How to treat IGA nephropathy with atrasentan

Abstract

To provide compositions for treating IgA nephropathy.SOLUTION: Provided is a composition comprising atrasentan, or a pharmaceutically acceptable salt thereof, characterized in that the composition is administered to a subject diagnosed with IgA nephropathy at a dose of about 0.20 mg to about 1.5 mg of atrasentan, or an equivalent amount of a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of 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 on September 31, 2020; No. 63 / 084,739, filed on December 14, 2020, and This application claims priority to U.S. Provisional Application No. 63 / 125,205, filed on Dec. 1, 2002, which is incorporated herein by reference. The entirety of these is incorporated. [Background technology]

[0002] IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Aberrant glycosylation of β-glucan is recognized by glycan-specific IgA and IgG autoantibodies. This results in increased serum levels of galactose-deficient IgA1 (Gd-IgA1), which is responsible for the immune response. Aggregates of the complex form in situ and / or are deposited in the glomerular mesangium. This is due to the proliferation of mesangial cells, the production of extracellular matrix proteins, cytokines, and chemokines. This promotes increased synthesis of inflammatory cytokines and infiltration of immune cells into surrounding tissues, thus contributing to the progression of the disease. The progression of the disease involves (1) the production of Gd-IgA1 and (2) its recognition by anti-glycan autoantibodies. (3) immune complex formation in the kidney, and (4) activation of mesangial cells. For example, Penfold et al., Int. J. Nephrol. and See Renovascular Dis.11, pp.137-148(2017) thing. Unlike other progressive kidney diseases, such as diabetic nephropathy, IgAN primarily affects people in their 20s and 30s. It occurs in healthy subjects in their 20s. Patients present with a variety of symptoms, typically micro- or macro- Symptoms include hematuria and increased excretion of protein in the urine. Patients also experience persistent kidney damage. Current treatment approaches include angiotensin-converting enzyme inhibitors or administration of maximum tolerated doses of angiotensin receptor blockers or immunosuppressants It only provides persistent care, and the benefits far outweigh the side effects. 30-40% of patients will develop end-stage renal disease (ESRD) within 20-30 years of IgAN diagnosis. During this time, patients experience a decline in kidney function as well as many other symptoms that significantly reduce their quality of life. IgAN patients often experience high levels of endothelin-1 (ET-1) in the kidneys. ) and ET-RA. Increased expression of endothelin is associated with Ig It is positively correlated with proteinuria, one of the characteristic symptoms of AN. [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 is approximately 34 pM, ETB Ki is approximately 63 nM, and ETA selectivity is approximately 1800x. For example, , Wu-Wong et al., Clin.Sci.(Lond.), 103(48) , pp. 107s-111s (2002). It blocks ETA function, promoting vasodilation and vasorelaxation, while minimizing its effect on ETB receptors. It has beneficial effects on the kidney, such as reduced urinary retention and inflammation, while also promoting the clearance of ET-1. For example, Jandeleith-Dahm and Watson, Cur r.Opin.Nephrol.Hypertens.,21(1),pp.66-71 (2012) and Nakamura, et al., Nephron, Vo See also I. 72, pp. 454-460 (1996). ETA receptor antagonists It increases sodium and water retention by the kidney, which is usually clinically manageable. For example, Saleh, et al., J. Pharm. Exp. Ther., 338(1), pp.263-270(2011). Atrasentan is a glycoside. In patients with diabetic kidney disease (DKD), doubling of serum creatinine or end-stage renal disease It has been shown to significantly reduce the risk of renal events defined as erspink,et al.,The Lancet,393,pp1937-194 7 (2019). DKD is a secondary glomerular disease characterized by specific systemic Kidney disease develops secondary to the cause, and in the case of DKD, microvascular complications occur in combination with long-standing diabetes. For example, Dattani and McAdoo, Medicine, 47(10), pp.644-648(2019). The etiology of DKD is multifactorial. The condition is complicated by chronic diabetes, which causes glucose toxicity in kidney cells, especially renal endothelial cells. Associated with hypertension is increased blood glucose levels and shear stress transmitted to resident glomerular cells. Systemic and renal hemodynamic factors are major contributors to the development of DKD. as et al.,Nat.Rev.Disease Primers.1,pp.1 5018-15026 (2015). Hyperglycemia, dyslipidemia, and oxidative stress metabolic components such as stress, and hemodynamic factors such as vasoactive substances associated with hypertension. Multiple dysregulated factors in the diabetic milieu, including EGFR-1, EGFR-2, EGFR-3, EGFR-4, EGFR-5, EGFR-6, EGFR-7, EGFR-8, EGFR-9, EGFR-10, EGFR-11, EGFR-12, EGFR-13, EGFR-14, EGFR-15, EGFR-16, EGFR-17, In addition, DKD is generally considered a rare condition because long-term diabetes is usually required before DKD manifests. It has been observed primarily in older populations, and aging is also associated with increased ET-1 production in the kidney. For example, Kohan, Kidney Int., 86(5), pp.896-904 (2014). In combination, this all contributes to the development of ETA receptor blockers. Obtaining solid scientific evidence for the treatment of DKD with trasentan. Dhaun, et al., See Hypertension, Vol. 57, pp. 772-779 (2011) thing.

[0005] In contrast to DKD, IgA nephropathy is a primary nephropathy in which focal or intrinsic renal lesions are present. The peak incidence of IgA nephropathy is in young individuals in the second or third decade of life. IgA nephropathy is an autoimmune disease that affects the glomerular mesangial system, unlike DKD. It is caused by the deposition of pathogenic IgA / immune complexes in the gut. l.,Nature Reviews Disease Primers,2,pp.1 See 6001, 2016. A definitive diagnosis is made by renal biopsy and immunofluorescence microscopy. The deposition of IgA in the blood must be confirmed. Recent advances in the field have revealed that aberrant mucosal immune responses are driven by circulating anti-glycan autoantibodies. It has been shown to stimulate the production of galactose-deficient IgA1, which is recognized as an autoantigen. Immune recognition is associated with the formation of nephritogenic immune complexes that deposit in the kidney and activate mesangial cells. Activated mesangial cells proliferate and produce excessive amounts of extracellular matrix. They produce cytokines, cytokines, and chemokines. al., J. Am. Soc. Nephrol., Vol. 22, pp. 1795-180 3 (2011). Up to 40% of patients with biopsy-proven IgA nephropathy have long-term Progression to end-stage renal failure at some point during follow-up. The role of ET-1 or ETA receptors in mitochondrial function has not been reported previously. Sentan has not been previously tested in IgA nephropathy. As further described herein, In addition, atrasentan can be administered at effective doses with acceptable toxicity, and is suitable for use in patients with rheumatoid arthritis. Treat the underlying IgAN and improve the subject's quality of life while minimizing unwanted side effects Some embodiments provide a method for treating IgA nephropathy in a subject with IgA nephropathy. A method for inhibiting mesangial cell activation in a subject, comprising administering to the subject a therapeutically effective amount of atlantoic acid. The method comprises administering Sentan or a pharmaceutically acceptable salt thereof to a subject suffering from diabetic nephropathy. have ever been diagnosed with one or more of the following: No, we provide a way.

[0006] Some embodiments provide for the determination of P in mesangial cells in subjects with IgA nephropathy. Inhibits DGF (e.g., PIK3R1, PDGFRA, NFKBIA, PIK3CG , PLA2G4A, TIAM1, PDGFB, NFKB1, and MAP3K1 a therapeutically effective amount of an The method comprises administering trasentan or a pharmaceutically acceptable salt thereof to a subject suffering from diabetes. Have ever been diagnosed with one or more of the following: nephropathy, HIV / AIDS, or acute renal failure There is no way to provide this.

[0007] Some embodiments provide a method of treating IgA nephropathy, comprising administering to a subject in need thereof administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof; The subjects were those with one or more of the following conditions: diabetic nephropathy, HIV / AIDS, or acute renal failure. It provides a method for those who have never been diagnosed with the condition.

[0008] Some embodiments provide a method of treating IgA nephropathy, comprising administering to a subject in need thereof administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof; The subject has one or more of the following: diabetic nephropathy, HIV / AIDS, or acute renal failure. No, we provide a way.

[0009] Some embodiments provide a method of treating IgA nephropathy, comprising administering to a subject in need thereof administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof; Subjects were diagnosed with one or more of the following conditions: diabetic nephropathy, HIV / AIDS, or acute renal failure. Not provided, how to do it.

[0010] Some embodiments provide a method of treating IgA nephropathy, comprising administering to a subject in need thereof administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof; The subjects were those with one of the following conditions: diabetic nephropathy, HIV / AIDS, prostate cancer, or acute renal failure. The present invention provides a method for treating a patient who has never been previously diagnosed with the above condition.

[0011] Some embodiments provide a method of treating IgA nephropathy, comprising administering to a subject in need thereof administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof; The subjects were those with one or more of the following conditions: diabetic nephropathy, HIV-associated nephropathy, prostate cancer, or acute renal failure. Above and have never been diagnosed before, provide a method.

[0012] Some embodiments provide a method of treating IgA nephropathy, comprising administering to a subject in need thereof administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof; Subjects were those with at least one of the following conditions: diabetic nephropathy, HIV-associated nephropathy, or acute renal failure. has never been diagnosed, provides a method.

[0013] Some embodiments provide a method of treating IgA nephropathy, comprising administering to a subject in need thereof administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof; Subjects were treated for one or more of the following: diabetic nephropathy, HIV-associated nephropathy, or acute renal failure. We provide a method that has not been used before.

[0014] Some embodiments provide a method of treating IgA nephropathy, comprising administering to a subject in need thereof administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof; The subject is determined to have a controlled serum glucose level, and the subject is diagnosed with HIV-related The method provides a method in which the patient has not been diagnosed with one or more of: renal failure or acute renal failure.

[0015] Some embodiments provide a method for treating kidney inflammation and / or fibrosis in a subject with IgA nephropathy. 1. A method for reducing fibrosis comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0016] Some embodiments provide a method for reducing the incidence of hematuria in a subject with IgA nephropathy. administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof The method includes administering an acceptable salt thereof.

[0017] Some embodiments provide a method for stabilizing eGFR in a subject with IgA nephropathy. administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof The method includes administering an acceptable salt thereof.

[0018] Some embodiments provide for the prevention of IgA nephropathy-associated disease flares in subjects with IgA nephropathy. 1. A method for reducing the number of leukemia cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of atrasentan or or a pharmaceutically acceptable salt thereof.

[0019] Some embodiments delay the onset of ESRD in subjects with IgA nephropathy The method comprises administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutical and administering an acceptable salt thereof to the subject.

[0020] Some embodiments provide a method for reducing proteinuria in a subject with IgA nephropathy. administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof The method includes administering an 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 pharmaceutically acceptable salt thereof; and administering to the subject a therapeutically effective amount of steroids, including but not limited to steroids for diabetic nephropathy, HIV-associated nephropathy, prostate cancer, or acute kidney injury. The method provides a method for treating a kidney disease, wherein the kidney is determined to be free of one or more of the following:

[0022] Some embodiments provide a method of inhibiting activation of mesangial cells, comprising: contacting a mouse cell with an effective amount of atrasentan or a pharmaceutically acceptable salt thereof The present invention provides a method including:

[0023] Some embodiments involve the activation of mesangial cells in contact with IgA immune complexes. 1. A method for reducing mesangial cells, comprising administering an effective amount of atrasentan or a pharmaceutical and contacting the compound with a salt that is acceptable to the subject.

[0024] Some embodiments provide a method for treating IgA nephropathy in a subject in need thereof. a) determining that a subject has an elevated serum Gd-IgA1 level; and b) administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. providing a signal to the device.

[0025] Some embodiments provide a method for treating IgA nephropathy in a subject in need thereof. A method of administering a therapeutic agent to a subject, the method 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. providing a signal to the device.

[0026] Some embodiments provide a method for treating IgA nephropathy in a subject in need thereof. A method for administering a therapeutic agent to a subject, the method comprising: a) administering to the subject an IgA immune complex; b) administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof; and administering a salt thereof. [Brief explanation 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] Figure 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] Figure 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 an increase in IL-6 production (approximately 6-fold increase) by primary human mesangial cells exposed to ET-1 for 48 hours and a decrease in IL-6 levels upon treatment with increasing concentrations of atrasentan, shown on a logarithmic scale, demonstrating an IC50 of approximately 1 nM. [Figure 3B]Figure 1 shows an increase in IL-6 production by primary human mesangial cells exposed to ET-1 for 72 hours (approximately a 2.2-fold increase) and a decrease in IL-6 levels upon treatment with increasing concentrations of atrasentan, shown on a logarithmic scale, demonstrating an IC50 of approximately 1 nM. [Figure 4] UACR levels in g-ddY mice are shown 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). [Figure 5] Changes in UACR levels (% of baseline) in g-ddY mice after approximately 5 days of atrasentan administration at 0 (control), 10, 20, or 30 mg / kg / day in drinking water are shown. (*P<0.05 compared with the control group (0 mg / kg / day), unpaired t-test). [Figure 6] Figure 1 shows the top 100 differentially expressed genes in kidney tissue after 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 after treatment of g-ddY mice with 0 (control) and 10 mg / kg / day atrasentan. Black dots indicate genes that are not significantly differentially expressed. Gray dots above 0 log fold change indicate upregulated genes. Gray dots below 0 log fold change indicate downregulated genes. [Figure 7B] 1 shows differential gene expression in kidney tissue after treatment of g-ddY mice with 0 (control) and 20 mg / kg / day atrasentan. Black dots indicate genes that are not significantly differentially expressed. Gray dots above 0 log fold change indicate upregulated genes. Gray dots below 0 log fold change indicate downregulated genes. [Figure 7C]1 shows differential gene expression in kidney tissue after treatment of g-ddY mice with 0 (control) and 30 mg / kg / day atrasentan. Black dots indicate genes that are not significantly differentially expressed. Gray dots above 0 log fold change indicate upregulated genes. Gray 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] Shows 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 ET-1 stimulated HRMCs compared with untreated HRMCs (control), and following treatment of g-ddY mice with 10, 20, or 30 mg / kg / day atrasentan compared with 0 (control). [Figure 11A] Gene signature overlap is shown between a 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 after treatment of g-ddY mice with 30 mg / kg / day atrasentan (labeled as g-ddY), and differentially expressed genes after treatment of HRMC with 25 nM atrasentan in the presence of ET1 (labeled as HRMC). [Figure 11B] Figure 1 shows the expression levels (log(2) counts per million) 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] Comparisons between human- and mouse-based potential biomarkers are shown, with an "x" indicating translatability and indicating whether the potential biomarker is found 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] The log2 (CPM) of each potential biomarker is shown following treatment of g-ddY mice with 0 (control), 10, 20, or 30 mg / kg / day atrasentan. DETAILED DESCRIPTION OF THE INVENTION

[0028] Table 1. Comparison of atrasentan at 10 mg / kg / day compared with 0 mg / kg / day (control) The top 40 DEGs (25 of which were upregulated) were identified by treatment of g-ddY mice with atrasentan. and 15 down-regulated).

[0029] Table 2. Comparison of atrasentan at 20 mg / kg / day compared with 0 mg / kg / day (control) The top 50 DEGs (25 were upregulated) were identified by treatment of g-ddY mice with atrasentan. and 25 downregulated).

[0030] Table 3. Comparison of atrasentan at 30 mg / kg / day compared with 0 mg / kg / day (control) The top 50 DEGs (25 were upregulated) were identified by treatment of g-ddY mice with atrasentan. and 25 downregulated).

[0031] Table 4. Comparison of atrasentan at 10, 20, or 3 mg / kg / day compared with 0 mg / kg / day (control) Concentrated signal after treatment of g-ddY mice with 0 mg / kg / day atrasentan Z-score values ​​indicate the magnitude of the effect seen at each dose.

[0032] Table 5. Comparison of atrasentan at 10, 20, or 3 mg / kg / day compared with 0 mg / kg / day (control) Characteristic gene sequences after treatment of g-ddY mice with 0 mg / kg / day atrasentan Gene set enrichment analysis showing the enrichment of DEGs in gene sets. NES shows the representation of DEGs in gene sets. is the normalized enrichment score that takes into account the size of the gene set. An NES of >1.5 is considered biologically significant. Adj p-values ​​are the mean p-values ​​for a given enrichment. The calculated NES for the selected gene set is the estimated probability of a false positive result.

[0033] Table 6. List of upstream regulators of cytokines and growth factors classified by molecular type The overlap P-value is the number of overlapping genes between the dataset and the IPKB gene targets. The significance of enrichment based on the number of genes is shown. Activation z-score thresholds of <-2 or >2 and A p value for the overlap threshold of <0.05 was considered significant.

[0034] Table 7. Molecular tags for transmembrane receptors, G protein-coupled receptors, and protein complexes List of upstream regulators categorized by type. P-values ​​for overlap are shown for datasets and IPKB genes. The significance of enrichment is based on the number of overlapping genes between the gene target and the target. An activation z-score threshold of >2 and an overlap threshold of <0.05 p-value were considered significant. It was.

[0035] Table 8. Upstream transcription factors and ligand-dependent nuclear receptors classified by molecular type List of regulators. Overlap P-values ​​indicate overlap between the dataset and IPKB gene targets. The significance of enrichment is based on the number of genes that overlap. Activation z-score thresholds of <-2 or >2 are used. values ​​and p values ​​for overlap threshold of <0.05 were considered significant.

[0036] Table 9. Comparison of atrasentan at 10, 20, or 3 mg / kg / day compared with 0 mg / kg / day (control) NF-kB signaling after treatment of g-ddY mice with 0 mg / kg / day atrasentan Gene expression of components of the IL transduction pathway.

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

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

[0039] Table 12. Comparison of atrasentan at 10, 20, or 0 mg / kg / day (control) Cell proliferation signals after treatment of g-ddY mice with 30 mg / kg / day atrasentan Genetics of components of the mitotic spindle and G2M cell cycle checkpoint signaling pathways Child manifestation.

[0040] Table 13. Comparison of atrasentan at 10, 20, or 0 mg / kg / day (control) Inflammatory response signals after treatment of g-ddY mice with 30 mg / kg / day atrasentan Gene expression of components of the IL transduction pathway.

[0041] Table 14. Comparison of atrasentan at 10, 20, or 0 mg / kg / day (control) Mesangial cells after treatment of g-ddY mice with 30 mg / kg / day atrasentan Gene expression of 44 genes associated with the cytoplasmic signature. [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 provided herein: Each term in this application shall have the meaning set forth below. Additional definitions are set forth throughout the application. will be explained throughout.

[0043] Unless otherwise defined, all technical and scientific terms used herein are defined by the It has the same meaning as commonly understood by a person skilled in the art to which the disclosure pertains. For example, ise Dictionary of Biomedicine and Molecule lar Biology, Juo, Pei-Show, 2nd ed., 2002, CR C Press, The Dictionary of Cell and Molec ular Biology,3rd ed.,1999,Academic Press , and Oxford Dictionary of Biochemistry An d Molecular Biology,Revised,2000,Oxford University Press provides a general dictionary of many of the terms used in this disclosure. For purposes of this disclosure, the following terms are defined:

[0044] Units, prefixes and symbols are listed in the Systeme International de The numerical range is expressed in the form accepted by SI Units. The headings provided herein are incorporated by reference in their entirety. The terms "a," "b," "c," "d," "e," "f," "g," "h," "i," "j," "j," "j," "k," "k," "k," "i," "j ... Terms are more fully defined by reference to the specification as a whole.

[0045] As used herein, the terms "a," "an," or "the" mean one This invention includes embodiments having at least one member, as well as embodiments having two or more members. When used in this document, the singular forms "a," "an," and "the" are used unless the context clearly indicates otherwise. Unless otherwise indicated, a reference to a "cell" includes multiple referents. and includes a plurality of such cells, and reference to an "agent" refers to one or more agents known to those skilled in the art. This includes references to the following.

[0046] As used herein, the term "or" is generally to be construed as non-exclusive. For example, a claim to "a composition comprising A or B" should typically include A and However, "or" may be used to refer to embodiments having compositions containing both A and B. , which cannot be combined without contradiction (e.g., compositions with pH values ​​of 9-10 or 7-8) ) should be construed to exclude the stated embodiment.

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

[0048] As used herein, the term "and / or" refers to one or more should be construed as a specific disclosure of each of the two particular features or components. Therefore, when used herein in a phrase such as "A and / or B," it should be understood that "and The term "and / or" does not include "A and B," "A or B," "A" (only), and "B" (only) is intended to include "A, B, and / or C," etc. When used in the phrase, the term "and / or" refers to 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) This is the intention.

[0049] As used herein, the terms "about" and "approximately" generally refer to the quality of a measurement. It refers to the degree of acceptable error in a measured quantity, taking into account its quality or precision. The indicated degree of error is within 20 percent (%), 10% or less of a given value or range of values. , within 5%. References to "about X" include at least the value X, 0.95X, 0.96X, 0 .97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X , and 1.05X are specifically shown. Therefore, "about X" is, for example, "0.98X". It is intended to provide a written explanation supplement to the claim limitations. The terms "about" and "approximately," particularly with respect to a given amount, are inclusive of and include the given amount itself. explain.

[0050] When "about" is applied to the beginning of a numerical range, it applies to both ends of the range. "5% to 20%" is equivalent to "about 5% to about 20%." "About" applies to the first value in the set of values. If a value is specified, it applies to all values ​​in that set. 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" refers to a series of peak positions in an X-ray powder diffraction ( For example, if the 2θ value (for example, 2θ value) is preceded by a variance of ±0.1°, all peaks in the preceding group This means that the angle is reported in terms of the angle position. 9.7°, 10.0°, 13.0°, 15.6°, 17.2°, or 19.5° The phrases were 8.3°±0.1°, 9.7°±0.1°, 10.0°±0.1°, and 13.0°± 0.1°, 15.6°±0.1°, 17.2°±0.1°, or 19.5°+0.1° means.

[0052] The subject's "treatment" or "therapy" is intended to address the symptoms, complications, conditions, or biochemical reactions associated with a disease. reverse, alleviate, ameliorate, inhibit, or slow the onset, progression, development, severity, or recurrence of clinical symptoms; Any kind of intervention or process carried out on a subject with the purpose of or refers to the administration of an active agent to a subject.

[0053] "Administering" or "administration" refers to any of a variety of methods and delivery systems known to those skilled in the art. It refers to the physical introduction of a therapeutic agent into a subject using a device or device. Routes of administration include oral, intravenous, Intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration, e.g., injection or infusion Administration can also include, for example, single, multiple, and / or intravenous infusion. Or it can be carried out over one or more extended periods.

[0054] The terms "prophylactic" or "prophylactically" mean the prevention of a disease or Prevent or prevent the condition from developing, or at least prevent it from developing completely (e.g. administering to a subject for the purpose of reducing the symptoms or severity of a disease or condition refers to any type of intervention or process performed through or administering an active agent to a subject .

[0055] A "subject" includes any human or non-human animal. The study was carried out in non-human primates, sheep, dogs, and other animals such as mice, rats, and guinea pigs. In some embodiments, the mammalian species may be a vertebrate, such as a rodent, but is not limited to such a vertebrate. In this specification, the subject is a human. The terms "subject" and "patient" and "individual" are used interchangeably throughout this specification. are used interchangeably in the literature.

[0056] An "effective amount" or "therapeutically effective amount" or "therapeutically effective dosage" of a drug or therapeutic agent is simply When used alone or in combination with other treatments, it may delay the onset of the disease or a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease-free periods, or Any treatment that promotes regression of the disease as evidenced by improvement in functional impairment or disability due to pain. The ability of a therapeutic agent to promote disease regression is evaluated, for example, by human subjects in clinical trials. in elephants, in animal model systems predictive of efficacy in humans, or in vitro Evaluating the activity of drugs in assays allows for a variety of methods known to the skilled practitioner. It can be evaluated using

[0057] The phrase "pharmaceutically acceptable" means that a substance or composition is chemically and / or toxicologically acceptable. must be physiologically compatible with the other ingredients comprising the formulation and / or the mammal being treated therewith. This indicates that it is necessary.

[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 exist in various polymorphic forms. Each form may have a different solubility profile, melting temperature, flowability, dissolution rate, and / or or have different distinct solid-state physical properties, such as different X-ray diffraction peaks. The actual physical characteristics are the conformation and structure of molecules within the unit cell that define a particular polymorphic form of a substance. The polymorphic forms of a compound can be determined in the laboratory using X-ray powder diffraction (XRP). D"), 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 can be formulated as a pharmaceutical product (pharmaceutical composition), for example, by dissolving the drug substance. consistency, stability, flowability, ease of handling, and compressibility, as well as the safety and effectiveness of the drug. It is well known in the pharmaceutical industry that this can affect the efficacy of drugs. For more information, see Hilfik er, Rolf (ed.), Polymorphism in the Pharmac. eutical Industry.Weinheim,Germany:Wiley- See VCH 2006.

[0059] As used herein, the term "amorphous" refers to a solid state solid that is in a non-crystalline state. Amorphous solids generally have short-range molecular arrangements like crystals, but unlike crystalline solids The solid-state morphology of solids is not clearly visible under polarized light microscopy. Microscopy, X-ray powder diffraction ("XRPD"), differential scanning calorimetry ("DSC"), or other techniques known in the art The amount of the ion exchange reaction may be determined by other standard techniques known to those skilled in the art.

[0060] As used herein, the term "crystalline" refers to a structure with a regularly repetitive pattern of molecules or external surfaces. The solid-state morphology of a solid is determined by polarized light microscopy. microscopy, X-ray powder diffraction ("XRPD"), differential scanning calorimetry ("DSC"), or other techniques known to those skilled in the art. It can be determined by other standard techniques known to those skilled in the art. The term "crystalline purity" as used herein refers to the degree of crystalline purity of amorphous atrasentan or its pharmaceutically acceptable salts. The specific results of atrasentan or a pharmaceutically acceptable salt thereof in a sample that may contain the salt are Crystalline polymorphs of atrasentan or its pharmaceutically acceptable salts, or mixtures thereof The percentage of one or more additional crystalline polymorphs of atrasentan or When a crystalline polymorph of a pharmaceutically acceptable salt is described as having "substantial crystalline purity," In this case, it is assumed that the polymorph is substantially free of other polymorphs (amorphous and / or crystalline). and (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%).

[0061] As used herein, the term "chemical purity" refers to the purity of a particular compound (e.g., atrasentan or a pharmaceutically acceptable salt thereof). atrasentan or a pharmaceutically acceptable salt thereof, and a composition containing or consisting of the same. The composition made from 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,4 S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl) -1-((N-(n-butyl)-N-ethyl)aminocarbonylmethyl)pyrrolidine-3 -carboxylic acid, (2R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzo Dioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl) Pyrrolidine, or ethyl (2R,3R,4S)-2-(4-methoxyphenyl)-4- (1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)amino) carboxylate, but not limited to, A sample of atrasentan or a pharmaceutically acceptable salt thereof may contain one or more impurities. When described as having "substantially pure," the sample is substantially free of impurities (e.g., For example, less than 10%, less than 5%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, or contains less than 0.05%).

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

[0063] As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier that is capable of transporting a cell, organism, or a substance that assists in the administration of an active agent to a subject. can be included in the compositions of the present disclosure and do not cause significant adverse toxicological effects in subjects "Carrier" refers to a carrier or excipient. Non-limiting examples of pharmaceutically acceptable carriers include water, NaCl, Normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, bulking agents , disintegrants, lubricants, coatings, sweeteners, flavors and colors, liposomes, dispersion media , microcapsules, cationic lipid carriers, isotonic agents, and absorption delaying agents. Carriers also include those that provide stability, sterility, and isotonicity to the formulation (e.g., antibacterial agents). preservatives, antioxidants, chelating agents, and buffering agents), to prevent the action of microorganisms (e.g., antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, and sorbic acid ), or substances to provide edible flavorings, etc. to the formulation. In the present invention, a carrier is a drug that facilitates the delivery of a small molecule drug or antibody to a target cell or tissue. Those skilled 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 production of a protein or protein in mammalian cells. Refers to the level of mRNA.

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

[0066] As used herein, the term "IL-6 signaling" refers to the activation of the IL-6 receptor. Expression of one or more proteins in a signaling pathway that begins with activation and ends with gene expression and / or activity, which begins with activation of the IL-6 receptor and ends with gene expression. Non-limiting examples of proteins in signal transduction pathways include IL-6 receptor, JAK, S TAT3, PI3K, Akt / PKB, IKKs, IkBs, NF-kB, MAPK, R as, Raf, MEK, and ERK.

[0067] As used herein, the term "NF-kB signaling" refers to the expression of IKKα, IKKβ , IkB, and NF-kB, and / or by the activity of NF-kB. one or more genes that regulate the expression of TNF-α, IL-1, CAM, COX-2, and By "expression" is meant the expression and / or activity of one or more of: iNOS, NF-κB, and iNOS.

[0068] As used herein, the term "PDGF signaling" refers to the signal transduction pathways that regulate the activity of PDGF receptors, PK C, PI3K, Src, Ras, ERK1 / 2, Rho, Rac, Akt, mTOR, N Expression and / or function of one or more of APDH oxidase, MAPK, and cPLA2 or activity.

[0069] As used herein, the term "SGLT-2 inhibitor" refers to a sodium glucose co- SGLT-2 inhibitors are compounds that inhibit the SGLT-2 transporter. SGLT-2 blocks the reabsorption of glucose from the blood and thus exerts a glucose-lowering effect. Inhibitors are used to treat type 2 diabetes and improve cardiovascular health by enhancing glycosuria independently of insulin. It has been shown to improve vascular outcomes. Wright, 2001, Am. J. Phys. iol.Renal Physiol.280:F10 and Scheen, 2018, See Circ. Res. 122:1439. In some embodiments, "S The term "GLT-2 inhibitor" refers to compounds whose primary effect is the inhibition of SGLT-2. , is not limited to compounds that inhibit only SGLT-2, and therefore, SGLT-2 inhibitors (e.g. These include compounds that have other activities in addition to their therapeutic activity (e.g., SGLT-1 inhibition).

[0070] In some embodiments, the SGLT-2 inhibitor is a drug known as gliflozin. In some embodiments, the SGLT-2 inhibitor is a compound of the FD A or compounds approved as SGLT-2 inhibitors by regulatory authorities such as the EMA Non-limiting examples of SGLT-2 inhibitors include bexagliflozin, canagliflozin, (INVOKANA®), dapagliflozin (FARXIGA®), ), empagliflozin (JARDIANCE®), ertugliflozin (S TEGLATRO™), ipragliflozin (SUGLAT®), Ruse Ogliflozin (LUSEFI®), remogliflozin, sergliflozin, Licogliflozin, sotagliflozin (ZYNQUISTA™), and tofogliflozin These include, but are not limited to, phlozin.

[0071] In some embodiments, the SGLT-2 inhibitors include dapagliflozin, canagliptin, Ipragliflozin, Empaglifosin, Bexagliflozin, Licogliflozin Jin, 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), Tagliflozin, luseogliflozin, sergliflozin etabonate (ethyl carbonate), Remogliflozin, remogliflozin etabonate, and T-1095(((2R,3 S,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 is dapagliflozin, canagliptin, Rosin, Ipragliflozin, Empaglifosin, Bexagliflozin, Licogliflozin Janagliflozin (XZP-5695), Tofogliflozin, Ertugliflozin , Henagliflozin (SHR-3824), Enavogliflozin (DWP-16001) In some embodiments, the SGLT-2 inhibitor includes a C-glycoside such as Fogliflozin, ertugliflozin, and henagliflozin (SHR-3824) Some embodiments include C-glycosides having bicyclic or spiropyran groups. In this study, SGLT-2 inhibitors were dapagliflozin, canagliflozin, and ipragliflozin. Rosin, empagliflozin, bexagliflozin, licogliflozin, janagliflozin gin (XZP-5695), and enavogliflozin (DWP-16001), Includes C-glycosides that do not have bicyclic or spiropyran groups.

[0073] In some embodiments, the SGLT-2 inhibitor is TA-1887 (3-(4-cyclohexyl)methylpropional). Chloropropylbenzyl)-4-fluoro-1-(β-D-glucopyranosyl)-1H-isopropyl indole) and indole-N-glycoside 18 (3-(4-ethylbenzyl)-1- (β-D-glucopyranosyl)-1H-indole) and other N-glycosides.

[0074] In some embodiments, the SGLT-2 inhibitor is a 2-methylpropional stearate inhibitor, such as sotagliflozin. Contains thithio-C-glycoside.

[0075] In some embodiments, the SGLT-2 inhibitor is a thiol, such as luseogliflozin. Contains pyran-C-glycoside.

[0076] In some embodiments, the SGLT-2 inhibitor is sergliflozin etabonate (ethyl carbonate), remogliflozin, remogliflozin etabonate, and T-109 5(((2R,3S,4S,5R,6S)-6-(2-(3-(benzofuran-5-yl )Propanoyl)-3-hydroxy-5-methylphenoxy)-3,4,5-trihydro O-glycosides such as (2H-pyran-2-yl)ethoxytetrahydro- and O-glycoside prodrugs.

[0077] In some embodiments, the SGLT-2 inhibitor as defined herein is an SGLT In some embodiments, the present invention includes any compound that exhibits SGLT-2 inhibitory activity. An inhibitor may, for example, have approximately greater activity against SGLT-2 than against SGLT-1. 2x, approx. 5x, approx. 10x, approx. 20x, approx. 50x, approx. 100x, approx. 200x, approx. 300x, Approximately 400 times, approximately 500 times, approximately 750 times, approximately 1,000 times, approximately 1,250 times, approximately 1,500 times, approximately 1,750 times, approximately 2,000 times, approximately 2,500 times, or any value in between. By having the above structure, the compound is selective for SGLT-2 over SGLT-1. A potent SGLT-2 inhibitor has a potency of less than about 1000 nM as measured by the assay described herein. 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 of inhibitory activity against SGLT-2 (IC 50 In some embodiments, the SGLT-2 inhibitor may be less than about 25 nM, less than about 10 nM, less than about 5 nM when measured in the assay provided in or inhibitory activity against SGLT-2 (IC 50 ) can be shown An exemplary assay for determining SGLT-2 inhibitory activity is described by Ryan, et al. ,Kidney International,Vol.45,pp.48-57(19 94). Briefly, CHO cells were transfected with human SGLT-2 (GenBank Stably transfected with a cDNA encoding the IL-11 β-lactamase (kM95549). Wash the cells. Then, 10 μM [ 14 C]α-methylglucopyranoside (AMG) and 10μ Incubate with inhibitors of M. 14 [C]AMG uptake is associated with phlorizin The cells are then quenched with cold buffer containing ATP and lysed using a suitable reagent. 14 C ] to quantify AMG uptake.

[0078] SGLT-2 inhibitors include pharmaceutically acceptable salts, solvates, complexes, and their derivatives. This includes salts of solvates. For example, "dapagliflozin" includes salts of dapagliflozin (salts salts, etc.) and solvates (e.g., propylene glycol hydrate), and Canagliflozin includes solvates (e.g., canagliflozin hemihydrate) and solvates It also contains salts (such as the hydrochloride salt of the hydrate). and dapagliflozin are conjugated (henagliflozin proline and dapagliflozin conjugates, respectively). and dapagliflozin proline).

[0079] As used herein, a subject is described as having "controlled serum glucose levels." When the test is performed, it indicates that the subject has a serum glucose level within the normal or healthy range. In some embodiments, the subject has a blood glucose level of about 70 mg / dL to about 130 mg / dL. g / dL. For example, the subject has a fasting serum glucose level of about 130 mg / dL , 125mg / dL, 120mg / dL, 115mg / dL, 110mg / dL, 105 mg / dL, 100mg / dL, 95mg / dL, 90mg / dL, 85mg / dL, 8 Determined to have a fasting serum glucose level of 0 mg / dL or less than 75 mg / dL It has been done.

[0080] As used in the methods herein, the term "reducing" refers to reducing atrasentan or a pharmaceutically acceptable salt thereof. A reduction in the indicated parameter compared to a baseline measurement (or measurements) of or a baseline of the same parameters in healthy subjects (e.g., subjects without IgA nephropathy). Refers to the reduction of a given parameter compared to a line measurement (or measurements). Therefore, the term "increase" as used herein refers to the Baseline measurements of the same parameters in subjects taken before the start of administration of a commercially acceptable salt An increase in the indicated parameter compared to a baseline value (or multiple measurements) or a decrease in the normal range of values ​​in healthy subjects ( For example, baseline measurements (or refers to an increase in a given parameter compared to a single measurement (or measurements).

[0081] The term "glomerular filtration rate (GFR)" refers to the amount of blood that leaves the renal (kidney) glomerular capillaries per unit of time. It is defined as the volume of fluid filtered into Bowman's capsule per 1000 stool. It is an indicator of overall kidney function. The glomerular filtration rate (GFR) is the rate at which blood is filtered out and released freely by the kidneys. Calculated by measuring any chemical that is filtered and not reabsorbed or secreted Therefore, the measured ratio is the amount of substance in the urine that comes from the calculated amount of blood. GFR is commonly recorded in units of volume per hour, e.g., milliliters per minute. The following formula can be used: GFR = (urine concentration x urine volume) / plasma concentration. R can be measured by injecting inulin into plasma. It is neither reabsorbed nor secreted by the kidney after glomerular filtration, so its excretion rate is The normal GFR is 90-125 m L / min / 1.73m 2 , especially GFR = 100-125 mL / min / 1.73 m 2 G Other principles for measuring FR include 51Cr-EDTA, [125I]iothalamate or "Estimated glomerular filtration rate (eGFR)" refers to the measurement of iohexol or iohexol. c Kidney Disease Epidemiology Collaborat ion (CKD-EPI) formula, Cockcroft-Gault formula, or Modified Based on the cation of Diet in Renal Disease (MDRD) formula These are defined as screening based on serum creatinine levels. All are known in the art. As used herein, "stabilizing eGFR" refers to " reduces the rate of decline in eGFR and / or attenuates the rate of decline in eGFR. In some embodiments, the rate of decrease in the subject's eGFR 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 or any value therebetween. This decay may be, 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, Approximately 20 weeks, approximately 30 weeks, approximately 40 weeks, approximately 50 weeks, approximately 60 weeks, approximately 70 weeks, approximately 80 weeks 90 weeks, 100 weeks, 110 weeks, 120 weeks, 130 weeks, 140 weeks weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, if The treatment may be for about 200 weeks or after any value therebetween. In this condition, the subject is administered atrasentan or a pharmaceutically acceptable salt thereof for about 15 to about 30 days. In some embodiments, the subject is treated with a salt of are being treated with atrasentan or a pharmaceutically acceptable salt thereof.

[0082] "ESRD" is an abbreviation for end-stage renal disease. As used herein, the onset of ESRD The patient's blood flow rate is approximately 15 mL / min / 1.73 m 2and / or is defined as the time when a subject starts chronic dialysis. If the condition is defined as "high in vasopressin," the subject is not required to receive atrasentan or its pharmaceutically acceptable salts. Prior to the first administration of salt, the patient had >1 g / day of protein in the urine and and / or have an eGFR of less than 60.

[0083] As used herein, "IgA nephropathy-associated disease flare" refers to a flare of hematuria, worsening proteinuria, This refers to disease flares associated with physical symptoms and a decline in eGFR. Symptoms include increased edema, fatigue, increased hematuria, gross hematuria, and generally progressive disease progression. Other symptoms that negatively impact the

[0084] As used herein, a subject is "in a state where they are unable to maintain potassium levels within the normal physiological range." When the phrase "is used to describe a patient who is taking steroids," the subject is required to have a blood potassium level of between about 3.5 mEq / L and about 5.2 mEq / L. It has a level.

[0085] As used herein, a subject "maintains sodium levels within the normal physiological range." If the phrase "to be administered to a patient with a blood sodium level of about 135 to about 145 mEq / L" is used, the patient must have a blood sodium level of about 135 to about 145 mEq / L. It has a

[0086] As used herein, the term "proteinuria" refers to the presence of protein in the urine above normal levels. It refers to the presence of protein. "Proteinuria" includes "albuminuria" and "microalbuminuria." Normal human protein levels range from approximately 0 to 30 mg / L in urine. However, in any given urine sample, levels can reach approximately 80 mg / L. Normal human urinary protein levels range from approximately 0 to 150 mg per urine sample. Proteinuria is determined by the urinary total protein / creatinine ratio (UPCR) or approximately 30 m specific protein ratios, such as a urinary albumin-to-creatinine ratio (ACR) of > g / g Typically, urinary UACR values ​​in mg / g can be expressed as mg / day of subject-induced acupuncture. Albuminuria and microalbuminuria are both types of proteinuria. Often, it causes or indicates disease, but is not limited to the development of disease. Proteinuria includes physiological proteinuria, functional proteinuria, and functional proteinuria after excessive muscle exertion. Any of the following, including but not limited to, exercise proteinuria, which is associated with a form of proteinuria: Furthermore, proteinuria is intended to encompass any form of proteinuria in the kidney. Benign proteinuria ("essential" type) refers to types or proteinuria that are not the result of pathological changes. Proteinuria also encompasses pathological proteinuria. , for example, encompasses levels of protein in urine that are higher than normal physiological levels.

[0087] As used herein, "albuminuria" (also known as "macroalbuminuria") The term "albumin in urine" refers to the presence of albumin in urine above normal levels. Since the substance is mainly albumin, normal human urinary UACR levels are approximately 0-30 mg / As used herein, the term "microalbuminuria" in humans, at a rate of about 20-200 μg / min or a level of about 30-300 mg / L This refers to the presence of albumin in the urine, which is excreted in urine. "Albuminuria" is defined as a urinary UACR of more than approximately 30 mg / g, or approximately 3.5 mg / g in women. g / mmol or more, and in men it refers to a urinary UACR of approximately 2.5 mg / mmol or more. Hyperalbuminuria is often an early warning sign of kidney disease, but it can also occur for other reasons.

[0088] As used herein, the term "hematuria" refers to the presence of blood in the urine. as gross hematuria (visible traces of blood cells) or microscopic hematuria (microscopic traces of blood) Confirmed evidence of microscopic hematuria is based on at least three properly collected urine specimens. is defined as three or more red blood cells per microscopic high-power field (HPF). Microscopic hematuria can also be detected in the clinic by dipstick testing (colorimetric comparative estimate). Hematuria (either microscopic or macroscopic) may be present in asymptomatic cases (follow-up cases associated with hematuria). Additional symptoms may include dysuria (painful urination) or symptomatic. ), including a sensation of incomplete bladder emptying, increased frequency or urination, or flank pain .

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

[0090] The terms "synergy" or "synergistic" are used herein to describe the combination of two therapeutic agents. This means that the combined effect is greater than the sum of the effects of each drug when administered alone. For example, Chou and Talalay, Advances in See Enzyme Regulation (1984), 22, 27-55 A "synergistically effective amount" is an amount that produces a synergistic effect (as "synergistic" is defined herein). In some embodiments, the amount of a combination of two or more therapeutic agents acting synergistically. An effective amount of a combination is one or more compounds in the combination that is more effective than the compound administered alone. They can be therapeutically effective even when administered at doses that may be sub-therapeutic in some cases.

[0091] Various art-recognized factors, such as the patient's height, weight, sex, age, It will be appreciated that different concentrations of each compound may be used depending on the patient and clinical history. Exemplary synergistic effects include enhanced therapeutic efficacy, reduced dosage at equivalent or increased levels of efficacy, and the like. , reduction or delay in the development of drug resistance, and simultaneous enhancement or equivalent therapeutic effect (e.g. , the same therapeutic effect as at least one of the therapeutic agents) and at least one undesirable side effect of the therapeutic agent. These include, but are not limited to, reducing unwanted drug effects (e.g., side effects and adverse events). stomach.

[0092] In some embodiments, "synergy," as used herein, refers to an effect, e.g., Atrasentan or its pharmaceutically acceptable salt and an SGLT-2 inhibitor are administered alone. The efficacy, including the clinical results described herein, is greater than the sum of the effects observed when the Atrasentan or its pharmaceutically acceptable salts, which produce any of the following beneficial or desired results: acceptable salts, and combinations of one or more additional therapeutic agents (e.g., SGLT-2 inhibitors) Such clinical results include treating IgA nephropathy, reducing renal inflammation and / or fibrosis. Reduce fibrosis, reduce hematuria, reduce proteinuria (e.g., albuminuria) It reduces the number of disease flares associated with IgA nephropathy, stabilizes eGFR, and Delaying the onset of ESRD, reducing fatigue, and These include, but are not limited to, reducing activation of um cells.

[0093] In some embodiments, "synergy," as used herein, refers to the synergistic effect of atrasentan or a pharmaceutically acceptable salt thereof, and when the SGLT-2 inhibitor is administered alone A greater reduction in proteinuria, including albuminuria, than the sum of the observed effects atrasentan or a pharmaceutically acceptable salt thereof, and an SGLT-2 inhibitor It refers to a combination of

[0094] In some embodiments, "synergy," as used herein, refers to a combination of a desired therapeutic effect and a and a reduction in the occurrence and / or severity of undesired drug effects, side effects, or adverse events. atrasentan or a pharmaceutically acceptable salt thereof, and SGLT-2, which result in a reduction In some embodiments, the combination of inhibitors may be used to treat unwanted drug effects, side effects, and Use, or adverse events, may occur after administration of atrasentan or its pharmaceutically acceptable salts, and SGL These findings are associated with or observed in monotherapy with T-2 inhibitors. In embodiments, the undesired drug effect, side effect, or adverse event is fluid retention, anemia, Nausea, constipation, increased thirst, bowel movements, increased urination, urinary tract infections, yeast infections, vaginal itching, increased elevated LDL cholesterol levels, increased brain natriuretic peptide (BNP) levels one or more of the following: urinary tract infection, acute sodium retention, and a sudden increase in creatinine levels In some embodiments, the fluid retention is associated with a weight gain of greater than about 3 kg. In some embodiments, the increased BNP level is greater than about 300 pg / mL. stomach.

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

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

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

[0098] B. Introduction Most subjects with IgAN present with single or transient gross hematuria or with routine urinary Symptoms may first appear after microscopic hematuria and / or proteinuria are detected during testing. The subject is considered to have a condition such as crescentic IgAN or gross hematuria resulting in renal tubular obstruction. The definitive diagnosis of IgAN is typically established by renal biopsy. Immunofluorescence and / or immunoperoxidase studies of IgA deposits are performed. Prominent spherical deposits of less prominent IgA within the glomerulus and along the glomerular capillary walls (C 3 and IgG) are characteristic of IgAN. Histopathological features of the disease include mesangial proliferation, endocapillary proliferation, segmental scarring, and urinary Includes tubular atrophy.

[0099] C. Treatment Methods In normal healthy human kidneys, ET-1 and ET-RA expression is stronger in vascular tissues. In contrast, subjects with IgAN had elevated levels of ET in the kidneys. In this population, the expression of ET-1 was increased by the protein It is positively correlated with urinary tract infection and is at least partially ameliorated by the administration of ACE inhibitors. Current treatments for IgAN include antihypertensive and antiproteinuric drugs (e.g., angiotensin inhibitors). angiotensin-converting enzyme inhibitors and / or angiotensin II receptor blockers) with corticosteroids Optimize the course of the disease to slow disease progression. t al.,Int.J.Nephrol.and Renovascular Dis .11, pp.137-148(2017). However, the combination of these drugs The combination can have serious dose-limiting side effects such as hyperkalemia, and in more severe cases Further immunosuppression may be required.

[0100] Clinically, IgAN is diagnosed by kidney biopsy and is characterized by mesangial cell proliferation and / or or matrix expansion (or advanced focal segmental glomerulosclerosis), Immunofluorescence shows predominant mesangial granular deposition of IgA (2+ or higher). Unlike other progressive kidney diseases such as diabetic nephropathy, diabetic nephropathy typically develops in the peripheral Diffuse capillary basement membrane thickening with PAS-positive nodules, segmental or global thickening in advanced stages It presents with thickened arteries accompanied by glomerular sclerosis and hyaline deposits. For example, Zanatta, et al. al.,Renal Failure,34(3),pp.308-315(2012 ) for more information.

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

[0102] In some embodiments, the subject has diabetic nephropathy, HIV / AIDS, HIV-associated Have never been previously diagnosed with one or more of the following: nephropathy, prostate cancer, or acute renal failure In some embodiments, the subject is diagnosed with diabetic nephropathy, HIV / AIDS, HIV-related Have you ever been diagnosed with any of the following: kidney disease, prostate cancer, or acute kidney failure? In some embodiments, the subject has not been previously diagnosed with diabetic nephropathy. In some embodiments, the subject has never been diagnosed with HIV / AIDS. In some embodiments, the subject has not been previously diagnosed with HIV-associated nephropathy. In some embodiments, the subject has never been diagnosed with prostate cancer. In some embodiments, the subject has never been diagnosed with acute renal failure. In some embodiments, the subject has not had diabetic nephropathy, HIV / AIDS, Previous diagnosis of one or more of the following: HIV-associated nephropathy, cancer, or acute renal failure In some embodiments, the subject is free of diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject has not been previously diagnosed with diabetes. Have been previously diagnosed with a type 1 or type 2 diabetes mellitus. In embodiments, the subject has previously been diagnosed with diabetes and has diabetic nephropathy. In some embodiments, the subject has not been previously diagnosed with type 2 diabetes. In some embodiments, the subject has not been previously diagnosed with type 2 diabetes. In some embodiments, the subject has previously been diagnosed with type 2 diabetes. Have 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 the present invention, the cancer is lung cancer or prostate cancer.

[0104] In some embodiments, the subject has diabetic nephropathy, HIV / AIDS, HIV-associated The patient does not have one or more of nephropathy, prostate cancer, or acute renal failure. The subjects are diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, prostate cancer, In some embodiments, the subject does not have any of the following: diabetes mellitus or acute renal failure. 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. one or more of the following: 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 has 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. , have type 2 diabetes, and do not have diabetic nephropathy.

[0105] In some embodiments, the subject has diabetic nephropathy, HIV / AIDS, HIV-associated Not suffering from one or more of the following: nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject is a patient with diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, or prostate cancer. In some embodiments, the patient is not suffering from any of the following: 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 is free of cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the subject is not suffering from acute renal failure. In some embodiments, the subject is diagnosed with diabetic nephropathy, HIV / AIDS, HIV-related The patient does not have one or more of the following: kidney disease, cancer, or acute renal failure. In some embodiments, the cancer is lung cancer or prostate cancer. The elephants are free of 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 diabetes or type 2 diabetes. In some embodiments, the subject has type 2 diabetes but does not have diabetic nephropathy. In some embodiments, the subject does not have diabetes. In some embodiments, the subject does not have type 2 diabetes. In some embodiments, the subject has type 2 diabetes but does not have diabetic nephropathy. He is not suffering from any disease.

[0106] In some embodiments, the subject has diabetic nephropathy, HIV / AIDS, HIV-associated Not receiving treatment for one or more of the following: nephropathy, prostate cancer, or acute kidney failure. In one embodiment, the subject is diagnosed with diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, prostate cancer, or In some embodiments, the patient has not received treatment for any of the following: adenocarcinoma, adenocarcinoma, or acute renal failure. In some embodiments, the subject is not undergoing treatment for diabetic nephropathy. The elephant is not receiving treatment for HIV / AIDS. In some embodiments, the subject is not undergoing treatment for HIV-associated nephropathy. In some embodiments, the subject is not receiving treatment for acute renal failure. In some embodiments, the subject is diagnosed with diabetic nephropathy, HIV / AIDS, Not receiving treatment for one or more of the following: HIV-associated nephropathy, cancer, or acute renal failure. In some embodiments, the cancer is lung cancer or prostate cancer. In the present study, the subject is not undergoing treatment for diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject is receiving treatment for diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject is undergoing treatment for diabetes, such as type 1 diabetes or type 2 diabetes. who are receiving treatment for diabetes but are not receiving treatment for diabetic nephropathy. In some embodiments, the subject is not undergoing treatment for type 2 diabetes. In some embodiments, the subject is undergoing treatment for type 2 diabetes. Being treated for diabetes but not for diabetic nephropathy.

[0107] In certain embodiments, the subject is determined to have controlled serum glucose levels. In some embodiments, the subject has controlled serum glucose levels. In some embodiments, the patient is not receiving treatment for diabetes. In some embodiments, the subject with the low blood sugar level is undergoing treatment for diabetes. Subjects with controlled serum glucose levels are not receiving treatment for type 2 diabetes. In some embodiments, the subject with controlled serum glucose levels has type 2 diabetes. In some embodiments, the subject is undergoing treatment for a disease. The subject is determined to have HIV-associated nephropathy or acute renal failure. For example, subjects may have a blood glucose level of about 130 mg / dL, about 125 mg / dL, or / dL, approx. 120mg / dL, approx. 115mg / dL, approx. 110mg / dL, approx. 105mg / dL, approx. 100mg / dL, approx. 95mg / dL, approx. 90mg / dL, approx. 85mg / dL , about 80 mg / dL, or less than about 75 mg / dL, or any value therebetween. In certain embodiments, the subject has been determined to have a fasting serum glucose level. , HIV-associated nephropathy, or acute renal failure. In embodiments, the subject receives controlled serum group therapy, as described elsewhere herein. The subject is determined to have a course of HIV-associated nephropathy or acute renal failure. In certain embodiments, the subject has not been diagnosed with one or more of the following: The subject is determined to have a high serum glucose level, and the subject is diagnosed with HIV-associated nephropathy or acute renal failure. Have never been diagnosed with one or more of the following:

[0108] In another embodiment, the present invention relates to a method for reducing renal inflammation and / or fibrosis in a subject with IgA nephropathy. The present invention relates to a method for reducing the risk of rheumatoid arthritis, comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or its derivatives. Provided herein are methods comprising administering a pharmaceutically acceptable salt of

[0109] In some embodiments, the renal inflammation in a subject with IgA nephropathy is atrial fibrillation. After treatment with Sentan or a pharmaceutically acceptable salt thereof (e.g., about 1 week, about 2 weeks, Approximately 3 weeks, approximately 4 weeks, approximately 5 weeks, approximately 6 weeks, approximately 7 weeks, approximately 8 weeks, approximately 9 weeks, approximately 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 14 0 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks after treatment, or any value therebetween), at least about a 10% reduction In certain embodiments, the inflammation in the kidney in the subject is at least about 20%, at least about 30%, 0%, approximately 40%, approximately 50%, approximately 60%, approximately 70%, approximately 80%, approximately 90%, or approximately 95% %, or any value therebetween. In some of the foregoing embodiments, the subject and being treated with atrasentan or a pharmaceutically acceptable salt thereof for about 15 to about 30 days. There are.

[0110] In some embodiments, renal fibrosis in subjects with IgA nephropathy is treated with atlas therapy. After treatment with entamin or a pharmaceutically acceptable salt thereof (e.g., 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, Approximately 20 weeks, approximately 30 weeks, approximately 40 weeks, approximately 50 weeks, approximately 60 weeks, approximately 70 weeks, approximately 80 weeks 90 weeks, 100 weeks, 110 weeks, 120 weeks, 130 weeks, 140 weeks weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, if at least about 10% reduction after about 200 weeks of treatment, or any value therebetween In certain embodiments, renal fibrosis in a subject is at least about 20%, about 30%, or , 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 is decreased by about Have been treated with atrasentan or its pharmaceutically acceptable salt for 15 to approximately 30 days .

[0111] In some embodiments, renal fibrosis in subjects with IgA nephropathy is treated with atlas therapy. After treatment with entamin or a pharmaceutically acceptable salt thereof (e.g., 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, Approximately 20 weeks, approximately 30 weeks, approximately 40 weeks, approximately 50 weeks, approximately 60 weeks, approximately 70 weeks, approximately 80 weeks 90 weeks, 100 weeks, 110 weeks, 120 weeks, 130 weeks, 140 weeks weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, if (approximately 200 weeks, or any value therebetween, after treatment) In certain embodiments, renal fibrosis in a subject is reduced by less than about 50%. For example, in some embodiments, the subject Renal fibrosis in the cortical area was approximately 35%, 30%, 25%, 20%, 15%, and more. or to less than about 10%, or any value therebetween. In some cases, subjects receive atrasentan or a pharmaceutically acceptable salt thereof for about 15 to about 30 days. It is treated with salt.

[0112] In another embodiment, there is provided a method for reducing the incidence of hematuria in a subject with IgA nephropathy, comprising: and administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. Provided herein are methods that include administering a salt.

[0113] In some embodiments, a high power (microscopic) field in a subject with IgA nephropathy The number of urinary red blood cells per hpf (rbc / hpf) was measured by atrasentan or its pharmaceutically acceptable salts. After treatment with the salt (e.g., about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, Approximately 6 weeks, approximately 7 weeks, approximately 8 weeks, approximately 9 weeks, approximately 10 weeks, approximately 20 weeks, approximately 30 weeks, approximately 4 0 weeks, approximately 50 weeks, approximately 60 weeks, approximately 70 weeks, approximately 80 weeks, approximately 90 weeks, approximately 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 In certain embodiments, the IL-10 level is reduced by at least about 10% (after treatment with any value between IL-10 and IL-10). The subject's urinary RBC / hpf is 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 above embodiments, the subject is administered the are being treated with atrasentan or a pharmaceutically acceptable salt thereof.

[0114] In another aspect, there is provided a method of stabilizing eGFR in a subject with IgA nephropathy, comprising: and administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. Provided herein are methods that include administering a salt.

[0115] In some embodiments, the rate of decline in eGFR in subjects with IgA nephropathy is reduced. The present invention relates to a method for reducing urinary tract infections, comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or its derivatives. Provided herein are methods comprising administering a pharmaceutically acceptable salt of In some embodiments, the rate of decline in the subject's eGFR is measured by administering atrasentan or its pharmaceutically acceptable salts thereof. After treatment with an acceptable salt (e.g., 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, approximately 50 weeks, approximately 60 weeks, approximately 70 weeks, approximately 80 weeks, approximately 90 weeks, approximately 100 weeks 110 weeks, 120 weeks, 130 weeks, 140 weeks, 150 weeks, 16 0 weeks, approximately 170 weeks, approximately 180 weeks, approximately 190 weeks, or approximately 200 weeks, or In some embodiments, the IL-10 level is reduced by at least about 10% after treatment (or any value therebetween). In this case, the subject's eGFR decline is at least about 20%, at least about 30%, or at least at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least at least about 80%, at least about 90%, or at least about 95%, or any value therebetween. In some of the above embodiments, the subject is administered 24 hours a day for about 15 to about 30 days. The patient is being treated with atrasentan or a pharmaceutically acceptable salt thereof. In some cases, subjects receive atrasentan or a pharmaceutically acceptable salt thereof for about 6 months to about 1 year. It is treated with salt.

[0116] In some embodiments, the rate of decrease in eGFR in a subject with IgA nephropathy is After treatment with Sentan or its pharmaceutically acceptable salt, approximately 10 mL / min / 1.73 m 2 For example, 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, Approximately 7 weeks, approximately 8 weeks, approximately 9 weeks, approximately 10 weeks, approximately 20 weeks, approximately 30 weeks, approximately 40 weeks, approximately 50 weeks, approximately 60 weeks, approximately 70 weeks, approximately 80 weeks, approximately 90 weeks, approximately 100 weeks, approximately 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 1 70 weeks, approximately 180 weeks, approximately 190 weeks, or approximately 200 weeks, or any period therebetween In certain embodiments, the rate of decline in a subject's eGFR is measured by atracentral thrombus analysis. After about 6 months to about 1 year of treatment with fluconazole or its pharmaceutically acceptable salt, the dose is about 9 mL / min. / 1.73m 2 , approximately 8 mL / min / 1.73 m 2 , about 7mL / min / 1.73m 2 , approximately 6 mL / min / 1.73m 2 , about 5mL / min / 1.73m 2 , approximately 4 mL / min / 1.73 m 2 , about 3 mL / min / 1.73m 2 , about 2mL / min / 1.73m 2 , about 1mL / min / 1.73m 2 , or approximately 0.75 mL / min / 1.73 m 2 Reduce to less than or any value between The typical decline in eGFR with age is, for example, approximately 10% per year in subjects aged 20 to 30 years. 1mL / min / 1.73m 2 is.

[0117] In another aspect, the method comprises reducing the number of IgA nephropathy-associated disease flares in a subject with IgA nephropathy. The method comprises administering to a subject in need thereof a therapeutically effective amount of atrasentan or Methods are provided herein that include administering a pharmaceutically acceptable salt thereof. In some embodiments, the method reduces flares of disease associated with hematuria. In embodiments, the method reduces disease flares associated with proteinuria. In some embodiments, the method includes detecting a phenotype of IgA nephropathy-related disease associated with systemic symptoms. In some embodiments, the method reduces the amount of hydroxybenzoates described elsewhere herein. In some embodiments, the method reduces the decline in eGFR such that the patient is able to Reduce one or more of the following: swelling, fatigue, hematuria, or gross hematuria. In some embodiments, the method positively impacts disease progression.

[0118] In another embodiment, a method for delaying the onset of ESRD in a subject with IgA nephropathy. and administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0013] Methods are provided herein that include administering a salt thereof.

[0119] In some embodiments, the method includes diagnosing IgA nephropathy in a subject and determining whether the subject has e GFR 15 mL / min / 1.73 m 2 Increase the time between the time when the In embodiments, the method includes diagnosing IgA nephropathy in a subject and determining whether the subject's eGFR is 15m or lower. L / min / 1.73m 2 Increase the time between the time when the temperature drops below 10% by at least about 10%. For example, in some embodiments, the method includes diagnosing IgA nephropathy in a subject and administering to the subject eGFR 15 mL / min / 1.73 m 2 At least about 20% of the time between , about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100 %, approx. 150%, approx. 200%, approx. 250%, approx. 300%, approx. 350%, approx. 400%, approx. 4 Increase by 50%, or about 500%, or any value in between.

[0120] In certain embodiments, the method includes diagnosing IgA nephropathy in a subject and administering eGF to the subject. R is 15 mL / min / 1.73 m 2 Increase the time between the time For example, the method may be used if the subject's eGFR is 15 mL / min / 1.73 m 2 The time when it is below 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, 1 1 year, 12 years, 13 years, 15 years, 15 years, 16 years, 17 years, 18 years, 19 years, or 20 years It can be delayed by a year.

[0121] In another aspect, there is provided a method for reducing proteinuria in a subject with IgA nephropathy, comprising: A therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof.

[0013] A method is provided herein that includes administering

[0122] In some embodiments, proteins (e.g., The amount of albumin) after treatment with atrasentan or its pharmaceutically acceptable salt (e.g. For example, 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks 9 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, 50 weeks, 60 weeks weeks, approximately 70 weeks, approximately 80 weeks, approximately 90 weeks, approximately 100 weeks, approximately 110 weeks, approximately 120 weeks 130 weeks, 140 weeks, 150 weeks, 160 weeks, 170 weeks, 18 0 weeks, approximately 190 weeks, or approximately 200 weeks after treatment, or any value in between) In some embodiments, the protein in the urine of the subject is reduced by at least about 10%. The amount of is at least about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, approx. 55%, approx. 60%, approx. 65%, approx. 70%, approx. 75%, approx. 80%, approx. 85%, approx. 90%, or about 95%, or any value therebetween. In some cases, the subject receives atrasentan or a pharmaceutically acceptable salt thereof for about 15 to about 30 days. Treated with tolerated salts.

[0123] In certain embodiments, proteins (e.g., arginine) in the urine of a subject with IgA nephropathy are The amount of atrasentan or its pharmaceutically acceptable salt is measured within about 2 days of treatment. In certain embodiments, the level of IgA nephropathy is reduced by about 20% to about 80% after about 30 days. The amount of protein (e.g., albumin) in the urine of a subject receiving atrasentan or its Approximately 20% to approximately 80% reduction after approximately 15 to approximately 30 days of treatment with a pharmaceutically acceptable salt In some of these embodiments, the amount of protein in the subject's urine is about 25% In some of these embodiments, the level of protein in the subject's urine is reduced by about 80%. In some of these embodiments, the amount of urinary The amount of protein is reduced by about 35% to about 80%. As a result, the amount of protein in the subject's urine is reduced by about 40% to about 80%. In some cases, 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 between about 50% and about 80% In the foregoing embodiment, a protein (e.g., a protein fragment) in the urine of a subject with IgA nephropathy is reduced. The reduction in the amount of vasoconstrictor (e.g., albumin) is due to atrasentan or a pharmaceutically acceptable salt thereof. It is related to the amount of protein (e.g., albumin) in the urine before treatment begins.

[0124] In some embodiments, proteins (e.g., The amount of albumin) after treatment with atrasentan or its pharmaceutically acceptable salt (e.g. For example, 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks 9 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, 50 weeks, 60 weeks weeks, approximately 70 weeks, approximately 80 weeks, approximately 90 weeks, approximately 100 weeks, approximately 110 weeks, approximately 120 weeks 130 weeks, 140 weeks, 150 weeks, 160 weeks, 170 weeks, 18 0 weeks, approximately 190 weeks, or approximately 200 weeks after treatment, or any value in between) In certain embodiments, the blood glucose level is reduced by about 100 mg / dL to about 3,000 mg / dL. The amount of protein in the elephant's urine is reduced by approximately 100 mg / dL to approximately 2,500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is between about 100 mg / dL and about 2, In certain embodiments, the amount of protein in the subject's urine is reduced by: In certain embodiments, the subject's blood glucose level is reduced by about 100 mg / dL to about 1,500 mg / dL. The amount of protein in the urine is reduced by approximately 100 mg / dL to approximately 1,000 mg / dL. In certain embodiments, the amount of protein in the subject's urine is between about 100 mg / dL and about 500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 10 mg / dL. In certain embodiments, the subject's urine is reduced by between about 0 mg / dL and about 400 mg / dL. The amount of protein is reduced by about 100 mg / dL to about 300 mg / dL. The amount of protein in the subject's urine is reduced by approximately 100 mg / dL to 200 mg / dL. In certain embodiments, the amount of protein in the subject's urine is about 500 mg / dL to In certain embodiments, the level of protein in the urine of the subject is reduced by about 2,500 mg / dL. The amount is reduced by about 500 mg / dL to about 2,000 mg / dL. The amount of protein in the subject's urine is reduced by approximately 500 mg / dL to approximately 1,500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is between about 500 mg / dL and about In certain embodiments, the amount of protein in the urine of a subject is reduced by 1,000 mg / dL. In certain embodiments, the subject's blood glucose level is reduced by about 500 mg / dL to about 900 mg / dL. The amount of protein in the urine is reduced by approximately 500 mg / dL to approximately 800 mg / dL. In an embodiment, the amount of protein in the subject's urine is between about 600 mg / dL and about 900 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 700 ml In certain embodiments, the subject's urine protein level is reduced by about 900 mg / dL to about 900 mg / dL. The amount of carbon dioxide is reduced by approximately 1,000 mg / dL to approximately 2,000 mg / dL. In some embodiments, the subject receives atrasentan or a pharmaceutical composition thereof for about 15 to about 30 days. In the foregoing embodiment, the subject with IgA nephropathy is treated with a commercially available steroid or steroids. A reduction in the amount of protein (e.g., albumin) in the urine of atrasentan or its The amount of protein (e.g., albumin) in the urine before the start of treatment with a biologically acceptable salt is related to.

[0125] In certain embodiments, proteins (e.g., arginine) in the urine of a subject with IgA nephropathy are The amount of bumin) is about 15 minutes after treatment with atrasentan or a pharmaceutically acceptable salt thereof. After about 30 days, the blood glucose level is reduced by about 100 mg / dL to about 500 mg / dL. In the present study, the amount of protein in the urine of the subject was measured by administering atrasentan or a pharmaceutically acceptable salt thereof. Approximately 15 to 30 days after treatment with chloramphenicol, the blood glucose level was approximately 200 mg / dL to 500 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by administration of atrasentan or or a pharmaceutically acceptable salt thereof, about 15 to about 30 days after treatment, about 300 mg / d In the aforementioned embodiment, the blood glucose level of a subject with IgA nephropathy is reduced by about 500 mg / dL. A reduction in the amount of protein (e.g., albumin) in the urine may be achieved by administering atrasentan or its pharmaceutical The amount of protein (e.g., albumin) in the urine before initiation of treatment with a commercially acceptable salt It is related.

[0126] In certain embodiments, proteins (e.g., arginine) in the urine of a subject with IgA nephropathy are The amount of bumin) is about 15 minutes after treatment with atrasentan or a pharmaceutically acceptable salt thereof. After about 30 days, the blood cholesterol level is reduced by about 500 mg / dL to about 900 mg / dL. In one embodiment, the amount of protein in the urine of the subject is measured by administering atrasentan or a pharmaceutically acceptable salt thereof. Approximately 600mg / dL to 900mg / dL reduction after approximately 15 to 30 days of salt treatment In certain embodiments, the amount of protein in the urine of the subject is measured using atrasentan or About 15 to about 30 days after treatment with the pharmaceutically acceptable salt thereof, about 700 mg / dL to In the above embodiment, the urinary concentration of a subject with IgA nephropathy is reduced by about 900 mg / dL. The reduction in the amount of proteins (e.g., albumin) in the Related to the amount of protein (e.g., albumin) in the urine before the start of treatment with acceptable salts is doing.

[0127] In some embodiments, a subject with IgA nephropathy is treated with atrasentan or After treatment with a pharmaceutically acceptable salt (e.g., 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 Between, 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 after 200 weeks of treatment), less than about 1.0 gram / day of protein in urine (e.g., In certain embodiments, the subject has a reduced level of about 0.9 grams of erythrocyte membrane protein (erythrocyte membrane protein, albumin). In certain embodiments, the patient has reduced levels of protein in the urine of less than 1000 mg / day. The subject has a reduced level of protein in the urine of less than about 0.8 grams per day. In an embodiment, 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 less than about 0.6 grams of protein in the urine per day. In certain embodiments, the subject has reduced levels of niacin. In certain embodiments, the subject has a reduced level of protein in the urine of less than and having reduced levels of protein in the urine of less than about 0.4 grams / day. In the method, 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 low level of protein in the urine of less than about 0.2 grams / day. In some of the foregoing embodiments, the subject has a reduced level of The patient has been treated with atrasentan or a pharmaceutically acceptable salt thereof for 10 days. In one embodiment, the amount of protein (e.g., albumin) in the urine of a subject with IgA nephropathy is The reduction is based on the level of urinary tacrolimus before the start of treatment with atrasentan or a pharmaceutically acceptable salt thereof. It is related to the amount of proteins (e.g., albumin).

[0128] In another aspect, there is provided a method for reducing fatigue in a subject with IgA nephropathy, comprising administering to said subject a dose of 200 mg of steroid hormone-lowering agent to said subject. and administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is Diabetic nephropathy, HIV-associated nephropathy, prostate cancer, or acute renal failure In certain embodiments, the subject is determined to be not suffering from diabetic nephropathy. In certain embodiments, the subject is determined to not have HIV-associated neurological disorders. In certain embodiments, the subject is determined to be free of prostate cancer. In certain embodiments, the subject is determined to be suffering from acute renal failure. It has been determined that there is no

[0129] In some embodiments, fatigue in a subject with IgA nephropathy is treated with atrasentan or or a pharmaceutically acceptable salt thereof (e.g., 1 week, about 2 weeks, about 3 weeks, about 4 weeks, approximately 5 weeks, approximately 6 weeks, approximately 7 weeks, approximately 8 weeks, approximately 9 weeks, approximately 10 weeks, approximately 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 1 50 weeks, approximately 160 weeks, approximately 170 weeks, approximately 180 weeks, approximately 190 weeks, or approximately 20 0 weeks after treatment, or any value therebetween), reduction of approximately 5% to approximately 80%. In certain embodiments, fatigue is reduced by about 10% to about 75%. Fatigue is reduced by about 10% to about 70%. In certain embodiments, fatigue is reduced by about 10% to about 70%. 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 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 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 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 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 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 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%. Fatigue is reduced by about 40% to about 70%. In certain embodiments, fatigue is reduced by about 40% 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 65%. In some embodiments, fatigue is reduced by about 50% to about 60%. In this method, the subject is administered atrasentan or a pharmaceutically acceptable salt thereof for about 15 to about 30 days. In certain embodiments, the reduction in fatigue is measured by a Fatigue Severity Scale. , Chalder Fatigue Scale, FACIT Fatigue Scale, Brief Fatigue Inventory, FA CT-F subscales, overall vitality and affect, May and Kline adjective criteria Checklist, Pearson-Byars Fatigue Feeling Checklist, Rhoten Fatigue Fatigue scale, fatigue and anergy schedule, visual analogue scale, and The above embodiment includes a reduction in the score of one or more of the individual strengths of the checklist. In this case, the reduction in fatigue experienced by a subject with IgA nephropathy is due to administration of atrasentan or It is associated with fatigue experienced by the subject prior to initiation of treatment with the pharmaceutically acceptable salt thereof. In some embodiments, the reduction in fatigue comprises a reduction in the score on the Brief Fatigue Inventory. .

[0130] Selecting a target Subjects with IgA nephropathy, as described elsewhere herein, can be treated with any of the methods known in the art. Non-limiting examples include kidney biopsy, gastroscopy, and the like. Detecting lactose-deficient IgA (e.g., Gd-IgA1), detecting anti-glycan antibodies, detection of IgA immune complex deposition in the kidneys, or In some embodiments, the diagnosis of IgA nephropathy is determined by: In certain embodiments, detecting IgA immune complex deposition in the kidney. Diagnosis of IgA nephropathy includes kidney biopsy. In certain embodiments, diagnosis of IgA nephropathy includes kidney biopsy. In certain embodiments, the diagnosis of IgA nephropathy includes detecting lactose-deficient IgA. Diagnosis includes detecting anti-glycan antibodies (e.g., KM55). In this context, the diagnosis of IgA nephropathy is based on renal biopsy followed by (e.g., light microscopy and / or This involves detecting the deposition of IgA immune complexes in the kidney (by immunofluorescence microscopy). nothing.

[0131] In some embodiments, the presence and / or level of a particular protein in a subject is determined. The level is determined prior to administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, serum levels of Gd-IgA1, serum levels of Gd-IgA1-specific autoantibodies, etc. and / or serum and / or urine levels of IgA1-containing immune complexes. oppova,et al.,Front.Immunol.,Vol.17,Art. 117 (2016), which is incorporated herein by reference in its entirety. In some embodiments, the subject is administered atrasentan or a pharmaceutically acceptable salt thereof. Prior to administration of the salt, patients had Gd-IgA levels above the 90th percentile. In embodiments, the subject receives, prior to administration of atrasentan or a pharmaceutically acceptable salt thereof: In some embodiments, the patient has a Gd-IgA level at or above the 95th percentile. Subjects' Gd-IgA levels were monitored for approximately 6 months to 1 year with atrasentan or its pharmaceutically acceptable salts. After treatment with tolerated salt, the level decreases to below the 90th percentile.

[0132] In certain embodiments, the subject has about 50% or more (e.g., about 60% or more, about 70% or more, or approximately 80% or more) have mesangial cellularity, and mesangial cellularity is , defined as more than four mesangial cells in any mesangial region of the glomerulus In certain embodiments, endocapillary hyperplasia (endocapillary hyperplasia) Intravascular pleocytosis is present in the subject, and intravascular pleocytosis is present in the glomerular capillary tubules. It is defined as hypercellularity with an increased number of cells in the cavity. Segmental sclerosis is present in subjects with glomerular tufts that are adhesions or fibrosis in parts of the glomerular tuft but not the entire tuft. or sclerosis (obstruction of the capillary lumen by matrix). In this embodiment, the subject has about 50% or more (e.g., about 60% or more, about 65% or more, tubular atrophy / interstitial fibrosis in approximately 70% or more, approximately 75% or more, or approximately 80% or more Tubular atrophy / interstitial fibrosis is a putative pattern of cortical areas showing tubular atrophy or interstitial fibrosis. In certain embodiments, the subject has a crescent on the glomerulus. In some of these embodiments, the subject has less than about 25% of the glomeruli (e.g., For example, less than about 20%, about 15%, about 10%, or about 5% of the cells have crescents. In one embodiment, the subject is classified as M1, E1, or , S1, T1 or T2, and / or a MEST-C score of C0 or C1 The Oxford MEST-C classification system is based on the Kidney International al(2009)76,546-556 and Nature Reviews Neph rology (2017) 13, 385-386, and each of these is referenced (Kidney Research and d Clinical Practice(2016)35,197-203; and I gA Nephropathy in Medscape (accessed November 4, 2019) See also U.S. Pat. No. 6,229,999, which is incorporated herein by reference in its entirety. be included).

[0133] In some embodiments, the subject is at high risk of progressing to ESRD. In some embodiments, the subject receives a dose of atrasentan or a pharmaceutically acceptable salt thereof. an average of about 1 gram or more of protein per day for at least about 3 months prior to the first administration In certain embodiments, the subject is receiving atrasentan or its derivatives. 60 mL / min / 1.7 mL / min for at least about 3 months prior to the first dose of a biologically acceptable salt. 3m2 or less (e.g., about 55 or less, about 50 or less, about 45 or less, about 40 or less, about 35 or less) In some of these embodiments, the subject has a mean eGFR of 30 mL / min / 1.73 m before the first dose of fluticasone or a pharmaceutically acceptable salt thereof. 2 super have an eGFR of

[0134] In some embodiments, the subject is receiving atrasentan or a pharmaceutically acceptable salt thereof. The first administration of the salt may be preceded by at least about 3 months (e.g., at least about 4 months, e.g., For each of the following periods: about 5 months, at least about 6 months, at least about 7 months, and at least about 8 months , at least about 9 months, at least about 10 months, at least about 11 months, at least at least about 1 year, at least about 1.5 years, or at least about 2 years), averaging about Excreting 1 gram or more of protein in the urine. For example, the subject is taking atrasentan or on average per day for at least about 3 months prior to the first administration of the pharmaceutically acceptable salt thereof. Average weight: 1.1 grams, 1.2 grams, 1.3 grams, 1.4 grams, 1.5 grams, 1.6 grams grams, 1.7 grams, 1.8 grams, 1.9 grams, 2.0 grams, 2.1 grams, 2 0.2 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 rum, 3.4 grams, 3.5 grams, 5 grams, 7.5 grams, or 10 grams, or or any value therebetween may be excreted in urine.

[0135] In some embodiments, the subject is receiving atrasentan or a pharmaceutically acceptable salt thereof. The first administration of the salt may be preceded by at least about 3 months (e.g., at least about 4 months, e.g., For each of the following periods: about 5 months, at least about 6 months, at least about 7 months, and at least about 8 months , at least about 9 months, at least about 10 months, at least about 11 months, at least at least about 1 year, at least about 1.5 years, or at least about 2 years), averaging about The subject excretes between 0.3 grams and about 2 grams of protein in the urine. Both are for about three months, about 0.3 to 0.5 grams, 0.5 to 1 gram per day, Approximately 0.5 grams to 1.5 grams, approximately 1 gram to 1.5 grams, or approximately 1.5 grams to 2 Grams of protein can be excreted in the urine.

[0136] In some embodiments, the subject is receiving atrasentan or a pharmaceutically acceptable salt thereof. Before the first dose of salt, for 1 year, at least 2 of 3 consecutive measurements For example, the subject excretes at least about 1 gram of protein per 1000 mg of urine. Three consecutive doses of Sentan or its pharmaceutically acceptable salts must be administered within one year prior to the first dose. At least two of the measurements were about 1.1 grams, 1.2 grams, and 1.3 grams per day. 1.4 grams, 1.5 grams, 1.6 grams, 1.7 grams, 1.8 grams, 1.9 grams grams, 2.0 grams, 2.1 grams, 2.2 grams, 2.3 grams, 2.4 grams, 2 0.5 grams, 2.6 grams, 2.7 grams, 2.8 grams, 2.9 grams, 3.0 grams , 3.1g, 3.2g, 3.3g, 3.4g, 3.5g, 5g , 7.5 grams, or 10 grams of protein, or any value in between. Proteins are excreted in the urine.

[0137] In some embodiments, the subject is receiving atrasentan or a pharmaceutically acceptable salt thereof. at least about 300 mg / g, e.g., 3 mg / g, for at least 3 months prior to the first administration of the salt. In some embodiments, the UACR value is from about 0.5 mg / g to about 5,000 mg / g. Therefore, the subject may receive at least one dose of atrasentan or a pharmaceutically acceptable salt thereof prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For at least about 3 months, about 800 mg / g, for example, 800 mg / g to about 5,000 mg / g In some embodiments, the subject has a UACR value of and administering to the patient a pharmaceutically acceptable salt of 0mg / g, approx. 600mg / g, approx. 700mg / g, approx. 800mg / g, approx. 900mg / g, approx. 1,000mg / g, approx. 1,500mg / g, approx. 2,000mg / g, approx. 2,50 0mg / g, approx. 3,000mg / g, approx. 3,500mg / g, approx. 4,000mg / g, approx. UA of 4,500 mg / g, or about 5,000 mg / g, or any value therebetween It has a CR value.

[0138] In some embodiments, the subject is receiving atrasentan or a pharmaceutically acceptable salt thereof. For at least 3 months prior to the first administration of the salt, A decrease in UACR value of about 30% was observed in both cases, e.g., atrasentan or its pharmaceutically acceptable salts. and for at least three months prior to the first administration of the salt, the subject's mean UACR value is increased by about 3 times compared to the subject's mean UACR value. In some embodiments, the subject has a reduction of between 0% and about 100%. The subject's average daily intake of 100 mg of acetaminophen or a pharmaceutically acceptable salt thereof is 20 mg of acetaminophen or a pharmaceutically acceptable salt thereof for at least 3 months prior to the first administration of acetaminophen or a pharmaceutically acceptable salt thereof. At least about 30%, about 40%, about 50%, about 60%, about 70% compared to the mean UACR value %, approximately 80%, approximately 90%, or approximately 100%, or any value in between. In some embodiments, a subject with a decrease in UACR value also has Do not experience significant sodium retention and / or significant fluid retention. In the present study, significant fluid retention is about 1 kg to about 4 kg, for example, about 4 kg, over a 6-week period. g, approximately 3.5 kg, approximately 3 kg, approximately 2.5 kg, approximately 2 kg, approximately 1.5 kg, or approximately 1 kg g, or any value over a period of six weeks or more. Subjects with significant fluid retention exhibit clinical symptoms of edema.

[0139] In certain embodiments, the subject is receiving atrasentan or a pharmaceutically acceptable salt thereof. At least 3 months (e.g., about 3 months, about 4 months, about 5 months) prior to the first administration , about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, approximately 1.5 years, or approximately 2 years), approximately 20 to approximately 90 mL / min / 1.73 m 2 For example, the first Approximately 20 to 50 mL / min / 1.73 m for at least 3 months prior to administration of 1. 2 , about 30 ~Approx. 60mL / min / 1.73m 2 , about 40~70mL / min / 1.73m 2 , about 50 to about 80mL / min / 1.73m 2 , or approximately 60 to 90 mL / min / 1.73 m 2 .some In one embodiment, the subject receives a first dose of atrasentan or a pharmaceutically acceptable salt thereof. 60 mL / min / 1.73 m for at least approximately 3 months before administration 2 A mean eGFR of In certain embodiments, the subject has a blood flow rate of 55 mL / min / 1. 73m 2 In certain embodiments, the subject has a mean eGFR of at least about 50 mL / min / 1.73 m for 3 months 2 In certain embodiments, the patient has a mean eGFR of: In this study, subjects were required to maintain a blood pressure of 45 mL / min / 1.73 m for at least approximately 3 months. 2 Average eGF below In certain embodiments, the subject has a blood pressure of 40 mL / min / min for at least about 3 months. 1.73m 2 In certain embodiments, the subject has a mean eGFR of at least: 35mL / min / 1.73m for about 3 months 2 and having a mean eGFR of: In this condition, subjects were required to maintain a blood pressure of 25 mL / min / 1.73 m for at least approximately 3 months. 2 The average e In certain embodiments, the subject has a GFR of 20 mL / min or less for at least about 3 months. min / 1.73m 2 In some of the foregoing embodiments, the patient has a mean eGFR of: Elephants were euthanized for at least 3 months prior to administration of atrasentan or its pharmaceutically acceptable salts. Approximately 30mL / min / 1.73m 2 ~Approx. 60mL / min / 1.73m 2 With mean eGFR For example, the subject's blood flow rate is approximately 30 mL / min / 1.73 m 2 ~Approx. 55mL / min / 1.73m 2 , about 30mL / min / 1.73m 2 ~About 50mL / min / 1.73m 2 , about 30mL / min / 1 .73m 2 ~About 45mL / min / 1.73m 2 , or approximately 30 mL / min / 1.73 m 2 ~about 40mL / min / 1.73m 2 may have a mean eGFR of

[0140] In certain embodiments, the subject is receiving atrasentan or a pharmaceutically acceptable salt thereof. The first administration may be administered for at least three months (e.g., at least about four 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 for at least about 1.5 years, or at least about 2 years), approximately 30 mL / min / 1.73 m 2 ~About 45mL / min / 1.73m 2 , for example, about 45 or less, about 40 or less, about 35 or less, or an average eGFR of about 30 or less. In some embodiments, the subject at least about 3 months prior to the first administration of lasentan or a pharmaceutically acceptable salt thereof , about 25mL / min / 1.73m 2 ~Approx. 75mL / min / 1.73m 2 have a mean eGFR of For example, prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, Approximately 25 mL / min / 1.73 m for at least 3 months 2 , about 30mL / min / 1.73m 2 , about 3 5mL / min / 1.73m 2 , approximately 40 mL / min / 1.73 m 2 , about 45mL / min / 1.73 m 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 7 5mL / min / 1.73m2 , or any value in between.

[0141] In some embodiments, the subject is receiving atrasentan or a pharmaceutically acceptable salt thereof. For at least three months (e.g., at least about four months, e.g., at least about four months) prior to the first administration of the salt. 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 for about 1 year, at least about 1.5 years, or at least about 2 years), with an average of about 4% to about 6% For example, the subject may have an average HbA1c of about 4.2%, about 4.4%, about 4.6%, about 4. 8%, approximately 5.0%, approximately 5.2%, approximately 5.4%, approximately 5.6%, approximately 5.8%, or approximately 6, Or, the average HbA1c may be any value therebetween.

[0142] In some embodiments, the subject is receiving atrasentan or a pharmaceutically acceptable salt thereof. For at least three months (e.g., at least about four months, e.g., at least about four months) prior to the first administration of the salt. 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), about 125 mg / dL For example, a subject may have an average fasting blood glucose level of about 120 mg / dL, about 115 mg / dL, or / dL, approx. 110mg / dL, approx. 105mg / dL, approx. 100mg / dL, approx. 95mg / dL, approximately 90 mg / dL, approximately 85 mg / dL, approximately 80 mg / dL, or approximately 75 mg / The blood glucose level may be in the range of 0.01 to 0.05 dL, or any value therebetween.

[0143] In some embodiments, the subject maintains potassium levels within the normal physiological range. In certain embodiments, the subject is administered atrasentan or a pharmaceutically acceptable salt thereof. For at least three months (e.g., at least about four months, e.g., at least about four months) prior to the first administration of the salt. 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 maintain normal potassium levels for at least about 1 year, at least about 1.5 years, or at least about 2 years In certain embodiments, the subject maintains potassium levels within a normal physiological range. Maintain blood pressure within 0.5-5.2 mEq / L. For example, the subject should maintain blood pressure at approximately 3.5 mEq / L, approximately 3. 6mEq / L, approximately 3.7mEq / L, approximately 3.8mEq / L, approximately 3.9, approximately mEq / L, approximately 4.0mEq / L, approx. 4.1mEq / L, approx. 4.2mEq / L, approx. 4.3mEq / L, approx. 4.4mEq / L, approx. 4.5mEq / L, approx. 4.6mEq / L, approx. 4.7mEq / L, approx. 4.8mEq / L, approximately 4.9mEq / L, approximately 5.0mEq / L, approximately 5.1mEq / L, Maintain a mean potassium level of approximately 5.2 mEq / L or any value therebetween. do.

[0144] In some embodiments, the subject maintains sodium levels within the normal physiological range. In certain embodiments, the subject is receiving atrasentan or a pharmaceutically acceptable salt thereof. For at least three months (e.g., at least about four months, e.g., at least about four months) prior to the first administration of the salt. For each of the following periods: about 5 months, at least about 6 months, at least about 7 months, and at least about 8 months , at least about 9 months, at least about 10 months, at least about 11 months, at least for at least about 1 year, at least about 1.5 years, or at least about 2 years) In certain embodiments, the subject maintains sodium levels within the normal physiological range. Maintain blood pressure within 135-145 mEq / L. For example, subjects should maintain blood pressure at approximately 135 mEq / L, 136mEq / L, approx. 137mEq / L, approx. 138mEq / L, approx. 139mEq / L, approx. 140mEq / L, approx. 141mEq / L, approx. 142mEq / L, approx. 143mEq / L, approx. A mean of 144 mEq / L, approximately 145 mEq / L, or any value therebetween Maintain thorium levels.

[0145] In some embodiments, the subject is receiving atrasentan or a pharmaceutically acceptable salt thereof. Before the first administration of salt, ALT / AST levels were measured that were approximately the same as the ALT / AST levels. , during administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the subject may about 25% of the level prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof , about 20%, about 15%, about 10%, about 5%, about 2.5%, or any value therebetween. ALT / AST levels within the desired range were maintained by atrasentan or its pharmaceutically acceptable salts. During administration of salt.

[0146] In some embodiments, the subject is receiving atrasentan or a pharmaceutically acceptable salt thereof. Before the first administration of salt, the bilirubin level was measured by a transaminase test, which was approximately the same as the bilirubin level. For example, a subject may have a history of steroid use during administration of atlas steroids or a pharmaceutically acceptable salt thereof. before the first administration of entanganosinate or a pharmaceutically acceptable salt thereof, %, about 15%, about 10%, about 5%, or about 2.5%, or any value therebetween. maintain bilirubin levels within range during administration of atrasentan or its pharmaceutically acceptable salts has.

[0147] In some embodiments, fluid retention in a subject is controlled by a steroid (e.g., atrasentan) or a combination of both. or its pharmaceutically acceptable salts, and / or atrasentan or The diuretic may be used to treat fluid retention (e.g., before the first administration of a pharmaceutically acceptable salt thereof). The retention can be a weight gain of less than about 3 kilograms (kg) over a 6-week period. In embodiments, fluid retention is about 4 kg, about 3.5 kg, about 3 kg, or about 4 kg for 6 weeks or more. kg, about 2.5 kg, about 2 kg, about 1.5 kg, or less than about 1 kg, or any of these It is any value between

[0148] In some embodiments, the subject is receiving atrasentan as disclosed herein. or a pharmaceutically acceptable salt thereof, In some embodiments, the subject undergoes surgery and / or other regimens described herein. As disclosed in the document, prior to administration of atrasentan or a pharmaceutically acceptable salt thereof, Substantially simultaneously with or subsequent to administration of other chemical and / or biological therapeutic agents. can be.

[0149] In some embodiments, the subject is receiving atrasentan or a pharmaceutically acceptable salt thereof. and administering to a patient a dose of at least about 60 weeks prior to the first administration of the salt one or more of the renin-angiotensin system. For example, in some embodiments, the subject is receiving atlas and administering the compound or a pharmaceutically acceptable salt thereof for at least about 12 weeks prior to the first administration of the compound or a pharmaceutically acceptable salt thereof. For 24 weeks, about 48 weeks, or about 60 weeks, or any value therebetween, renin - Receiving one or more inhibitors of the angiotensin system.

[0150] In some embodiments, the subject is taking one or more renin-angiotensin system inhibitors For example, the subject is receiving a maximum tolerated stable dose of atrasentan or at least about 12 weeks, about 14 weeks, about 16 weeks, approximately 18 weeks, approximately 20 weeks, approximately 25 weeks, approximately 30 weeks, approximately 35 weeks, approximately 40 weeks , about 45 weeks, or about 50 weeks, or any value therebetween, Patients may receive a maximally tolerated stable dose of angiotensin-angiotensin system inhibitor. In an embodiment, one or more inhibitors of the renin-angiotensin system are ACE inhibitors, angiotensin II receptor blockers (ARBs), and aldosterone antagonists. Inhibitors of one or more of the renin-angiotensin system include ACE inhibitors, ARBs, and or combinations thereof, and the ACE inhibitor or ARB is also referred to elsewhere herein. For example, ACE inhibitors include quinapril, fosinopril, and perindopril. , Captopril, Enalapril, Enalaprilat, Ramipril, Cilazapril, Delapr lisinopril, fosenopril, zofenopril, indolapril, benazepril, lisinopril , spirapril, trandolapril, perindep, pentopril, moexipril, For example, the ARB may be selected from the group consisting of Candesartan, fluprevir ... candesartan cilexetil, eprosartan, irbesartan, losartan, Mesartan, olmesartan medoxomil, telmisartan, valsartan, azilsartan The agent can be selected from tammedoxomil, and BRA-657.

[0151] In some embodiments, the subject is also receiving one or more additional medications. In some embodiments, the one or more additional agents are a calcineurin inhibitor, a protease inhibitor, a Teasome inhibitors, aminoquinolines, complement inhibitors, B cell inhibitors, cytotoxic agents, mTOR In some embodiments, one or more additional The dose of the additional agent is approximately 10 minutes after treatment with atrasentan or a pharmaceutically acceptable salt thereof. After 15 to about 30 days, the level decreases. In some embodiments, the one or more additional agents , an immunosuppressant.

[0152] In some embodiments, the subject is not currently receiving one or more additional medications. In certain embodiments, the subject is receiving a first dose of atrasentan or a pharmaceutically acceptable salt thereof. No one or more additional medications were used for 2 weeks or more within 6 months prior to administration of 1.

[0153] In some embodiments, the one or more additional agents are a calcineurin inhibitor, a protease inhibitor, Loteasome inhibitors, aminoquinolines, complement inhibitors, B cell inhibitors, cytotoxic agents, mTO R inhibitors, and steroids.

[0154] In certain embodiments, one or more of the additional agents is a steroid. These additional medications include prednisone, dexamethasone, hydrocortisone, and cyclosporine. and any combination of the foregoing.

[0155] In certain embodiments, the one or more additional agents are aminoquinolines. For example, The one or more additional agents can be hydroxychloroquine.

[0156] In some embodiments, the subject receives one or more additional In certain embodiments, the dosage of one or more additional agents is After treatment with lasentan or a pharmaceutically acceptable salt thereof (e.g., 1 week, 2 weeks, 3 weeks), 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, 11 0 weeks, 120 weeks, 130 weeks, 140 weeks, 150 weeks, 160 weeks, 170 weeks, These embodiments are shown to be effective after 180, 190, or 200 weeks of treatment. In some of the methods, the dosage of one or more additional agents is atrasentan or its pharmaceutical equivalents. The decrease occurs after about 15 to about 30 days of treatment with a commercially acceptable salt of the present invention. In some cases, the dosage of the additional agent is reduced 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%. The dosage of the additional agent is reduced by about 35% to about 100%. The dosage of the drug is reduced by about 40% to about 100%. In certain embodiments, the dose of the additional agent is reduced by about 45% to about 100%. The dosage is reduced by about 50% to about 100%. In certain embodiments, the dosage of the additional agent is is reduced by about 55% to about 100%. In certain embodiments, the dose of the additional agent is In certain embodiments, the dose of the additional agent is reduced by about 60% to about 100%. In certain embodiments, the dose of the additional agent is reduced by about 70%. In certain embodiments, the dose of the additional agent is reduced by about 75% to about 100%. In certain embodiments, the dose of the additional agent is reduced by about 80% to about 10%. In certain embodiments, the dose 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 one or more additional agents is at least 20 mg / kg of atrazine. About 15 to about 30 days (e.g., about 15 to about 30 days) after treatment with entanganosin or a pharmaceutically acceptable salt thereof The amount of erythrocyte proliferation is reduced after about 15 days, about 20 days, about 25 days, or about 30 days. Thus, when the dose of additional medication is reduced by 100%, the subject no longer requires additional medication. do not have.

[0157] In certain embodiments, the dosage of one or more steroids is atrasentan or its equivalent. after treatment with a pharmaceutically acceptable salt of, for example, atrasentan or a pharmaceutically acceptable salt thereof The decrease occurs after about 15 to about 30 days of treatment with the salt. Therefore, the steroid dosage may be reduced by about 10% to about 100%, as described herein. In some embodiments, prednisone, dexamethasone, hydrocortisone, The dose of cyclosporine, or any combination of the above, is or a pharmaceutically acceptable salt thereof, the level of urinary tract infection is reduced by about 10% to about 100% after treatment with the drug.

[0158] In certain embodiments, the dosage of one or more aminoquinolines is atrasentan or after treatment with a pharmaceutically acceptable salt thereof, e.g., atrasentan or a pharmaceutically acceptable salt thereof The decrease occurs after about 15 to about 30 days of treatment with an acceptable salt. In this case, the dosage of the aminoquinoline is about 10% to about 100%, as described herein. In some embodiments, the dose of hydroxychloroquine is at least 100 mg / kg of atrazine. After treatment with entamin or its pharmaceutically acceptable salt, the .

[0159] In some embodiments, the subject is concurrently receiving one or more additional therapeutic agents. The one or more additional therapeutic agents are described herein. For example, the subject may be receiving renin-anticoagulation therapy. Concurrently receiving inhibitors of one or more components of the giotensin-aldosterone system. In certain embodiments, the subject is taking an SGLT-2 inhibitor, an ACE inhibitor, an ARB, a statin inhibitor, or a combination of these. diuretics, calcium channel blockers, beta-blockers, aldosterone antagonists , fish oil, hydroxychloroquine, or a combination of any of the aforementioned In some of these embodiments, the subject is not concurrently receiving an SGLT-2 inhibitor. In some of these embodiments, the subject is taking an ACE inhibitor, an ARB, or In certain embodiments, the subject is receiving atorvastatin. fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin and concurrently receiving one or more statins, such as pitavastatin. In the study, the subject was taking hydrochlorothiazide, trichlormethiazide, hydroflumethiazide, Do, quinethazone, metolazone, chlorothiazide, chlorthalidone, indapamide, methicone Lothiazide, bemetanide, torsemide, piretanide, ethacrynic acid, bumetanide, furosemide one or more of the following: methadone, triamterene, spironolactone, eplerenone, and amiloride In certain embodiments, the subject is concurrently receiving canagliflozin, SGLT-2s such as dapagliflozin, empagliflozin, or ertugliflozin In certain embodiments, the subject is concurrently receiving an inhibitor such as quinapril, fosinopeptide, or rituximab. Rilperindopril, captopril, enalapril, enalaprilat, ramipril, Cilazapril, delapril, fosenopril, zofenopril, indolapril, benapril Pril, lisinopril, spirapril, trandolapril, perindep, pentopril, Concurrent use of one or more ACE inhibitors, such as moexipril, rescinnamine, and pivopril In certain embodiments, the subject is receiving candesartan, candesartan cilex. Cetyl, eprosartan, irbesartan, losartan, olmesartan, olmesartan medoxomil, telmisartan, valsartan, azilsartan medoxomil, and In certain embodiments, the subject is concurrently receiving an ARB, such as BRA-657. Concurrently receiving urinary medication and an ACE inhibitor or ARB. The elephant is concurrently receiving a diuretic, an ACE inhibitor, and an ARB. Therefore, subjects were treated with diuretics and SGLT-2 inhibitors, as well as ACE inhibitors or ARBs. In certain embodiments, the subject is receiving a diuretic, an SGLT-2 inhibitor, an ACTH, or In certain embodiments, the patient is concurrently receiving one or more additional EGFR inhibitors, and an ARB. Subjects receiving concurrent treatments were those who had not previously received one or more of the treatments. For example, patients who had not previously received SGLT-2 inhibitors Subjects who are receiving the following at the same time.

[0160] In some embodiments, the subject is treated with one or more additional Subjects may have previously received additional therapeutic agents, but not concurrently. As detailed in the specification, SGLT-2 inhibitors, ACE inhibitors, ARBs, statins, diuretics Drugs, calcium channel blockers, beta blockers, aldosterone antagonists, fish oil, hydroxybenzoates have previously received cyclochloroquine, or any of the above combinations, but In some of these embodiments, the subject has not received an SGLT-2 inhibitor I have received both in the past, but not at the same time.

[0161] In some embodiments, the subject is receiving atrasentan or a pharmaceutically acceptable salt thereof. Cellular glomerular crescents present in less than approximately 25% of glomeruli within 6 months prior to the first administration of salt For example, the subject may have about 25%, about 20%, about 15%, about 10%, about 5%, or about 6% of the glomeruli. %, or about 1%, or any value therebetween, of cellular glomerular crescents In some embodiments, the subject has cellular glomerular crescents present in the glomeruli. In certain embodiments, the subject has a clinical diagnosis of rapidly progressive glomerulonephritis (RPGN). Not under suspicion.

[0162] In some embodiments, the subject is receiving atrasentan or a pharmaceutically acceptable salt thereof. Not having undergone an organ transplant prior to the first administration of salt.

[0163] In some embodiments, the subject is receiving atrasentan or a pharmaceutically acceptable salt thereof. Prior to the first administration of the salt, the subject has a systolic blood pressure of less than about 160 mmHg. less than about 155 mmHg, less than about 150 mmHg, less than about 145 mmHg, or less than about 140 In some embodiments, the subject may have a systolic blood pressure of less than 100 mmHg. a dilation of less than about 100 mmHg prior to the first administration of entane 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 In some embodiments, the subject may have a diastolic blood pressure of less than about 90 mmHg. Systolic blood pressure of approximately 100mmHg to approximately 130mmHg and systolic blood pressure of approximately 70mmHg to approximately 90mmHg g of diastolic blood pressure.

[0164] In some embodiments, the subject is receiving atrasentan or a pharmaceutically acceptable salt thereof. The patient has not been diagnosed with heart failure prior to the first administration of the salt. The subject is administered a dose of atrasentan or a pharmaceutically acceptable salt thereof in a dose-dependent manner. Have not been previously hospitalized for a condition related to: In some embodiments, the following may be present: peripheral edema, pleural effusion, or ascites that has not been treated with anticoagulant therapy. Subjects were to have clinically significant steroid use prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not been diagnosed with a major liver disease. The enzyme or bilirubin levels were measured after the first administration of atrasentan or a pharmaceutically acceptable salt thereof. Prior to administration, the subject's ALT level is less than or equal to two times the upper limit of normal. For example, the subject's ALT level is approximately 110 U. / L (e.g., less than about 100U / L, less than 90U / L, less than about 80U / L, less than about 70U / L) / L, less than about 60 U / L, less than about 50 U / L, or less than about 40 U / L, or In another example, the subject's AST level is less than 100 U / L. (For example, less than 90U / L, less than about 80U / L, less than about 70U / L, less than about 60U / 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 Less than 2 mg / dL, less than about 1.5 mg / dL, less than about 1.4 mg / dL, less than about 1.3 mg / Less than 1.2 mg / dL, less than 1.1 mg / dL, less than 1.0 mg / dL , or less than about 0.9 mg / dL, or any value therebetween).

[0165] In some embodiments, the subject is receiving atrasentan or a pharmaceutically acceptable salt thereof. Prior to the first administration of the salt, a blood glucose level of greater than about 9 g / dL (e.g., about 10 g / dL, about 11 g / dL, about Hemoglobin levels above 12 g / dL, or above about 13 g / dL, or any value therebetween In some embodiments, the subject has atrasentan or its derivatives. and for at least about 3 months (e.g., about 4 months) prior to the first administration of the physiologically acceptable salt. Have not received a blood transfusion for anemia for the past 5 months, 6 months, or 1 year. In some embodiments, the subject is receiving atrasentan or a pharmaceutically acceptable salt thereof. Not having been diagnosed with cancer for at least five years prior to the first administration. In some embodiments, the subject receives a first dose of atrasentan or a pharmaceutically acceptable salt thereof. have not been diagnosed with cancer (e.g., lung or prostate cancer) for at least five years In some embodiments, the cancer is a non-melanoma skin cancer that does not require ongoing treatment. The subject is not taking any of the following drugs prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, unless In some embodiments, the patient has not been diagnosed with cancer for at least five years. Subjects were randomly assigned to receive atrasentan unless their cancer was non-melanoma and did not require ongoing treatment. or a pharmaceutically acceptable salt thereof. In this form, subjects are not required to undergo treatment unless the cancer is non-melanoma skin cancer that is ongoing. and, prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, In some embodiments, the cancer is a non-melanoma skin cancer that does not require treatment. Unless the subject has cancer, the subject will receive a first dose of atrasentan or a pharmaceutically acceptable salt thereof. Have not been treated for cancer for at least 5 years prior to

[0166] In some embodiments of the methods, uses, or products for use herein, the subject have a history of one or more of the following: diabetic nephropathy, HIV / AIDS, or acute renal failure Some of the methods, uses, or products for use described herein have not been diagnosed. In embodiments, the subject is diagnosed with diabetic nephropathy, HIV / AIDS, cancer (e.g., prostate cancer), or lung cancer), or acute renal failure In some embodiments, the subject is diagnosed with diabetic nephropathy, HIV / AIDS, prostate cancer, or acute renal failure. In some embodiments, the subject has diabetic nephropathy, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the patient has not been previously diagnosed with one or more of the following: The subjects were those with diabetic nephropathy, HIV-associated nephropathy, cancer (e.g., lung cancer or prostate cancer), or acute renal failure. In some embodiments, the subject is diagnosed with one 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 DS. 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 diagnosed with prostate cancer. In certain embodiments, the subject has not been diagnosed with lung cancer. The subjects were those with one of the following conditions: diabetic nephropathy, HIV / AIDS, and acute renal failure. In certain embodiments, the subject has not been previously diagnosed with diabetic nephropathy. , HIV / AIDS, prostate cancer, and acute kidney failure In certain embodiments, the subject has not been diagnosed with diabetic nephropathy, HIV-associated nephropathy, or had been previously diagnosed with one of the following: liver cirrhosis, prostate cancer, and acute renal failure In certain embodiments, the subject is diagnosed with diabetic nephropathy, HIV-associated nephropathy, and acute nephropathy. The method, use, and / or administration of the present invention may be carried out in a patient who has not previously been diagnosed with any of the following disorders: In some embodiments of the product for use, the subject is previously diagnosed with diabetes. Some implementations of the methods, uses, or products for use herein have not been tested. In some embodiments, the subject has not been previously diagnosed with type 2 diabetes. In some embodiments, the subject receives a controlled serum It has been determined that the patient has a high blood glucose level.

[0167] In some embodiments, the subject has diabetic nephropathy, HIV / AIDS, or acute In some embodiments, the subject does not have one or more of the following: diabetic renal failure; do not have one or more of the following conditions: breast cancer, HIV / AIDS, prostate cancer, or acute renal failure. In some embodiments, the subject is diagnosed with diabetic nephropathy, HIV-associated nephropathy, prostate cancer, or In some embodiments, the subject does not have one or more of acute renal failure. The patient does not have one or more of the following: chronic kidney disease, HIV-associated nephropathy, or acute renal failure. In certain embodiments, the subject does not have diabetic nephropathy. In certain embodiments, the subject has acute renal failure and does not have HIV / AIDS. In certain embodiments, the subject does not have HIV-associated nephropathy. In embodiments, the subject does not have prostate cancer. also have one of the following conditions: diabetic nephropathy, HIV / AIDS, and acute renal failure In certain embodiments, the subject is diagnosed with diabetic nephropathy, HIV / AIDS, prostate cancer, or In certain embodiments, the patient does not have any one of the following: The subjects were those with diabetic nephropathy, HIV-associated nephropathy, prostate cancer, and acute renal failure. In certain embodiments, the subject has one or more of the following: diabetic nephropathy, HIV-associated nephropathy, or none of the following: In some embodiments, the patient does not have any one of the following: In some embodiments, the subject does not have diabetes. In some embodiments, the subject has type 2 diabetes. In some of the foregoing embodiments, the subject does not have any of the features described elsewhere herein. As described above, the subjects have been determined to have controlled serum glucose levels.

[0168] In some embodiments, the subject has diabetic nephropathy, HIV / AIDS, or acute In some embodiments, the subject is free of one or more of the following: diabetes, have one or more of the following conditions: chronic kidney disease, HIV / AIDS, prostate cancer, or acute renal failure In some embodiments, the subject is diagnosed with diabetic nephropathy, HIV-associated nephropathy, prostate cancer, or In some embodiments, the patient is not suffering from one or more of the following: adenocarcinoma; adenocarcinoma; or acute renal failure. The subjects are those suffering from 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 is not suffering from acute renal failure. In certain embodiments, the subject does not have prostate cancer. In certain embodiments, the subject is diagnosed with diabetic nephropathy, HIV / AIDS, and acute In certain embodiments, the subject does not suffer from any one of the following conditions: diabetes, Patients with any one of the following conditions: nephropathy, HIV / AIDS, prostate cancer, and acute renal failure In certain embodiments, the subject is not suffering from diabetic nephropathy, HIV-associated nephropathy, prostate cancer, or In certain embodiments, the patient does not have any one of adenocarcinoma, adenocarcinoma, and acute renal failure. The subjects were those with one of the following conditions: 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 cases, the subject receives controlled serum group testing, as described elsewhere herein. It has been determined that the course level is met.

[0169] In some embodiments, the subject has diabetic nephropathy, HIV / AIDS, or acute In some embodiments, the subject is not undergoing treatment for one or more of the following: Treatment for one or more of the following: diabetic nephropathy, HIV / AIDS, prostate cancer, or acute renal failure In some embodiments, the subject is not receiving treatment for diabetic nephropathy, HIV-associated nephropathy, or are not receiving treatment for one or more of the following: diabetes, prostate cancer, or acute renal failure. In embodiments, the subject is diagnosed with one of diabetic nephropathy, HIV-associated nephropathy, or acute renal failure. In certain embodiments, the subject is naive to one or more treatments for diabetic nephropathy. In certain embodiments, the subject is not receiving treatment for HIV / AIDS. In certain embodiments, the subject is not receiving treatment for acute renal failure. In certain embodiments, the subject is not undergoing treatment for HIV-associated nephropathy. In certain embodiments, the subject has not been treated for prostate cancer. not receiving treatment for any of the following: chronic kidney disease, HIV / AIDS, or acute renal failure In certain embodiments, the subject is diagnosed with diabetic nephropathy, HIV / AIDS, prostate cancer, and acute renal failure. The subjects were those with diabetic nephropathy, HIV-associated nephropathy, prostate cancer, and acute renal failure. In certain embodiments, the subject is not receiving any of the following treatments: diabetic nephropathy, HI Not receiving treatment for either V-related nephropathy or acute renal failure. In some embodiments, the subject is not receiving treatment for diabetes. In some of the foregoing embodiments, the subject is not undergoing treatment for type 2 diabetes. have controlled serum glucose levels as described elsewhere herein. It has been determined that:

[0170] In some embodiments, the subject is determined to have controlled serum glucose levels. or the subject has been diagnosed with one or more of HIV-associated nephropathy or acute renal failure. In certain embodiments, the subject has never been diagnosed with steroids. For example, subjects have been determined to have a blood glucose level of about 130 mg / dL, about 125 mg / dL, or L, approx. 120mg / dL, approx. 115mg / dL, approx. 110mg / dL, approx. 105mg / d L, approx. 100mg / dL, approx. 95mg / dL, approx. 90mg / dL, approx. 85mg / dL, approx. Fasting levels of 80 mg / dL or less than about 75 mg / dL, or any value in between In certain embodiments, the subject has been determined to have a serum glucose level of H Have not been diagnosed with one or more of the following: IV-associated nephropathy or acute renal failure. In this embodiment, the subject is administered controlled serum glucose as described elsewhere herein. The subject is determined to have HIV-associated nephropathy or acute renal failure. Never been diagnosed with more than one.

[0171] In some embodiments, the subject has previously been diagnosed with a chronic kidney disease other than IgA nephropathy. Non-limiting examples include diabetic kidney disease, hypertensive kidney disease, or IgA In certain embodiments, primary glomerulopathies determined to be unrelated to nephropathy are included. The elephant has not been previously diagnosed with diabetic kidney disease. The elephant has not been previously diagnosed with hypertensive kidney disease. No elephants have been diagnosed with primary glomerulopathy not associated with IgA nephropathy.

[0172] In some embodiments, the subject does not have chronic kidney disease other than IgA nephropathy. Typical examples include diabetic kidney disease, hypertensive kidney disease, or IgA nephropathy not determined to be associated with In certain embodiments, the subject has diabetic kidney disease. In certain embodiments, the subject does not have hypertensive kidney disease. In this embodiment, the subject does not have a primary glomerulopathy determined to be unassociated with IgA nephropathy.

[0173] In some embodiments, the subject does not suffer from chronic kidney disease other than IgA nephropathy. Non-limiting examples include those not associated with diabetic kidney disease, hypertensive kidney disease, or IgA nephropathy. In certain embodiments, the subject is diagnosed with diabetic nephropathy. In certain embodiments, the subject is free of hypertensive kidney disease. In certain embodiments, the subject has a primary fibroid that is determined to be not associated with IgA nephropathy. Not suffering from globulopathy.

[0174] In some embodiments, the subject is undergoing treatment for a chronic kidney disease other than IgA nephropathy. Non-limiting examples include those associated with diabetic kidney disease, hypertensive kidney disease, or IgA nephropathy. In certain embodiments, the subject is diagnosed as having diabetes. In certain embodiments, the subject is not undergoing treatment for hypertensive kidney disease. In certain embodiments, the subject is not receiving treatment for a condition determined not to be associated with IgA nephropathy. are not receiving treatment for a primary glomerulopathy.

[0175] Treatment outcome In some embodiments of the methods, uses, or products for use herein, nephritis Symptoms are reduced after treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the renal inflammation in the subject is treated with atrasentan or its pharmaceutically acceptable salts. After treatment with an acceptable salt (e.g., 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, approximately 50 weeks, approximately 60 weeks, approximately 70 weeks, approximately 80 weeks, approximately 90 weeks, approximately 100 weeks 110 weeks, 120 weeks, 130 weeks, 140 weeks, 150 weeks, 16 0 weeks, approximately 170 weeks, approximately 180 weeks, approximately 190 weeks, or approximately 200 weeks, or In some embodiments, the IL-10 level is reduced by at least about 10% after treatment (or any value therebetween). and the subject has kidney inflammation of at least about 20%, about 30%, about 40%, about 50%, or , about 60%, about 70%, about 80%, about 90%, or about 95%, or any value therebetween. In some of the above embodiments, the subject is administered the are being treated with atrasentan or a pharmaceutically acceptable salt thereof.

[0176] In some embodiments, renal fibrosis is treated with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, renal fibrosis in a subject is reduced after treatment with a salt comprising the compound of formula (I). , after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., 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 1 0 weeks, approximately 20 weeks, approximately 30 weeks, approximately 40 weeks, approximately 50 weeks, approximately 60 weeks, approximately 70 weeks, Approximately 80 weeks, approximately 90 weeks, approximately 100 weeks, approximately 110 weeks, approximately 120 weeks, approximately 130 weeks, Approximately 140 weeks, approximately 150 weeks, approximately 160 weeks, approximately 170 weeks, approximately 180 weeks, approximately 190 weeks or about 200 weeks, or any value therebetween), at least about 10 In certain embodiments, renal fibrosis in a subject is reduced by at least about 20%, Approximately 30%, approximately 40%, approximately 50%, approximately 60%, approximately 70%, approximately 80%, approximately 90%, or approximately 95%, or any value therebetween. The elephants are treated with atrasentan or a pharmaceutically acceptable salt thereof for about 15 to about 30 days. It is being done.

[0177] In some embodiments, renal fibrosis in a subject is treated with atrasentan or its derivatives. After treatment with a biologically acceptable salt (e.g., 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, approximately 6 weeks, approximately 7 weeks, approximately 8 weeks, approximately 9 weeks, approximately 10 weeks, approximately 20 weeks, approximately 30 weeks 40 weeks, 50 weeks, 60 weeks, 70 weeks, 80 weeks, 90 weeks, 1 00 weeks, approximately 110 weeks, approximately 120 weeks, approximately 130 weeks, approximately 140 weeks, approximately 150 weeks, Approximately 160 weeks, approximately 170 weeks, approximately 180 weeks, approximately 190 weeks, or approximately 200 weeks or any value therebetween), resulting in less than about a 50% reduction in cortical area. In some embodiments, renal fibrosis in the subject is reduced by less than about 40% of the cortical area. In some embodiments, the renal fibrosis in the subject is about 35%, about 30%, about 10%, or about 20% of the cortical area. to less than 25%, about 20%, about 15%, or about 10%, or any value therebetween In some of the foregoing embodiments, the subject is administered atrauma for about 15 to about 30 days. are being treated with Sentan or a pharmaceutically acceptable salt thereof.

[0178] In some embodiments, the occurrence of hematuria is controlled by the administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a decreased risk of developing cerebrovascular disease after treatment with a salt containing the compound. The number of urinary red blood cells per high-power (microscopic) field (rbc / hpf) in or a pharmaceutically acceptable salt thereof (e.g., 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, approximately 100 weeks, approximately 110 weeks, approximately 120 weeks, approximately 130 weeks, approximately 140 weeks, Approximately 150 weeks, approximately 160 weeks, approximately 170 weeks, approximately 180 weeks, approximately 190 weeks, or approximately 2 In certain embodiments, the subject has a reduction of at least about 10% (after 00 weeks of treatment). The urinary RBC / HPF in the urinary In the present invention, the urinary RBC / HPF in a subject is at least about 30%, about 40%, about 50%, or %, about 60%, about 70%, about 80%, about 90%, or about 95%, or any range therebetween In some of the above embodiments, the subject is maintained at 20°C for about 15 to about 30 days. , being treated with atrasentan or a pharmaceutically acceptable salt thereof.

[0179] In some embodiments, the rate of decline in a subject's eGFR is determined by administering atrasentan or its After treatment with a pharmaceutically acceptable salt (e.g., 1 week, 2 weeks, 3 weeks, about 4 weeks, about 5 weeks, weeks, approximately 6 weeks, approximately 7 weeks, approximately 8 weeks, approximately 9 weeks, approximately 10 weeks, approximately 20 weeks, approximately 30 weeks , about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 10 0 weeks, approx. 110 weeks, approx. 120 weeks, approx. 130 weeks, approx. 140 weeks, approx. 150 weeks, approx. 160 weeks, approximately 170 weeks, approximately 180 weeks, approximately 190 weeks, or approximately 200 weeks, or (or any value therebetween after treatment) is reduced by at least about 10%. In this case, the rate of decline in the subject's eGFR is reduced by at least about 20%. In some embodiments, the subject's eGFR is reduced by at least about 30%, about 40%, or 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 is administered 24 hours a day for about 15 to about 30 days. The patient is being treated with atrasentan or a pharmaceutically acceptable salt thereof. In some cases, subjects receive atrasentan or a pharmaceutically acceptable salt thereof for about 6 months to about 1 year. It is treated with salt.

[0180] In some embodiments, the rate of decline in a subject's eGFR is determined by administering atrasentan or its After treatment with a pharmaceutically acceptable salt (e.g., 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 3 0 weeks, approximately 40 weeks, approximately 50 weeks, approximately 60 weeks, approximately 70 weeks, approximately 80 weeks, approximately 90 weeks, Approximately 100 weeks, approximately 110 weeks, approximately 120 weeks, approximately 130 weeks, approximately 140 weeks, approximately 150 weeks 160 weeks, 170 weeks, 180 weeks, 190 weeks, or 200 weeks or any value therebetween after treatment), a reduction of less than about 10 mL / min per year. In this embodiment, the subject's rate of decline in eGFR 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 less than about 8 mL / min per year, Less than approximately 7 mL / min per year, Less than approximately 6 mL / min per year, Less than approximately 5 mL / min per year, Less than approximately 4 mL / min per year less than 3 mL / min per year, less than 2 mL / min per year, or less than 1 mL / min per year , or any value therebetween. Patients who have been treated with atrasentan or a pharmaceutically acceptable salt thereof for about 15 to about 30 days In some of the foregoing embodiments, the subject receives atrasentan for about 6 months to about 1 year. or a pharmaceutically acceptable salt thereof.

[0181] In some embodiments, a subject's risk of developing ESRD can be reduced by administering atrasentan or or a pharmaceutically acceptable salt thereof (e.g., 1 week, about 2 weeks, about 3 weeks, about 4 weeks, approximately 5 weeks, approximately 6 weeks, approximately 7 weeks, approximately 8 weeks, approximately 9 weeks, approximately 10 weeks, approximately 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 1 50 weeks, approximately 160 weeks, approximately 170 weeks, approximately 180 weeks, approximately 190 weeks, or approximately 20 0 weeks after treatment, or any value therebetween), is reduced by about 20% to about 99%. , the subject's risk of developing ESRD is about 20%, about 25%, about 30%, about 35%, about 4%. 0%, approx. 45%, approx. 50%, approx. 55%, approx. 60%, approx. 65%, approx. 70%, approx. 75%, approx. 8 It may be reduced by 0%, about 85%, about 90%, or about 99%, or any value therebetween. In some of the foregoing embodiments, the subject has been receiving treatment for about 90 days to about 180 days. In certain embodiments, a subject's risk of developing ESRD is reduced by administering atrasentan or or a pharmaceutically acceptable salt thereof, about 20% to about 90% of the patients In some of the foregoing embodiments, the subject is treated with attenuation for about 6 months to about 1 year. are being treated with lasentan or a pharmaceutically acceptable salt thereof.

[0182] In some embodiments, the method includes diagnosing IgA nephropathy in a subject and determining whether the subject has e GFR is approximately 15 mL / min / 1.73 m 2 Increase the time between the time when the In embodiments, the method includes diagnosing IgA nephropathy in a subject and determining whether the subject's eGFR is 15m or lower. L / min / 1.73m 2 Increase the time between the time when the temperature drops below 10% by at least about 10%. For example, in some embodiments, the method includes diagnosing IgA nephropathy in a subject and administering to the subject eGFR 15 mL / min / 1.73 m 2 At least about 20% of the time between , about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95% ,approximately 100%,approximately 150%,approximately 200%,approximately 250%,approximately 300%,approximately 350%,approximately 40 The increase may be 0%, 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 has e GFR 15 mL / min / 1.73 m 2 Increase the time between the time below 1 year by at least For example, the method may be used to determine if a subject's eGFR is 15 mL / min / 1.73 m 2 Time below 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 1 5 years, approximately 16 years, approximately 17 years, approximately 18 years, approximately 19 years, or approximately 20 years, or any period therebetween It can be delayed by any value.

[0184] In some embodiments, the method comprises administering atrasentan or a pharmaceutically acceptable salt thereof. For at least about 3 months (e.g., at least about 4 months), at least At least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months for at least about 9 months, at least about 10 months, at least about 11 months, (for at least about 1 year, at least about 1.5 years, or at least about 2 years), and the mean eGFR The method reduces the rate of decline by about 0.75 mL / min / year to about 6 mL / min / year. For example, The average rate of decline in GFR was approximately 0.75 mL / min / year, approximately 1 mL / min / year, and approximately 1.5 mL / min. / year, approx. 2mL / min / year, approx. 2.5mL / min / year, approx. 3mL / min / year, approx. 3.5mL / min / year, approx. 4mL / min / year, approx. 4.5mL / min / year, approx. 5mL / min / year, approx. 5.5mL / min / year, or about 6 mL / min / year. In some embodiments, the method e for at least about 3 months prior to the first administration of lasentan or a pharmaceutically acceptable salt thereof The average rate of decline in GFR is reduced by approximately 4 mL / min / year to approximately 5 mL / min / year. In some embodiments, the method further comprises administering a dose of atrasentan or a pharmaceutically acceptable salt thereof prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For at least about 3 months, the average rate of decline in eGFR is about 3 mL / min / year to about 6 mL / min / year. In some embodiments, the method comprises administering atrasentan or a pharmaceutically acceptable salt thereof to a subject. and for at least about 3 months prior to the first administration of the salt to be administered, the average rate of decline in eGFR is reduced by about 4 mL. / min / year to about 5 mL / min / year. In some embodiments, the reduction in mL / min / year The decrease in eGFR was 1.73 m 2 Refers to the unit of measure.

[0185] In some embodiments, the method comprises administering atrasentan or a pharmaceutically acceptable salt thereof. Approximately 6 to 24 months after treatment with this salt, the average decrease in eGFR was approximately 15% to 3%. In some embodiments, the mean decrease in eGFR is 0%. or a pharmaceutically acceptable salt thereof, , 18 months, 21 months, or 24 months, the reduction may be about 15%. In the study, the mean rate of decline in eGFR was Approximately 6, 9, 12, 15, 18, 21, or 24 months after treatment with After about 1 month, the eGFR may be reduced by about 20%. In some embodiments, the average reduction in eGFR is , at about 6 months, 9 months, 1 month, or 2 months after treatment with atrasentan or a pharmaceutically acceptable salt thereof. After 2, 15, 18, 21, or 24 months, there may be a reduction of approximately 25%. In some embodiments, the mean percent decrease in eGFR is greater than or equal to 100 mg / kg of atrasentan or its pharmaceutical equivalents. Approximately 6 months, 9 months, 12 months, 15 months, 18 months, and 21 months after treatment with a salt that is tolerated by After 1 month, or 24 months, there may be a reduction of about 30%.

[0186] In another aspect, a method for reducing proteinuria comprises administering to a subject in need thereof a therapeutic 2. A method comprising administering an effective amount of atrasentan or a pharmaceutically acceptable salt thereof. , provided herein.

[0187] In some embodiments, the amount of protein (e.g., albumin) in the urine of the subject is , after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., 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, approximately 20 weeks, approximately 30 weeks, approximately 40 weeks, approximately 50 weeks, approximately 60 weeks, approximately 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), at least about 1 In some embodiments, the amount of protein in the urine of the subject is reduced by at least For example, in some embodiments, the level of protein in the urine of a subject is reduced by about 15%. The amount is at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 210%, about 220%, about 23 The reduction may be 0%, about 90%, or about 95%, or any value therebetween. In some embodiments, the subject receives atrasentan or its derivatives for about 15 to about 30 days. Treated with a biologically acceptable salt.

[0188] In certain embodiments, the amount of protein (e.g., albumin) in the urine of a subject is determined by about 15 to about 30 days after treatment with trasentan or a pharmaceutically acceptable salt thereof, In some of these embodiments, the subject's urinary ... In some of these embodiments, the amount of protein is reduced by about 25% to about 80%. The amount of protein in the elephant's urine is reduced by about 30% to about 80%. In these experiments, the amount of protein in the subject's urine is reduced by about 35% to about 80%. In some 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 about 45% to In some of these embodiments, the amount of protein in the subject's urine is reduced by about 80%. is reduced by approximately 50% to approximately 80%.

[0189] In some embodiments, the amount of protein (e.g., albumin) in the urine of the subject is , after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., 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, approximately 20 weeks, approximately 30 weeks, approximately 40 weeks, approximately 50 weeks, approximately 60 weeks, approximately 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 after treatment), about 100 mg / In certain embodiments, the protein in the urine of the subject is reduced by about 3,000 mg / dL. The amount of carbohydrates is reduced by about 100 mg / dL to about 2500 mg / dL. The amount of protein in the subject's urine is approximately 100 mg / dL to approximately 2,000 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL. In certain embodiments, the protein in the urine of the subject is reduced by about 1,500 mg / dL. The amount of is reduced by about 100 mg / dL to about 1,000 mg / dL. As a result, the amount of protein in the subject's urine is reduced by approximately 100 mg / dL to approximately 500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is between about 100 mg / dL and about 4 In certain embodiments, the amount of protein in the subject's urine is reduced by about In certain embodiments, the subject's urinary The amount of protein is reduced by about 100 mg / dL to about 200 mg / dL. In this state, the amount of protein in the subject's urine is between about 500 mg / dL and about 2,500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg In certain embodiments, the subject's urinary titer is reduced by between about 2,000 mg / dL and about 2,000 mg / dL. Protein levels are reduced by about 500 mg / dL to about 1,500 mg / dL. In this study, the amount of protein in the subject's urine was approximately 500 mg / dL to approximately 1,000 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / L. In certain embodiments, the protein in the urine of the subject is reduced by between about 900 mg / dL and about 900 mg / dL. In certain embodiments, the amount of 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 between about 700 mg / dL and about 900 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 1, In some of the above-described embodiments, the blood cholesterol level is reduced by about 2,000 mg / dL to about 2,000 mg / dL. The subject is administered atrasentan or a pharmaceutically acceptable salt thereof for about 15 to about 30 days. He is being treated.

[0190] In certain embodiments, the amount of protein (e.g., albumin) in the urine of a subject is determined by About 15 to about 30 days after treatment with trasentan or a pharmaceutically acceptable salt thereof, In certain embodiments, the subject's urinary The amount of protein is approximately After 15 to 30 days, blood sugar levels will decrease by approximately 200 mg / dL to 500 mg / dL. In one embodiment, the amount of protein in the subject's urine is measured by administering atrasentan or a pharmaceutically acceptable salt thereof. Approximately 15 to 30 days after treatment with the salt, the blood glucose level is approximately 300 mg / dL to 500 mg / dL. Reduce L.

[0191] In certain embodiments, the amount of protein (e.g., albumin) in the urine of a subject is determined by about 15 to about 30 days after treatment with trasentan or a pharmaceutically acceptable salt thereof, In certain embodiments, the subject's urine The amount of protein in After about 15 to 30 days, blood sugar levels will decrease by about 600 mg / dL to about 900 mg / dL. In one embodiment, the amount of protein in the subject's urine is measured by administering atrasentan or a pharmaceutically acceptable salt thereof. Approximately 15 to 30 days after treatment with the salt, the blood glucose level is approximately 700 mg / dL to 900 mg / dL. Reduce L.

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

[0193] In some embodiments, the subject is between about 15 and 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 years old, In some embodiments, the subject is between about 40 years old and about 40 years old, or any age therebetween. In some embodiments, the age is about 20 to about 30 years old, or any age therebetween. The target ages are about 20, 21, 22, 23, 24, 25, and 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 determined by the administration of atrasentan or its derivatives. In some embodiments, fatigue is reduced after treatment with a physiologically acceptable salt. After treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., 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 1 0 weeks, approximately 20 weeks, approximately 30 weeks, approximately 40 weeks, approximately 50 weeks, approximately 60 weeks, approximately 70 weeks, Approximately 80 weeks, approximately 90 weeks, approximately 100 weeks, approximately 110 weeks, approximately 120 weeks, approximately 130 weeks, Approximately 140 weeks, approximately 150 weeks, approximately 160 weeks, approximately 170 weeks, approximately 180 weeks, approximately 190 weeks or about 200 weeks, or any value therebetween), about 5% to about 80% In certain embodiments, fatigue is reduced by about 10% to about 75%. In certain embodiments, fatigue is reduced by about 10% to about 70%. Fatigue is reduced by about 10% to about 65%. In certain embodiments, fatigue is reduced by about 10% to about 65%. 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 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 some of the foregoing embodiments, the subject is administered 15 to 30 days of In certain embodiments, the patient is being treated with atrasentan or a pharmaceutically acceptable salt thereof. The reduction in fatigue was measured by the Fatigue Severity Scale, Chalder Fatigue Scale, and FAC. IT Fatigue Scale, Brief Fatigue Inventory, FACT-F subscale, General Vitality and and influence, May and Kline adjective checklist, Pearson-Byar s Fatigue Feeling Checklist, Rhoten Fatigue Scale, Fatigue and Anergy A decrease in the score of one or more of the individual strengths of the schedule or checklist include.

[0195] Some embodiments provide methods for activating mesangial cells in subjects with IgA nephropathy. A method for inhibiting steroid hormone receptor agonism, comprising administering to a subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. and administering to the subject a salt thereof comprising the compound of formula (I) or (II), wherein the subject is suffering from diabetic nephropathy, HIV / AIDS, or acute kidney injury. The method provides a method in which the patient has not previously been diagnosed with one or more of the following disorders:

[0196] Some embodiments provide for the determination of P in mesangial cells in subjects with IgA nephropathy. Inhibits DGF signaling activity (e.g., PIK3R1, PDGFRA, NFKBI A, PIK3CG, PLA2G4A, TIAM1, PDGFB, NFKB1, and MA 2. A method for reducing the expression and / or activity of one or more of P3K1 in a subject, comprising administering to a subject administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof; The subjects were those with one or more of the following conditions: diabetic nephropathy, HIV / AIDS, or acute renal failure. It provides a method for those who have never been diagnosed with the condition.

[0197] Some embodiments provide a method of inhibiting activation of mesangial cells, comprising: contacting a mouse cell with an effective amount of atrasentan or a pharmaceutically acceptable salt thereof The present invention provides a method including:

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

[0199] In some embodiments, inhibiting mesangial cell activation is reducing the expression and / or activity of one or more biomarkers indicative of proliferation of umbilical cord blood cells In some embodiments, inhibiting mesangial cell activation includes In some embodiments, the mesangial cells are treated with a steroid hormone, which reduces inflammation of the mesangial cells. Reducing mesangial cell inflammation is associated with increased levels of IL6, MCP1, or mesangial cells. reducing the expression and / or activity of one or more other biomarkers indicative of inflammation In some embodiments, reducing inflammation of mesangial cells includes In some embodiments, the method comprises reducing the expression and / or activity of IL-6. and the expression and / or activity of one or more biomarkers indicative of mesangial cell inflammation. The efficacy of the treatment was evaluated after treatment with atrasentan or its pharmaceutically acceptable salt (e.g., approximately 1 week after the treatment). , 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 1 After approximately 90 weeks of treatment, or approximately 200 weeks, or any value in between, approximately 25% In some embodiments, one or more of the following indicative of mesangial cell inflammation are reduced by about 99%: The expression and / or activity of the above biomarkers is about 25% to about 50%, about 40% to about 60%, 0%, about 50% to about 75%, about 60% to about 80%, about 75% to about 90%, about 85% to about 9 9%, or any value therebetween. For example, in some such embodiments In the method, the one or more biomarkers may be IL-6.

[0200] In some embodiments, inhibiting mesangial cell activation is In some embodiments, the method comprises reducing inflammation in mesangial cells. Reducing cell inflammation can be achieved by reducing IL-6 signaling (e.g., IL- 6. Expression and / or activity of one or more proteins involved in a signal transduction pathway Reducing, for example, Cntfr, Il1b, Csf1, Il2ra, Map3k8 In some embodiments, the membrane comprises a reduction in one or more of Il1r1, Il2r2, and Il1r1. Reducing inflammation in sanial cells is associated with Cntfr, Il1b, Csf1, and Il2ra , Map3k8, Il1r1 (for example, 1, 2, 3, 4, or 5) expression and / or activity.

[0201] In some embodiments, inhibiting mesangial cell activation is In some embodiments, the method comprises reducing the fibrotic response in mesenchymal cells. Attenuating the fibrotic response in sanguineous cells is associated with the activation of NF-κB, TGF, and PDGF , CTGF, MMPs, TIMPS, or other biomarkers indicative of mesangial cell fibrosis Some examples include reducing the expression and / or activity of one or more of the following proteins: In embodiments, NF-κB, TGF, PDGF, CTGF, MMP, and TIMPS The expression and / or activity of one or more of the following may be mediated by atrasentan or a pharmaceutically acceptable salt thereof: the onset and / or activity of atrasentan or its salts compared to that prior to administration of the compound. After treatment with a biologically acceptable salt (e.g., about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, Approximately 5 weeks, approximately 6 weeks, approximately 7 weeks, approximately 8 weeks, approximately 9 weeks, approximately 10 weeks, approximately 20 weeks, approximately 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, approximately 110 weeks, approximately 120 weeks, approximately 130 weeks, approximately 140 weeks, approximately 150 weeks , approximately 160 weeks, approximately 170 weeks, approximately 180 weeks, approximately 190 weeks, or approximately 200 weeks, or any value therebetween), reduction of about 25% to about 99%. In morphology, NF-κB, TGF, PDGF, CTGF, MMPs, and TIMPS The expression and / or activity of one or more of these is 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 between them.

[0202] In some embodiments, inhibiting mesangial cell activation is In some embodiments, the method includes reducing the fibrotic response in fibroblasts. Reducing the fibrotic response includes reducing NF-κB signaling. In some embodiments, reducing the fibrotic response comprises inhibiting Pfkfb3, Nr4a1, G em, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2 , Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, T rib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4 a3, Nfkb1, serpin1, Ccl20, Per1, Cxcl2, Map3k8, T Expression of one or more (e.g., one, two, three, four, or five) of raf1 and and / or reducing the activity of Ehd1, Snn, Tnfaip 8, Ackr3, Id2, Ccn1, Efna1, Ccnd1, Cdkn1a, Pnrc 1 (where the component inhibits NF-κB signaling) or increasing the expression and / or activity of one, two, three, four, or five of the .

[0203] In some embodiments, reducing the fibrotic response is achieved by inhibiting PDGF signaling. In some embodiments, reducing the fibrotic response includes reducing , Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tia m1, Pdgfb, Nfkb1 (e.g., one, two, three, four, or or 5) expression and / or activity, and / or Hras ( one or more (e.g., one, two) of the components inhibiting PDGF signaling. The present invention includes increasing the expression and / or activity of one, three, four, or five of the genes.

[0204] In some embodiments, the expression of NF-κB and / or PDGF and / or The onset and / or activity of atrasentan or a pharmaceutically acceptable salt thereof is The expression and / or activity of atrasentan or its pharmaceutically acceptable salts compared to that prior to administration After treatment with the salt (e.g., about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, Approximately 6 weeks, approximately 7 weeks, approximately 8 weeks, approximately 9 weeks, approximately 10 weeks, approximately 20 weeks, approximately 30 weeks, approximately 4 0 weeks, approximately 50 weeks, approximately 60 weeks, approximately 70 weeks, approximately 80 weeks, approximately 90 weeks, approximately 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 In some embodiments, the reduction is between about 25% and about 99%. Therefore, 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 the fibrotic response in mesangial cells Some of the methods include reducing matrix secretion by mesangial cells. In morphology, reducing matrix secretion by mesangial cells enhances mesangial function. Reduce the expression and / or activity of one or more excessive matrix secretion proteins by umbilical cord blood cells. This includes:

[0206] Some embodiments involve the activation of mesangial cells in contact with IgA immune complexes. The present invention relates to a method for reducing mesangial cells, the method comprising administering an effective amount of atrasentan or a pharmaceutical The present invention provides a method for activating mesangial cells, comprising contacting the cells with a physiologically acceptable salt. Reducing the expression of one or more biomarkers indicative of mesangial cell proliferation and This includes reducing the activity and / or activity of the protein.

[0207] In some embodiments, reducing mesangial cell activation is achieved by increasing the activity of mesangial cells. In some embodiments, the method comprises reducing inflammation in mesangial cells. Reducing cell inflammation is associated with increased expression of IL6, MCP1, or mesangial cell inflammation. and reducing the expression and / or activity of one or more of the other biomarkers. nothing.

[0208] In some embodiments, reducing mesangial cell activation is achieved by increasing the activity of mesangial cells. In some embodiments, the method comprises: reducing a fibrotic response in glial cells; Reducing the fibrotic response in mesangial cells is associated with increased activity of TGF, PDGF, and CTGF. , MMPs, TIMPS, or other biomarkers indicative of mesangial cell fibrosis The present invention includes reducing the expression and / or activity of one or more of the following:

[0209] In some embodiments, reducing the fibrotic response in mesangial cells Some of the methods include reducing matrix secretion by mesangial cells. In morphology, reducing matrix secretion by mesangial cells enhances mesangial function. Expression of one or more biomarkers indicative of excessive matrix secretion by umbilical cord cells and / or or reducing the activity.

[0210] In some embodiments, reducing mesangial cell activation is desirable. In some embodiments, the method comprises reducing the migration of unwanted mesangial cells. Reducing unwanted mesangial cell migration may be achieved by administering atrasentan or its pharmaceutical compositions. In some embodiments, the symptom occurs after about 15 to about 30 days of treatment with a physiologically acceptable salt. In this case, reducing undesired mesangial cell migration is achieved by atrasentan or This occurs about 3 to 6 months after treatment with the pharmaceutically acceptable salt.

[0211] In some embodiments, reducing mesangial cell activation is desirable. In some embodiments, the method comprises reducing proliferation of non-human mesangial cells. Reducing unwanted mesangial cell proliferation is a benefit of atrasentan or its The symptom occurs about 15 to about 30 days after treatment with a physiologically acceptable salt. In this condition, reducing unwanted mesangial cell proliferation is achieved by atrasentan. or a pharmaceutically acceptable salt thereof, the symptoms appear about 3 to 6 months after treatment.

[0212] In some embodiments, unwanted mesangial cell proliferation is atresia. or a pharmaceutically acceptable salt thereof (e.g., about 1 week, about 2 weeks, about 3 weeks 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 2 0 weeks, approximately 30 weeks, approximately 40 weeks, approximately 50 weeks, approximately 60 weeks, approximately 70 weeks, approximately 80 weeks, Approximately 90 weeks, approximately 100 weeks, approximately 110 weeks, approximately 120 weeks, approximately 130 weeks, approximately 140 weeks , approximately 150 weeks, approximately 160 weeks, approximately 170 weeks, approximately 180 weeks, approximately 190 weeks, or After approximately 200 weeks of treatment, or any value therebetween, there is a reduction of approximately 25% to approximately 99%. In some embodiments, unwanted mesangial cell proliferation is reduced by about 25% to about 5%. 0%, approx. 40% to approx. 60%, approx. 50% to approx. 75%, approx. 60% to approx. 80%, approx. 75% to approx. 9 The reduction may be 0%, about 85% to about 99%, or any value therebetween.

[0213] In some embodiments, mesangial cell activation can be measured using serum analysis, urine analysis, and and microscopic examination of renal biopsy samples (e.g., light microscopy and / or immunofluorescence microscopy) ) can be evaluated by one or more of the following:

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

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

[0217] In some embodiments, determining elevated levels of mesangial activation involves administering to the subject obtaining samples from the same and assessing the level of mesangial activation therein; In some embodiments, the sample is a kidney biopsy sample. In the method, the sample is a blood sample, a urine sample, a kidney biopsy sample, or a combination of two or three of the aforementioned. is selected from a combination.

[0218] In some embodiments, the sample contains elevated levels of myelin by mesangial cells. secretion, IgA immune complex deposition, mesangial cell proliferation, and capillary cytotoxicity. In some embodiments, the sample exhibits one or more of the following: elevated levels of cytotoxicity, ... Showing IgA immune complex deposition in the le.

[0219] In some embodiments, the subject is administered a therapeutically effective amount of atrasentan or a pharmaceutical At least three consecutive measurements over a period of one year before administration of a commercially acceptable salt Both tests have determined that the patient has at least about 1 g / day of proteinuria. 1 g / day, approximately 1.2 g / day, approximately 1.4 g / day, approximately 1.6 g / day, approximately 1.8 g / day, or At least about 2g / day.

[0220] In some embodiments, the subject is administered a therapeutically effective amount of atrasentan or a pharmaceutical Patients should be on a maximally tolerated stable dose of RAS inhibitors for at least 12 weeks before administration of a suitably tolerated salt. In some embodiments, the subject is receiving a maximally tolerated stable dose of a vasopressin-releasing agent. and a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the RAS inhibitor is administered at an angiotensin converting In some embodiments, the RAS inhibitor is an angiotensin receptor enzyme inhibitor. It is an antiretroviral drug (ARB).

[0221] In some embodiments, the subject is administered a therapeutically effective amount of atrasentan or a pharmaceutical In some embodiments, the patient has been determined to have hematuria prior to administration of the therapeutically acceptable salt. In some embodiments, the hematuria is microscopic hematuria. In some embodiments, the hematuria is macroscopic hematuria. is.

[0222] In some embodiments, the subject is administered a therapeutically effective amount of atrasentan or a pharmaceutical Before administration of tolerated salts, administer at least 30 mL / min / 1.73 m 2 have an eGFR of In some embodiments, the subject receives a therapeutically effective amount of atracentrotherapy. Approximately 30 mL / min / 1.73 m before administration of the fluticasone or its pharmaceutically acceptable salt. 2 ~about 6 0mL / min / 1.73m 2 It has been determined that the patient has an eGFR of .

[0223] In some embodiments, the subject has diabetic nephropathy, HIV / AIDS, or acute In some embodiments, the patient has not been previously diagnosed with one or more of the following renal failures: 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. The cancers are lung cancer or prostate cancer.

[0224] Some embodiments provide a method for treating IgA nephropathy in a subject in need thereof. A method for administering a therapeutic agent to a subject, the method comprising: a) administering to the subject an IgA immune complex; b) administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof; and administering a salt thereof.

[0225] In some embodiments, determining elevated levels of IgA immune complexes in the kidney obtaining a sample from a subject and assessing the level of IgA immune complexes in the same In some embodiments, the sample is a kidney biopsy sample. In embodiments, the sample is a blood sample, a urine sample, a kidney biopsy sample, or a combination of two or more of the foregoing. In some embodiments, the IgA immune complex is selected from the following three combinations: Deposited in the mesangium.

[0226] In some embodiments, the levels of IgA immune complexes are measured by serum analysis, urine analysis, and and microscopic examination of renal biopsy samples (e.g., light microscopy and / or immunofluorescence microscopy) ) can be evaluated by one or more of the following:

[0227] In some embodiments, the sample contains elevated levels of myelin by mesangial cells. secretion of IgA immune complexes in the mesangium, and activation of mesangial cells The cells exhibit one or more of the following: proliferation of vascularized blood vessels, proliferation of mesangial cells, and proliferation of cells within capillaries.

[0228] In some embodiments, the subject is administered a therapeutically effective amount of atrasentan or a pharmaceutical At least three consecutive measurements over a period of one year before administration of a commercially acceptable salt Both tests have determined that the patient has at least about 1 g / day of proteinuria. 1 g / day, approximately 1.2 g / day, approximately 1.4 g / day, approximately 1.6 g / day, approximately 1.8 g / day, or At least about 2g / day.

[0229] In some embodiments, the subject is administered a therapeutically effective amount of atrasentan or a pharmaceutical Patients should be on a maximally tolerated stable dose of RAS inhibitors for at least 12 weeks before administration of a suitably tolerated salt. In some embodiments, the subject is receiving a maximally tolerated stable dose of a vasopressin-releasing agent. and a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the RAS inhibitor is administered at an angiotensin converting In some embodiments, the RAS inhibitor is an angiotensin receptor enzyme inhibitor. It is an antiretroviral drug (ARB).

[0230] In some embodiments, the subject is administered a therapeutically effective amount of atrasentan or a pharmaceutical In some embodiments, the patient has been determined to have hematuria prior to administration of the therapeutically acceptable salt. In some embodiments, the hematuria is microscopic hematuria. In some embodiments, the hematuria is macroscopic hematuria. is.

[0231] In some embodiments, the subject is administered a therapeutically effective amount of atrasentan or a pharmaceutical Before administration of tolerated salts, administer at least 30 mL / min / 1.73 m 2 have an eGFR of In some embodiments, the subject receives a therapeutically effective amount of atracentrotherapy. Approximately 30 mL / min / 1.73 m before administration of the fluticasone or its pharmaceutically acceptable salt. 2 ~about 6 0mL / min / 1.73m 2 It has been determined that the patient has an eGFR of .

[0232] In some embodiments, the subject has diabetic nephropathy, HIV / AIDS, or acute In some embodiments, the patient has not been previously diagnosed with one or more of the following renal failures: 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. The cancers are lung cancer or prostate cancer.

[0233] In some embodiments, the method comprises administering to a subject: CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, S Expression and / or activity of one or more of LC6A19, IL-6, and NF-kB In some embodiments, the expression and / or activity is determined by a therapeutic This is determined prior to administration of an effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the expression and / or activity is measured by administering a therapeutically effective amount of atrasentan. or a pharmaceutically acceptable salt thereof.

[0234] In some embodiments, determining expression and / or activity is a therapeutically effective amount. This is done before the administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, determining expression and / or activity includes administering a therapeutically effective amount of attracentrifugation. For example, about 1 week, about 2 weeks, about 3 weeks, or Approximately 4 weeks, approximately 5 weeks, approximately 6 weeks, approximately 7 weeks, approximately 8 weeks, approximately 9 weeks, approximately 10 weeks, approximately 20 weeks 30 weeks, 40 weeks, 50 weeks, 60 weeks, 70 weeks, 80 weeks, 9 0 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, approximately 160 weeks, approximately 170 weeks, approximately 180 weeks, approximately 190 weeks, or approximately 2 00 weeks, or any value therebetween after treatment.

[0235] In some embodiments, the subject is diagnosed with ET1, TGF, PDGF, CTGF, MMP , TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, I L-6, NF-kB, PKC, PI3K, Src, Ras, ERK1 / 2, Rho, Ra c, Akt, mTOR, NAPDH oxidase, MAPK, cPLA2, TNF-α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt / P KB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK, MCP1, Cntfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, If it2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Bt g2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat 5, Edn1, Rel, Nr4a3, Nfkb1, Serpin1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Expression of one or more of Pik3cg, Pla2g4a, Tiam1, and Pdgfb and / or activity. In some embodiments, the subject is determined to have: ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, A SL, AMN, ALPL, SLC6A19, IL-6, NF-kB, PKC, PI3K, Src, Ras, ERK1 / 2, Rho, Rac, Akt, mTOR, NAPDH oxidant Dase, MAPK, cPLA2, TNF-α, IL-1, CAM, COX-2, iNOS , JAK, STAT3, PI3K, Akt / PKB, IKKs, IkBs, NF-kB, Elevated levels of one or more of MAPK, Ras, Raf, MEK, ERK, and MCP1 In some embodiments, the target gene is determined to have the same expression and / or activity as the target gene. Elephants are Cntfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1, and Pf kfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit 2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2 , Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, Serpin1, Ccl20, Per1, Cx cl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pi Elevated one or more of k3cg, Pla2g4a, Tiam1, and Pdgfb In some embodiments, the subject is determined to have expression and / or activity. 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 of the nucleotides of interest is elevated. In this state, the subject is exposed to ET1, TGF, PDGF, CTGF, MMP, TIMPS, IG one or more of F1, DPEP1, ASL, AMN, ALPL, and SLC6A19 It has been determined that the individual has elevated expression and / or activity of

[0236] Some embodiments provide a method of treating IgA nephropathy in a subject, comprising: (a) administering to the subject However, ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1 , ASL, AMN, ALPL, SLC6A19, IL-6, NF-kB, PKC, PI3 K, Src, Ras, ERK1 / 2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA2, TNF-α, IL-1, CAM, COX-2, iN OS, JAK, STAT3, PI3K, Akt / PKB, IKKs, IkBs, NF-k B, MAPK, Ras, Raf, MEK, ERK, MCP1, Cntfr, Il1b, C sf1, Il2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Ja g1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib 1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, Serpin1, Ccl20, Per1, Cxcl2, Map3k8, Traf 1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Ti am1, and Pdgfb. (b) administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof and administering an acceptable salt thereof.

[0237] Some embodiments include ET1, TGF, PDGF, CTGF, MMPs, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, NF- kB, PKC, PI3K, Src, Ras, ERK1 / 2, Rho, Rac, Akt, m TOR, NAPDH oxidase, MAPK, cPLA2, TNF-α, IL-1, CA M, COX-2, iNOS, JAK, STAT3, PI3K, Akt / PKB, IKKs , IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK, MCP1, Cn tfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4 a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3 , Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, serpin1, Ccl20, Per1, Cxcl2, M ap3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, elevated expression of one or more of Pla2g4a, Tiam1, and Pdgfb and and / or a method for treating IgA nephropathy in a subject determined to have activity, The method comprises administering to a subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. Well, we provide a method.

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

[0239] Atrasentan and its method of preparation are disclosed in U.S. Patent No. 7,208,517 and International Patent No. As described in U.S. Patent Application Publication No. 1997 / 030045 (see, e.g., Example 501), No. 6,229,999, each of which is incorporated herein by reference in its entirety.

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

[0241] Atrasentan is an ET A inhibitor, ET B Compared to ET A About 1.86 0-fold selective. As used herein, "ET A " is an endothelin receptor A It is an abbreviation, "ET B " is an abbreviation for endothelin receptor B. For example, Ann Rh eum Dis.,66(11),pp.1467-1472(2007),Eur.R esp.J.,37,pp.475-476(2011), Plos One,9,e8 7548(2014), J.Clin.Oncol.,10,31(14),pp.17 40-7(2013), Pharmacol.Rev.,68(2)pp.357-41 8(2016), and Nephrol.Dial.Transplant.,29,p. See 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 compound of the present disclosure, e.g. , atrasentan). Exemplary salts include: Acids formed by the reaction between atrasentan and an acid (e.g., an organic acid or an inorganic acid) Addition salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, nitrate, bromide, iodide, nitrate, hydrogen sulfate, phosphate, acid phosphate, isonicotinate , lactate, salicylate, acid citrate, tartrate, oleate, tannate, pa Anthrate, bitartrate, ascorbate, succinate, maleate, mandelate mandelate (e.g., (S)-mandelate or (R)-mandelate), gentisate, Fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamine Acid salt, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate , and p-toluenesulfonate, pamoate (i.e., 4,4'-methylene-bis- (2-hydroxy-3-naphthoate) salts. Exemplary salts also include athracene Also included are base addition salts formed by the reaction between amine and a base. Potassium metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts Pharmaceutically acceptable salts include acetate ions, sodium salts, and ammonium salts. The counterion may involve the inclusion of another molecule such as a carboxyl ion, a succinate ion, or other counterion. It can be any organic or inorganic moiety that stabilizes the charge of the parent compound. A physiologically acceptable salt may have more than one charged atom in its structure. When part of a physiologically acceptable salt, it can have multiple counter ions. Therefore, a pharmaceutically acceptable salt contains one or more charged atoms and / or one or more counter ion. When referring to atrasentan, the term "salt(s)" may include: Salts of atrasentan which may exist alone or in mixtures with free atrasentan It is understood.

[0243] In some embodiments, atrasentan is in the form of the hydrochloride salt. Atrasentan hydrochloride, also known as atrasentan hydrochloride (CAS number: 195733-43-8); Lasentan Hydrochloride; Atrasentan Hydrochloride; Atrasentan Chloride Salt; Atrasentan HCl; Atrasentan monohydrochloride; (2R,3R,4S)-4-(1,3-benzodioxane) 4-(2-(4-isothiazolinone)-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-isothiazolinone) (Methoxyphenyl)pyrrolidine-3-carboxylic acid, monohydrochloride;3-Pyrrolidinecarboxylic acid , 4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2 -oxoethyl]-2-(4-methoxyphenyl)-, hydrochloride (1:1), (2R,3R ,4S)-;(2R,3R,4S)-1-[(dibutylcarbamoyl)methyl]-2-( p-Methoxyphenyl)-4-[3,4-(methylenedioxy)phenyl]-3-pyrrolyl 3-Pyrrolidinecarboxylic acid, 4-(1,3-benzodioxo) (4-methyl-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-( ... (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. The manufacturing method is described in U.S. Pat. No. 7,208,517 and International Patent Application Publication No. 1997 / 030 '045 (see, e.g., Example 501), each of which is incorporated herein by reference. No. 6,299,499, all of which are incorporated herein by reference in their entireties.

[0244] In some embodiments, atrasentan is in the form of a mandelate salt. In an embodiment, atrasentan is in the form of the (S)-mandelate salt. In certain embodiments, atrasentan is in the form of the (R)-mandelate salt. In atrasentan mandelate, atrasentan and mandelate are In certain embodiments, in atrasentan mandelate, In this formulation, the atrasentan and mandelate salts have a molar ratio of 2:1. Mandelate salts and methods for their preparation are described in U.S. Patent Nos. 8,962,675 and 9,662,676. 37,476, each of which is incorporated herein by reference in its entirety. INCORPORATED INTO THE SPECIFICATION.

[0245] In some embodiments, atrasentan is in the form of a hemisulfate salt. The salts and methods for their preparation are described in U.S. Patent Nos. 8,962,675 and 9,637,477. No. 6, each of which is incorporated herein by reference in its entirety. be absorbed.

[0246] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof is In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is in the form of a water gypsum. In certain embodiments, the salt is in the form of a hydrate. Pharmaceutically acceptable salts are in the form of solvates.

[0247] stereochemistry Atrasentan has three asymmetric centers and is described in U.S. Pat. No. 7,208,517 and As described in International Patent Application Publication No. WO 1997 / 030045, the individual stereoisomers ( For example, enantiomers or diastereomers) or mixtures thereof. In some embodiments, the atrasentan described herein can , (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2- (Dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine- In certain embodiments, the carboxylic acid is a (2R,3R,4S)-stereoisomer. Atrasentan is a (2R,3R,4S)-stereoisomer that is substantially free of other stereoisomers. isomers (e.g., <10%, <5%, <2%, <1%, <0. (Contains 5%, <0.1%, <0.05%)

[0248] polymorph As described herein, atrasentan or a pharmaceutically acceptable salt thereof may be In some embodiments, atrasentan or its derivatives may be in one or more polymorphic forms. The pharmaceutically acceptable salt of >90%, >95%, >98%, >99%, or >99.5% amorphous). In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof is substantially Crystalline (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >9 9%, or >99.5% crystalline).

[0249] In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is Sentan hydrochloride crystalline Form 1. In certain embodiments, atrasentan or its The pharmaceutically acceptable salt is substantially atrasentan hydrochloride crystalline Form 1 (e.g., >75% , >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% Atrasentan hydrochloride crystalline Form 1 and the method for producing it are disclosed in the International Patent Application Publication No. 2006 / 034094, the entire contents of which are incorporated herein by reference. (See the attached document).

[0250] In some embodiments, atrasentan hydrochloride crystalline Form 1 is irradiated with Cu-Kα radiation. When measured at approximately 25°C using a At least three (e.g., 3) with 2θ values ​​of 0°, 15.6°, 17.2°, or 19.5° For example, three, four, five, six, or seven peaks in the X-ray powder diffraction pattern. In certain embodiments, atrasentan hydrochloride crystalline Form 1 is characterized by: When measured at about 25°C using Cu-Kα radiation, the angles are approximately 8.3°, 9.7°, and 1°, respectively. A small number of 2θ values ​​of 0.0°, 13.0°, 15.6°, 17.2°, or 19.5° were used. At least three peaks, essentially less than about 6.2° and / or between about 6.6° and 8° It is characterized by an X-ray powder diffraction pattern having no peaks with a 2θ value of 0.0°.

[0251] In some embodiments, atrasentan hydrochloride crystalline Form 1 is orthorhombic and P 2 l 2 l 2 lIn the space group, when measured with Cu-Kα radiation at about 25°C, 17.663 ű0.005 Å, 21.24 ű0.01 Å, and 8.005 ű0.01 Å, respectively. It is characterized by lattice parameters a, b, and c of 0.002 Å.

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

[0253] Representative characteristic peak positions in the X-ray powder diffraction pattern of atrasentan hydrochloride crystalline form I The position is expressed as an angle relative to 2θ and is 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%), 15.8 °((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 given with its associated Miller index (hkl) value and its integrated intensity (peak height Peak heights may vary with temperature, crystal size, or morphology. , sample preparation, or analysis of the Scintag x2 diffraction pattern system. It is understood that the results are dependent on variables such as the radiation intensity, etc., when measured with different radiation sources. It is also understood that the peak locations may vary. For example, 1.5406, respectively. Cu-K with wavelengths of 0 Å, 0.7107 Å, 1.7902 Å, and 1.9373 Å α1, Mo-Kα, Co-Kα, and Fe-Kα radiation measured with Cu-Kα radiation This can provide different peak positions than those obtained by

[0254] In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is Sentan hydrochloride crystalline Form 2. In certain embodiments, atrasentan or its The pharmaceutically acceptable salt is substantially atrasentan hydrochloride crystalline Form 2 (e.g., >75% , >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% Atrasentan hydrochloride crystalline Form 2 and the method for producing it are disclosed in the International Patent Application Publication No. 2006 / 034094, the entire contents of which are incorporated herein by reference. (See the attached document).

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

[0256] In certain embodiments, atrasentan hydrochloride crystalline Form 2 has substantial crystalline purity. and 22°C, respectively, when measured at about 25°C using Cu-Kα radiation. and a peak with a 2θ value of approximately 8.4°, 15.6°, and 18.0°, respectively. At least one peak with a 2θ value of 18.5°, 19.8°, or 20.6° It is characterized by an X-ray powder diffraction pattern having

[0257] In certain embodiments, atrasentan hydrochloride crystalline Form 2 has substantial crystalline purity and and has substantial chemical purity, and the atrasentan hydrochloride crystalline Form 2 has a crystallinity of about 25° C. When measured using -Kα radiation, the 2θ values ​​were approximately 6.7° and 22.05°, respectively. The peaks are approximately 8.4°, 15.6°, 18.0°, 18.5°, and 19. X-ray powder diffraction with at least one peak having a 2θ value of 8° or 20.6° Characterized by patterns.

[0258] In certain embodiments, atrasentan hydrochloride crystalline Form 2 has substantial crystalline purity, The atrasentan salt has qualitative chemical purity and substantial diastereomeric purity. The salt crystalline form 2 has a molecular weight of about 6.5g, respectively, as measured using Cu-Kα radiation at about 25°C. The peaks with 2θ values ​​of 7° and 22.05° and those with 2θ values ​​of approximately 8.4° and 15.6°, respectively , 18.0°, 18.5°, 19.8°, or 20.6° It is characterized by an X-ray powder diffraction pattern with one peak.

[0259] In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is Sentan hydrochloride crystalline Form 3. In certain embodiments, atrasentan or its The pharmaceutically acceptable salt is substantially atrasentan hydrochloride crystalline Form 3 (e.g., >75% , >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% Atrasentan hydrochloride crystalline Form 3 and the method for preparing it are disclosed in the International Patent Application Publication No. 2006 / 034234 and U.S. Patent No. 9,051,301 (which each of which is incorporated herein by reference in its entirety.

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

[0261] In certain embodiments, atrasentan hydrochloride crystalline Form 3 has substantial crystalline purity. and 21°C, respectively, when measured at about 25°C using Cu-Kα radiation. 0.95° and a peak with a 2θ value of approximately 8.4°, 15.6°, and 18.0°, respectively. At least one peak with a 2θ value of 18.5°, 19.8°, or 20.6° It is characterized by an X-ray powder diffraction pattern having

[0262] In certain embodiments, atrasentan hydrochloride crystalline Form 3 has substantial crystalline purity and and has substantial chemical purity, and the atrasentan hydrochloride crystalline Form 3 has a crystallinity of Cu at about 25°C. When measured using -Kα radiation, the 2θ values ​​were approximately 6.7° and 21.95°, respectively. The peaks are approximately 8.4°, 15.6°, 18.0°, 18.5°, and 19. X-ray powder diffraction with at least one peak having a 2θ value of 8° or 20.6° Characterized by patterns.

[0263] In certain embodiments, atrasentan hydrochloride crystalline Form 3 has substantial crystalline purity, The atrasentan salt has qualitative chemical purity and substantial diastereomeric purity. The salt crystalline form 3 has a solubility of approximately 6.5% by mass, respectively, as measured using Cu-Kα radiation at approximately 25°C. The peaks with 2θ values ​​of 7° and 21.95° and those with 2θ values ​​of approximately 8.4° and 15.6°, respectively , 18.0°, 18.5°, 19.8°, or 20.6° It is characterized by an X-ray powder diffraction pattern with one peak.

[0264] In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is amorphous. In certain embodiments, the atrasentan hydrochloride is substantially Partially amorphous (e.g., >75%, >80%, >85%, >90%, >95%, >98%, Amorphous atrasentan hydrochloride and its The method for making it is described in International Patent Application Publication No. WO 2006 / 034085 (the entire contents of which are hereby incorporated by reference). (the entirety of which is incorporated herein by reference).

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

[0266] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof In certain embodiments, atrasentan or The pharmaceutically acceptable salt thereof is a substantially crystalline atrasentan mandelate salt (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >9 9.5% crystalline atrasentan mandelate).

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

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

[0269] In certain embodiments, the crystalline (S)-mandelate salt is chromatographed using monochromatic Kα1 radiation. 5.5±0.2, 9.7±0.2, and 19.4±0.2 degrees when measured at approximately 25°C In certain embodiments, the crystalline ( S)-Mandelate has a pH of 5.5±0 when measured at approximately 25°C using monochromatic Kα1 radiation. The peaks at 0.2, 9.7±0.2, 12.1±0.2, and 19.4±0.2 degrees 2θ were included. In certain embodiments, the crystalline (S)-macro-(2-methyl-2-propanol) compound has an X-ray powder diffraction pattern of 100% or more. The α-indenate has a pH of 5.5±0.2, 9 when measured at approximately 25°C using monochromatic Kα radiation. .7±0.2, 12.1±0.2, 18.0±0.2, 18.4±0.2, and 19. It has an X-ray powder diffraction pattern including peaks at 4±0.2 degrees 2θ. Therefore, 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 is: It 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 the P212121 space group. In certain embodiments, the crystalline (S)-mandelate salt has an average molecular weight of about 9.95, respectively. with unit cell a, b, and c values ​​of approximately 4 Å, approximately 11.049 Å, and approximately 30.861 Å In certain embodiments, the crystalline (S)-mandelate salt is at about 90° and about 90° and about 90° unit cell α, β, and γ values. The crystalline (S)-mandelate salt has the following characteristics: (a) orthorhombic lattice type; (b) P21212 1 space group, (c) approximately 9.954 Å, approximately 11.049 Å, and approximately 30.861 Å, respectively and / or (d) the unit cell a, b, and c values ​​in Å and / or (e) the unit cell a, b, and c values ​​in Å and / or (f) the unit cell a, b, and c values ​​in Å and / or (g ... b, b, and c values ​​in Å and / or (f) the unit cell c, b, and c values ​​in Å and / or (g) the unit cell c, b, At least three of the values ​​of α, β, and γ of the unit cell at 0° and approximately 90° In certain embodiments, the crystalline (S)-mandelate salt has: (a) an orthorhombic lattice type, (b) P212121 space group, (c) approximately 9.954 Å and approximately 11.049 Å, respectively. , and unit cell a, b, and c values ​​of about 30.861 Å, and / or (d) and γ values ​​of unit cell α, β, and γ of about 90°, about 90°, and about 90°, respectively. In certain embodiments, the crystalline (S)-mandelate salt is an anhydrous salt. In an embodiment, 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, and the molar ratio of atrasentan to (S)-mandelate is about 2:1 In certain embodiments, the crystalline atrasentan (S)-mandelate salt is anhydrous In certain embodiments, the crystalline atrasentan (S)-mandelate salt is a soluble salt. In certain embodiments, the crystalline atrasentan (S)-mandelate salt is In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is The salts are substantially (e.g., >75%, >80%, >85%, >90%, >95%, >9 8%, >99%, or >99.5%) of crystalline atrasentan (S)-mandelate and the molar ratio of atrasentan to (S)-mandelate is about 2:1.

[0272] In certain embodiments, the crystalline (S)-mandelate salt is chromatographed using monochromatic Kα1 radiation. 4.5±0.2, 8.6±0.2, and 18.1±0.2 degrees when measured at approximately 25°C In certain embodiments, the crystalline ( S)-Mandelate has a pH of 4.5±0 when measured at approximately 25°C using monochromatic Kα1 radiation. The peaks at 0.2, 8.6±0.2, 18.1±0.2, and 18.7±0.2 degrees 2θ were included. In certain embodiments, the crystalline (S)-mandelic acid has an X-ray powder diffraction pattern The salt has an average pH of 4.5±0.2 and 8.6±0 when measured at approximately 25°C using monochromatic Kα1 radiation. The peaks at 0.2, 9.1±0.2, 18.1±0.2, and 18.7±0.2 degrees 2θ were included. In certain embodiments, the X-ray powder diffraction pattern is The experimental error associated with the listed X-ray powder diffraction peak values ​​is ±0.1 degrees 2θ. In certain embodiments, the crystalline (S)-mandelate salt is an anhydrous salt. The crystalline (S)-mandelate salt is a hydrated salt.

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

[0274] In certain embodiments, the crystalline atrasentan (R)-mandelate salt is a crystalline atrasentan (R)-mandelate salt. Lasentan (R)-mandelate, and the molar ratio of atrasentan to (R)-mandelate The ratio is about 1:1. In certain embodiments, the crystalline atrasentan (R)-mande In certain embodiments, the crystalline atrasentan (R)-mannose salt is an anhydrous salt. The delta salt is a solvated salt. In certain embodiments, the crystalline atrasentan (R)- The mandelate salt is a hydrated salt. In certain embodiments, atrasentan or its derivatives A physiologically acceptable salt is substantially (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5%) crystalline atrasentan®- The molar ratio of atrasentan to (R)-mandelate is about 1:1. do.

[0275] In certain embodiments, the crystalline atrasentan (R)-mandelate salt has a monochromatic Kα1 When measured at approximately 25°C using radiation, the values ​​were 5.7±0.2, 11.8±0.2, and 2 It has an X-ray powder diffraction pattern including a peak at 0.9±0.2 degrees 2θ. In this study, crystalline atrasentan (R)-mandelate exhibited a 2000 Hz IR spectrum using monochromatic Kα1 radiation. When measured at 5°C, the values ​​were 5.7±0.2, 8.2±0.2, 11.8±0.2, and 20 and an X-ray powder diffraction pattern including peaks at 0.9±0.2 degrees 2θ. Crystalline atrasentan (R)-mandelate exhibited a luminescence intensity of approximately 250 nm using monochromatic Kα1 radiation. When measured in °C, the values ​​were 5.7±0.2, 8.2±0.2, 8.6±0.2, and 11.8±0. 2, and has an X-ray powder diffraction pattern including peaks at 20.9±0.2 degrees 2θ. In this embodiment, the X-ray powder diffraction peak values ​​associated with those listed in the various embodiments above are The experimental error is ±0.1 degrees 2θ. In certain embodiments, the crystalline atrasentan The (R)-mandelate salt is an anhydrous salt.

[0276] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof is a non- In certain embodiments, atrasentan or The pharmaceutically acceptable salt thereof is a substantially amorphous atrasentan mandelate salt (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >9 9.5% amorphous atrasentan mandelate).

[0277] In certain embodiments, the amorphous atrasentan mandelate is In certain embodiments, amorphous atrasentan (S) is atrasentan (S)-mandelate salt. -mandelate salt is an anhydrous salt. In certain embodiments, amorphous atrasentan (S )-mandelate salt is a solvated salt. In certain embodiments, amorphous atrasentan The (S)-mandelate salt is available as an acetonitrile solvate, an ethanol solvate, and a pyridine solvate. In certain embodiments, the amorphous salt is a solvated salt selected from the group consisting of amorphous ammonium salts, ... Atrasentan (S)-mandelate is a hydrated salt. In certain embodiments, the atrasentan (S)-mandelate is an amorphous salt. In the modified atrasentan (S)-mandelate, atrasentan and (S)-mandelate In certain embodiments, the molar ratio of amorphous atrasentan ( In the (S)-mandelate salt, the molar ratio of atrasentan and (S)-mandelate is It's about 2:1.

[0278] In certain embodiments, the amorphous atrasentan mandelate is In certain embodiments, amorphous atrasentan(R)-mandelate is -mandelate salt is an anhydrous salt. In certain embodiments, amorphous atrasentan (R )-mandelate salt is a solvated salt. In certain embodiments, amorphous atrasentan The (R)-mandelate salt is available as an acetonitrile solvate, an ethanol solvate, and a pyridine solvate. In certain embodiments, the amorphous salt is a solvated salt selected from the group consisting of amorphous ammonium salts, ... Atrasentan (R)-mandelate is a hydrated salt. In certain embodiments, the amorphous In the modified atrasentan (R)-mandelate, atrasentan and (R)-mandelate In certain embodiments, the molar ratio of amorphous atrasentan ( In the (R)-mandelate salt, the molar ratio of atrasentan and (R)-mandelate is It's about 2:1.

[0279] Crystalline and amorphous atrasentan mandelate are disclosed in U.S. Pat. No. 8,962,675. and 9,637,476, each of which is incorporated by reference. No. 6,299,333, filed on Oct. 1, 2003, which are incorporated herein in their entirety.

[0280] E. Preparation The term "pharmaceutical composition" as used herein refers to a pharmaceutical composition comprising an active ingredient and a carrier. Products containing inactive ingredients, as well as combinations, complexes, or from aggregation, or from dissociation of one or more components, or from other types of one or more components and includes any product obtained directly or indirectly from the reaction or interaction of Thus, the pharmaceutical compositions of the present disclosure may comprise a compound of the present disclosure or a pharmaceutically acceptable salt thereof. or a solvate or solvate of the salt thereof, and a pharmaceutically acceptable carrier. The present invention also encompasses any composition made by

[0281] The amount administered varies depending on the compound formulation, route of administration, etc., and is generally determined experimentally. The activity of a unit dose of a formulation is determined by the target, host, route of administration, etc. The amount of the active compound may range from about 0.1 milligrams (mg) to about 10 mg or The total daily dose can be varied or adjusted to about 0.5 mg to about 2 mg. , which may be administered in divided doses throughout the day.

[0282] The pharmaceutical compositions of the present disclosure for injection may be prepared in a pharmaceutically acceptable sterile aqueous or non-aqueous solution, Dispersions, suspensions, or emulsions, as well as sterile injectable solutions or dispersions immediately before use Suitable aqueous and non-aqueous carriers, diluents, solvents, or Examples of the vehicle include water, ethanol, polyols (glycerol, propylene glycol), polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (olive oil, etc.), Injectable organic esters such as ethyl oleate, and injectable organic esters such as ethyl oleate. Fluidity can be improved, as required in the case of dispersions, for example, by the use of coating materials such as lecithin. This can be maintained by maintaining the desired particle size and by the use of surfactants. .

[0283] These pharmaceutical compositions may also contain additives such as preservatives, wetting agents, emulsifying agents, and dispersing agents. The prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, e.g., parabens. This can be ensured by including benzophenone, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents such as sugars, sodium chloride, etc. Prolonged absorption can be achieved by using drugs that delay absorption, such as aluminum monostearate and gelatin. The compound may be provided by including a polymer matrix, a liposome, and can be incorporated into sustained release or targeted delivery systems such as microspheres. Such formulations may provide a more effective distribution of the compound.

[0284] Pharmaceutical compositions that are injectable formulations may be filtered, for example, through a bacteria-retaining filter. or by dissolving or dispersing in sterile water or other sterile injectable medium before use. Sterilization can be achieved by incorporating a sterilizing agent in the form of a sterile solid pharmaceutical composition. It is possible.

[0285] Solid dosage forms of extemporaneous pharmaceutical compositions for oral administration include capsules, tablets, pills, powders, and In such solid dosage forms, the active compound is present in a granule containing at least one inactive pharmaceutical ingredient. a physiologically acceptable excipient or carrier, such as sodium citrate or dibasic phosphate calcium, and / or a) starch, lactose, sucrose, glucose, maize b) fillers or extenders such as cellulose acetate, methylcellulose, and silicic acid; sugar, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia binding agents, c) humectants such as glycerol, d) agar, calcium carbonate, potato or disintegrating agents such as tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarding agents such as paraffin; f) absorption enhancers such as quaternary ammonium compounds; g) humectants, such as cetyl alcohol and glycerol monostearate, h) kaolin and adsorbents such as bentonite clay, and i) talc, calcium stearate. , magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of tablets and pills, the dosage form may also comprise buffering agents.

[0286] Solid pharmaceutical compositions of a similar type also include those containing lactose or milk sugar and high molecular weight polymers. Filling of soft and hard gelatin capsules using excipients such as ethylene glycol It can be used as a filler.

[0287] The solid dosage forms of the extemporaneous pharmaceutical compositions of tablets, dragees, capsules, pills, and granules are enteric-coated. Prepared with coatings and shells such as coatings and other pharmaceutical coatings They may optionally contain opacifying agents, which may mask the active ingredient. Only, or preferentially, optionally in a delayed manner, in a specific part of the intestinal tract. Examples of embedded pharmaceutical compositions that can be used include polymeric substances and Contains wax.

[0288] The active compound may also be packaged in microcapsules, where appropriate, with one or more of the above-mentioned excipients. It may be in a packaged form.

[0289] Liquid dosage forms of extemporaneous pharmaceutical compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, etc. Liquid dosage forms include suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain, e.g., For example, water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, Phenyl 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 and sorbitan fatty acid esters, and mixtures thereof. The composition may contain an inert diluent which is used.

[0290] Besides inert diluents, oral pharmaceutical compositions may also contain wetting agents, emulsifying and suspending agents, sweetening agents, or the like. Adjuvants such as flavorings, flavorings, and fragrances may also be included.

[0291] The suspension of the compound may contain, in addition to the active compound, for example, ethoxylated isostearyl alcohol. Cholesterol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose Suspensions such as cellulose, metahydroxyaluminum, bentonite, agar, and tragacanth The composition may contain turbiding agents, as well as mixtures thereof.

[0292] The compounds and compositions described herein can be administered orally or parenterally in doses ranging from 4 to 120 minutes. timely or as needed for the specific drug, dosage form, and / or route of administration. Doses ranging from about 0.01 milligrams per program (mg / kg) to about 0.05 mg / kg The relationship between animal and human dosage (per square meter of body surface) (based on milligrams per ton) is from Freireich et al., Cancer Chemother.Rep.50,219-244(1966) Body surface area can be roughly determined from the patient's height and weight. tific Tables,Geigy Pharmaceuticals,Ardsl See, NY, 537 (1970). In certain embodiments, the composition The methods herein may be administered orally or by injection. To achieve the effect, an effective amount of the compound or compound composition is contemplated to be administered. Typically, the pharmaceutical compositions of the present disclosure are 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 a patient will depend on the activity of the particular compound used, Age, weight, general health condition, sex, diet, administration time, excretion rate, drug combination, disease the severity and course of the disease, condition, or symptom, the patient's predisposition to the disease, and the extent of treatment The risk of death depends on a variety of factors, including the judgment of the treating physician.

[0294] Dosage forms include approximately 0.01 mg to approximately 10 mg (approximately 0.1 mg to approximately 5 mg, approximately 0.2 mg to approximately 4mg, about 0.3mg to about 3mg, about 0.4mg to about 2mg, about 0.5mg to about 1.5m g, or about 0.6 mg to about 1 mg) of the compound atrasentan or a pharmaceutical In some embodiments, the dosage form contains about 0.1 mg, about 0.2mg, about 0.3mg, about 0.4mg, about 0.5mg, about 0.6mg, about 0.65, Approximately 0.7 mg, approximately 0.75, approximately 0.8 mg, approximately 0.85, approximately 0.9 mg, approximately 1 mg, approximately 1 .1mg, about 1.2mg, about 1.3mg, about 1.4mg, about 1.5mg, about 1.6mg, About 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 mg, or any value therebetween , atrasentan, or a pharmaceutically acceptable salt thereof. The dosage form contains about 0.75 mg of the compound atrasentan or a pharmaceutically acceptable salt thereof. include.

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

[0296] Suitable dosage levels may be determined by any suitable method. Preferably, the active The substance is administered topically one to four times daily or via a drug delivery system. If used, it may be administered less frequently. Nevertheless, the pharmaceutical compositions of the present disclosure The actual dosage levels and time course of administration of the active ingredients in the composition may be so high that they are intolerable to the patient. achieve the desired therapeutic response for a particular patient, composition, and method of administration without significant toxicity In some cases, the dosage may be varied to obtain an amount of active ingredient effective for the treatment of a range of conditions. The dosage may vary depending on factors such as the age, sex, weight, diet, and general health of the patient, the route of administration, and the active ingredient. Depending on the individual response to the drug, the nature of the formulation, and the time or interval at which administration is performed, Therefore, in some cases, less than the minimum amount specified above may be used. In some cases, it may be sufficient to exceed the specified limit, while in other cases it may exceed the specified limit. When administered, it may be advisable to divide these into several individual doses over the course of a day. .

[0297] Exemplary Dosage Forms of Atrasentan In some embodiments, (a) about 0.25 mg to about 1.25 mg of atracentrifuge or an equivalent amount of atrasentan or its pharmaceutically acceptable salt (in the dosage form) The weight percent of the commercially acceptable salt is about 0.05 on an atrasentan free base equivalent basis. 1.0 to about 2.0 weight percent), and (b) a pharmaceutically acceptable diluent. and a stable solid pharmaceutical dosage form comprising:

[0298] In some embodiments, (a) about 0.25 mg to about 1.25 mg of atracentrifuge or an equivalent amount of atrasentan or its pharmaceutically acceptable salt (in the dosage form) The weight percent of the commercially acceptable salt is about 0.05 on an atrasentan free base equivalent basis. (b) a pharmaceutically acceptable antioxidant, The molar ratio of the antioxidant to atrasentan or a pharmaceutically acceptable salt thereof is about 10: (c) a pharmaceutically acceptable diluent; and (d) a stable solid pharmaceutical composition comprising: Pharmaceutical dosage forms are provided herein.

[0299] In some of these embodiments, the degradation of atrasentan in the dosage form occurs when the dosage form is about 4 Other antioxidant-deficient products have a shelf life of 6 months when stored at 0°C and approximately 75% relative humidity. In terms of degradation, this is less than that of atrasentan in the same dosage form.

[0300] In some embodiments, the dosage form is provided in a semi-permeable or substantially impermeable container during storage. In some embodiments, the dosage form is stored in a sealed container during the storage period. In some embodiments, the container is stored in an HDPE bottle or blister package. The dosage form is stored in a sealed HDPE bottle throughout its shelf life. In this method, the dosage form is stored in a blister package for the duration of the storage period.

[0301] (i) Atrasentan The dosage form may comprise atrasentan free base, a pharmaceutically acceptable salt of atrasentan, or In some embodiments, the dosage form may comprise atlantoic acid, thiazolinone ... In some embodiments, the dosage form comprises the free base of atrasentan. In some embodiments, the dosage form comprises atrasentan hydrochloride and a physiologically acceptable salt thereof. In some embodiments, the dosage form comprises amorphous atrasentan hydrochloride, atrasentan salt. Sentan hydrochloride crystalline form 1, atrasentan hydrochloride crystalline form 2, and atrasentan salts and atrasentan hydrochloride having a polymorphic form selected from the group consisting of 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 certain embodiments, the dosage form comprises atrasentan mandelate. crystalline atrasentan mandelate (e.g., crystalline atrasentan (S)-mandelate and and / or crystalline atrasentan (R)-mandelate). In this case, the dosage form is amorphous atrasentan mandelate (e.g., amorphous atrasentan (S )-mandelate and / or amorphous atrasentan (R)-mandelate). In some of the foregoing embodiments (where the dosage form is crystalline and / or amorphous atraquadrant), (including (S)- and / or (R)-mandelate salts), atrasentan and mandelate In certain other embodiments, the molar ratio of atrasentan to the malonate is 1:1. The molar ratio of the benzoate to the benzoate is 2:1.

[0302] In certain embodiments, the dosage form comprises amorphous atrasentan hydrochloride, is substantially free (e.g., free of other forms of the compound (e.g., other salts and / or other polymorphs) , <10%, <5%, <1%, <0.5%, <0.1%, <0.05% contained). In an embodiment, the dosage form comprises atrasentan hydrochloride crystalline Form 1, is substantially free (e.g., other salts and / or other polymorphs) of (Contains <10%, <5%, <1%, <0.5%, <0.1%, <0.05%). In an embodiment, the dosage form comprises atrasentan hydrochloride crystalline Form 2, Substantially free of other forms (e.g., other salts and / or other polymorphs). In one embodiment, the dosage form contains atrasentan hydrochloride crystalline Form 3 and other atrasentan substantially free (e.g., <10 %, <5%, <1%, <0.5%, <0.1%, <0.05%). In one embodiment, the dosage form comprises crystalline atrasentan (S)-mandelate, is substantially free (e.g., free of other forms of the compound (e.g., other salts and / or other polymorphs) , <10%, <5%, <1%, <0.5%, <0.1%, <0.05% contained). In one embodiment, the dosage form comprises crystalline atrasentan (R)-mandelate salt, Substantially free of other forms of Lasentan (e.g., other salts and / or other polymorphs) (e.g., <10%, <5%, <1%, <0.5%, <0.1%, <0.05% In certain embodiments, the dosage form comprises amorphous atrasentan (S)-mandelate. and other forms of atrasentan (e.g., other salts and / or other polymorphs) are not substantially Does not contain (e.g., <10%, <5%, <1%, <0.5%, <0.1%, <0.05% In certain embodiments, the dosage form contains amorphous atrasentan (R)-mandelate. and other forms of atrasentan (e.g., other salts and / or other polymorphs), including atrasentan acid salts. Substantially free (e.g., <10%, <5%, <1%, <0.5%, <0.1%, <0 (Contains 0.05%)

[0303] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof in a dosage form. The weight percent of the salt is about 0.1 weight percent to about 0.1 weight percent on an atrasentan free base equivalent basis. In some embodiments, the atrasentan in the dosage form is about 2.0 weight percent. or a pharmaceutically acceptable salt thereof is based on atrasentan free base equivalents. In some embodiments, the amount is about 0.2 weight percent to about 1.0 weight percent. In this case, the weight percentage of atrasentan or a pharmaceutically acceptable salt thereof in the dosage form is About 0.3 weight percent to about 0.8 weight percent of Trasentan free base equivalents In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof in a dosage form. The weight percent of the salt to be used is about 0.40 weight percent on an atrasentan free base equivalent basis. In some embodiments, the amount of acetaminophen in the dosage form is between about 0.45 weight percent. The weight percentage of atrasentan or a pharmaceutically acceptable salt thereof is On an equivalent basis, it is about 0.60 weight percent to about 0.65 weight percent.

[0304] In some embodiments, the dosage form contains from about 0.40 mg to about 1.00 mg of atrazene. In some embodiments, the agent comprises an amount of acetaminophen, or an equivalent amount of a pharmaceutically acceptable salt thereof. The dosage form contains about 0.40 mg to about 0.85 mg of atrasentan, or an equivalent amount thereof. In some embodiments, the dosage form contains about 0.50 mg of athracene. In some embodiments, the agent comprises an amount of acetaminophen, or an equivalent amount of a pharmaceutically acceptable salt thereof. The formulation contains about 0.75 mg of atrasentan, or an equivalent amount of a pharmaceutically acceptable salt thereof. .

[0305] (ii) Diluent Suitable diluents for use in the disclosed dosage forms include lactose (lactose monohydrate, Lactose Anhydrous, and PHARMATOSE® DCL21, etc.), sucrose cellulose, glucose, mannitol, sorbitol, isomalt, microcrystalline cellulose (A VICEL® PH101 and AVICEL® PH102, etc. Silicified microcrystalline cellulose (PROSOLV® SMCC50 and SMCC 90), dibasic calcium phosphate, starch, and combinations thereof. In some embodiments, the diluent may be lactose, mannitol, or the like. tallow, isomalt, microcrystalline cellulose, dibasic calcium phosphate, and combinations thereof In some embodiments, the diluent is selected from the group consisting of lactose, lactic acid bacteria, lactic acid bacteria, and combinations thereof. is.

[0306] In some embodiments, the weight percent of the diluent in the dosage form is about 70 weight percent. In some embodiments, the weight percent of the diluent in the dosage form is between about 100 and about 99 weight percent. The weight percent is from about 80 weight percent to about 99 weight percent. In some embodiments, the weight percent of the diluent in the dosage form is from about 85 weight percent to about 99 weight percent. In some of the foregoing embodiments, the diluent is lactose, mannitol, or the like. Non-limiting examples of the preferred glycerols include glycerol, ... By way of example, the diluent may be lactose.

[0307] (iii) Binder In some embodiments, the dosage form contains a pharmaceutically acceptable binder (e.g., a polymer Suitable binders for use in the disclosed dosage forms include hydroxypropyl methylcellulose, ... Hydroxymethylcellulose (e.g., Hypromellose E5 (Premium LV)), Hydroxymethylcellulose celluloses such as hydroxypropyl ethyl cellulose and hydroxypropyl cellulose; as well as other pharmaceutically acceptable substances with coagulation properties. In some embodiments, the binder is hydroxymethylpropyl cellulose, The group consisting of hydroxyethylpropyl cellulose and hydroxypropyl cellulose In some embodiments, the binder is selected from hydroxypropylmethylceramide. In some embodiments, the binder is hydroxypropyl cellulose. In some embodiments, the binder is hydroxyethylpropyl cellulose. It is.

[0308] In some embodiments, the dosage form further comprises a pharmaceutically acceptable binder, The weight percent of the binder in the composition is about 1.0 weight percent to about 10.0 weight percent. In some embodiments, the weight percent of binder in the dosage form is about 1.0 wt. In some embodiments, the crystalline form of the present invention is from about 8.0 weight percent to about 8.0 weight percent. The weight percent of the combination is about 1.0 weight percent to about 5.0 weight percent. In some of the embodiments described above, the binder is hydroxymethylpropylcellulose, ... from the group consisting of hydroxyethylpropylcellulose, and hydroxypropylcellulose The polymer binder is selected from the group consisting of:

[0309] In some embodiments, the dosage form further comprises a pharmaceutically acceptable binder. The weight-to-weight ratio of the agent to atrasentan or a pharmaceutically acceptable salt thereof is In some embodiments, the ratio is from about 2:1 to about 25:1 on an amino acid free base equivalent basis. The weight-to-weight ratio of the combination to atrasentan or a pharmaceutically acceptable salt thereof is In some embodiments, the ratio is from about 1:1 to about 20:1 on a methyl free base equivalent basis. The weight to weight ratio of binder to atrasentan or a pharmaceutically acceptable salt thereof is In certain embodiments, the ratio is from about 1:1 to about 15:1 on a methyl ether free base equivalent basis. The combination drug is hydroxymethylpropyl cellulose, hydroxyethylpropyl cellulose, and a polymeric binder selected from the group consisting of hydroxypropyl cellulose.

[0310] (iv) disintegrant In some embodiments, the dosage form optionally comprises a pharmaceutically acceptable disintegrant. Suitable disintegrants for use in the disclosed dosage forms include cross-linked polyvinylpyrrolidone (PO LYPLASDONE(TM) XL, etc.), corn starch, potato starch, Sorghum starch and modified starches (including sodium starch glycolate), Natural alginate, microcrystalline cellulose, croscarmellose sodium, and combinations thereof In some embodiments, the disintegrant is a combination of, but not limited to, , crospovidone, sodium starch glycolate, and sodium croscarmellose In some embodiments, the disintegrant is selected from the group consisting of cross-linked polyvinyl chloride. In some embodiments, the disintegrant is crospovidone.

[0311] In some embodiments, the dosage form further comprises a pharmaceutically acceptable disintegrant. In embodiments, the weight percent of disintegrant in the dosage form is from about 1.0 weight percent to about In some embodiments, the weight percent of the disintegrant in the dosage form is 10.0 weight percent. The content of the cellulose acetate is about 1.0 weight percent to about 6.0 weight percent. In this embodiment, 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. is.

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

[0313] (v) Additional excipients In a further embodiment, the dosage form optionally comprises a pharmaceutically acceptable lubricant and and / or glidants. Lubricants and glidants suitable for use in the disclosed dosage forms. The agents include silicon dioxide (SYLOID® 244FP and AEROSIL® (Registered Trademark) 200, etc.), glyceryl behenate (COMPRITOL (registered trademark), etc.), Talc, stearic acid, solid polyethylene glycol, silica gel and mixtures thereof and other substances that have lubricating or gliding properties. In certain embodiments, the lubricant is glyceryl behenate (COMPRITOL®). In certain embodiments, the glidant is silicon dioxide (SYLOI). In certain embodiments, the lubricant is behenic acid. The glidant is glyceryl and the glidant is silicon dioxide.

[0314] In some embodiments, the dosage form further comprises a pharmaceutically acceptable glidant. In another embodiment, the weight percent of the glidant in the dosage form is from about 0.1 weight percent to about 1 In some embodiments, the weight percent of the glidant in the dosage form is 0.5 weight percent. The concentration 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 from about 0.1 weight percent to about 0 In some embodiments, the glidant is silicon dioxide. is.

[0315] In some embodiments, the dosage form further comprises a pharmaceutically acceptable lubricant. In some embodiments, the dosage form further comprises a pharmaceutically acceptable hydrophobic lubricant. In some embodiments, the weight percent of the lubricant in the dosage form is about 0.05 weight percent. In some embodiments, the weight percent of the lubricant in the dosage form is between about 5 and about 5.0 weight percent. The amount percent is about 0.2 weight percent to about 3.0 weight percent. In embodiments, the weight percent of the lubricant in the dosage form is from about 0.5 weight percent to about 2 In certain embodiments, the lubricant is glyceryl behenate. be.

[0316] In some embodiments, the dosage form further comprises a disintegrant, a glidant, and a lubricant. nothing.

[0317] (vi) antioxidants Antioxidants suitable for use in the disclosed dosage forms include those that function as reducing agents and that are pharmaceutically acceptable in the dosage form. In some embodiments, antioxidants are oxidized to environmentally acceptable reduction products. Therefore, antioxidants have a lower redox potential than atrasentan (i.e., less than about 900 mV). Some have redox potentials of less than 500 mV, and others have redox potentials of greater than about 550 mV. In some embodiments, the antioxidant has a redox potential of less than about 550 mV. In this embodiment, the antioxidant has a redox potential of about 1 mV to about 550 mV. In some embodiments, the solubility of the antioxidant in water at about 25° C. is about 24 mg / mL. In some embodiments, the antioxidant is an amino acid or a pharmaceutical In some embodiments, the antioxidant is a hydroxybenzoate or a hydroxybenzoate. In some embodiments, the antioxidant is L-cysteine, or In some embodiments, the antioxidant is a pharmaceutically acceptable salt or ester of The agents are L-cysteine ​​hydrochloride monohydrate, L-cysteine ​​hydrochloride anhydrous, and L-cysteine In some embodiments, the dosage form is selected from the group consisting of: Contains L-cysteine ​​hydrochloride monohydrate.

[0318] In some embodiments, the weight percent of antioxidant in the dosage form is about 0.05 wt. In some embodiments, the amount of the anti-inflammatory agent in the dosage form is from about 1.0 weight percent to about 1.0 weight percent. The weight percent of the oxidizer is about 0.07 weight percent to about 0.7 weight percent. In some embodiments, the weight percent of antioxidant in the dosage form is about 0.09 wt. percent to about 0.5 percent by weight.

[0319] In some embodiments, the antioxidant and atrasentan or a pharmaceutically acceptable salt thereof are combined. In some embodiments, the molar ratio of the agent to the salt is about 10:1 to about 1:10. The molar ratio of the antioxidant to the atrasentan or a pharmaceutically acceptable salt thereof in the formulation is about 5 In some embodiments, the ratio of the antioxidant and the atrasentan or The molar ratio of the compound to its pharmaceutically acceptable salt is about 2:1 to about 1:2. In the form, the molar ratio of the antioxidant to atrasentan or a pharmaceutically acceptable salt thereof is approximately 1:1.

[0320] In some embodiments, the antioxidant is L-cysteine ​​or a pharmaceutically acceptable salt thereof. In certain embodiments, the L-cysteine ​​or a pharmaceutically acceptable salt thereof in the dosage form is The weight percent of the salt or ester to be tolerated is from about 0.05 weight percent to about 1.0 In certain embodiments, the L-cysteine ​​or its derivatives in the dosage form is in a weight percent. The weight percent of the biologically acceptable salt or ester is about 0.07 weight percent to In certain embodiments, the L-cysteine ​​or The weight percent of the pharmaceutically acceptable salt or ester thereof is about 0.09 weight percent. 100 to about 0.5 weight percent.

[0321] In certain embodiments, the dosage form also contains L-cysteine ​​or a pharmaceutically acceptable salt thereof. or ester to atrasentan or a pharmaceutically acceptable salt thereof is about 1: In certain embodiments, the L-cysteine ​​or its derivatives in the dosage form is 0:1 to about 1:10. and atrasentan or a pharmaceutically acceptable salt or ester thereof. In certain embodiments, the molar ratio of the L-cysteine ​​salt to the L-cysteine ​​salt is about 5:1 to about 1:5. cin or a pharmaceutically acceptable salt or ester thereof and atrasentan or a The molar ratio of the physiologically acceptable salt is from about 2:1 to about 1:2. , L-cysteine ​​or a pharmaceutically acceptable salt or ester thereof, and atrasentan or a pharmaceutically acceptable salt thereof, the molar ratio is about 1:1.

[0322] In certain embodiments, the antioxidant is L-cysteine ​​hydrochloride monohydrate, L-cysteine and L-cysteine ​​ethyl ester. In some embodiments, the dosage form includes L-cysteine ​​hydrochloride monohydrate.

[0323] (vii) Additional Embodiments In some embodiments, the dosage form comprises atrasentan or a pharmaceutically acceptable salt thereof. In some of these embodiments, the antioxidant comprises an L-cis- In some embodiments, the compound is tetrahydrofuran, or a pharmaceutically acceptable salt or ester thereof. In the present invention, an antioxidant (e.g., L-cysteine, or a pharmaceutically acceptable salt thereof) The molar ratio of the ester to the hydroxyl group is from about 5:1 to about 1:5. The dosage form is hydroxymethylpropyl cellulose, hydroxyethylpropyl cellulose hydroxypropyl cellulose, and a pharmaceutically acceptable The composition may further comprise a polymer binder and an antioxidant (e.g., L-cysteine, or its pharmaceutically acceptable salts). and a pharmaceutically acceptable salt or ester thereof) and atrasentan or a pharmaceutically acceptable salt thereof. The molar ratio of the binder to atrasentan or its pharmaceutically acceptable salts is about 5:1 to about 1:5. The weight-to-weight ratio of acceptable salts is about 1:1 to about 2:1 based on atrasentan free base equivalents. In some embodiments, the dosage form further comprises a disintegrant. and an antioxidant (e.g., L-cysteine, or a pharmaceutically acceptable salt or ester thereof). In some embodiments, the weight to weight ratio of the hydroxybenzoate to the hydroxybenzoate is about 60:1 to about 3:1. The weight percentage of atrasentan or a pharmaceutically acceptable salt thereof in this dosage form is About 0.2 weight percent to about 1.0 weight percent on a trasetan free base equivalent basis In some embodiments, the dosage form contains about 0.40 mg to about 0.85 mg of Trasentan, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0324] In some embodiments, the dosage form comprises hydroxymethylpropylcellulose, hydroxamic acid, hydroxyethylpropylcellulose, and hydroxypropylcellulose. and a pharmaceutically acceptable polymer binder selected from the group consisting of an antioxidant (e.g., L-cysteine). or a pharmaceutically acceptable salt or ester thereof) and atrasentan or a The molar ratio of the binder to the biologically acceptable salt is about 2:1 to about 1:2, and the binder and the attracenta The weight to weight ratio of atrasentan or its pharmaceutically acceptable salt is based on atrasentan free base equivalent basis. In some embodiments, the dosage form further comprises a disintegrant. Also included are a disintegrant and an antioxidant (e.g., L-cysteine, or a pharmaceutically acceptable salt thereof). The weight-to-weight ratio of the hydroxybenzoate (salt or ester thereof) is about 50:1 to about 4:1. In an embodiment, the weight of atrasentan or a pharmaceutically acceptable salt thereof in the dosage form The percentage is from 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 Contains 0.85 mg of atrasentan, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0325] In some embodiments, the dosage form comprises hydroxymethylpropylcellulose, hydroxamic acid, hydroxyethylpropylcellulose, and hydroxypropylcellulose. and a pharmaceutically acceptable polymer binder selected from the group consisting of an antioxidant (e.g., L-cysteine). or a pharmaceutically acceptable salt or ester thereof) and atrasentan or a The molar ratio of the binder to the atrasentan or a physiologically acceptable salt thereof is about 1:1. and a pharmaceutically acceptable salt thereof in a weight-to-weight ratio of about 1 on an atrasentan free base equivalent basis. :1 to about 15:1. In some embodiments, the dosage form further comprises a disintegrant. Also included are disintegrants and antioxidants (e.g., L-cysteine, or a pharmaceutically acceptable salt thereof). The weight to weight ratio of the hydroxybenzoate (or ester) is from about 35:1 to about 5:1. In this embodiment, the weight percentage of atrasentan or a pharmaceutically acceptable salt thereof in this dosage form is The component 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 0.8 mg. 5 mg of atrasentan, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0326] In some embodiments, the dosage form comprises hydroxymethylpropylcellulose, hydroxamic acid, hydroxyethylpropylcellulose, and hydroxypropylcellulose. and the dosage form comprises about 0.05 weight percent of a pharmaceutically acceptable polymer binder selected from the group consisting of: about 1.0 weight percent of an antioxidant (e.g., L-cysteine, or a pharmaceutically acceptable salt thereof); and the dosage form contains from about 1.0 weight percent to about 10.0 weight percent of the hydroxybenzoates (an acceptable salt or ester thereof), In some embodiments, the dosage form further comprises a disintegrant. 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 atrasentan or its derivatives in the dosage form are The weight percent of the pharmaceutically acceptable salt of is about 0.05 wt. In some embodiments, the amount is between about 0.1 weight percent and about 2.0 weight percent. The dosage form contains about 0.40 mg to about 0.85 mg of atrasentan, or an equivalent amount of its pharmaceutical Including salts that are acceptable for.

[0327] In some embodiments, the dosage form comprises hydroxymethylpropylcellulose, hydroxamic acid, hydroxyethylpropylcellulose, and hydroxypropylcellulose. and the dosage form comprises about 0.07 weight percent of a pharmaceutically acceptable polymer binder selected from the group consisting of: about 0.70 weight percent of an antioxidant (e.g., L-cysteine, or its pharmaceutical equivalents) and an acceptable salt or ester thereof), and the dosage form comprises from about 1.0 weight percent to about 1.0 weight percent of the binder. In some embodiments, the dosage form further comprises a disintegrant. The weight percentage of the disintegrant in the dosage form is about 1.0 weight percent to about 6.0 weight percent. In some embodiments, the atrasentan or its derivatives in this dosage form The weight percent of the pharmaceutically acceptable salt is about 0.05 g on an atrasentan free base equivalent basis. 2 weight percent to about 1.0 weight percent. In some embodiments, The dosage form contains about 0.40 mg to about 0.85 mg of atrasentan, or an equivalent amount thereof. Including acceptable salts.

[0328] In some embodiments, the dosage form comprises hydroxymethylpropylcellulose, hydroxamic acid, hydroxyethylpropylcellulose, and hydroxypropylcellulose. and the dosage form comprises about 0.09 weight percent of a pharmaceutically acceptable polymer binder selected from the group consisting of: about 0.80 weight percent of an antioxidant (e.g., L-cysteine, or its pharmaceutical equivalents) and an acceptable salt or ester thereof), and the dosage form comprises from about 1.0 weight percent to about 1.0 weight percent of the binder. In some embodiments, the dosage form further comprises a disintegrant. The weight percentage of the disintegrant in the dosage form is about 1.0 weight percent to about 4.0 weight percent. In some embodiments, the atrasentan or its derivatives in this dosage form The weight percent of the pharmaceutically acceptable salt is about 0.05 g on an atrasentan free base equivalent basis. 3 weight percent to about 0.8 weight percent. The dosage form contains about 0.40 mg to about 0.85 mg of atrasentan, or an equivalent amount thereof. Including acceptable salts.

[0329] In some embodiments, the dosage form comprises: (a) about 0.1 weight percent to about 2.0 weight percent on an atrasentan free base equivalent basis - atrasentan or a pharmaceutically acceptable salt thereof; (b) about 0.05 weight percent to about 1.0 weight percent of an antioxidant (e.g., L-cysteine) steine, or a pharmaceutically acceptable salt or ester thereof), (c) 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 pharmaceutically acceptable binder , (e) optionally, about 1.0 weight percent to about 10.0 weight percent of a pharmaceutically acceptable salt thereof Acceptable disintegrants, (f) optionally, from about 0 weight percent to about 1.5 weight percent of a pharmaceutically acceptable glidants, and (g) optionally, from about 0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable a lubricant containing The cumulative weight percentages of all components of the 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 on an atrasentan free base equivalent basis - atrasentan or a pharmaceutically acceptable salt thereof; (b) about 0.05 weight percent to about 1.0 weight percent of an antioxidant (e.g., L-cysteine) or a pharmaceutically acceptable salt or ester thereof), (c) 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 pharmaceutically acceptable binder , (e) about 1.0 weight percent to about 10.0 weight percent of a pharmaceutically acceptable disintegrant , (f) optionally, from about 0 weight percent to about 1.5 weight percent of a pharmaceutically acceptable glidants, and (g) optionally, from about 0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable a lubricant containing The cumulative weight percentages of all components of the 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 on an atrasentan free base equivalent basis - atrasentan or a pharmaceutically acceptable salt thereof; (b) about 0.07 weight percent to about 0.7 weight percent of an antioxidant (e.g., L-cysteine) or a pharmaceutically acceptable salt or ester thereof), (c) about 82 weight percent to about 99 weight percent diluent; (d) about 1.0 weight percent to about 8.0 weight percent of a pharmaceutically acceptable binder; (e) optionally, about 1.0 weight percent to about 6.0 weight percent of a pharmaceutically acceptable Disintegrants used, (f) optionally, from about 0 weight percent to about 1.0 weight percent of a pharmaceutically acceptable glidants, and (g) optionally, from about 0 weight percent to about 3.0 weight percent of a pharmaceutically acceptable a lubricant containing The cumulative weight percentages of all components of the 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 on an atrasentan free base equivalent basis - atrasentan or a pharmaceutically acceptable salt thereof; (b) about 0.07 weight percent to about 0.70 weight percent L-cysteine, or a pharmaceutically acceptable salt or ester thereof; (c) about 82 weight percent to about 99 weight percent diluent; (d) about 1.0 weight percent to about 8.0 weight percent of a pharmaceutically acceptable binder; (e) about 1.0 weight percent to about 6.0 weight percent of a pharmaceutically acceptable disintegrant; (f) optionally, from about 0 weight percent to about 1.0 weight percent of a pharmaceutically acceptable glidants, and (g) optionally, from about 0 weight percent to about 3.0 weight percent of a pharmaceutically acceptable a lubricant containing The cumulative weight percentages of all components of the 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 on an atrasentan free base equivalent basis - atrasentan or a pharmaceutically acceptable salt thereof; (b) about 0.09 weight percent to about 0.50 weight percent L-cysteine, or a pharmaceutically acceptable salt or ester thereof; (c) about 87 weight percent to about 99 weight percent of a pharmaceutically acceptable diluent; (d) about 1.0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable binder; (e) optionally, about 1.0 weight percent to about 4.0 weight percent of a pharmaceutically acceptable salt thereof Disintegrants used, (f) optionally, from about 0 weight percent to about 0.75 weight percent of a pharmaceutically acceptable glidants, and (g) optionally, about 0 weight percent to about 2.0 weight percent of a pharmaceutically acceptable a lubricant containing The cumulative weight percentages of all components of the 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 on an atrasentan free base equivalent basis - atrasentan or a pharmaceutically acceptable salt thereof; (b) about 0.09 weight percent to about 0.50 weight percent L-cysteine, or a pharmaceutically acceptable salt or ester thereof; (c) about 87 weight percent to about 99 weight percent of a pharmaceutically acceptable diluent; (d) about 1.0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable binder; (e) about 1.0 weight percent to about 4.0 weight percent of a pharmaceutically acceptable disintegrant; (f) optionally, from about 0 weight percent to about 0.75 weight percent of a pharmaceutically acceptable glidants, and (g) optionally, about 0 weight percent to about 2.0 weight percent of a pharmaceutically acceptable a lubricant containing The cumulative weight percentages of all components of the 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 on an atrasentan free base equivalent basis - atrasentan or a pharmaceutically acceptable salt thereof; (b) about 75 weight percent to about 99 weight percent diluent; (c) about 1.0 weight percent to about 10.0 weight percent of a pharmaceutically acceptable binder , (d) optionally, about 1.0 weight percent to about 10.0 weight percent of a pharmaceutically acceptable salt thereof Acceptable disintegrants, (e) optionally, from about 0 weight percent to about 1.5 weight percent of a pharmaceutically acceptable glidants, and (f) optionally, from about 0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable a lubricant containing The cumulative weight percentages of all components of the 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 on an atrasentan free base equivalent basis - atrasentan or a pharmaceutically acceptable salt thereof; (b) about 75 weight percent to about 99 weight percent diluent; (c) about 1.0 weight percent to about 10.0 weight percent of a pharmaceutically acceptable binder , (d) about 1.0 weight percent to about 10.0 weight percent of a pharmaceutically acceptable disintegrant , (e) optionally, from about 0 weight percent to about 1.5 weight percent of a pharmaceutically acceptable glidants, and (f) optionally, from about 0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable a lubricant containing The cumulative weight percentages of all components of the 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 on an atrasentan free base equivalent basis - atrasentan or a pharmaceutically acceptable salt thereof; (b) about 82 weight percent to about 99 weight percent diluent; (c) about 1.0 weight percent to about 8.0 weight percent of a pharmaceutically acceptable binder; (d) optionally, about 1.0 weight percent to about 6.0 weight percent of a pharmaceutically acceptable Disintegrants used, (e) optionally, about 0 weight percent to about 1.0 weight percent of a pharmaceutically acceptable glidants, and (f) optionally, from about 0 weight percent to about 3.0 weight percent of a pharmaceutically acceptable a lubricant containing The cumulative weight percentages of all components of the 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 on an atrasentan free base equivalent basis - atrasentan or a pharmaceutically acceptable salt thereof; (b) about 82 weight percent to about 99 weight percent diluent; (c) about 1.0 weight percent to about 8.0 weight percent of a pharmaceutically acceptable binder; (d) about 1.0 weight percent to about 6.0 weight percent of a pharmaceutically acceptable disintegrant; (e) optionally, about 0 weight percent to about 1.0 weight percent of a pharmaceutically acceptable glidants, and (f) optionally, from about 0 weight percent to about 3.0 weight percent of a pharmaceutically acceptable a lubricant containing The cumulative weight percentages of all components of the 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 on an atrasentan free base equivalent basis - atrasentan or a pharmaceutically acceptable salt thereof; (b) about 87 weight percent to about 99 weight percent of a pharmaceutically acceptable diluent; (c) about 1.0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable binder; (d) optionally, about 1.0 weight percent to about 4.0 weight percent of a pharmaceutically acceptable Disintegrants used, (e) optionally, from about 0 weight percent to about 0.75 weight percent of a pharmaceutically acceptable glidants, and (f) optionally, from about 0 weight percent to about 2.0 weight percent of a pharmaceutically acceptable a lubricant containing The cumulative weight percentages of all components of the 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 on an atrasentan free base equivalent basis - atrasentan or a pharmaceutically acceptable salt thereof; (b) about 87 weight percent to about 99 weight percent of a pharmaceutically acceptable diluent; (c) about 1.0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable binder; (d) about 1.0 weight percent to about 4.0 weight percent of a pharmaceutically acceptable disintegrant; (e) optionally, from about 0 weight percent to about 0.75 weight percent of a pharmaceutically acceptable glidants, and (f) optionally, from about 0 weight percent to about 2.0 weight percent of a pharmaceutically acceptable a lubricant containing The cumulative weight percentages of all components of the dosage form equal 100 percent.

[0341] In some embodiments, the dosage form comprises: (a) the diluent is lactose; (b) the dosage form comprises a pharmaceutically acceptable binder, the binder being hydroxypropylmethyl It is cellulose, (c) the dosage form comprises a pharmaceutically acceptable disintegrant, wherein the disintegrant is crospovidone; (d) the dosage form comprises a pharmaceutically acceptable glidant, the glidant being silicon dioxide. Ru, (e) the dosage form comprises a pharmaceutically acceptable lubricant, wherein the lubricant is glyceryl behenate. , satisfy one or more of the conditions.

[0342] In some embodiments, the dosage form contains about 0.25 ml of atrasentan parent equivalents. g to about 1.25 mg of atrasentan or a pharmaceutically acceptable salt thereof (e.g., atrasentan In some embodiments, the pharmaceutical composition is a solid pharmaceutical dosage form comprising benzodiazepine hydrochloride. The composition contains approximately 0.40 mg to approximately 1.00 mg of atrasentan on an atrasentan parent equivalent basis. or a pharmaceutically acceptable salt thereof (e.g., atrasentan hydrochloride). In some embodiments, the pharmaceutical composition comprises about 0.40 ml of atrasentan parent equivalents. g to about 0.85 mg of atrasentan or a pharmaceutically acceptable salt thereof (e.g., atrasentan In some embodiments, the pharmaceutical composition comprises atrasentan hydrochloride. Approximately 0.50 mg of atrasentan or a pharmaceutically acceptable salt thereof (on a parent equivalent basis) In some embodiments, the pharmaceutical composition comprises atrasentan hydrochloride. , on an atrasentan parent equivalent basis, about 0.75 mg of atrasentan or its pharmaceutically acceptable salts In some of the foregoing embodiments, the compound may be a hydroxybenzoate or a hydroxybenzoate, and may be an acceptable salt thereof (e.g., atrasentan hydrochloride). The dosage form is a tablet.

[0343] In some embodiments, the dosage form is a tablet. In some embodiments, the agent has a weight of about 37.5 mg to about 1500 mg. The tablet has a weight of about 50 mg to about 750 mg. In some embodiments, the tablet 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 100 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 10% to about 230 mg. In certain embodiments, the tablet has a moisture content of about 4% to 6% (e.g., about 4 It has a moisture content of 100% to 5%.

[0344] Generally, tablets are optionally surrounded or coated with at least one non-rate-controlling layer. The non-rate-controlling layer may be a single layer, coating, or film, or It can be formed as multiple single layers, coatings, or films. These functions include, for example, providing additional stability of atrasentan and aiding in the processing of the formulation. to function as a cosmetic agent and / or cosmetic enhancer and / or to be associated with a formulation To reduce any undesirable odors (such as those commonly associated with L-cysteine) It may also act as a masking agent for the above.

[0345] If the dosage form includes a non-rate-controlling layer, the non-rate-controlling layer may comprise one or more polymers and a soluble polymer. These additives include, but are not limited to, plasticizers, pigments / emulsifiers, waxes, etc. Examples of polymers that can be used include hydrogels, Hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, poly These include, but are not limited to, vinyl alcohol, and polyethylene glycol. Examples of plasticizers that can be used include polyethylene glycol, glycerin, trimethylsilyl alcohol, and the like. Contains acetin, 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. dyes (e.g., sunset yellow, quinoline yellow, erythrosine, and tart radish) pigments (e.g., aluminum lake, titanium oxide, iron oxide, and talc), and natural products (e.g., riboflavin, carotenoids, chlorophyll, anthocyanins, Waxes that can be used include, but are not limited to, waxes such as cinnamon and carmine. Examples of waxes include, but are not limited to, paraffin wax.

[0346] In some embodiments, the dosage form is coated with a pharmaceutically acceptable polymer. It is a tablet.

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

[0348] In some embodiments, the dosage form is packaged in a semi-permeable container. In the above, 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. The dosage form is an immediate release tablet, and the dissolution rate is measured using a USP dissolution apparatus 2 (Paddle apparatus), 0.01 In vitro dissolution tests were performed using N hydrochloric acid dissolution medium and paddle rotation at 50 RPM. Within about 45 minutes, at least about 85% of the atrasentan or In some embodiments, the dosage form is an immediate release tablet. and within about 30 minutes, at least about 75% of atrasentan or its pharmaceutically acceptable salts is removed. Releases the salts that are tolerated.

[0351] In some embodiments, the dosage form has a shelf life of 6 months at about 40° C. and about 75% relative humidity. After the storage period, a 1.0% or greater decrease in the solubility of atrasentan or its pharmaceutically acceptable salts occurs. In some embodiments, atrasentan or The decomposition of the compound or its pharmaceutically acceptable salts was analyzed using high performance liquid chromatography. can be.

[0352] In some embodiments, the dosage form has a shelf life of 6 months at about 40° C. and about 75% relative humidity. After the storage period, approximately 0.6% of the total mass of atrasentan or its pharmaceutically acceptable salt is lost due to decomposition of the atrasentan or its pharmaceutically acceptable salt. In some embodiments, the atlas contains less than one percent by weight of any single impurity. The resolution of pentane or its pharmaceutically acceptable salts can be determined using high performance liquid chromatography. and analyzed.

[0353] In some embodiments, the dosage form has a shelf life of 6 months at about 40° C. and about 75% relative humidity. After the storage period, a 1.0% or greater decrease in the solubility of atrasentan or its pharmaceutically acceptable salts occurs. less than about 0.6 weight percent of any single impurity In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof The degradation 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 pharmaceutically acceptable salt thereof and methods of making same are provided herein. Further described in U.S. Patent Nos. 9,364,458 and 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 pharmaceutically acceptable salt thereof is approximately 0.001 mg to 0.1 mg per kg of subject's body weight (e.g., 1 kg of subject's body weight) Approximately 0.001, approximately 0.002, approximately 0.003, approximately 0.004, approximately 0.005, approximately 0 0.006, approx. 0.007, approx. 0.008, approx. 0.009, approx. 0.01, approx. 0.015, approx. 0.02, approx. 0.025, approx. 0.03, approx. 0.035, approx. 0.04, approx. 0.045, approx. 0 .05, approximately 0.055, approximately 0.06, approximately 0.065, approximately 0.07, approximately 0.075, approximately 0. 0.08, about 0.085, about 0.09, about 0.095, or about 0.10 mg / kg, or or any value therebetween) or an equivalent amount of atrasentan or a pharmaceutically acceptable salt thereof. do.

[0358] In some embodiments, the dose of atrasentan or a pharmaceutically acceptable salt thereof is about 0.1 mg to 10 mg (e.g., about 0.1, about 0.2, about 0.3, about 0.4, about 0 0.5, approx. 0.6, approx. 0.7, approx. 0.75, approx. 0.8, approx. 0.9, approx. 1.0, approx. 1.1, approx. 1.2, approx. 1.3, approx. 1.4, approx. 1.5, approx. 1.6, approx. 1.7, approx. 1.8, approx. 1.9, approx. 2.0, approx. 2.5, approx. 3.0, approx. 3.5, approx. 4.0, approx. 4.5, approx. 5.0, approx. 5.5, approx. 6.0, approx. 6.5, approx. 7.0, approx. 7.5, approx. 8.0, approx. 8.5, approx. 9.0, approx. 9.5, or or about 10.0 mg, or any value therebetween) of atrasentan or an equivalent amount thereof In certain embodiments, atrasentan or its pharmaceutical equivalents are pharmaceutically acceptable salts. A commercially acceptable dose of the salt is about 0.75 mg (e.g., when given once daily). In certain embodiments, the compound is selected from the group consisting of lasentan and an equivalent amount of a pharmaceutically acceptable salt thereof. The dose of trasentan or a pharmaceutically acceptable salt thereof is about 0.25 mg (e.g., 1 mg / day) when administered once) of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, the dose of atrasentan or a pharmaceutically acceptable salt thereof is about 0.35 mg (e.g., when given once daily) of atrasentan or an equivalent amount of that drug In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof An acceptable dose of the salt is about 1.0 mg (e.g., when given once daily) of atlas. In certain embodiments, the compound is acetaminophen or an equivalent amount of a pharmaceutically acceptable salt thereof. The dose of Sentan or a pharmaceutically acceptable salt thereof is about 1.25 mg (e.g., once daily) When administered, the amount of atrasentan is 20 mg or an equivalent amount of a pharmaceutically acceptable salt thereof. In one embodiment, the dose of atrasentan or a pharmaceutically acceptable salt thereof is about 1. 5 mg (e.g., when administered once daily) of atrasentan or its pharmaceutical equivalent In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is The dose of the salt to be administered is about 1.75 mg (e.g., when administered once daily) of atracentra. or an equivalent amount of a pharmaceutically acceptable salt thereof. The dose of atrasentan or a pharmaceutically acceptable salt thereof is 0.75 mg (e.g., 1 x 0.75 mg tablets; or 1.5 x 0.50 mg tablets) of atrasentan or amount of a pharmaceutically acceptable salt thereof, administered once daily.

[0359] In some embodiments, the dose of atrasentan, or a salt ...

Claims

1. 1. A composition for treating primary IgA nephropathy, comprising a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof, the composition is administered to a human subject; The composition, wherein the subject does not have a chronic kidney disease other than IgA nephropathy and / or has not been previously diagnosed with a chronic kidney disease other than IgA nephropathy.

2. 2. The composition of claim 1, wherein the subject does not have and / or has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure.

3. The composition of claim 1 or 2, wherein the human subject has primary IgA nephropathy.

4. 4. The composition of claim 3 for treating IgA nephropathy, wherein the diagnosis of IgA nephropathy is established by kidney biopsy.

5. The composition of any one of claims 1 to 4, wherein the human subject is at high risk of progressing to end-stage renal disease.

6. 6. The composition of any one of claims 1 to 5, wherein the human subject excretes at least 1.0 g / day, or at least 1.5 g / day of urinary protein prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

7. 7. The composition of claim 6, wherein the human subject excretes at least 1.0 g / day, or at least 1.5 g / day of urinary protein for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

8. 7. The composition of claim 6, wherein the human subject excretes at least 1.0 g / day, or at least 1.5 g / day of urinary protein on at least two of three consecutive measurements for one year prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

9. The human subject has an airway pressure of at least 30 mL / min / 1.73 m prior to administration of atrasentan or a pharmaceutically acceptable salt thereof. ２ 9. The composition of claim 1, having an estimated glomerular filtration rate (eGFR) of

10. 10. The composition of any one of claims 1 to 9 for use in delaying the onset of end-stage renal disease in a human subject with primary IgA nephropathy.

11. The composition of any one of claims 1 to 10 for use in reducing proteinuria in a human subject with primary IgA nephropathy.

12. 12. The composition of claim 11, wherein proteinuria is reduced to less than 1.0 grams / day, or less than 0.5 grams / day, or less than 0.3 grams / day after treatment with atrasentan or a pharmaceutically acceptable salt thereof.

13. The composition of any one of claims 1 to 12 for use in stabilizing eGFR in a human subject with primary IgA nephropathy.

14. The composition of any one of claims 1 to 13, for use in reducing the rate of decline in eGFR in a human subject with primary IgA nephropathy.

15. 15. The composition of claim 14, wherein the rate of decrease in eGFR is attenuated by at least 20%, or at least 30%, or at least 40% after treatment with atrasentan or a pharmaceutically acceptable salt thereof.

16. 16. The composition of any one of claims 1 to 15 for use in reducing the incidence of hematuria in a human subject with primary IgA nephropathy.

17. A composition according to any one of claims 1 to 16, wherein atrasentan is administered in a dose of 0.20 mg to 1.5 mg, or an equivalent amount of a pharmaceutically acceptable salt thereof.

18. 18. The composition of claim 17, wherein atrasentan is administered in a dose of 0.40 mg to 0.85 mg, or an equivalent amount of a pharmaceutically acceptable salt thereof.

19. The composition of claim 17, wherein atrasentan is administered at a dose of 0.20 mg, or 0.30 mg, or 0.40 mg, or 0.60 mg, or an equivalent amount of a pharmaceutically acceptable salt thereof.

20. The composition of claim 17, wherein atrasentan is administered at a dose of 0.30 mg, or 0.40 mg, or 0.60 mg, or an equivalent amount of a pharmaceutically acceptable salt thereof.

21. 18. The composition of claim 17, wherein atrasentan is administered at a dose of 0.75 mg, or an equivalent amount of a pharmaceutically acceptable salt thereof.

22. 18. The composition of claim 17, wherein atrasentan is administered at a dose of 0.75 mg once daily, or an equivalent amount of a pharmaceutically acceptable salt thereof.

23. 23. The composition of any one of claims 1 to 18, 21 to 22, wherein the composition is orally administered once daily as a tablet containing 0.75 mg of atrasentan, or an equivalent amount of a pharmaceutically acceptable salt thereof.

24. The composition of any one of claims 1 to 23, wherein atrasentan is administered as atrasentan hydrochloride.

25. 25. The composition of any one of claims 1 to 24, wherein the human subject has been receiving a maximally tolerated stable dose of one or more renin-angiotensin system (RAS) inhibitors for at least 12 weeks prior to administration of atrasentan or a pharmaceutically acceptable salt thereof.

26. 26. The composition of any one of claims 1 to 25, wherein the human subject is concurrently administered a maximally tolerated stable dose of a RAS inhibitor and a therapeutically effective amount of atrasentan, or a pharmaceutically acceptable salt thereof.

27. 27. The composition of claim 25 or 26, wherein the RAS inhibitor is an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker (ARB).

28. 28. The composition of any one of claims 1 to 27, wherein the human subject has previously received an SGLT-2 inhibitor or is concurrently receiving an SGLT-2 inhibitor.

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