan or a pharma- ceutically acceptable salt thereof. When the dosage of the additional agent is reduced by 100% as described herein, the subject no longer requires the additional agent.

[0157] In certain embodiments, the dosage of one or more steroids is reduced following treatment with atrasentan or a pharma- ceutically acceptable salt thereof, e.g., about 15 to about 30 days after treatment with atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage of the steroid is reduced by about 10% to about 100%, as described herein. In some embodiments, the dosage of prednisone, dexamethasone, hydrocortisone, cyclosporine, or a combination of any of the foregoing, is reduced by about 10% to about 100% following treatment with atrasentan or a pharma- ceutically acceptable salt thereof.

[0158] In certain embodiments, the dosage of one or more aminoquinolines is reduced following treatment with atrasentan or a pharma- ceutically acceptable salt thereof, e.g., about 15 to about 30 days after treatment with atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage of the aminoquinoline is reduced by about 10% to about 100%, as described herein. In some embodiments, the dosage of hydroxychloroquine is reduced by about 10% to about 100% following treatment with atrasentan or a pharma- ceutically acceptable salt thereof.

[0159] In some embodiments, the subject is receiving one or more additional therapeutic agents at the same time. The one or more additional therapeutic agents are described herein. For example, the subject is receiving an inhibitor of one or more elements of the renin-angiotensin-aldosterone system at the same time. In certain embodiments, the subject is receiving an SGLT-2 inhibitor, an ACE inhibitor, an ARB, a statin, a diuretic, a calcium channel blocker, a beta blocker, an aldosterone antagonist, fish oil, hydroxychloroquine, or any combination of the above at the same time. In some of these embodiments, the subject is receiving an SGLT-2 inhibitor at the same time. In some of these embodiments, the subject is receiving an ACE inhibitor, an ARB, or a combination thereof at the same time. In certain embodiments, the subject is receiving one or more statins at the same time, such as atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin. In certain embodiments, the subject is concurrently receiving one or more diuretics, such as hydrochlorothiazide, trichlormethiazide, hydroflumethiazide, quinethazone, metolazone, chlorothiazide, chlorthalidone, indapamide, methyclothiazide, bemethanide, torsemide, piretanide, ethacrynic acid, bumetanide, furosemide, triamterene, spironolactone, eplerenone, and amiloride. In certain embodiments, the subject is concurrently receiving an SGLT-2 inhibitor, such as canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin. In certain embodiments, the subject is concurrently receiving one or more ACE inhibitors, such as quinapril, fosinopril perindopril, captopril, enalapril, enalaprilat, ramipril, cilazapril, delapril, fosenopril, zofenopril, indolapril, benazepril, lisinopril, spirapril, trandolapril, perindep, pentopril, moexipril, rescinnamine, and pivopril.In certain embodiments, the subject is concurrently receiving an ARB, such as candesartan, candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan, olmesartan medoxomil, telmisartan, valsartan, azilsartan medoxomil, and BRA-657. In certain embodiments, the subject is concurrently receiving a diuretic and an ACE inhibitor or an ARB. In certain embodiments, the subject is concurrently receiving a diuretic, an ACE inhibitor, and an ARB. In certain embodiments, the subject is concurrently receiving a diuretic and an SGLT-2 inhibitor, and an ACE inhibitor or an ARB. In certain embodiments, the subject is concurrently receiving a diuretic, an SGLT-2 inhibitor, an ACE inhibitor, and an ARB. In certain embodiments, the subject concurrently receiving one or more additional therapeutic agents has not previously received one or more therapeutic agents. For example, a subject concurrently receiving an SGLT-2 inhibitor who has not previously received an SGLT-2 inhibitor.

[0160] In some embodiments, the subject has previously received one or more additional therapeutic agents, such as those described herein, but not simultaneously.For example, the subject has previously received, but not simultaneously, SGLT-2 inhibitors, ACE inhibitors, ARBs, statins, diuretics, calcium channel blockers, beta blockers, aldosterone antagonists, fish oil, hydroxychloroquine, or any combination of the above, as described herein.In some of these embodiments, the subject has previously received, but not simultaneously, SGLT-2 inhibitors.

[0161] In some embodiments, the subject has cellular crescents present in about 25% or less of the glomerulus within 6 months prior to the first administration of atrasentan or its pharma- ceutically acceptable salt.For example, the subject may have cellular crescents present in about 25%, about 20%, about 15%, about 10%, about 5%, or about 1% of the glomerulus, or any value therebetween.In some embodiments, the subject has no cellular crescents present in the glomerulus.In certain embodiments, the subject is not under clinical suspicion of rapidly progressive glomerulonephritis (RPGN).

[0162] In some embodiments, the subject has not undergone an organ transplant prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof.

[0163] In some embodiments, the subject has a systolic blood pressure of less than about 160 mmHg before the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the subject may have a systolic blood pressure of less than about 155 mmHg, less than about 150 mmHg, less than about 145 mmHg, or less than about 140 mmHg. In some embodiments, the subject has a diastolic blood pressure of less than about 100 mmHg before the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the subject may have a diastolic blood pressure of less than about 100 mmHg, less than about 95 mmHg, or less than about 90 mmHg. In some embodiments, the subject has a systolic blood pressure of about 100 mmHg to about 130 mmHg and a diastolic blood pressure of about 70 mmHg to about 90 mmHg.

[0164] In some embodiments, the subject has not been diagnosed with heart failure prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not been previously hospitalized for a condition associated with fluid overload prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. Non-limiting examples of conditions include uncontrolled peripheral edema, pleural effusion, or ascites. In some embodiments, the subject has not been diagnosed with clinically significant liver disease prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's transaminase or bilirubin value is less than or equal to two times the upper limit of normal prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the subject's ALT level is less than about 110 U / L (e.g., less than about 100 U / L, less than 90 U / L, less than about 80 U / L, less than about 70 U / L, less than about 60 U / L, less than about 50 U / L, or less than about 40 U / L, or any value therebetween). As another example, the subject's AST level is less than 100 U / L (e.g., less than 90 U / L, less than about 80 U / L, less than about 70 U / L, less than about 60 U / L, less than about 50 U / L, or less than about 40 U / L, or any value therebetween).As yet another example, the subject's bilirubin level is less than about 2.5 mg / dL (e.g., less than about 2 mg / dL, less than about 1.5 mg / dL, less than about 1.4 mg / dL, less than about 1.3 mg / dL, less than about 1.2 mg / dL, less than about 1.1 mg / dL, less than about 1.0 mg / dL, or less than about 0.9 mg / dL, or any value therebetween).

[0165] In some embodiments, the subject has a hemoglobin level of greater than about 9 g / dL (e.g., greater than about 10 g / dL, about 11 g / dL, about 12 g / dL, or about 13 g / dL, or any value therebetween) prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not received a blood transfusion for anemia for at least about 3 months (e.g., about 4 months, about 5 months, about 6 months, or about 1 year) prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not been diagnosed with cancer for at least 5 years prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not been diagnosed with cancer (e.g., lung cancer or prostate cancer) for at least 5 years prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not been diagnosed with cancer for at least 5 years prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, unless the cancer is a non-melanoma skin cancer that does not require ongoing treatment. In some embodiments, the subject does not have cancer prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, unless the cancer is a non-melanoma skin cancer that does not require ongoing treatment. In some embodiments, the subject does not have cancer prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, unless the cancer is a non-melanoma skin cancer that does not require ongoing treatment. In some embodiments, the subject has not been treated for cancer for at least 5 years prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, unless the cancer is a non-melanoma skin cancer that does not require ongoing treatment.

[0166] In some embodiments of the methods, uses, or products for use herein, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure. In some embodiments of the methods, uses, or products for use herein, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, cancer (e.g., prostate cancer or lung cancer), or acute renal failure. In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, prostate cancer, or acute renal failure. In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV-associated nephropathy, cancer (e.g., lung cancer, or prostate cancer), or acute renal failure. In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV-associated nephropathy, or acute renal failure. In certain embodiments, the subject has not been previously diagnosed with diabetic nephropathy. In certain embodiments, the subject has not been previously diagnosed with HIV / AIDS. In certain embodiments, the subject has not been previously diagnosed with acute renal failure. In certain embodiments, the subject has not been previously diagnosed with HIV-associated nephropathy. In certain embodiments, the subject has not been previously diagnosed with cancer. In certain embodiments, the subject has not been previously diagnosed with prostate cancer. In certain embodiments, the subject has not been previously diagnosed with lung cancer. In certain embodiments, the subject has not been previously diagnosed with any one of diabetic nephropathy, HIV / AIDS, and acute renal failure. In certain embodiments, the subject has not been previously diagnosed with any one of diabetic nephropathy, HIV / AIDS, prostate cancer, and acute renal failure. In certain embodiments, the subject has not been previously diagnosed with any one of diabetic nephropathy, HIV-associated nephropathy, prostate cancer, and acute renal failure.In certain embodiments, the subject has not been previously diagnosed with any one of diabetic nephropathy, HIV-associated nephropathy, and acute renal failure. In some embodiments of the methods, uses, or products for use herein, the subject has not been previously diagnosed with diabetes. In some embodiments of the methods, uses, or products for use herein, the subject has not been previously diagnosed with type 2 diabetes. In some of the foregoing embodiments, the subject has been determined to have a controlled serum glucose level as described elsewhere herein.

[0167] In some embodiments, the subject does not have one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure. In some embodiments, the subject does not have one or more of diabetic nephropathy, HIV / AIDS, prostate cancer, or acute renal failure. In some embodiments, the subject does not have one or more of diabetic nephropathy, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject does not have one or more of diabetic nephropathy, HIV-associated nephropathy, or acute renal failure. In certain embodiments, the subject does not have diabetic nephropathy. In certain embodiments, the subject does not have HIV / AIDS. In certain embodiments, the subject does not have acute renal failure. In certain embodiments, the subject does not have HIV-associated nephropathy. In certain embodiments, the subject does not have prostate cancer. In certain embodiments, the subject does not have any one of diabetic nephropathy, HIV / AIDS, and acute renal failure. In certain embodiments, the subject does not have any one of diabetic nephropathy, HIV / AIDS, prostate cancer, and acute renal failure. In certain embodiments, the subject does not have any one of diabetic nephropathy, HIV-associated nephropathy, prostate cancer, and acute renal failure. In certain embodiments, the subject does not have any one of diabetic nephropathy, HIV-associated nephropathy, and acute renal failure. In some embodiments, the subject does not have diabetes. In some embodiments, the subject does not have type 2 diabetes. In some of the above embodiments, the subject has been determined to have a controlled serum glucose level as described elsewhere herein.

[0168] In some embodiments, the subject does not suffer from one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure. In some embodiments, the subject does not suffer from one or more of diabetic nephropathy, HIV / AIDS, prostate cancer, or acute renal failure. In some embodiments, the subject does not suffer from one or more of diabetic nephropathy, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject does not suffer from one or more of diabetic nephropathy, HIV-associated nephropathy, or acute renal failure. In certain embodiments, the subject does not suffer from diabetic nephropathy. In certain embodiments, the subject does not suffer from HIV / AIDS. In certain embodiments, the subject does not suffer from acute renal failure. In certain embodiments, the subject does not suffer from HIV-associated nephropathy. In certain embodiments, the subject does not suffer from prostate cancer. In certain embodiments, the subject does not suffer from any one of diabetic nephropathy, HIV / AIDS, and acute renal failure. In certain embodiments, the subject does not suffer from any one of diabetic nephropathy, HIV / AIDS, prostate cancer, and acute renal failure. In certain embodiments, the subject does not suffer from any one of diabetic nephropathy, HIV-associated nephropathy, prostate cancer, and acute renal failure. In certain embodiments, the subject does not suffer from any one of diabetic nephropathy, HIV-associated nephropathy, and acute renal failure. In some embodiments, the subject does not suffer from diabetes. In some embodiments, the subject does not suffer from type 2 diabetes. In some of the above embodiments, the subject has been determined to have a controlled serum glucose level as described elsewhere herein.

[0169] In some embodiments, the subject is not being treated for one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure. In some embodiments, the subject is not being treated for one or more of diabetic nephropathy, HIV / AIDS, prostate cancer, or acute renal failure. In some embodiments, the subject is not being treated for one or more of diabetic nephropathy, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject is not being treated for one or more of diabetic nephropathy, HIV-associated nephropathy, or acute renal failure. In certain embodiments, the subject is not being treated for diabetic nephropathy. In certain embodiments, the subject is not being treated for HIV / AIDS. In certain embodiments, the subject is not being treated for acute renal failure. In certain embodiments, the subject is not being treated for HIV-associated nephropathy. In certain embodiments, the subject is not being treated for prostate cancer. In certain embodiments, the subject is not being treated for any one of diabetic nephropathy, HIV / AIDS, and acute renal failure. In certain embodiments, the subject is not being treated for any one of diabetic nephropathy, HIV / AIDS, prostate cancer, and acute renal failure. In certain embodiments, the subject is not receiving treatment for any one of diabetic nephropathy, HIV-associated nephropathy, prostate cancer, and acute renal failure. In certain embodiments, the subject is not receiving treatment for any one of diabetic nephropathy, HIV-associated nephropathy, and acute renal failure. In some embodiments, the subject is not receiving treatment for diabetes. In some embodiments, the subject is not receiving treatment for type 2 diabetes. In some of the above embodiments, the subject has been determined to have a controlled serum glucose level as described elsewhere herein.

[0170] In some embodiments, the subject is determined to have a controlled serum glucose level, or the subject has not been diagnosed with one or more of HIV-associated nephropathy or acute renal failure. In certain embodiments, the subject is determined to have a controlled serum glucose level. For example, the subject is determined to have a fasting serum glucose level of less than about 130 mg / dL, about 125 mg / dL, about 120 mg / dL, about 115 mg / dL, about 110 mg / dL, about 105 mg / dL, about 100 mg / dL, about 95 mg / dL, about 90 mg / dL, about 85 mg / dL, about 80 mg / dL, or about 75 mg / dL, or any value therebetween. In certain embodiments, the subject has not been diagnosed with one or more of HIV-associated nephropathy or acute renal failure. In certain embodiments, the subject has been determined to have controlled serum glucose levels as described elsewhere herein, and the subject has not been diagnosed with one or more of HIV-associated nephropathy or acute renal failure.

[0171] In some embodiments, the subject has never been diagnosed with a chronic kidney disease other than IgA nephropathy. Non-limiting examples include diabetic kidney disease, hypertensive kidney disease, or primary glomerulopathy determined to be unrelated to IgA nephropathy. In certain embodiments, the subject has never been diagnosed with diabetic kidney disease. In certain embodiments, the subject has never been diagnosed with hypertensive kidney disease. In certain embodiments, the subject has never been diagnosed with primary glomerulopathy determined to be unrelated to IgA nephropathy.

[0172] In some embodiments, the subject does not have chronic kidney disease other than IgA nephropathy.Non-limiting examples include diabetic kidney disease, hypertensive kidney disease, or primary glomerulopathy determined to be not associated with IgA nephropathy.In certain embodiments, the subject does not have diabetic kidney disease.In certain embodiments, the subject does not have hypertensive kidney disease.In certain embodiments, the subject does not have primary glomerulopathy determined to be not associated with IgA nephropathy.

[0173] In some embodiments, the subject does not suffer from chronic kidney disease other than IgA nephropathy.Non-limiting examples include diabetic kidney disease, hypertensive kidney disease, or primary glomerulopathy determined to be not related to IgA nephropathy.In certain embodiments, the subject does not suffer from diabetic kidney disease.In certain embodiments, the subject does not suffer from hypertensive kidney disease.In certain embodiments, the subject does not suffer from primary glomerulopathy determined to be not related to IgA nephropathy.

[0174] In some embodiments, the subject is not being treated for chronic kidney disease other than IgA nephropathy. Non-limiting examples include diabetic kidney disease, hypertensive kidney disease, or primary glomerulopathy determined to be not associated with IgA nephropathy. In certain embodiments, the subject is not being treated for diabetic kidney disease. In certain embodiments, the subject is not being treated for hypertensive kidney disease. In certain embodiments, the subject is not being treated for primary glomerulopathy determined to be not associated with IgA nephropathy.

[0175] Treatment outcome In some embodiments of the methods, uses, or products for use herein, renal inflammation is reduced after treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, renal inflammation in a subject is reduced by at least about 10% after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In some embodiments, renal inflammation in the subject is reduced by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%, or any value therebetween. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 to about 30 days.

[0176] In some embodiments, renal fibrosis is reduced after treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, renal fibrosis in a subject is reduced by at least about 10% after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In certain embodiments, renal fibrosis in the subject is reduced by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%, or any value therebetween. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 to about 30 days.

[0177] In some embodiments, renal fibrosis in a subject is reduced by less than about 50% of the cortical area after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween).In certain embodiments, renal fibrosis in a subject is reduced by less than about 40% of the cortical area. For example, in some embodiments, renal fibrosis in the subject is reduced to less than about 35%, about 30%, about 25%, about 20%, about 15%, or about 10% of the cortical area, or any value therebetween. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days.

[0178] In some embodiments, the occurrence of hematuria is reduced in a subject after treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the number of urinary red blood cells per high power (microscopic) field (rbc / hpf) in a subject is reduced by at least about 10% after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks of treatment). In certain embodiments, the subject's urinary RBC / HPF is reduced by at least about 20%. For example, in some embodiments, the subject's urinary RBC / HPF is reduced by at least about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%, or any value therebetween. In some of the above embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days.

[0179] In some embodiments, the subject's eGFR decline rate is reduced by at least about 10% after treatment with atrasentan or its pharma- ceutically acceptable salt (e.g., after 1 week, 2 weeks, 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween).In certain embodiments, the subject's eGFR decline rate is reduced by at least about 20%. For example, in some embodiments, the subject's eGFR decline is at least about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%, or any value therebetween. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 6 months to about 1 year.

[0180] In some embodiments, the subject's eGFR decline rate is reduced by less than about 10 mL / min per year after treatment with atrasentan or its pharma- ceutically acceptable salt (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween).In some embodiments, the subject's eGFR decline rate is reduced by less than about 9 mL / min per year. For example, in some embodiments, the subject's rate of decline in eGFR is reduced by less than about 8 mL / min per year, less than about 7 mL / min per year, less than about 6 mL / min per year, less than about 5 mL / min per year, less than about 4 mL / min per year, less than about 3 mL / min per year, less than about 2 mL / min per year, or less than about 1 mL / min per year, or any value therebetween. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 to about 30 days. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 6 months to about 1 year.

[0181] In some embodiments, a subject's risk of developing ESRD is reduced by about 20% to about 99% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). For example, the subject's risk of developing ESRD may be reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 99%, or any value therebetween. In some of the foregoing embodiments, the subject has been treated for about 90 days to about 180 days. In certain embodiments, the subject's risk of developing ESRD is reduced by about 20% to about 99% after about 90 days to about 180 days of treatment with atrasentan or a pharma- ceutically acceptable salt thereof. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 6 months to about 1 year.

[0182] In some embodiments, the method includes diagnosing IgA nephropathy in a subject and determining whether the subject's eGFR is about 15 mL / min / 1.73 m 2 In certain embodiments, the method includes determining whether the subject has a diagnosis of IgA nephropathy and whether the subject's eGFR is below 15 mL / min / 1.73 m. 2 By at least about 10%. For example, in some embodiments, the method includes determining whether a subject has IgA nephropathy and whether the subject's eGFR is below 15 mL / min / 1.73 m. 2by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 100%, about 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, or about 500%, or any value therebetween.

[0183] In some embodiments, the method includes diagnosing IgA nephropathy in a subject and determining whether the subject's eGFR is 15 mL / min / 1.73 m 2 For example, the method increases the time between when a subject's eGFR is below 15 mL / min / 1.73 m by at least about 1 year. 2 may be delayed by at least about 1.5 years, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about 5 years, about 5.5 years, about 6 years, about 6.5 years, about 7 years, about 7.5 years, about 8 years, about 8.5 years, about 9 years, about 9.5 years, about 10 years, about 11 years, about 12 years, about 13 years, about 15 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years, or about 20 years, or any value therebetween.

[0184] In some embodiments, the method reduces the average rate of decline of eGFR by about 0.75 mL / min / year to about 6 mL / min / year for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years) prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the method reduces the average rate of decline in eGFR by about 0.75 mL / min / year, about 1 mL / min / year, about 1.5 mL / min / year, about 2 mL / min / year, about 2.5 mL / min / year, about 3 mL / min / year, about 3.5 mL / min / year, about 4 mL / min / year, about 4.5 mL / min / year, about 5 mL / min / year, about 5.5 mL / min / year, or about 6 mL / min / year. In some embodiments, the method reduces the average rate of decline in eGFR by about 4 mL / min / year to about 5 mL / min / year for at least about 3 months prior to the first administration of atrasentan or a pharma- ceutically acceptable salt. In some embodiments, the method reduces the average rate of decline in eGFR by about 3 mL / min / year to about 6 mL / min / year for at least about 3 months prior to the first administration of atrasentan or a pharma-ceutically acceptable salt. In some embodiments, the method reduces the average rate of decline in eGFR by about 4 mL / min / year to about 5 mL / min / year for at least about 3 months prior to the first administration of atrasentan or a pharma- ceutical acceptable salt. In some embodiments, the decline in eGFR in mL / min / year is about 1.73 msec. 2 Refers to the unit of measure.

[0185] In some embodiments, the method reduces the mean percent decline in eGFR by about 15% to about 30% after about 6 months to about 24 months of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the mean percent decline in eGFR may be reduced by about 15% after about 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the mean percent decline in eGFR may be reduced by about 20% after about 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the mean percent decline in eGFR may be reduced by about 25% after about 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the average rate of decline in eGFR may be reduced by about 30% after about 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months of treatment with atrasentan or a pharma- ceutically acceptable salt thereof.

[0186] In another aspect, provided herein is a method of reducing proteinuria, comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof.

[0187] In some embodiments, the amount of protein (e.g., albumin) in the urine of the subject is reduced by at least about 10% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween).In some embodiments, the amount of protein in the urine of the subject is reduced by at least about 15%. For example, in some embodiments, the amount of protein in the subject's urine is reduced by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%, or any value therebetween. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 to about 30 days.

[0188] In certain embodiments, the amount of protein (e.g., albumin) in the subject's urine is reduced by about 20% to about 80% after about 15 to about 30 days of treatment with atrasentan or a pharma- ceutically acceptable salt thereof. In some of these embodiments, the amount of protein in the subject's urine is reduced by about 25% to about 80%. In some of these embodiments, the amount of protein in the subject's urine is reduced by about 30% to about 80%. In some of these embodiments, the amount of protein in the subject's urine is reduced by about 35% to about 80%. In some of these embodiments, the amount of protein in the subject's urine is reduced by about 40% to about 80%. In some of these embodiments, the amount of protein in the subject's urine is reduced by about 45% to about 80%. In some of these embodiments, the amount of protein in the subject's urine is reduced by about 50% to about 80%.

[0189] In some embodiments, the amount of protein (e.g., albumin) in the subject's urine is reduced by about 100 mg / dL to about 3,000 mg / dL after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 2500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 2,000 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 1,500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 1,000 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 400 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 300 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 200 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 2,500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 2,000 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 1,500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 1,000 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 900 mg / dL.In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 800 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 600 mg / dL to about 900 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 700 mg / dL to about 900 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 1,000 mg / dL to about 2,000 mg / dL. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days.

[0190] In certain embodiments, the amount of protein (e.g., albumin) in the subject's urine is reduced by about 100 mg / dL to about 500 mg / dL about 15 to about 30 days after treatment with atrasentan or a pharma- ceutically acceptable salt thereof. In certain embodiments, the amount of protein in the subject's urine is reduced by about 200 mg / dL to about 500 mg / dL about 15 to about 30 days after treatment with atrasentan or a pharma- ceutically acceptable salt thereof. In certain embodiments, the amount of protein in the subject's urine is reduced by about 300 mg / dL to about 500 mg / dL about 15 to about 30 days after treatment with atrasentan or a pharma- ceutically acceptable salt thereof.

[0191] In certain embodiments, the amount of protein (e.g., albumin) in the subject's urine is reduced by about 500 mg / dL to about 900 mg / dL about 15 to about 30 days after treatment with atrasentan or a pharma- ceutically acceptable salt thereof. In certain embodiments, the amount of protein in the subject's urine is reduced by about 600 mg / dL to about 900 mg / dL about 15 to about 30 days after treatment with atrasentan or a pharma- ceutically acceptable salt thereof. In certain embodiments, the amount of protein in the subject's urine is reduced by about 700 mg / dL to about 900 mg / dL about 15 to about 30 days after treatment with atrasentan or a pharma- ceutically acceptable salt thereof.

[0192] In some embodiments, the subject has a reduced level of urinary protein (e.g., albumin) of less than about 1.0 gram / day after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks of treatment). In some embodiments, the subject has a reduced level of urinary protein of less than about 0.9 gram / day. For example, in some embodiments, the subject has a reduced level of protein in the urine of less than about 0.8 grams / day, about 0.7 grams / day, about 0.6 grams / day, 0.5 grams / day, about 0.4 grams / day, about 0.3 grams / day, or about 0.2 grams / day, or any value therebetween. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days.

[0193] In some embodiments, the subject is about 15 to about 40 years old. In some embodiments, the subject is about 15 to about 25 years old, about 20 to about 30 years old, about 25 to about 35 years old, about 30 to about 40 years old, or any age therebetween. In some embodiments, the subject is about 20 to about 30 years old, or any age therebetween. In some embodiments, the subject is about 20 years old, about 21 years old, about 22 years old, about 23 years old, about 24 years old, about 25 years old, about 26 years old, about 27 years old, about 28 years old, about 29 years old, or about 30 years old.

[0194] In some embodiments, the patient's level of fatigue is reduced after treatment with atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, fatigue is reduced by about 5% to about 80% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In certain embodiments, fatigue is reduced by about 10% to about 75%. In certain embodiments, fatigue is reduced by about 10% to about 70%. In certain embodiments, fatigue is reduced by about 10% to about 65%. In certain embodiments, fatigue is reduced by about 10% to about 60%. In certain embodiments, fatigue is reduced by about 10% to about 55%. In certain embodiments, fatigue is reduced by about 10% to about 50%. In certain embodiments, fatigue is reduced by about 10% to about 45%. In certain embodiments, fatigue is reduced by about 10% to about 40%. In certain embodiments, fatigue is reduced by about 10% to about 35%. In certain embodiments, fatigue is reduced by about 10% to about 30%. In certain embodiments, fatigue is reduced by about 10% to about 25%. In certain embodiments, fatigue is reduced by about 10% to about 20%. In certain embodiments, fatigue is reduced by about 10% to about 15%. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days.In certain embodiments, the reduction in fatigue comprises a reduction in scores on one or more of the Fatigue Severity Scale, the Chalder Fatigue Scale, the FACIT Fatigue Scale, the Brief Fatigue Inventory, the FACT-F subscale, overall energy and impact, the May and Kline adjective checklist, the Pearson-Byars Fatigue Feelings Checklist, the Rhoten Fatigue Scale, the Schedule of Fatigue and Anergy, or individual intensities of the checklists.

[0195] Some embodiments provide a method of inhibiting mesangial cell activation in a subject having IgA nephropathy, comprising administering to the subject a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof, wherein the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure.

[0196] Some embodiments provide a method of inhibiting PDGF signaling activity (e.g., reducing the expression and / or activity of one or more of PIK3R1, PDGFRA, NFKBIA, PIK3CG, PLA2G4A, TIAM1, PDGFB, NFKB1, and MAP3K1) in mesangial cells in a subject with IgA nephropathy, comprising administering to the subject a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof, wherein the subject has not previously been diagnosed with one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure.

[0197] Some embodiments provide a method of inhibiting mesangial cell activation, comprising contacting mesangial cells with an effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof.

[0198] In some embodiments, mesangial activation is induced by IgA immune complexes. In some embodiments, mesangial activation is associated with the presence of IgA immune complexes. The presence and / or amount of IgA immune complexes can be detected by various methods. For example, complexes can be detected in serum or urine, and can also be detected in kidney biopsy samples.

[0199] In some embodiments, inhibiting mesangial cell activation comprises reducing expression and / or activity of one or more biomarkers indicative of mesangial cell proliferation. In some embodiments, inhibiting mesangial cell activation comprises reducing inflammation of mesangial cells. In some embodiments, reducing inflammation of mesangial cells comprises reducing expression and / or activity of one or more of IL6, MCP1, or other biomarkers indicative of mesangial cell inflammation. In some embodiments, reducing inflammation of mesangial cells comprises reducing expression and / or activity of IL-6. In some embodiments, the expression and / or activity of one or more biomarkers indicative of mesangial cell inflammation is reduced by about 25% to about 99% following treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks of treatment, or any value therebetween). In some embodiments, the expression and / or activity of one or more biomarkers indicative of mesangial cell inflammation is reduced by about 25% to about 50%, about 40% to about 60%, about 50% to about 75%, about 60% to about 80%, about 75% to about 90%, about 85% to about 99%, or any value therebetween. For example, in some such embodiments, the one or more biomarkers can be IL-6.

[0200] In some embodiments, inhibiting mesangial cell activation comprises reducing mesangial cell inflammation. In some embodiments, reducing mesangial cell inflammation comprises reducing IL-6 signaling (e.g., reducing expression and / or activity of one or more proteins involved in the IL-6 signaling pathway, e.g., reducing one or more of Cntfr, Il1b, Csf1, Il2ra, Map3k8, and Il1r1). In some embodiments, reducing mesangial cell inflammation comprises reducing expression and / or activity of one or more (e.g., one, two, three, four, or five) of Cntfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1.

[0201] In some embodiments, inhibiting activation of mesangial cells comprises reducing a fibrotic response in mesangial cells, hi some embodiments, reducing a fibrotic response in mesangial cells comprises reducing the expression and / or activity of one or more of NF-κB, TGF, PDGF, CTGF, MMPs, TIMPS, or other biomarkers indicative of mesangial cell fibrosis. In some embodiments, the expression and / or activity of one or more of NF-κB, TGF, PDGF, CTGF, MMPs, and TIMPS is reduced by about 25% to about 99% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween), compared to the expression and / or activity prior to administration of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the expression and / or activity of one or more of NF-κB, TGF, PDGF, CTGF, MMPs, and TIMPS is reduced by about 25% to about 50%, about 40% to about 60%, about 50% to about 75%, about 60% to about 80%, about 75% to about 90%, about 85% to about 99%, or any value therebetween.

[0202] In some embodiments, inhibiting activation of mesangial cells comprises reducing a fibrotic response in mesangial cells. In some embodiments, reducing a fibrotic response comprises reducing NF-κB signaling. In some embodiments, reducing a fibrotic response comprises reducing Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, Serpin1, Ccl20, Per1, Cxcl2, Map3k8, Reducing the expression and / or activity of one or more (e.g., one, two, three, four, or five) of Traf1, and / or increasing the expression and / or activity of one or more (e.g., one, two, three, four, or five) of Ehd1, Snn, Tnfaip8, Ackr3, Id2, Ccn1, Efna1, Ccnd1, Cdkn1a, Pnrc1 (where the component inhibits NF-κB signaling).

[0203] In some embodiments, reducing the fibrotic response comprises reducing PDGF signaling. In some embodiments, reducing the fibrotic response comprises reducing the expression and / or activity of one or more (e.g., one, two, three, four, or five) of Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1, Pdgfb, Nfkb1, and / or increasing the expression and / or activity of one or more (e.g., one, two, three, four, or five) of Hras (where the component inhibits PDGF signaling).

[0204] In some embodiments, the expression and / or activity of NF-κB and / or PDGF expression and / or activity is reduced by about 25% to about 99% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks of treatment, or any value therebetween), compared to the expression and / or activity before administration of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the expression and / or activity of NF-κB and / or PDGF is reduced by about 25% to about 50%, about 40% to about 60%, about 50% to about 75%, about 60% to about 80%, about 75% to about 90%, about 85% to about 99%, or any value therebetween.

[0205] In some embodiments, reducing a fibrotic response in mesangial cells comprises reducing matrix secretion by mesangial cells, hi some embodiments, reducing matrix secretion by mesangial cells comprises reducing expression and / or activity of one or more excessive matrix secretion by mesangial cells.

[0206] Some embodiments provide a method of reducing activation of mesangial cells in contact with IgA immune complexes, comprising contacting mesangial cells with an effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof. Reducing activation of mesangial cells comprises reducing expression and / or activity of one or more biomarkers indicative of mesangial cell proliferation.

[0207] In some embodiments, reducing mesangial cell activation comprises reducing mesangial cell inflammation, hi some embodiments, reducing mesangial cell inflammation comprises reducing expression and / or activity of one or more of IL6, MCP1, or other biomarkers indicative of mesangial cell inflammation.

[0208] In some embodiments, reducing mesangial cell activation comprises reducing a fibrotic response in mesangial cells, hi some embodiments, reducing a fibrotic response in mesangial cells comprises reducing the expression and / or activity of one or more of TGF, PDGF, CTGF, MMPs, TIMPS, or other biomarkers indicative of mesangial cell fibrosis.

[0209] In some embodiments, reducing a fibrotic response in mesangial cells comprises reducing matrix secretion by mesangial cells, hi some embodiments, reducing matrix secretion by mesangial cells comprises reducing the expression and / or activity of one or more biomarkers indicative of excessive matrix secretion by mesangial cells.

[0210] In some embodiments, reducing mesangial cell activation comprises reducing unwanted mesangial cell migration. In some embodiments, reducing unwanted mesangial cell migration occurs about 15 to about 30 days after treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, reducing unwanted mesangial cell migration occurs about 3 to about 6 months after treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0211] In some embodiments, reducing mesangial cell activation comprises reducing unwanted mesangial cell proliferation. In some embodiments, reducing unwanted mesangial cell proliferation occurs about 15 days to about 30 days after treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, reducing unwanted mesangial cell proliferation occurs about 3 months to about 6 months after treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0212] In some embodiments, unwanted mesangial cell proliferation is reduced by about 25% to about 99% following treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In some embodiments, unwanted mesangial cell proliferation is reduced by about 25% to about 50%, about 40% to about 60%, about 50% to about 75%, about 60% to about 80%, about 75% to about 90%, about 85% to about 99%, or any value therebetween.

[0213] In some embodiments, mesangial cell activation can be assessed by one or more of serum analysis, urine analysis, and microscopic examination (eg, light microscopy and / or immunofluorescence microscopy) of a kidney biopsy sample.

[0214] In some embodiments, the contacting occurs in vitro. In some embodiments, the contacting occurs in vivo.

[0215] Some embodiments provide a method of treating IgA nephropathy in a subject in need thereof, comprising: a) determining that the subject has an elevated serum Gd-IgA1 level; and b) administering to the subject a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure. In some embodiments, the subject has not been previously diagnosed with HIV-associated nephropathy. In some embodiments, the subject has not been previously diagnosed with cancer. In some embodiments, the cancer is lung cancer or prostate cancer.

[0216] Some embodiments provide a method of treating IgA nephropathy in a subject in need of such treatment, comprising: a) determining that the subject has an elevated level of mesangial activation; and b) administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, determining an elevated level of mesangial activation comprises obtaining a sample from the subject and assessing the level of mesangial activation in the same. In some embodiments, the sample is a kidney biopsy sample. In some embodiments, the sample is selected from a blood sample, a urine sample, a kidney biopsy sample, or a combination of two or three of the foregoing.

[0218] In some embodiments, the sample exhibits elevated levels of one or more of matrix secretion by mesangial cells, IgA immune complex deposition, mesangial cell proliferation, and intracapillary cell proliferation, hi some embodiments, the sample exhibits elevated levels of IgA immune complex deposition.

[0219] In some embodiments, the subject has been determined to have proteinuria of at least about 1 g / day on at least two of three consecutive measurements over a one-year period prior to administration of a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof, e.g., about 1 g / day, about 1.2 g / day, about 1.4 g / day, about 1.6 g / day, about 1.8 g / day, or at least about 2 g / day.

[0220] In some embodiments, the subject has been administered a maximally tolerated stable dose of a RAS inhibitor for at least 12 weeks prior to administration of a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject is administered a maximally tolerated stable dose of a RAS inhibitor and a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof simultaneously. In some embodiments, the RAS inhibitor is an angiotensin-converting enzyme inhibitor. In some embodiments, the RAS inhibitor is an angiotensin receptor blocker (ARB).

[0221] In some embodiments, the subject has been determined to have hematuria prior to administration of a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the hematuria is microscopic hematuria. In some embodiments, the hematuria is gross hematuria.

[0222] In some embodiments, the subject is administered at least 30 mL / min / 1.73 m prior to administration of a therapeutically effective amount of atrasentan or a pharma- ceutical acceptable salt thereof. 2 In some embodiments, the subject has been determined to have an eGFR of about 30 mL / min / 1.73 m prior to administration of a therapeutically effective amount of atrasentan or a pharmacologic acceptable salt thereof. 2 ~Approx. 60mL / min / 1.73m 2 It has been determined that the patient has an eGFR of .

[0223] In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure. In some embodiments, the subject has not been previously diagnosed with HIV-associated nephropathy. In some embodiments, the subject has not been previously diagnosed with cancer. In some embodiments, the cancer is lung cancer or prostate cancer.

[0224] Some embodiments provide a method of treating IgA nephropathy in a subject in need of such treatment, comprising: a) determining that the subject has elevated levels of IgA immune complexes in the kidney; and b) administering to the subject a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof.

[0225] In some embodiments, determining elevated levels of IgA immune complexes in the kidney comprises obtaining a sample from the subject and evaluating the level of IgA immune complexes in the same. In some embodiments, the sample is a kidney biopsy sample. In some embodiments, the sample is selected from a blood sample, a urine sample, a kidney biopsy sample, or a combination of two or three of the foregoing. In some embodiments, the IgA immune complexes are deposited in the mesangium.

[0226] In some embodiments, the level of IgA immune complexes can be assessed by one or more of serum analysis, urinalysis, and microscopic examination (e.g., light microscopy and / or immunofluorescence microscopy) of a kidney biopsy sample.

[0227] In some embodiments, the sample exhibits elevated levels of one or more of matrix secretion by mesangial cells, IgA immune complex deposition in the mesangium, mesangial cell activation, mesangial cell proliferation, and intracapillary cell proliferation.

[0228] In some embodiments, the subject has been determined to have proteinuria of at least about 1 g / day on at least two of three consecutive measurements over a one-year period prior to administration of a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof, e.g., about 1 g / day, about 1.2 g / day, about 1.4 g / day, about 1.6 g / day, about 1.8 g / day, or at least about 2 g / day.

[0229] In some embodiments, the subject has been administered a maximally tolerated stable dose of a RAS inhibitor for at least 12 weeks prior to administration of a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject is administered a maximally tolerated stable dose of a RAS inhibitor and a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof simultaneously. In some embodiments, the RAS inhibitor is an angiotensin-converting enzyme inhibitor. In some embodiments, the RAS inhibitor is an angiotensin receptor blocker (ARB).

[0230] In some embodiments, the subject has been determined to have hematuria prior to administration of a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the hematuria is microscopic hematuria. In some embodiments, the hematuria is gross hematuria.

[0231] In some embodiments, the subject is administered at least 30 mL / min / 1.73 m prior to administration of a therapeutically effective amount of atrasentan or a pharma- ceutical acceptable salt thereof. 2 In some embodiments, the subject has been determined to have an eGFR of about 30 mL / min / 1.73 m prior to administration of a therapeutically effective amount of atrasentan or a pharmacologic acceptable salt thereof. 2 ~Approx. 60mL / min / 1.73m 2 It has been determined that the patient has an eGFR of .

[0232] In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure. In some embodiments, the subject has not been previously diagnosed with HIV-associated nephropathy. In some embodiments, the subject has not been previously diagnosed with cancer. In some embodiments, the cancer is lung cancer or prostate cancer.

[0233] In some embodiments, the method includes determining in the subject the expression and / or activity of one or more of ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, and NF-kB. In some embodiments, the expression and / or activity is determined prior to administration of a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the expression and / or activity is determined after administration of a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof.

[0234] In some embodiments, determining expression and / or activity is performed prior to administration of a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, determining expression and / or activity is performed after administration of a therapeutically effective amount of atrasentan or a pharma- ceutically acceptable salt thereof, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks of treatment, or any value therebetween.

[0235] In some embodiments, the subject is diagnosed with ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, NF-kB, PKC, PI3K, Src, Ras, ERK1 / 2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA 2 , TNF-α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt / PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK, MCP1, Cntfr , Il1b, Csf1, Il2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, and have been determined to have expression and / or activity of one or more of Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, serpin1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1, and Pdgfb. In some embodiments, the subject is diagnosed with ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, NF-kB, PKC, PI3K, Src, Ras, ERK1 / 2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA 2, TNF-α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt / PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK, and MCP1. In some embodiments, the subject has been determined to have elevated expression and / or activity of one or more of Cntfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, Serpin1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1, and Pdgfb. In some embodiments, the subject is determined to have elevated expression and / or activity of one or more of ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, and NF-kB. In some embodiments, the subject is determined to have elevated expression and / or activity of one or more of ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, and SLC6A19.

[0236] Some embodiments include a method of treating IgA nephropathy in a subject, the method comprising: (a) administering to the subject an amount of ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, NF-kB, PKC, PI3K, Src, Ras, ERK1 / 2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA 2, TNF-α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt / PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK, MCP1, Cntfr, Il1b, Csf1, Il2r a, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1 , Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, serpin1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1, and Pdgfb; and (b) administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutical acceptable salt thereof.

[0237] Some embodiments include ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, NF-kB, PKC, PI3K, Src, Ras, ERK1 / 2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA 2, TNF-α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt / PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK, MCP1, Cntfr, Il1b, Csf1, Il2ra, Ma p3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10 The present invention provides a method for treating IgA nephropathy in a subject determined to have elevated expression and / or activity of one or more of: Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, serpin1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1, and Pdgfb, comprising administering to the subject a therapeutically effective amount of atrasentan or a pharma- ceutical acceptable salt thereof.

[0238] D. Atrasentan Atrasentan, also known as (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid, ABT-627, A-147627, or A-127722, is a small molecule of the following chemical structure: [ka]

[0239] Atrasentan and methods for its preparation are described in U.S. Pat. No. 7,208,517 and International Patent Application Publication No. WO 1997 / 030045 (see, e.g., Example 501), each of which is incorporated herein by reference in their entirety.

[0240] In some embodiments, atrasentan is administered as a free base. In some other embodiments, atrasentan is administered as a pharma- ceutically acceptable salt, as described elsewhere herein.

[0241] Atrasentan is an ET A Inhibitor, ET B Compared to E.T. A As used herein, "ET A " is an abbreviation for endothelin receptor A, and "ET B " is an abbreviation for endothelin receptor B. See, e.g., Ann Rheum Dis., 66(11), pp. 1467-1472 (2007), Eur.Resp.J., 37, pp. 475-476 (2011), Plos One, 9, e87548 (2014), J.Clin.Oncol., 10, 31(14), pp. 1740-7 (2013), Pharmacol.Rev., 68(2) pp. 357-418 (2016), and Nephrol.Dial.Transplant., 29, pp. i69-i73 (2014).

[0242] salt In some embodiments, atrasentan is in the form of a pharmaceutically acceptable salt. As used herein, the phrase "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the present disclosure (e.g., atrasentan). Exemplary salts include acid addition salts formed by the reaction between atrasentan and an acid (e.g., an organic or inorganic acid). Non-limiting examples include sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, hydrogen sulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, mandelate (e.g., (S)-mandelate or (R)-mandelate), gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate, and p-toluenesulfonate, pamoate (i.e., 4,4'-methylene-bis-(2-hydroxy-3-naphthoate)) salt. Exemplary salts also include base addition salts formed by the reaction between atrasentan and a base. Non-limiting examples include alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule, such as an acetate ion, a succinate ion, or other counterion. A counterion may be any organic or inorganic moiety that stabilizes the charge of the parent compound. In addition, a pharmaceutically acceptable salt may have more than one charged atom in its structure. When multiple charged atoms are part of a pharmaceutically acceptable salt, it may have multiple counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions. When referring to atrasentan, the term "salt(s)" is understood to be a salt of atrasentan that may be present alone or in a mixture with free atrasentan.

[0243] In some embodiments, atrasentan is in the form of a hydrochloride salt. Atrasentan hydrochloride, also known as atrasentan hydrochloride (CAS number: 195733-43-8); Atrasentan hydrochloride; Atrasentan hydrochloride; Atrasentan chloride salt; Atrasentan HCl; Atrasentan monohydrochloride; (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid, monohydrochloride; 3-pyrrolidine carboxylic acid, 4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid, monohydrochloride; methoxyphenyl)-, hydrochloride (1:1), (2R,3R,4S)-; (2R,3R,4S)-1-[(dibutylcarbamoyl)methyl]-2-(p-methoxyphenyl)-4-[3,4-(methylenedioxy)phenyl]-3-pyrrolidinecarboxylic acid, monohydrochloride; 3-Pyrrolidinecarboxylic acid, 4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)-, monohydrochloride, [2R-(2α,3β,4α)]; ABT-627; A-147627.1; Abbott-147627.1 has the following structure: [ka] The molar ratio of atrasentan to chloride is 1: 1. Atrasentan hydrochloride and methods for its preparation are further described in U.S. Patent No. 7,208,517 and International Patent Application Publication No. WO 1997 / 030045 (see, e.g., Example 501), each of which is incorporated herein by reference in their entirety.

[0244] In some embodiments, atrasentan is in the form of a mandelate salt. In certain embodiments, atrasentan is in the form of an (S)-mandelate salt. In certain embodiments, atrasentan is in the form of an (R)-mandelate salt. In certain embodiments, in the atrasentan mandelate salt, atrasentan and the mandelate salt have a molar ratio of 1:1. In certain embodiments, in the atrasentan mandelate salt, atrasentan and the mandelate salt have a molar ratio of 2:1. Atrasentan mandelate salt and methods for its preparation are further described in U.S. Patent Nos. 8,962,675 and 9,637,476, each of which is incorporated herein by reference in its entirety.

[0245] In some embodiments, atrasentan is in the form of a hemisulfate salt. Hemisulfate salts and methods for their preparation are further described in U.S. Patent Nos. 8,962,675 and 9,637,476, each of which is incorporated herein by reference in its entirety.

[0246] In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is in the form of anhydrous gypsum. In certain embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is in the form of a hydrate. In certain embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is in the form of a solvate.

[0247] stereochemistry Atrasentan has three asymmetric centers and can be produced as individual stereoisomers (e.g., enantiomers or diastereomers) or mixtures thereof, as described in U.S. Pat. No. 7,208,517 and International Patent Application Publication No. WO 1997 / 030045. In some embodiments, atrasentan described herein comprises the (2R,3R,4S)-stereoisomer, which is (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid. In certain embodiments, atrasentan is the (2R,3R,4S)-stereoisomer that is substantially free of other stereoisomers (e.g., contains <10%, <5%, <2%, <1%, <0.5%, <0.1%, <0.05% of other stereoisomers).

[0248] polymorph As described herein, atrasentan or a pharma- ceutically acceptable salt thereof may be in one or more polymorphic forms. In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is substantially amorphous (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% amorphous). In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is substantially crystalline (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% crystalline).

[0249] In certain embodiments, atrasentan or a pharma- ceutically acceptable salt thereof comprises atrasentan hydrochloride crystalline Form 1. In certain embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is substantially atrasentan hydrochloride crystalline Form 1 (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% Form 1). Atrasentan hydrochloride crystalline Form 1 and methods for making it are described in International Patent Application Publication No. WO 2006 / 034094, which is incorporated herein by reference in its entirety.

[0250] In some embodiments, atrasentan hydrochloride crystalline Form 1 is characterized by an X-ray powder diffraction pattern having at least three (e.g., three, four, five, six, or seven) peaks having 2θ values ​​of about 8.3°, 9.7°, 10.0°, 13.0°, 15.6°, 17.2°, or 19.5°, respectively, when measured with Cu-Kα radiation at about 25° C. In certain embodiments, atrasentan hydrochloride crystalline Form 1 is characterized by an X-ray powder diffraction pattern having at least three peaks having 2θ values ​​of about 8.3°, 9.7°, 10.0°, 13.0°, 15.6°, 17.2°, or 19.5°, respectively, and essentially no peaks having 2θ values ​​less than about 6.2° and / or between about 6.6° and 8.0°, when measured with Cu-Kα radiation at about 25° C.

[0251] In some embodiments, atrasentan hydrochloride crystalline Form 1 is orthorhombic and P2 l 2 l 2 l It is characterized by lattice parameters a, b, and c of 17.663 ű0.005 Å, 21.24 ű0.01 Å, and 8.005 ű0.002 Å, respectively, measured with Cu-Kα radiation at about 25° C. in the space group.

[0252] In some embodiments, atrasentan hydrochloride crystalline Form 1 has substantial crystalline purity. In some embodiments, atrasentan hydrochloride crystalline Form 1 has substantial chemical purity. In some embodiments, atrasentan hydrochloride crystalline Form 1 has substantial diastereomeric purity.

[0253] Representative characteristic peak positions of the X-ray powder diffraction pattern of atrasentan hydrochloride crystalline Form I, expressed as angles relative to 2θ, are approximately 8.3° ((020), 77.35%), 9.7° ((120), 76.37%), 10.0° ((200), 14.53%), 13.2° ((220), 28.03%), 13.6° ((130), 16.71%), 14.9° ((121), 38.93%) and 15.8° ((130), 16.72%), when measured at about 25°C with Cu-Ka radiation. ((310), 13.11%), 16.2° ((230), 18.09%), 17.4° ((320), 15.87%), 17.5° ((131), 37.80%), 19.6° ((240), 28.77%), 20.8° ((141), 46.26%), 23.3° ((112), 100.0%), 24.3° ((151), 52.6%), 25.3° ((341), 13.08%), and 25.9° ((132), 33.98%). Each peak position is shown with its associated Miller index (hkl) value and its integrated intensity (peak height). It is understood that peak heights may vary and are dependent on variables such as temperature, crystal size or morphology, sample preparation, or sample height in the analysis well of the Scintag x2 diffraction pattern system. It is also understood that peak positions may vary when measured with different radiation sources. For example, Cu-Kα1, Mo-Kα, Co-Kα, and Fe-Kα radiation, having wavelengths of 1.54060 Å, 0.7107 Å, 1.7902 Å, and 1.9373 Å, respectively, may provide peak positions that are different from those measured with Cu-Kα radiation.

[0254] In certain embodiments, atrasentan or a pharma- ceutically acceptable salt thereof comprises atrasentan hydrochloride crystalline Form 2. In certain embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is substantially atrasentan hydrochloride crystalline Form 2 (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% Form 2). Atrasentan hydrochloride crystalline Form 2 and methods for making it are described in International Patent Application Publication No. WO 2006 / 034094, which is incorporated herein by reference in its entirety.

[0255] In certain embodiments, atrasentan hydrochloride crystalline Form 2 is characterized by an X-ray powder diffraction pattern having peaks having 2θ values ​​of about 6.7° and 22.05°, respectively, and at least one peak having a 2θ value of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6°, respectively, when measured at about 25° C. using Cu-Kα radiation.

[0256] In certain embodiments, atrasentan hydrochloride crystalline Form 2 has substantial crystalline purity and is characterized by an X-ray powder diffraction pattern having peaks having 2θ values ​​of about 6.7° and 22.05°, respectively, and at least one peak having a 2θ value of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6°, respectively, when measured at about 25° C. using Cu-Kα radiation.

[0257] In certain embodiments, atrasentan hydrochloride crystalline Form 2 has substantial crystalline purity and substantial chemical purity, and the atrasentan hydrochloride crystalline Form 2 is characterized by an X-ray powder diffraction pattern having peaks having 2θ values ​​of about 6.7° and 22.05°, respectively, and at least one peak having a 2θ value of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6°, respectively, when measured using Cu-Kα radiation at about 25°C.

[0258] In certain embodiments, atrasentan hydrochloride crystalline Form 2 has substantial crystalline purity, substantial chemical purity, and substantial diastereomeric purity, and the atrasentan hydrochloride crystalline Form 2 is characterized by an X-ray powder diffraction pattern having peaks having 2θ values ​​of about 6.7° and 22.05°, respectively, and at least one peak having a 2θ value of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6°, respectively, when measured using Cu-Kα radiation at about 25°C.

[0259] In certain embodiments, atrasentan or a pharma- ceutically acceptable salt thereof comprises atrasentan hydrochloride crystalline Form 3. In certain embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is substantially atrasentan hydrochloride crystalline Form 3 (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% Form 3). Atrasentan hydrochloride crystalline Form 3 and methods of making it are described in International Patent Application Publication No. WO 2006 / 034234 and U.S. Patent No. 9,051,301, each of which is incorporated herein by reference in its entirety.

[0260] In certain embodiments, atrasentan hydrochloride crystalline Form 3 is characterized by an X-ray powder diffraction pattern having peaks having 2θ values ​​of about 6.7° and 21.95°, respectively, and at least one peak having a 2θ value of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6°, respectively, when measured at about 25° C. using Cu-Kα radiation.

[0261] In certain embodiments, atrasentan hydrochloride crystalline Form 3 has substantial crystalline purity and is characterized by an X-ray powder diffraction pattern having peaks having 2θ values ​​of about 6.7° and 21.95°, respectively, and at least one peak having a 2θ value of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6°, respectively, when measured at about 25° C. using Cu-Kα radiation.

[0262] In certain embodiments, atrasentan hydrochloride crystalline Form 3 has substantial crystalline purity and substantial chemical purity, and the atrasentan hydrochloride crystalline Form 3 is characterized by an X-ray powder diffraction pattern having peaks having 2θ values ​​of about 6.7° and 21.95°, respectively, and at least one peak having a 2θ value of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6°, respectively, when measured using Cu-Kα radiation at about 25°C.

[0263] In certain embodiments, atrasentan hydrochloride crystalline Form 3 has substantial crystalline purity, substantial chemical purity, and substantial diastereomeric purity, and the atrasentan hydrochloride crystalline Form 3 is characterized by an X-ray powder diffraction pattern having peaks having 2θ values ​​of about 6.7° and 21.95°, respectively, and at least one peak having a 2θ value of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6°, respectively, when measured using Cu-Kα radiation at about 25°C.

[0264] In certain embodiments, atrasentan or a pharma- ceutically acceptable salt thereof comprises amorphous atrasentan hydrochloride. In certain embodiments, atrasentan hydrochloride is substantially amorphous (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% amorphous). Amorphous atrasentan hydrochloride and methods for making it are described in International Patent Application Publication No. WO 2006 / 034085, which is incorporated herein by reference in its entirety.

[0265] In certain embodiments, the amorphous atrasentan hydrochloride has substantial chemical purity. In certain embodiments, the amorphous atrasentan hydrochloride has substantial diastereomeric purity.

[0266] In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof comprises crystalline atrasentan mandelate. In certain embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is substantially crystalline atrasentan mandelate (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% crystalline atrasentan mandelate).

[0267] In certain embodiments, the crystalline atrasentan mandelate is a crystalline atrasentan (S)-mandelate. In certain embodiments, the atrasentan (S)-mandelate is an anhydrous salt. In certain embodiments, the atrasentan (S)-mandelate is a solvated salt. In certain embodiments, the atrasentan (S)-mandelate is a solvated salt selected from the group consisting of an acetonitrile solvate, an ethanol solvate, and a pyridine solvate. In certain embodiments, the atrasentan (S)-mandelate is a hydrated salt. (a) (S)-Mandelate salt (1:1 stoichiometry)

[0268] In certain embodiments, the crystalline atrasentan (S)-mandelate is a crystalline atrasentan (S)-mandelate, and the molar ratio of atrasentan to (S)-mandelate is about 1:1. In certain embodiments, the atrasentan (S)-mandelate is an anhydrous salt. In certain embodiments, the atrasentan (S)-mandelate is a solvated salt. In certain embodiments, the atrasentan (S)-mandelate is a solvated salt selected from the group consisting of an acetonitrile solvate, an ethanol solvate, and a pyridine solvate. In certain embodiments, the atrasentan (S)-mandelate is a hydrated salt. In certain embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is substantially (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5%) crystalline atrasentan (S)-mandelate salt, and the molar ratio of atrasentan to (S)-mandelate salt is about 1:1.

[0269] In certain embodiments, the crystalline (S)-mandelate salt has an X-ray powder diffraction pattern comprising peaks at 5.5±0.2, 9.7±0.2, and 19.4±0.2 degrees 2θ when measured at about 25° C. using monochromatic Kα1 radiation. In certain embodiments, the crystalline (S)-mandelate salt has an X-ray powder diffraction pattern comprising peaks at 5.5±0.2, 9.7±0.2, 12.1±0.2, and 19.4±0.2 degrees 2θ when measured at about 25° C. using monochromatic Kα1 radiation. Radiation. In certain embodiments, the crystalline (S)-mandelate salt has an X-ray powder diffraction pattern comprising peaks at 5.5±0.2, 9.7±0.2, 12.1±0.2, 18.0±0.2, 18.4±0.2, and 19.4±0.2 degrees 2θ when measured at about 25° C. using monochromatic Kα1 radiation. In certain embodiments, the experimental error associated with the X-ray powder diffraction peak values ​​listed in the various embodiments above is ±0.1 degrees 2θ. In certain embodiments, the crystalline (S)-mandelate salt is an anhydrous salt. In certain embodiments, the molar ratio of atrasentan to (S)-mandelate salt is about 1:1.

[0270] In certain embodiments, the crystalline (S)-mandelate salt has an orthorhombic lattice type. In certain embodiments, the crystalline (S)-mandelate salt has a P2 1 2 1 2 1 The space group is 0.01 to 0.15. In certain embodiments, the crystalline (S)-mandelate salt has unit cell a, b, and c values ​​of about 9.954 Å, about 11.049 Å, and about 30.861 Å, respectively. In certain embodiments, the crystalline (S)-mandelate salt has unit cell α, β, and γ values ​​of about 90°, about 90°, and about 90°, respectively. In certain embodiments, the crystalline (S)-mandelate salt has the characteristics: (a) an orthorhombic lattice type; (b) a P2 1 2 1 2 1(c) unit cell a, b, and c values ​​of about 9.954 Å, about 11.049 Å, and about 30.861 Å, respectively, and / or (d) unit cell α, β, and γ values ​​of about 90°, about 90°, and about 90°, respectively. In certain embodiments, the crystalline (S)-mandelate salt has at least three or more of: (a) an orthorhombic lattice type; (b) a P2 1 2 1 2 1 space group, (c) unit cell a, b, and c values ​​of about 9.954 Å, about 11.049 Å, and about 30.861 Å, respectively, and / or (d) unit cell α, β, and γ values ​​of about 90°, about 90°, and about 90°, respectively. In certain embodiments, the crystalline (S)-mandelate salt is an anhydrous salt. In certain embodiments, the molar ratio of atrasentan to (S)-mandelate salt is about 1:1. (b) (S)-Mandelate salt (2:1 stoichiometry)

[0271] In certain embodiments, the crystalline (S)-mandelate salt is crystalline atrasentan (S)-mandelate salt, and the molar ratio of atrasentan to (S)-mandelate salt is about 2:1. In certain embodiments, the crystalline atrasentan (S)-mandelate salt is an anhydrous salt. In certain embodiments, the crystalline atrasentan (S)-mandelate salt is a solvated salt. In certain embodiments, the crystalline atrasentan (S)-mandelate salt is a hydrated salt. In certain embodiments, the atrasentan or a pharma- ceutically acceptable salt thereof is substantially (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5%) crystalline atrasentan (S)-mandelate salt, and the molar ratio of atrasentan to (S)-mandelate salt is about 2:1.

[0272] In certain embodiments, the crystalline (S)-mandelate salt has an X-ray powder diffraction pattern comprising peaks at 4.5±0.2, 8.6±0.2, and 18.1±0.2 degrees 2θ when measured at about 25° C. using monochromatic Kα1 radiation. In certain embodiments, the crystalline (S)-mandelate salt has an X-ray powder diffraction pattern comprising peaks at 4.5±0.2, 8.6±0.2, 18.1±0.2, and 18.7±0.2 degrees 2θ when measured at about 25° C. using monochromatic Kα1 radiation. In certain embodiments, the crystalline (S)-mandelate salt has an X-ray powder diffraction pattern comprising peaks at 4.5±0.2, 8.6±0.2, 9.1±0.2, 18.1±0.2, and 18.7±0.2 degrees 2θ when measured at about 25° C. using monochromatic Kα1 radiation. In certain embodiments, the experimental error associated with the X-ray powder diffraction peak values ​​listed in the various embodiments above is ±0.1 degrees 2θ. In certain embodiments, the crystalline (S)-mandelate salt is an anhydrous salt. In certain embodiments, the crystalline (S)-mandelate salt is a hydrated salt.

[0273] In certain embodiments, the crystalline atrasentan mandelate is a crystalline atrasentan (R)-mandelate. In certain embodiments, the crystalline atrasentan (R)-mandelate is an anhydrous salt. In certain embodiments, the crystalline atrasentan (R)-mandelate is a solvated salt. In certain embodiments, the crystalline atrasentan (R)-mandelate is a hydrated salt. (c) (R)-Mandelate salt (1:1 stoichiometry)

[0274] In certain embodiments, the crystalline atrasentan (R)-mandelate is crystalline atrasentan (R)-mandelate, and the molar ratio of atrasentan to (R)-mandelate is about 1:1. In certain embodiments, the crystalline atrasentan (R)-mandelate is an anhydrous salt. In certain embodiments, the crystalline atrasentan (R)-mandelate is a solvated salt. In certain embodiments, the crystalline atrasentan (R)-mandelate is a hydrated salt. In certain embodiments, the atrasentan or a pharma- ceutically acceptable salt thereof is substantially (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5%) crystalline atrasentan (R)-mandelate, and the molar ratio of atrasentan to (R)-mandelate is about 1:1.

[0275] In certain embodiments, the crystalline atrasentan (R)-mandelate has an X-ray powder diffraction pattern comprising peaks at 5.7±0.2, 11.8±0.2, and 20.9±0.2 degrees 2θ when measured at about 25° C. using monochromatic Kα1 radiation. In certain embodiments, the crystalline atrasentan (R)-mandelate has an X-ray powder diffraction pattern comprising peaks at 5.7±0.2, 8.2±0.2, 11.8±0.2, and 20.9±0.2 degrees 2θ when measured at about 25° C. using monochromatic Kα1 radiation. In certain embodiments, the crystalline atrasentan (R)-mandelate has an X-ray powder diffraction pattern comprising peaks at 5.7±0.2, 8.2±0.2, 8.6±0.2, 11.8±0.2, and 20.9±0.2 degrees 2θ when measured at about 25° C. using monochromatic Kα1 radiation. In certain embodiments, the experimental error associated with the X-ray powder diffraction peak values ​​recited in the various embodiments above is ±0.1 degrees 2θ. In certain embodiments, the crystalline atrasentan (R)-mandelate salt is an anhydrous salt.

[0276] In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof comprises amorphous atrasentan mandelate. In certain embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is substantially amorphous atrasentan mandelate (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% amorphous atrasentan mandelate).

[0277] In certain embodiments, the amorphous atrasentan mandelate is amorphous atrasentan (S)-mandelate. In certain embodiments, the amorphous atrasentan (S)-mandelate is an anhydrous salt. In certain embodiments, the amorphous atrasentan (S)-mandelate is a solvated salt. In certain embodiments, the amorphous atrasentan (S)-mandelate is a solvated salt selected from the group consisting of an acetonitrile solvate, an ethanol solvate, and a pyridine solvate. In certain embodiments, the amorphous atrasentan (S)-mandelate is a hydrated salt. In certain embodiments, in the amorphous atrasentan (S)-mandelate, the molar ratio of atrasentan and the (S)-mandelate is about 1:1. In certain embodiments, in the amorphous atrasentan (S)-mandelate, the molar ratio of atrasentan and the (S)-mandelate is about 2:1.

[0278] In certain embodiments, the amorphous atrasentan mandelate is amorphous atrasentan (R)-mandelate. In certain embodiments, the amorphous atrasentan (R)-mandelate is an anhydrous salt. In certain embodiments, the amorphous atrasentan (R)-mandelate is a solvated salt. In certain embodiments, the amorphous atrasentan (R)-mandelate is a solvated salt selected from the group consisting of an acetonitrile solvate, an ethanol solvate, and a pyridine solvate. In certain embodiments, the amorphous atrasentan (R)-mandelate is a hydrated salt. In certain embodiments, in the amorphous atrasentan (R)-mandelate, the molar ratio of atrasentan and the (R)-mandelate is about 1:1. In certain embodiments, in the amorphous atrasentan (R)-mandelate, the molar ratio of atrasentan and the (R)-mandelate is about 2:1.

[0279] Crystalline and amorphous atrasentan mandelate salts are further described in US Pat. Nos. 8,962,675 and 9,637,476, each of which is incorporated herein by reference in its entirety.

[0280] E. Preparation The term "pharmaceutical composition" as used herein includes a product that contains an active ingredient and an inactive ingredient that constitutes a carrier, as well as any product that is obtained directly or indirectly from the combination, complexation, or aggregation of any two or more ingredients, or from the dissociation of one or more ingredients, or from other types of reaction or interaction of one or more ingredients.Thus, the pharmaceutical composition of the present disclosure encompasses any composition made by mixing a compound of the present disclosure, or a pharmaceutically acceptable salt, or a solvate or solvate of the salt, and a pharmaceutically acceptable carrier.

[0281] The amount administered varies depending on the compound formulation, route of administration, etc., and is generally determined experimentally, and will necessarily vary depending on the target, host, route of administration, etc. The amount of active compound in a unit dose of the formulation may vary or be adjusted from about 0.1 milligrams (mg) to about 10 mg or from about 0.5 mg to about 2 mg depending on the specific application. For convenience, the total daily dose may be divided and administered in portions throughout the day.

[0282] The pharmaceutical compositions of the present disclosure for injection include pharma- ceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions immediately before use.Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0283] These pharmaceutical compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersing agents. Prevention of microbial action may be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of injectable dosage forms may be brought about by including agents that delay absorption, such as aluminum monostearate and gelatin. The compound may be incorporated into sustained release or targeted delivery systems, such as polymer matrices, liposomes, and microspheres. Such formulations may provide more effective distribution of the compound.

[0284] Pharmaceutical compositions that are injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0285] Solid dosage forms of the extemporaneous pharmaceutical compositions for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be optionally mixed with at least one inert pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants, such as glycerol, d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, for example, cetyl alcohol and glycerol monostearate, h) adsorbents, such as kaolin and bentonite clay, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0286] Solid pharmaceutical compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0287] The solid dosage forms of the instant pharmaceutical composition of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other pharmaceutical coatings. They can optionally contain opacifying agents, and they can be of the formulation that the active ingredient is only, or preferentially, optionally in a delayed manner, in a certain part of the intestinal tract. Examples of the embedded pharmaceutical composition that can be used include polymeric substances and waxes.

[0288] The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0289] The liquid dosage form of the ready-to-use pharmaceutical composition for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup and elixir.In addition to active compound, liquid dosage form can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan fatty acid ester and mixtures thereof.

[0290] Besides inert diluents, the oral pharmaceutical compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0291] Suspensions of the present compounds may contain, in addition to the active compound, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, metahydroxyaluminum, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0292] The compounds and compositions described herein can be administered, for example, orally or parenterally, at dosages ranging from about 0.01 milligrams per kilogram (mg / kg) to about 0.05 mg / kg, every 4-120 hours, or depending on the needs of the particular drug, dosage form, and / or route of administration. The interrelationship of animal and human dosages (based on milligrams per square meter of body surface) is described by Freireich et al., Cancer Chemother. Rep. 50, 219-244 (1966). Body surface area can be determined from the patient's height and weight. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, NY, 537 (1970). In certain embodiments, the compositions are administered orally or by injection. The methods herein contemplate administration of an effective amount of the compound or compound composition to achieve the desired or described effect. Typically, the pharmaceutical compositions of this disclosure will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.

[0293] Lower or higher doses than those listed above may be required. The specific dosage and treatment regimen for any particular patient depends on a variety of factors, including the activity of the particular compound used, age, body weight, general health, sex, diet, administration time, excretion rate, drug combination, severity and course of the disease, condition or symptom, the patient's predisposition to the disease, and the judgment of the treating physician.

[0294] The dosage form contains from about 0.01 mg to about 10 mg (including from about 0.1 mg to about 5 mg, from about 0.2 mg to about 4 mg, from about 0.3 mg to about 3 mg, from about 0.4 mg to about 2 mg, from about 0.5 mg to about 1.5 mg, or from about 0.6 mg to about 1 mg) of the compound atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage form comprises about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 mg, or any value therebetween of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage form comprises about 0.75 mg of the atrasentan compound or a pharma- ceutically acceptable salt thereof.

[0295] The dosage form may further comprise a pharma- ceutically acceptable carrier and / or an additional therapeutic agent.

[0296] Suitable dosage levels may be determined by any suitable method. Preferably, the active substance is administered at a frequency of 1 to 4 times a day for topical administration, or less frequently if a drug delivery system is used. Nevertheless, the actual dosage levels and time course of administration of the active ingredient in the pharmaceutical compositions of the present disclosure may be varied to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and method of administration without being intolerably toxic to the patient. In some cases, the dosage may deviate from the amounts described, depending in particular on the age, sex, weight, diet, and general health of the patient, the route of administration, the individual response to the active ingredient, the nature of the formulation, and the time or interval at which administration is performed. Thus, in some cases, it may be sufficient to use less than the minimum amount specified above, while in other cases the upper limit specified may be exceeded. When larger amounts are administered, it may be advisable to divide these into multiple individual doses over the course of a day.

[0297] Exemplary Dosage Forms of Atrasentan In some embodiments, provided herein is a stable solid pharmaceutical dosage form comprising: (a) about 0.25 mg to about 1.25 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof (wherein the weight percent of atrasentan or a pharma- ceutically acceptable salt thereof in the dosage form is about 0.05 weight percent to about 2.0 weight percent on an atrasentan free base equivalent basis); and (b) a pharma- ceutically acceptable diluent.

[0298] In some embodiments, provided herein is a stable solid pharmaceutical dosage form comprising: (a) about 0.25 mg to about 1.25 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof (the weight percentage of atrasentan or a pharma- ceutically acceptable salt thereof in the dosage form is about 0.05 weight percent to about 2.0 weight percent on an atrasentan free base equivalent basis); (b) a pharma- ceutically acceptable antioxidant (the molar ratio of antioxidant to atrasentan or a pharma- ceutically acceptable salt thereof is about 10:1 to about 1:10); and (c) a pharma- ceutically acceptable diluent.

[0299] In some of these embodiments, degradation of atrasentan in the dosage form is less than the degradation of atrasentan in an otherwise identical dosage form lacking the antioxidant when the dosage form is stored at about 40° C. and about 75% relative humidity for a storage period of six months.

[0300] In some embodiments, the dosage form is stored in a semi-permeable or substantially impermeable container during storage. In some embodiments, the dosage form is stored in a sealed HDPE bottle or blister package during storage. In some embodiments, the dosage form is stored in a sealed HDPE bottle during storage. In some embodiments, the dosage form is stored in a blister package during storage.

[0301] (i) Atrasentan The dosage form may comprise atrasentan free base, a pharma- ceutically acceptable salt of atrasentan, or a combination thereof. In some embodiments, the dosage form comprises atrasentan free base. In some embodiments, the dosage form comprises a pharma- ceutically acceptable salt of atrasentan. In some embodiments, the dosage form comprises atrasentan hydrochloride. In some embodiments, the dosage form comprises atrasentan hydrochloride having a polymorphic form selected from the group consisting of amorphous atrasentan hydrochloride, atrasentan hydrochloride crystalline form 1, atrasentan hydrochloride crystalline form 2, and atrasentan hydrochloride crystalline form 3. In some embodiments, the dosage form comprises amorphous atrasentan hydrochloride. In some embodiments, the dosage form comprises atrasentan hydrochloride crystalline form 1. In some embodiments, the dosage form comprises atrasentan hydrochloride crystalline form 2. In some embodiments, the dosage form comprises atrasentan hydrochloride crystalline form 3. In some embodiments, the dosage form comprises atrasentan mandelate. In certain embodiments, the dosage form comprises crystalline atrasentan mandelate salt (e.g., crystalline atrasentan (S)-mandelate salt and / or crystalline atrasentan (R)-mandelate salt). In certain embodiments, the dosage form comprises amorphous atrasentan mandelate salt (e.g., amorphous atrasentan (S)-mandelate salt and / or amorphous atrasentan (R)-mandelate salt). In some of the foregoing embodiments (where the dosage form comprises crystalline and / or amorphous atrasentan (S)- and / or (R)-mandelate salt), the molar ratio of atrasentan to mandelate salt is 1:1. In certain other embodiments, the molar ratio of atrasentan to mandelate salt is 2:1.

[0302] In certain embodiments, the dosage form comprises amorphous atrasentan hydrochloride and is substantially free (e.g., contains <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) of other forms of atrasentan (e.g., other salts and / or other polymorphs). In certain embodiments, the dosage form comprises atrasentan hydrochloride crystalline Form 1 and is substantially free (e.g., contains <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) of other forms of atrasentan (e.g., other salts and / or other polymorphs). In certain embodiments, the dosage form comprises atrasentan hydrochloride crystalline Form 2 and is substantially free of other forms of atrasentan (e.g., other salts and / or other polymorphs). In certain embodiments, the dosage form comprises atrasentan hydrochloride crystalline Form 3 and is substantially free (e.g., contains <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) of other forms of atrasentan (e.g., other salts and / or other polymorphs). In certain embodiments, the dosage form comprises crystalline atrasentan (S)-mandelate salt and is substantially free (e.g., contains <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) of other forms of atrasentan (e.g., other salts and / or other polymorphs). In certain embodiments, the dosage form comprises crystalline atrasentan (R)-mandelate salt and is substantially free (e.g., contains <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) of other forms of atrasentan (e.g., other salts and / or other polymorphs). In certain embodiments, the dosage form comprises amorphous atrasentan (S)-mandelate salt and is substantially free (e.g., contains <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) of other forms of atrasentan (e.g., other salts and / or other polymorphs). In certain embodiments, the dosage form comprises amorphous atrasentan (R)-mandelate salt and is substantially free (e.g., contains <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) of other forms of atrasentan (e.g., other salts and / or other polymorphs).

[0303] In some embodiments, the weight percentage of atrasentan or a pharma- ceutically acceptable salt thereof in the dosage form is about 0.1 weight percent to about 2.0 weight percent on an atrasentan free base equivalent basis. In some embodiments, the weight percentage of atrasentan or a pharma- ceutically acceptable salt thereof in the dosage form is about 0.2 weight percent to about 1.0 weight percent on an atrasentan free base equivalent basis. In some embodiments, the weight percentage of atrasentan or a pharma- ceutically acceptable salt thereof in the dosage form is about 0.3 weight percent to about 0.8 weight percent on an atrasentan free base equivalent basis. In some embodiments, the weight percentage of atrasentan or a pharma- ceutically acceptable salt thereof in the dosage form is about 0.40 weight percent to about 0.45 weight percent on an atrasentan free base equivalent basis. In some embodiments, the weight percentage of atrasentan or a pharma- ceutically acceptable salt thereof in the dosage form is about 0.60 weight percent to about 0.65 weight percent on an atrasentan free base equivalent basis.

[0304] In some embodiments, the dosage form contains about 0.40 mg to about 1.00 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage form contains about 0.40 mg to about 0.85 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage form contains about 0.50 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage form contains about 0.75 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0305] (ii) Diluent Suitable diluents for use in the disclosed dosage forms include, but are not limited to, lactose (such as lactose monohydrate, lactose anhydrous, and PHARMATOSE® DCL21), sucrose, glucose, mannitol, sorbitol, isomalt, microcrystalline cellulose (such as AVICEL® PH101 and AVICEL® PH102), silicified microcrystalline cellulose (such as PROSOLV® SMCC50 and SMCC 90), dicalcium phosphate, starch, and combinations thereof. In some embodiments, the diluent is selected from the group consisting of lactose, mannitol, isomalt, microcrystalline cellulose, dicalcium phosphate, and combinations thereof. In some embodiments, the diluent is lactose.

[0306] In some embodiments, the weight percent of the diluent in the dosage form is about 70 weight percent to about 99 weight percent. In some embodiments, the weight percent of the diluent in the dosage form is about 80 weight percent to about 99 weight percent. In some embodiments, the weight percent of the diluent in the dosage form is about 85 weight percent to about 99 weight percent. In some of the foregoing embodiments, the diluent is selected from the group consisting of lactose, mannitol, isomalt, and combinations thereof. As a non-limiting example, the diluent can be lactose.

[0307] (iii) Binder In some embodiments, the dosage form further comprises a pharma- ceutically acceptable binder (e.g., a polymeric binder). Binders suitable for use in the disclosed dosage forms include, but are not limited to, celluloses such as hydroxypropyl methylcellulose (e.g., hypromellose E5 (premium LV)), hydroxypropyl ethylcellulose, and hydroxypropylcellulose, as well as other pharma- ceutically acceptable substances having cohesive properties. In some embodiments, the binder is selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, and hydroxypropylcellulose. In some embodiments, the binder is hydroxypropylmethylcellulose. In some embodiments, the binder is hydroxypropylcellulose. In some embodiments, the binder is hydroxyethylpropylcellulose.

[0308] In some embodiments, the dosage form further comprises a pharma- ceutically acceptable binder, and the weight percent of the binder in the dosage form is about 1.0 weight percent to about 10.0 weight percent. In some embodiments, the weight percent of the binder in the dosage form is about 1.0 weight percent to about 8.0 weight percent. In some embodiments, the weight percent of the binder in the dosage form is about 1.0 weight percent to about 5.0 weight percent. In some of the foregoing embodiments, the binder is a polymeric binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, and hydroxypropylcellulose.

[0309] In some embodiments, the dosage form further comprises a pharma- ceutically acceptable binder, and the weight-to-weight ratio of the binder to atrasentan or a pharma- ceutically acceptable salt thereof is about 2:1 to about 25:1 on an atrasentan free base equivalent basis. In some embodiments, the weight-to-weight ratio of the binder to atrasentan or a pharma- ceutically acceptable salt thereof is about 1:1 to about 20:1 on an atrasentan free base equivalent basis. In some embodiments, the weight-to-weight ratio of the binder to atrasentan or a pharma- ceutically acceptable salt thereof is about 1:1 to about 15:1 on an atrasentan free base equivalent basis. In certain embodiments, the binder is a polymeric binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, and hydroxypropylcellulose.

[0310] (iv) Disintegrant In some embodiments, the dosage form optionally comprises a pharma- ceutically acceptable disintegrant. Disintegrants suitable for use in the disclosed dosage form include, but are not limited to, cross-linked polyvinylpyrrolidone (such as POLYPLASDONE™ XL), corn starch, potato starch, maize starch, and modified starches (including sodium starch glycolate), agar alginic acid, microcrystalline cellulose, croscarmellose sodium, and combinations thereof. In some embodiments, the disintegrant is selected from the group consisting of crospovidone, sodium starch glycolate, and croscarmellose sodium. In some embodiments, the disintegrant is cross-linked polyvinylpyrrolidone. In some embodiments, the disintegrant is crospovidone.

[0311] In some embodiments, the dosage form further comprises a pharma- ceutically acceptable disintegrant. In certain embodiments, the weight percent of the disintegrant in the dosage form is about 1.0 weight percent to about 10.0 weight percent. In some embodiments, the weight percent of the disintegrant in the dosage form is about 1.0 weight percent to about 6.0 weight percent. In some embodiments, the weight percent of the disintegrant in the dosage form is about 1.0 weight percent to about 4.0 weight percent. In some of the foregoing embodiments, the disintegrant is crospovidone.

[0312] In some embodiments, the dosage form further comprises a pharma- ceutically acceptable disintegrant, and the weight-to-weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine) or a pharma- ceutically acceptable salt or ester thereof is about 60:1 to about 3:1. In some embodiments, the weight-to-weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine) or a pharma- ceutically acceptable salt or ester thereof is about 50:1 to about 4:1. In some embodiments, the weight-to-weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine) or a pharma- ceutically acceptable salt or ester thereof is about 35:1 to about 5:1.

[0313] (v) Additional excipients In further embodiments, the dosage form optionally comprises a pharma- ceutically acceptable lubricant and / or glidant. Lubricants and glidants suitable for use in the disclosed dosage forms include, but are not limited to, silicon dioxide (such as SYLOID® 244FP and AEROSIL® 200), glyceryl behenate (such as COMPRITOL®), talc, stearic acid, solid polyethylene glycol, silica gel and mixtures thereof, and other substances with lubricating or gliding properties. In certain embodiments, the lubricant is glyceryl behenate (such as COMPRITOL®). In certain embodiments, the glidant is silicon dioxide (such as SYLOID® 244FP). In certain embodiments, the lubricant is glyceryl behenate and the glidant is silicon dioxide.

[0314] In some embodiments, the dosage form further comprises a pharma- ceutically acceptable glidant. In another aspect, the weight percent of the glidant in the dosage form is about 0.1 weight percent to about 1.5 weight percent. In some embodiments, the weight percent of the glidant in the dosage form is about 0.1 weight percent to about 1.0 weight percent. In some embodiments, the weight percent of the glidant in the dosage form is about 0.1 weight percent to about 0.8 weight percent. In some embodiments, the glidant is silicon dioxide.

[0315] In some embodiments, the dosage form further comprises a pharma- ceutically acceptable lubricant. In some embodiments, the dosage form further comprises a pharma- ceutically acceptable hydrophobic lubricant. In some embodiments, the weight percent of the lubricant in the dosage form is about 0.05 weight percent to about 5.0 weight percent. In some embodiments, the weight percent of the lubricant in the dosage form is about 0.2 weight percent to about 3.0 weight percent. In some embodiments, the weight percent of the lubricant in the dosage form is about 0.5 weight percent to about 2.0 weight percent. In certain embodiments, the lubricant is glyceryl behenate.

[0316] In some embodiments, the dosage form further comprises a disintegrant, a glidant, and a lubricant.

[0317] (vi) Antioxidants Antioxidants suitable for use in the disclosed dosage forms include antioxidants that function as reducing agents and are oxidized to pharma- ceutically acceptable reduction products in the dosage form. In some embodiments, the antioxidant has an oxidation-reduction potential lower than that of atrasentan (i.e., an oxidation-reduction potential less than about 900 mV) and greater than about 550 mV. In some embodiments, the antioxidant has an oxidation-reduction potential less than about 550 mV. In some embodiments, the antioxidant has an oxidation-reduction potential of about 1 mV to about 550 mV. In some embodiments, the antioxidant has a water solubility at about 25° C. greater than about 24 mg / mL. In some embodiments, the antioxidant is an amino acid, or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, the antioxidant is cysteine. In some embodiments, the antioxidant is L-cysteine, or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, the antioxidant is selected from the group consisting of L-cysteine ​​hydrochloride monohydrate, L-cysteine ​​hydrochloride anhydrate, and L-cysteine ​​ethyl ester. In some embodiments, the dosage form comprises L-cysteine ​​hydrochloride monohydrate.

[0318] In some embodiments, the weight percent of the antioxidant in the dosage form is about 0.05 weight percent to about 1.0 weight percent. In some embodiments, the weight percent of the antioxidant in the dosage form is about 0.07 weight percent to about 0.7 weight percent. In some embodiments, the weight percent of the antioxidant in the dosage form is about 0.09 weight percent to about 0.5 weight percent.

[0319] In some embodiments, the molar ratio of the antioxidant to atrasentan or a pharma- ceutically acceptable salt thereof is about 10:1 to about 1:10. In some embodiments, the molar ratio of the antioxidant to atrasentan or a pharma- ceutically acceptable salt thereof in the dosage form is about 5:1 to about 1:5. In some embodiments, the molar ratio of the antioxidant to atrasentan or a pharma- ceutically acceptable salt thereof is about 2:1 to about 1:2. In some embodiments, the molar ratio of the antioxidant to atrasentan or a pharma- ceutically acceptable salt thereof is about 1:1.

[0320] In some embodiments, the antioxidant is L-cysteine ​​or a pharma- ceutically acceptable salt thereof. In certain embodiments, the weight percent of L-cysteine ​​or a pharma- ceutically acceptable salt or ester thereof in the dosage form is about 0.05 weight percent to about 1.0 weight percent. In certain embodiments, the weight percent of L-cysteine ​​or a pharma- ceutically acceptable salt or ester thereof in the dosage form is about 0.07 weight percent to about 0.7 weight percent. In certain embodiments, the weight percent of L-cysteine ​​or a pharma- ceutically acceptable salt or ester thereof in the dosage form is about 0.09 weight percent to about 0.5 weight percent.

[0321] In certain embodiments, the molar ratio of L-cysteine ​​or a pharma- ceutically acceptable salt or ester thereof to atrasentan or a pharma- ceutically acceptable salt thereof in the dosage form is about 10:1 to about 1:10. In certain embodiments, the molar ratio of L-cysteine ​​or a pharma- ceutically acceptable salt or ester thereof to atrasentan or a pharma- ceutically acceptable salt thereof in the dosage form is about 5:1 to about 1:5. In certain embodiments, the molar ratio of L-cysteine ​​or a pharma- ceutically acceptable salt or ester thereof to atrasentan or a pharma- ceutically acceptable salt thereof is about 2:1 to about 1:2. In certain embodiments, the molar ratio of L-cysteine ​​or a pharma- ceutically acceptable salt or ester thereof to atrasentan or a pharma- ceutically acceptable salt thereof is about 1:1.

[0322] In certain embodiments, the antioxidant is selected from the group consisting of L-cysteine ​​hydrochloride monohydrate, L-cysteine ​​hydrochloride anhydrate, and L-cysteine ​​ethyl ester. In some embodiments, the dosage form comprises L-cysteine ​​hydrochloride monohydrate.

[0323] (vii) Additional Embodiments In some embodiments, the dosage form comprises atrasentan or a pharma- ceutically acceptable salt thereof and an antioxidant. In some of these embodiments, the antioxidant is L-cysteine, or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, the molar ratio of the antioxidant (e.g., L-cysteine, or a pharma- ceutically acceptable salt or ester thereof) is about 5:1 to about 1:5. In some of the foregoing embodiments, the dosage form further comprises a pharma- ceutically acceptable polymer binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, and hydroxypropylcellulose, the molar ratio of the antioxidant (e.g., L-cysteine, or a pharma- ceutically acceptable salt or ester thereof) to atrasentan or a pharma- ceutically acceptable salt thereof is about 5:1 to about 1:5, and the weight-to-weight ratio of the binder to atrasentan or a pharma- ceutically acceptable salt thereof is about 1:1 to about 20:1 on an atrasentan free base equivalent basis. In some embodiments, the dosage form further comprises a disintegrant, and the weight to weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine, or a pharma- ceutically acceptable salt or ester thereof) is about 60:1 to about 3:1. In some embodiments, the weight percent of atrasentan or a pharma- ceutically acceptable salt thereof in the dosage form is about 0.2 weight percent to about 1.0 weight percent on an atrasentan free base equivalent basis. In some embodiments, the dosage form comprises about 0.40 mg to about 0.85 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0324] In some embodiments, the dosage form comprises a pharma- ceutically acceptable polymeric binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, and hydroxypropylcellulose, and the molar ratio of the antioxidant (e.g., L-cysteine, or a pharma- ceutically acceptable salt or ester thereof) to atrasentan or a pharma- ceutically acceptable salt thereof is about 2:1 to about 1:2, and the weight-to-weight ratio of the binder to atrasentan or a pharma- ceutically acceptable salt thereof is about 1:1 to about 15:1 on an atrasentan free base equivalent basis. In some embodiments, the dosage form further comprises a disintegrant, and the weight-to-weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine, or a pharma- ceutically acceptable salt or ester thereof) is about 50:1 to about 4:1. In some embodiments, the weight percent of atrasentan or a pharma- ceutically acceptable salt thereof in the dosage form is about 0.2 weight percent to about 1.0 weight percent on an atrasentan free base equivalent basis. In some embodiments, the dosage form contains from about 0.40 mg to about 0.85 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0325] In some embodiments, the dosage form comprises a pharma- ceutically acceptable polymeric binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, and hydroxypropylcellulose, the molar ratio of the antioxidant (e.g., L-cysteine, or a pharma- ceutically acceptable salt or ester thereof) to atrasentan or a pharma- ceutically acceptable salt thereof is about 1:1, and the weight-to-weight ratio of the binder to atrasentan or a pharma- ceutically acceptable salt thereof is about 1:1 to about 15:1 on an atrasentan free base equivalent basis. In some embodiments, the dosage form further comprises a disintegrant, the weight-to-weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine, or a pharma- ceutically acceptable salt or ester thereof) is about 35:1 to about 5:1. In some embodiments, the weight percent of atrasentan or a pharma- ceutically acceptable salt thereof in the dosage form is about 0.3 weight percent to about 0.8 weight percent on an atrasentan free base equivalent basis. In some embodiments, the dosage form contains from about 0.40 mg to about 0.85 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0326] In some embodiments, the dosage form comprises a pharma- ceutically acceptable polymeric binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, and hydroxypropylcellulose, the dosage form comprises about 0.05 weight percent to about 1.0 weight percent of an antioxidant (e.g., L-cysteine, or a pharma- ceutically acceptable salt or ester thereof), and the dosage form comprises about 1.0 weight percent to about 10.0 weight percent of the binder. In some embodiments, the dosage form further comprises a disintegrant, and the weight percent of the disintegrant in the dosage form is about 1.0 weight percent to about 10.0 weight percent. In some embodiments, the weight percent of atrasentan or a pharma- ceutically acceptable salt thereof in the dosage form is about 0.1 weight percent to about 2.0 weight percent on an atrasentan free base equivalent basis. In some embodiments, the dosage form comprises about 0.40 mg to about 0.85 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0327] In some embodiments, the dosage form comprises a pharma- ceutically acceptable polymeric binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, and hydroxypropylcellulose, the dosage form comprises about 0.07 weight percent to about 0.70 weight percent of an antioxidant (e.g., L-cysteine, or a pharma- ceutically acceptable salt or ester thereof), and the dosage form comprises about 1.0 weight percent to about 8.0 weight percent of the binder. In some embodiments, the dosage form further comprises a disintegrant, and the weight percent of the disintegrant in the dosage form is about 1.0 weight percent to about 6.0 weight percent. In some embodiments, the weight percent of atrasentan or a pharma- ceutically acceptable salt thereof in the dosage form is about 0.2 weight percent to about 1.0 weight percent on an atrasentan free base equivalent basis. In some embodiments, the dosage form comprises about 0.40 mg to about 0.85 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0328] In some embodiments, the dosage form comprises a pharma- ceutically acceptable polymeric binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, and hydroxypropylcellulose, the dosage form comprises about 0.09 weight percent to about 0.80 weight percent of an antioxidant (e.g., L-cysteine, or a pharma- ceutically acceptable salt or ester thereof), and the dosage form comprises about 1.0 weight percent to about 5.0 weight percent of the binder. In some embodiments, the dosage form further comprises a disintegrant, and the weight percent of the disintegrant in the dosage form is about 1.0 weight percent to about 4.0 weight percent. In some embodiments, the weight percent of atrasentan or a pharma- ceutically acceptable salt thereof in the dosage form is about 0.3 weight percent to about 0.8 weight percent on an atrasentan free base equivalent basis. In some embodiments, the dosage form comprises about 0.40 mg to about 0.85 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0329] In some embodiments, the dosage form comprises: (a) about 0.1 weight percent to about 2.0 weight percent atrasentan or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) about 0.05 weight percent to about 1.0 weight percent of an antioxidant (e.g., L-cysteine, or a pharma- ceutically acceptable salt or ester thereof); (c) from about 75 weight percent to about 99 weight percent of a diluent; (d) about 1.0 weight percent to about 10.0 weight percent of a pharma- ceutically acceptable binder; (e) optionally, from about 1.0 weight percent to about 10.0 weight percent of a pharma- ceutically acceptable disintegrant; (f) optionally, from about 0 weight percent to about 1.5 weight percent of a pharma- ceutically acceptable glidant, and (g) optionally, from about 0 weight percent to about 5.0 weight percent of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100 percent.

[0330] In some embodiments, the dosage form comprises: (a) about 0.1 weight percent to about 2.0 weight percent atrasentan or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) about 0.05 weight percent to about 1.0 weight percent of an antioxidant (L-cysteine, or a pharma- ceutically acceptable salt or ester thereof); (c) from about 75 weight percent to about 99 weight percent of a diluent; (d) about 1.0 weight percent to about 10.0 weight percent of a pharma- ceutically acceptable binder; (e) about 1.0 weight percent to about 10.0 weight percent of a pharma- ceutically acceptable disintegrant; (f) optionally, from about 0 weight percent to about 1.5 weight percent of a pharma- ceutically acceptable glidant, and (g) optionally, from about 0 weight percent to about 5.0 weight percent of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100 percent.

[0331] In some embodiments, the dosage form comprises: (a) about 0.2 weight percent to about 1.0 weight percent atrasentan or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) about 0.07 weight percent to about 0.7 weight percent of an antioxidant (L-cysteine, or a pharma- ceutically acceptable salt or ester thereof); (c) about 82 weight percent to about 99 weight percent of a diluent; (d) about 1.0 weight percent to about 8.0 weight percent of a pharma- ceutically acceptable binder; (e) optionally, from about 1.0 weight percent to about 6.0 weight percent of a pharma- ceutically acceptable disintegrant; (f) optionally, from about 0 weight percent to about 1.0 weight percent of a pharma- ceutically acceptable glidant, and (g) optionally, from about 0 weight percent to about 3.0 weight percent of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100 percent.

[0332] In some embodiments, the dosage form comprises: (a) about 0.2 weight percent to about 1.0 weight percent atrasentan or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) about 0.07 weight percent to about 0.70 weight percent L-cysteine, or a pharma- ceutically acceptable salt or ester thereof; (c) about 82 weight percent to about 99 weight percent of a diluent; (d) about 1.0 weight percent to about 8.0 weight percent of a pharma- ceutically acceptable binder; (e) about 1.0 weight percent to about 6.0 weight percent of a pharma- ceutically acceptable disintegrant; (f) optionally, from about 0 weight percent to about 1.0 weight percent of a pharma- ceutically acceptable glidant, and (g) optionally, from about 0 weight percent to about 3.0 weight percent of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100 percent.

[0333] In some embodiments, the dosage form comprises: (a) about 0.3 weight percent to about 0.8 weight percent atrasentan or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) about 0.09 weight percent to about 0.50 weight percent L-cysteine, or a pharma- ceutically acceptable salt or ester thereof; (c) about 87 weight percent to about 99 weight percent of a pharma- ceutically acceptable diluent; (d) about 1.0 weight percent to about 5.0 weight percent of a pharma- ceutically acceptable binder; (e) optionally, from about 1.0 weight percent to about 4.0 weight percent of a pharma- ceutically acceptable disintegrant; (f) optionally, from about 0 weight percent to about 0.75 weight percent of a pharma- ceutically acceptable glidant, and (g) optionally, from about 0 weight percent to about 2.0 weight percent of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100 percent.

[0334] In some embodiments, the dosage form comprises: (a) about 0.3 weight percent to about 0.8 weight percent atrasentan or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) about 0.09 weight percent to about 0.50 weight percent L-cysteine, or a pharma- ceutically acceptable salt or ester thereof; (c) about 87 weight percent to about 99 weight percent of a pharma- ceutically acceptable diluent; (d) about 1.0 weight percent to about 5.0 weight percent of a pharma- ceutically acceptable binder; (e) about 1.0 weight percent to about 4.0 weight percent of a pharma- ceutically acceptable disintegrant; (f) optionally, from about 0 weight percent to about 0.75 weight percent of a pharma- ceutically acceptable glidant, and (g) optionally, from about 0 weight percent to about 2.0 weight percent of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100 percent.

[0335] In some embodiments, the dosage form comprises: (a) about 0.1 weight percent to about 2.0 weight percent atrasentan or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) from about 75 weight percent to about 99 weight percent of a diluent; (c) about 1.0 weight percent to about 10.0 weight percent of a pharma- ceutically acceptable binder; (d) optionally, from about 1.0 weight percent to about 10.0 weight percent of a pharma- ceutically acceptable disintegrant; (e) optionally, from about 0 weight percent to about 1.5 weight percent of a pharma- ceutically acceptable glidant, and (f) optionally, from about 0 weight percent to about 5.0 weight percent of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100 percent.

[0336] In some embodiments, the dosage form comprises: (a) about 0.1 weight percent to about 2.0 weight percent atrasentan or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) from about 75 weight percent to about 99 weight percent of a diluent; (c) about 1.0 weight percent to about 10.0 weight percent of a pharma- ceutically acceptable binder; (d) about 1.0 weight percent to about 10.0 weight percent of a pharma- ceutically acceptable disintegrant; (e) optionally, from about 0 weight percent to about 1.5 weight percent of a pharma- ceutically acceptable glidant, and (f) optionally, from about 0 weight percent to about 5.0 weight percent of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100 percent.

[0337] In some embodiments, the dosage form comprises: (a) about 0.2 weight percent to about 1.0 weight percent atrasentan or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) about 82 weight percent to about 99 weight percent of a diluent; (c) about 1.0 weight percent to about 8.0 weight percent of a pharma- ceutically acceptable binder; (d) optionally, from about 1.0 weight percent to about 6.0 weight percent of a pharma- ceutically acceptable disintegrant; (e) optionally, from about 0 weight percent to about 1.0 weight percent of a pharma- ceutically acceptable glidant, and (f) optionally, from about 0 weight percent to about 3.0 weight percent of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100 percent.

[0338] In some embodiments, the dosage form comprises: (a) about 0.2 weight percent to about 1.0 weight percent atrasentan or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) about 82 weight percent to about 99 weight percent of a diluent; (c) about 1.0 weight percent to about 8.0 weight percent of a pharma- ceutically acceptable binder; (d) about 1.0 weight percent to about 6.0 weight percent of a pharma- ceutically acceptable disintegrant; (e) optionally, from about 0 weight percent to about 1.0 weight percent of a pharma- ceutically acceptable glidant, and (f) optionally, from about 0 weight percent to about 3.0 weight percent of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100 percent.

[0339] In some embodiments, the dosage form comprises: (a) about 0.3 weight percent to about 0.8 weight percent atrasentan or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) about 87 weight percent to about 99 weight percent of a pharma- ceutically acceptable diluent; (c) about 1.0 weight percent to about 5.0 weight percent of a pharma- ceutically acceptable binder; (d) optionally, from about 1.0 weight percent to about 4.0 weight percent of a pharma- ceutically acceptable disintegrant; (e) optionally, from about 0 weight percent to about 0.75 weight percent of a pharma- ceutically acceptable glidant; and (f) optionally, from about 0 weight percent to about 2.0 weight percent of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100 percent.

[0340] In some embodiments, the dosage form comprises: (a) about 0.3 weight percent to about 0.8 weight percent atrasentan or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) about 87 weight percent to about 99 weight percent of a pharma- ceutically acceptable diluent; (c) about 1.0 weight percent to about 5.0 weight percent of a pharma- ceutically acceptable binder; (d) about 1.0 weight percent to about 4.0 weight percent of a pharma- ceutically acceptable disintegrant; (e) optionally, from about 0 weight percent to about 0.75 weight percent of a pharma- ceutically acceptable glidant; and (f) optionally, from about 0 weight percent to about 2.0 weight percent of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100 percent.

[0341] In some embodiments, the dosage form comprises: (a) the diluent is lactose; (b) the dosage form comprises a pharma- ceutically acceptable binder, wherein the binder is hydroxypropyl methylcellulose; (c) the dosage form comprises a pharma- ceutically acceptable disintegrant, wherein the disintegrant is crospovidone; (d) the dosage form comprises a pharma- ceutically acceptable glidant, wherein the glidant is silicon dioxide; (e) the dosage form contains a pharma- ceutically acceptable lubricant, and the lubricant is glyceryl behenate.

[0342] In some embodiments, the dosage form is a solid pharmaceutical dosage form comprising about 0.25 mg to about 1.25 mg of atrasentan or a pharma- ceutically acceptable salt thereof (e.g., atrasentan hydrochloride) on an atrasentan parent equivalent basis. In some embodiments, the pharmaceutical composition comprises about 0.40 mg to about 1.00 mg of atrasentan or a pharma- ceutically acceptable salt thereof (e.g., atrasentan hydrochloride) on an atrasentan parent equivalent basis. In some embodiments, the pharmaceutical composition comprises about 0.40 mg to about 0.85 mg of atrasentan or a pharma- ceutically acceptable salt thereof (e.g., atrasentan hydrochloride) on an atrasentan parent equivalent basis. In some embodiments, the pharmaceutical composition comprises about 0.50 mg of atrasentan or a pharma- ceutically acceptable salt thereof (e.g., atrasentan hydrochloride) on an atrasentan parent equivalent basis. In some embodiments, the pharmaceutical composition comprises about 0.75 mg of atrasentan or a pharma- ceutically acceptable salt thereof (e.g., atrasentan hydrochloride) on an atrasentan parent equivalent basis. In some of the foregoing embodiments, the dosage form is a tablet.

[0343] In some embodiments, the dosage form is a tablet. In some embodiments, the tablet has a weight of about 37.5 mg to about 1500 mg. In some embodiments, the tablet has a weight of about 50 mg to about 750 mg. In some embodiments, the tablet has a weight of about 50 mg to about 250 mg. In some embodiments, the tablet has a weight of about 75 mg to about 500 mg. In some embodiments, the tablet has a weight of about 75 mg to about 150 mg. In some embodiments, the tablet has a weight of about 100 mg to about 250 mg. In some embodiments, the tablet has a weight of about 100 mg to about 230 mg. In some embodiments, the tablet has a moisture content of less than about 10%. In certain embodiments, the tablet has a moisture content of about 4% to 6% (e.g., about 4% to 5%).

[0344] Generally, the tablet can be optionally surrounded or coated with at least one non-rate-controlling layer.The non-rate-controlling layer can be formed as a single layer, coating, or film, or multiple single layers, coatings, or films.The function of the non-rate-controlling layer can include, for example, providing additional stability of atrasentan, acting as a processing aid and / or cosmetic enhancer of the formulation, and / or acting as a masking agent to reduce any undesirable odor associated with the formulation (such as the odor commonly associated with L-cysteine).

[0345] If the dosage form includes a non-rate-controlling layer, the non-rate-controlling layer may be made of one or more polymers and other components known in the art, such as, but not limited to, plasticizers, pigments / emulsifiers, waxes, etc. Examples of polymers that can be used include, but are not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, and polyethylene glycol. Examples of plasticizers that can be used include, but are not limited to, polyethylene glycol, glycerin, triacetin, triethyl citrate, diethyl phthalate, L-cysteine, and mineral oil. Examples of pigments / opacifiers that can be used include, but are not limited to, water-soluble dyes (e.g., sunset yellow, quinoline yellow, erythrosine, and tartrazine), pigments (e.g., aluminum lake, titanium oxide, iron oxide, and talc), and natural products (e.g., riboflavin, carotenoids, chlorophyll, anthocyanins, and carmine). Examples of waxes that can be used include, but are not limited to, paraffin wax.

[0346] In some embodiments, the dosage form is a tablet coated with a pharma- ceutically acceptable polymer.

[0347] In some embodiments, the dosage form is a capsule.

[0348] In some embodiments, the dosage form is packaged in a semi-permeable container, hi some embodiments, the semi-permeable container is a blister pack.

[0349] In some embodiments, the dosage form is packaged in a substantially impermeable container.

[0350] In some embodiments, the dosage form is an immediate release dosage form. In some embodiments, the dosage form is an immediate release tablet and releases at least about 85% of the atrasentan or pharma- ceutically acceptable salt thereof within about 45 minutes as determined in an in vitro dissolution test performed using a USP dissolution apparatus 2 (Paddle apparatus), 0.01N hydrochloric acid dissolution medium, and a paddle rotation of 50 RPM. In some embodiments, the dosage form is an immediate release tablet and releases at least about 75% of the atrasentan or pharma- ceutically acceptable salt thereof within about 30 minutes.

[0351] In some embodiments, the dosage form contains less than about 1.0 weight percent total impurities resulting from decomposition of atrasentan or a pharma- ceutically acceptable salt thereof after a storage period of six months at about 40° C. and about 75% relative humidity. In some embodiments, the decomposition of atrasentan or a pharma- ceutically acceptable salt thereof is analyzed using high performance liquid chromatography.

[0352] In some embodiments, the dosage form contains less than about 0.6 percent by weight of any single impurity resulting from decomposition of atrasentan or a pharma- ceutically acceptable salt thereof after a storage period of six months at about 40° C. and about 75% relative humidity. In some embodiments, the decomposition of atrasentan or a pharma- ceutically acceptable salt thereof is analyzed using high performance liquid chromatography.

[0353] In some embodiments, the dosage form contains less than about 1.0 percent by weight total impurities and less than about 0.6 percent by weight of any single impurity resulting from decomposition of atrasentan or a pharma- ceutically acceptable salt thereof after a storage period of six months at about 40° C. and about 75% relative humidity. In some embodiments, the decomposition of atrasentan or a pharma- ceutically acceptable salt thereof is analyzed using high performance liquid chromatography.

[0354] In certain embodiments, the dosage form is selected from the group consisting of: [Table 1] [Table 2] [Table 3]

[0355] In certain embodiments, the dosage form is selected from the group consisting of: [Table 4] [Table 5] [Table 6]

[0356] Formulations of atrasentan or a pharma- ceutically acceptable salt thereof and methods of making the same are further described in U.S. Pat. No. 9,364,458 and U.S. Pat. No. 10,016,393, each of which is incorporated herein by reference in its entirety.

[0357] F. Dosage and Administration In some embodiments, the dose of atrasentan or a pharma- ceutically acceptable salt thereof is about 0.001 mg to 0.1 mg per kg of the subject's body weight (e.g., about 0.001, about 0.002, about 0.003, about 0.004, about 0.005, about 0.006, about 0.007, about 0.008, about 0.009, about 0.01, about 0.015, about 0 about 0.02, about 0.025, about 0.03, about 0.035, about 0.04, about 0.045, about 0.05, about 0.055, about 0.06, about 0.065, about 0.07, about 0.075, about 0.08, about 0.085, about 0.09, about 0.095, or about 0.10 mg / kg of atrasentan, or an equivalent amount of a pharma- ceutical acceptable salt thereof.

[0358] In some embodiments, the dose of atrasentan or a pharma- ceutically acceptable salt thereof is from about 0.1 mg to 10 mg (e.g., about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.75, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, about 8.5, about 9.0, about 9.5, or about 10.0 mg, or any value therebetween) of atrasentan or an equivalent amount of a pharma- ceutically acceptable salt thereof. In certain embodiments, the dose of atrasentan or a pharma- ceutically acceptable salt thereof is about 0.75 mg (e.g., when administered once daily) of atrasentan or an equivalent amount of a pharma- ceutically acceptable salt thereof. In certain embodiments, the dose of atrasentan or a pharma- ceutically acceptable salt thereof is about 0.25 mg (e.g., when administered once daily) of atrasentan or an equivalent amount of a pharma- ceutically acceptable salt thereof. In certain embodiments, the dose of atrasentan or a pharma- ceutically acceptable salt thereof is about 0.35 mg (e.g., when administered once daily) of atrasentan or an equivalent amount of a pharma- ceutically acceptable salt thereof. In certain embodiments, the dose of atrasentan or a pharma- ceutically acceptable salt thereof is about 1.0 mg (e.g., when administered once daily) of atrasentan or an equivalent amount of a pharma- ceutically acceptable salt thereof. In certain embodiments, the dose of atrasentan or a pharma- ceutically acceptable salt thereof is about 1.25 mg (e.g., when administered once daily) of atrasentan or an equivalent amount of a pharma- ceutically acceptable salt thereof. In certain embodiments, the dose of atrasentan or a pharma- ceutically acceptable salt thereof is about 1.5 mg (e.g., when administered once daily) of atrasentan or an equivalent amount of a pharma- ceutically acceptable salt thereof. In certain embodiments, the dose of atrasentan or a pharma- ceutically acceptable salt thereof is about 1.75 mg (e.g., when administered once daily) of atrasentan or an equivalent amount of a pharma- ceutically acceptable salt thereof.In some of these embodiments, the dose of atrasentan or a pharma- ceutically acceptable salt thereof is 0.75 mg (e.g., 1 x 0.75 mg tablet; or 1.5 x 0.50 mg tablets) of atrasentan or an equivalent amount of a pharma- ceutically acceptable salt thereof, administered once daily.

[0359] In some embodiments, the dose of atrasentan or a salt or solvate thereof comprises a therapeutically effective amount of atrasentan or a salt or solvate thereof. In other embodiments, the dose of atrasentan or a salt or solvate thereof comprises a less than therapeutically effective amount of atrasentan or a salt or solvate thereof (e.g., when multiple doses are given to achieve a desired clinical or therapeutic effect).

[0360] In some embodiments, the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof is about 0.20mg to about 1.5mg of atrasentan, or an equivalent amount of a pharmaceutically acceptable salt thereof. For example, the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof can be about 0.20mg, about 0.30mg, about 0.40mg, about 0.50mg, about 0.60mg, about 0.70mg, about 0.80mg, about 0.90mg, about 1.0mg, about 1.1mg, about 1.2mg, about 1.3mg, about 1.4mg, or about 1.5mg of atrasentan, or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof is about 0.25mg to about 1.25mg of atrasentan, or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof is about 0.40mg to about 0.85mg of atrasentan, or an equivalent amount of a pharmaceutically acceptable salt thereof.For example, the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof can be about 0.50mg, about 0.55mg, about 0.60mg, about 0.65mg, about 0.70mg, about 0.75mg, about 0.80mg, or about 0.85mg of atrasentan, or an equivalent amount of a pharmaceutically acceptable salt thereof.As a non-limiting example, the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof can be about 0.75mg of atrasentan, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0361] Atrasentan, or a salt or solvate thereof, may be administered by any suitable route and manner. Suitable routes of administration of the antibody and / or antibody-drug conjugate of the present disclosure are well known in the art and may be selected by the skilled artisan. In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is administered parenterally. Parenteral administration refers to modes of administration other than enteral and local administration, usually by injection, and includes epidermal, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural, and intrasternal injection and infusion. In some embodiments, the administration route of atrasentan is intravenous injection or infusion. In some embodiments, the administration route of atrasentan is intravenous infusion. In some embodiments, the administration route of atrasentan is intravenous injection or infusion. In some embodiments, the administration route of atrasentan is intravenous injection or infusion. In some embodiments, atrasentan is intravenous infusion. In some embodiments, the route of administration of atrasentan is oral.

[0362] In one embodiment of the methods or uses or products for use provided herein, atrasentan is administered to the subject daily, twice daily, three times daily, or four times daily. In some embodiments, atrasentan is administered to the subject every other day, about once every week, or about once every three weeks. In some embodiments, atrasentan is administered to the subject once daily. In some embodiments, atrasentan is administered to the subject twice daily. In some embodiments, atrasentan is administered to the subject at a dose of about 0.75 mg once daily. In some embodiments, atrasentan is administered to the subject at a dose of 0.75 mg once daily. In some embodiments, atrasentan is administered to the subject at a dose of about 0.25 mg once daily. In some embodiments, atrasentan is administered to the subject at a dose of 0.25 mg once daily. In some embodiments, atrasentan is administered to a subject at a dose of about 0.35 mg once per day. In some embodiments, atrasentan is administered to a subject at a dose of 0.35 mg once per day. In some embodiments, atrasentan is administered to a subject at a dose of about 0.5 mg once per day. In some embodiments, atrasentan is administered to a subject at a dose of 0.5 mg once per day. In some embodiments, atrasentan is administered to a subject at a dose of about 1.0 mg once per day. In some embodiments, atrasentan is administered to a subject at a dose of 1.0 mg once per day. In some embodiments, atrasentan is administered to a subject at a dose of about 1.75 mg once per day. In some embodiments, atrasentan is administered to a subject at a dose of 1.75 mg once per day.

[0363] G. Combination Therapy The method of the present disclosure also contemplates treatments that include administering atrasentan or a pharma- ceutically acceptable salt thereof in combination with one or more additional therapeutic agents (such as, for example, inhibitors of one or more elements of the renin-angiotensin-aldosterone system). Thus, as described elsewhere herein, atrasentan or a pharma- ceutically acceptable salt thereof can be administered alone or in combination with one or more additional therapeutic agents. When administered in combination with one or more additional therapeutic agents, separate dosage forms may be administered to the subject, or a single dosage form containing both atrasentan or a pharma- ceutically acceptable salt thereof and an additional therapeutic agent may be administered to the subject. When administered as separate dosage forms, the additional therapeutic agent may be administered simultaneously with the atrasentan dosage form of the present disclosure or sequentially (in either order) with the atrasentan dosage form of the present disclosure. Administering two or more agents in combination may be referred to herein as "co-administration."

[0364] Representative additional therapeutic agents include, for example, diuretics, antihypertensive agents, agents for treating diabetes or diabetic complications, and agents for treating hyperlipidemia.

[0365] In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof may be co-administered with one or more diuretics, such as hydrochlorothiazide (such as MICROZIDE™ or ORETIC™), hydroflumethiazide (such as SALURON™), bemethanide (such as BUMEX™), torsemide (such as DEMADEX™), metolazone (such as ZAROXOLYN™), chlorothiazide (such as DIURIL™, ESIDRIX™, or HYDRODIURIL™), triamterene (such as DYRENIUM™), ethacrynic acid (such as EDECRIN™), chlorothiazide (such as HYGROTON™), furosemide (such as LASIX™), indapamide (such as LOZOL™), or amiloride (such as MIDAMOR™ or MODURETIC™).

[0366] In some embodiments, atrasentan, or a pharma- ceutically acceptable salt thereof, may be co-administered with one or more thiazide diuretics, such as chlorothiazide, chlorthalidone, hydrochlorothiazide, trichlormethiazide, indapamide, or metolazone.

[0367] In some embodiments, atrasentan, or a pharma- ceutically acceptable salt thereof, may be co-administered with one or more loop diuretics, such as bumetanide, ethacrynic acid, furosemide, or torsemide.

[0368] In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof may be co-administered with one or more potassium-sparing diuretics, such as amiloride, eplerenone, spironolactone, and triamterene.

[0369] In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is selected from the group consisting of quinapril (such as ACCUPRIL™), fosinopril, perindopril (such as ACEON™), captopril (such as CAPOTEN™), enalapril (such as VASOTEC™), ENALAPRILAT™, ramipril (such as ALTACE™), cilazapril, delapril, fosenopril (such as MONOPRIL™), zofenopril, indolapril, benazepril (such as LOTENSIN™), lisinopril (PR It may be co-administered with one or more angiotensin-converting enzyme (ACE) inhibitors such as INIVIL™ or ZESTRIL™), spirapril, trandolapril (such as MAVIK™), perindep, pentopril, moexipril (such as UNIVASC™), pivopril, temocapril, omapatrilat, imidapril, rescinnamine, benazeprilat, fosinoprilat, ramiprilat, perindoprilat, quinaprilat, trandolaprilat, moexiprilat, quinoline yellow WS, or cilazaprilat. In certain embodiments, the ACE inhibitor is selected from quinapril, fosinopril perindopril, captopril, enalapril, enalaprilat, ramipril, cilazapril, delapril, fosenopril, zofenopril, indolapril, benazepril, lisinopril, spirapril, trandolapril, perindep, pentopril, moexipril, rescinnamine, and pivopril.

[0370] In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof may be co-administered with one or more angiotensin II receptor blockers (ARBs), such as candesartan (such as ATACAND™), candesartan cilexetil, eprosartan (such as TEVETEN™), irbesartan (such as AVEPRO™), losartan (such as COZAAR™), olmesartan, olmesartan medoxomil (such as BENICAR™), tasosartan, telmisartan (such as MICARDIS™), valsartan (such as DIOVAN™), zolasartan, azilsartan medoxomil, F1-6828K, RNH-6270, UR-7198, Way-126227, KRH-594, TAK-536, BRA-657, or TA-606. In certain embodiments, the ARB is selected from candesartan, candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan, olmesartan medoxomil, telmisartan, valsartan, azilsartan medoxomil, and BRA-657.

[0371] In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is selected from the group consisting of nifedipine (such as ADALAT™, ADALAT CC™, or PROCARDIA™), verapamil (such as GALAN™, COVERA-HS™, ISOPTIN SR™, or VERELAN™), diltiazem (such as CARDIZEM™, CARDIZEM CD™, CARDIZEM LA™, CARDIZEM SR™, DILACOR™, TIAMATE™, or TIAZAC™), isradipine (DYNACIRC™ or DYNACIRC™), It may be co-administered with one or more calcium channel blockers such as CR™, amlodipine (such as NORVASC™), felodipine (such as PLENDIL™), nisoldipine (such as SULAR™), bepridil (such as VASCOR™), vatanidipine, clevidipine, lercanidipine, or diltiazem.

[0372] In some embodiments, atrasentan, or a pharma- ceutically acceptable salt thereof, may be co-administered with one or more renin inhibitors, such as aliskiren (eg, TEKTURNA™).

[0373] In some embodiments, atrasentan, or a pharma- ceutically acceptable salt thereof, may be co-administered with one or more aldosterone receptor antagonists, such as eplerenone (such as INSPRA™) or spironolactone (such as ALDACTONE™).

[0374] In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof may be co-administered with one or more alpha blockers, such as doxazosin (such as CARDURA™), phenoxybenzamine (such as DIBENZYLINE™), terazosin (such as HYTRIN™), CDR1-93 / 478, or CR-2991.

[0375] In some embodiments, atenolol or a pharma- ceutically acceptable salt thereof may be co-administered with one or more beta-blockers, such as timolol (such as BLOCARDEN™), carteolol (such as CARTROL™), carvedilol (such as COREG™), nadolol (such as CORGARD™), propranolol (such as INNOPRAN XL™), betaxolol (such as KERLONE™), penbutolol (such as LEVATOL™), metoprolol (such as LOPRESSOR™ or TOPROL-XL™), atenolol (such as TENORMIN™), pindolol (such as VISKEN™), or bisoprolol.

[0376] In some embodiments, atrasentan, or a pharma- ceutically acceptable salt thereof, may be co-administered with one or more alpha-beta blockers, such as labetalol (such as NORMODYNE™ or TRANDATE™).

[0377] In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof may be co-administered with one or more central antiadrenergic agents, such as methyldopa (such as ALDOMET™), clonidine (such as CATAPRES™ or CATAPRES-TTS™), guanfacine (such as TENEX™), or guanabenz (such as WYTENSIN™).

[0378] In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof may be co-administered with one or more glycoside / inotropic agents, such as digoxin (eg, LANOXIN™).

[0379] In some embodiments, atrasentan, or a pharma- ceutically acceptable salt thereof, may be co-administered with one or more alpha-glucosidase inhibitors, such as miglitol (such as GLYSET™) or acarbose (such as PRECOSE™).

[0380] In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof may be co-administered with one or more biguanides, such as roseiglitazone (such as AVANDAMET™) or metformin (such as GLUCOPHAGE™ or GLUCOPHAGE XR™).

[0381] In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof may be co-administered with one or more insulins, such as, for example, HUMALOG™, HUMALOG 50 / 50™, HUMALOG 75 / 25™, HUMULIN 50 / 50™, HUMALIN 75 / 25™, HUMALIN L™, HUMALIN N™, HUMALIN R™, HUMALIN R U-500™, HUMALIN U™, ILETIN II LENTE™, ILETIN II NPH™, ILETIN II REGULAR™, LANTUS™, NOVOLIN 70 / 30™, NOVILIN N™, NOVILIN R™, NOVOLOG™, or VELOSULIN BR™, and EXUBERA™.

[0382] In some embodiments, atrasentan, or a pharma- ceutically acceptable salt thereof, may be co-administered with one or more meglitinides, such as repaglinide (such as PRANDIN™) or nateglinide (such as STARLIX™).

[0383] In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof may be co-administered with one or more sulfonylureas, such as glimepiride (such as AMARYL™), glyburide (such as DIABETA™, GLYNASE PRESTAB™, or MICRONASE™), or glipizide (such as GLUCOTROL™, or GLUCOTROL XL™).

[0384] In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof may be co-administered with one or more thiazolidinediones, such as pioglitazone (such as ACTOS™) or rosiglitazone (such as AVANDIA™).

[0385] In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof may be co-administered with niacin or one or more nicotinic acid derivatives, such as NIACOR™, NIASPAN™, NICOLAR™, or SLO-NIACIN™.

[0386] In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof may be co-administered with one or more fibrous acid derivatives, such as clofibrate (such as ATROMID-S™), gemfibrozil (such as LOPID™), or fenofibrate (such as TRICOR™).

[0387] In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof may be co-administered with one or more bile acid sequestrants, such as colestipol (such as COLESTID™), cholestyramine (such as LOCHOLEST™, PREVALITE™, QUESTRAN™, or QUESTRAN LIGHT™), or colesevelam (such as WELCHOL™).

[0388] In some embodiments, atrasentan, or a pharma- ceutically acceptable salt thereof, may be co-administered with one or more cholesterol absorption inhibitors, such as ezetimibe (eg, ZETIA™, etc.).

[0389] In some embodiments, atrasentan, or a pharma- ceutically acceptable salt thereof, may be co-administered with one or more 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), such as fluvastatin (such as LESCOL™), atorvastatin (such as LIPITOR™), lovastatin (such as ALTOCOR™ or MEVACOR™), pravastatin (such as PRAVACHOL™), rosuvastatin (such as CRESTOR™), simvastatin (such as ZOCOR™), or pitavastatin.

[0390] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be co-administered with one or more additional agents. In some embodiments, the one or more additional agents are immunosuppressants. In some embodiments, the one or more additional agents are selected from aminopterin, azathioprine, cyclosporine A, D-penicillamine, gold salts, hydroxychloroquine, leflunomide, methotrexate, minocycline, rapamycin, sulfasalazine, tacrolimus (FK506), and pharmaceutically acceptable salts thereof. As a non-limiting example, the one or more additional agents may be hydroxychloroquine.

[0391] In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof may be co-administered with one or more additional therapeutic agents selected from the group consisting of SGLT-2 inhibitors (such as canagliflozin), GR immunosuppressants (such as budesonide), MASP-2 antibodies (such as OMS721), dual ET1A / ARB inhibitors (such as sparsentan), B cell modulators (e.g., APRIL modulators such as atacicept, APL-2, VIS649), SYK inhibitors (such as fosamatinib), complement factor 3 convertase inhibitors (such as LNP023), NRF2 activators (such as bardoxolone), and RNAi therapeutics targeting the C5 component of the complement pathway (such as cemdisiram).

[0392] In some embodiments, the one or more additional agents are SGLT-2 inhibitors. In some embodiments, the one or more additional agents are dapagliflozin, canagliflozin, ipragliflozin, empaglifosin, bexagliflozin, licogliflozin, janagliflozin (XZP-5695), tofogliflozin, ertugliflozin, henagliflozin (SHR-3824), enavogliflozin (DWP-16001), TA-1887 (3-(4-cyclopropylbenzyl)-4-fluoro-1-(β-D-glucopyranosyl)-1H-indole), indole-N-glycoside 18 (3-(4-ethylbenzyl)-1-(β-D-glucopyranosyl)-1H-indole), sotagliflozin, luseogliflozin, sergliflozin etabonate, remogliflozin, remogliflozin etabonate, and T-1095 (((2R,3S,4S,5R,6S)-6-(2-(3-(benzofuran-5-yl)propanoyl)-3-hydroxy-5-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)etabonate). In some embodiments, the one or more additional agents are SGLT-2 inhibitors selected from bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin, serulliflozin, licofriglozin, sotagliflozin, and tofogliflozin. In some embodiments, the one or more additional agents are bexagliflozin. In some embodiments, the one or more additional agents are canagliflozin. In some embodiments, the one or more additional agents are dapagliflozin. In some embodiments, the one or more additional agents are empagliflozin. In some embodiments, the one or more additional agents are ertugliflozin. In some embodiments, the one or more additional agents are ipragliflozin. In some embodiments, the one or more additional agents are luseogliflozin. In some embodiments, the one or more additional agents are remogliflozin.In some embodiments, the one or more additional agents is autogliflozin. In some embodiments, the one or more additional agents is licofriglozin. In some embodiments, the one or more additional agents is sotagliflozin. In some embodiments, the one or more additional agents is tofogliflozin. In some embodiments, the SGLT-2 inhibitor is dapagliflozin propylene glycol hydrate. In some embodiments, the SGLT-2 inhibitor is canagliflozin hemihydrate.

[0393] In some embodiments, the amount of the SGLT-2 inhibitor is about 1 mg to about 350 mg, for example, about 1 mg to about 175 mg, about 175 mg to about 350 mg, or about 90 mg to about 260 mg. In some embodiments, the amount of the SGLT-2 inhibitor is about 85 mg to about 325 mg. In some embodiments, the amount of the SGLT-2 inhibitor is about 1 mg to about 50 mg, about 20 mg to about 70 mg, about 50 mg to about 100 mg, about 70 mg to about 120 mg, about 90 mg to about 140 mg, about 110 mg to about 160 mg, about 130 mg to about 180 mg, about 150 mg to about 200 mg, about 170 mg to about 220 mg, about 190 mg to about 240 mg, about 210 mg to about 260 mg, about 230 mg to about 280 mg, about 250 mg to about 300 mg, about 270 mg to about 320 mg, or about 290 mg to about 350 mg. For example, about 100 mg or about 300 mg. In some embodiments, the amount of the SGLT-2 inhibitor is about 1 to about 15 mg. For example, about 1 to about 10 mg or about 5 to about 15 mg. In some embodiments, the amount of the SGLT-2 inhibitor is from 1 mg to about 3 mg, from about 2 mg to about 4 mg, from about 3 mg to about 5 mg, from about 4 mg to about 6 mg, from about 5 mg to about 7 mg, from about 6 mg to about 8 mg, from about 7 mg to about 9 mg, from about 8 mg to about 10 mg, from about 9 mg to about 11 mg, from about 10 mg to about 12 mg, from about 11 mg to about 13 mg, from about 12 mg to about 14 mg, or from about 13 mg to about 15 mg.

[0394] In some embodiments, the SGLT-2 inhibitor is canagliflozin. In some embodiments, 100 mg or 300 mg of canagliflozin is administered. In some embodiments, 100 mg or 300 mg of canagliflozin hemihydrate is administered. In some embodiments, the SGLT-2 inhibitor is dapagliflozin. In some embodiments, the SGLT-2 inhibitor is dapagliflozin propylene glycol hydrate. In some embodiments, 5 mg or 10 mg of dapagliflozin is administered. In some embodiments, 5 mg or 10 mg of dapagliflozin propylene glycol hydrate is administered. In some embodiments, the SGLT-2 inhibitor is empagliflozin. In some embodiments, 10 mg or 25 mg of empagliflozin is administered. In some embodiments, the SGLT-2 inhibitor is ertugliflozin. In some embodiments, 5 mg or 15 mg of ertugliflozin is administered. In some embodiments, the SGLT-2 inhibitor is ipragliflozin. In some embodiments, 25 mg or 50 mg of ipragliflozin is administered. In some embodiments, the SGLT-2 inhibitor is bexagliflozin. In some embodiments, 20 mg of bexagliflozin is administered. In some embodiments, the SGL...

Claims

1. 1. A composition for treating IgA nephropathy comprising atrasentan, or a pharma- ceutically acceptable salt thereof, The composition is administered orally once daily at a dose of about 0.75 mg of atrasentan free base to a human subject diagnosed with IgA nephropathy as the primary glomerular disease.

2. The composition of claim 1 for treating IgA nephropathy, wherein the diagnosis of IgA nephropathy comprises a renal biopsy.

3. The composition of claim 1 or claim 2 for treating IgA nephropathy, wherein the diagnosis of IgA nephropathy comprises detecting deposition of IgA immune complexes in the serum or urine of the subject, or in a renal biopsy sample from the subject.

4. The composition according to any one of claims 1 to 3 for treating IgA nephropathy, wherein the diagnosis of IgA nephropathy comprises detecting galactosyl IgA or anti-glycan autoantibodies in the serum of the subject.

5. The composition according to any one of claims 1 to 4 for treating IgA nephropathy, wherein the subject is between about 15 and about 40 years old.

6. The composition according to any one of claims 1 to 5, for treating IgA nephropathy, wherein the subject has not previously been diagnosed with a chronic kidney disease other than IgA nephropathy.

7. 7. The composition of any one of claims 1 to 6 for treating IgA nephropathy, wherein the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure.

8. The composition according to any one of claims 1 to 7 for treating IgA nephropathy, characterized in that administration of the composition inhibits activation of mesangial cells in IgA nephropathy.

9. The composition of claim 9 for treating IgA nephropathy, wherein inhibiting activation of mesangial cells in IgA nephropathy comprises reducing inflammation of mesangial cells and / or reducing fibrotic reactions in the mesangial cells.

10. The composition according to any one of claims 1 to 9, for treating IgA nephropathy, wherein the subject is at high risk of progressing to end stage renal disease.

11. 11. The composition of any one of claims 1 to 10 for treating IgA nephropathy, characterized in that the subject is excreting an average of about 0.3 grams to about 2 grams, or about 0.5 grams to about 1.5 grams, or about 1 gram to about 1.5 grams, or about 1.5 grams to about 2 grams of protein in the urine per day for at least about 3 months prior to the first administration of the composition.

12. 11. The composition of any one of claims 1 to 10 for treating IgA nephropathy, wherein the subject is excreting an average of about 0.75 grams or more, or about 1 gram or more of protein in the urine per day for at least about 3 months prior to the first administration of the composition.

13. 11. The composition of any one of claims 1 to 10 for treating IgA nephropathy, characterized in that the subject is excreting at least about 1 gram of protein in the urine per day in at least two out of three consecutive measurements over a one-year period prior to the first administration of the composition.

14. 11. The composition of any one of claims 1 to 10 for treating IgA nephropathy, characterized in that the subject has proteinuria of at least about 1 g / day in at least two of three consecutive measurements over a one-year period prior to administration of the composition.

15. 15. The composition according to any one of claims 1 to 14 for treating IgA nephropathy, characterized in that after treatment with the composition, the amount of protein in the urine of the subject diagnosed with IgA nephropathy is reduced by at least about 20%.

16. The composition of claim 15 for treating IgA nephropathy, characterized in that after treatment with the composition, the amount of protein in the urine of the subject diagnosed with IgA nephropathy is reduced by at least about 40%.

17. The composition of claim 15 for treating IgA nephropathy, characterized in that after treatment with the composition, the amount of protein in the urine of the subject diagnosed with IgA nephropathy is reduced by at least about 50%.

18. 18. The composition of any one of claims 1 to 17 for treating IgA nephropathy, wherein after treatment with the composition, a subject with IgA nephropathy has a reduced level of protein in the urine of less than about 1.0 gram / day.

19. 20. The composition of claim 18 for treating IgA nephropathy, wherein after treatment with the composition, the subject with IgA nephropathy has a reduced level of protein in the urine of less than about 0.3 grams / day.

20. The composition according to any one of claims 1 to 19, for treating IgA nephropathy, wherein the proteinuria comprises albuminuria.

21. The composition according to any one of claims 1 to 20, for treating IgA nephropathy, wherein the subject does not experience significant fluid retention.

22. 22. The composition of claim 21 for treating IgA nephropathy, wherein the subject does not experience significant fluid retention of about 1 kg to about 4 kg over a period of 6 weeks.

23. Prior to administration of the composition, the subject has an airway pressure of at least 30 mL / min / 1.73 m ２ 23. The composition according to any one of claims 1 to 22 for treating IgA nephropathy, characterized in that the composition has an estimated glomerular filtration rate (eGFR) of 0.01 to 0.1%.

24. Prior to administration of the composition, the subject has an airway pressure of about 30 mL / min / 1.73 m for at least about 3 months. ２ ~Approx. 90mL / min / 1.73m ２ The composition according to claim 23 for treating IgA nephropathy, characterized in that it has a mean eGFR of 0.01 to 0.

01.

25. The composition according to any one of claims 1 to 24 for treating IgA nephropathy, characterized in that after treatment with the composition, the rate of decrease in eGFR is attenuated by at least 20%.

26. The composition for treating IgA nephropathy according to claim 25, wherein the rate of decrease in eGFR after treatment with the composition is attenuated by at least 30%.

27. The composition for treating IgA nephropathy according to claim 25, wherein the rate of decrease in eGFR after treatment with the composition is attenuated by at least 40%.

28. A composition according to any one of claims 1 to 27 for treating IgA nephropathy, characterized in that administration of said composition reduces the incidence of hematuria in said subject.

29. 29. The composition of claim 28 for treating IgA nephropathy, wherein the hematuria is microscopic hematuria, gross hematuria, symptomatic hematuria, or asymptomatic hematuria.

30. 30. The composition according to any one of claims 1 to 29, for treating IgA nephropathy, characterized in that the composition is administered to the subject in a tablet at a dosage of about 0.75 mg of atrasentan free base once daily.

31. A composition according to any one of claims 1 to 30 for treating IgA nephropathy, characterized in that atrasentan is administered in the form of atrasentan mandelate or atrasentan hydrochloride.

32. 32. The composition of any one of claims 1 to 31 for treating IgA nephropathy, wherein the composition is administered to the subject simultaneously with an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), or a combination thereof.

33. A composition according to any one of claims 1 to 32 for treating IgA nephropathy, characterized in that it is administered to the subject simultaneously with an SGLT-2 inhibitor.

34. 32. The composition of any one of claims 1 to 31 for treating IgA nephropathy, wherein the subject has been receiving a maximally tolerated stable dose of a renin angiotensin system (RAS) inhibitor for at least about 12 weeks prior to the first administration of the composition.

35. 35. The composition of claim 34 for treating IgA nephropathy, wherein the RAS inhibitor is an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), or a combination thereof.

36. The composition of claim 34 or claim 35 for treating IgA nephropathy, wherein the subject is simultaneously receiving an SGLT-2 inhibitor.

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