A method of treating IGA nephropathy with atrasentan

Abstract

This provides a method for treating IgA nephropathy. [Solution] A method is provided for treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof. Also provided herein is a method for reducing renal inflammation and / or fibrosis, reducing the occurrence of hematuria, stabilizing eGFR, reducing the number of disease flares associated with IgA nephropathy, delaying the onset of ESRD, reducing proteinuria, and reducing fatigue in a subject having IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject. In some embodiments, the subject has never been previously diagnosed with one or more of the following: diabetic nephropathy, HIV / AIDS, HIV-related nephropathy, prostate cancer, or acute renal failure.

Description

[Technical Field]

[0001] Cross-reference of related applications This application is U.S. Provisional Application No. 62 / 949,115, filed on December 17, 2019. U.S. Provisional Application No. 63 / 005,003, filed on April 3, 2020, August 2020 U.S. Provisional Application No. 63 / 072,699, filed on 31st of the month, was approved on September 29, 2020. U.S. Provisional Application No. 63 / 084,739 was filed, and the application filed on December 14, 2020. They claim priority to U.S. Provisional Application No. 63 / 125,205, which they refer to by reference. The whole thing is incorporated. [Background technology]

[0002] IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Abnormal glycosylation is recognized by glycan-specific IgA and IgG autoantibodies. This results in increased serum levels of galactose-deficient IgA1 (Gd-IgA1). The complex aggregates form in situ and / or deposit in the glomerular mesangium. This involves mesangial cell proliferation, extracellular matrix proteins, cytokines, and chemotherapy. It promotes increased synthesis of caynes and the infiltration of immune cells into surrounding tissues. Therefore, disease The progression of the disease involves (1) the production of Gd-IgA1 and (2) its recognition by anti-glycan autoantibodies. (3) formation of immune complexes 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 individuals in their 20s. Patients present with a variety of symptoms, typically micro or macro. This includes hematuria and increased excretion of protein in the urine. The patient also has persistent renal impairment as a result. This can present with hypertension. Current treatment approaches include angiotensin-converting enzyme inhibitors. or support including administration of the maximum tolerated dose of angiotensin receptor blockers or immunosuppressants. It only provides ongoing care, and the benefits far outweigh the side effects. Ultimately, the patient 30-40% of those diagnosed with IgAN develop end-stage renal disease (ESRD) within 20-30 years of their diagnosis. The disease develops. During this time, in addition to a decline in kidney function, many patients experience a significant decrease in their quality of life. Patients experience the following symptoms. IgAN patients often have endothelin 1 (ET-1) in their kidneys. ) and ET-RA show significantly increased expression. 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) [Overview of the Initiative] [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. , Wu-Wong et al., Clin.Sci.(Lond.), 103(48) See pp. 107s-111s (2002). Selective ETA receptor antagonist The drug blocks ETA function while minimizing its impact on ETB receptors, thus preventing vasodilation. It also has beneficial effects on the kidneys, such as reducing inflammation, and simultaneously increases ET-1 clearance. This makes it possible. For example, Jandeleith-Dahm and Watson, Cur r.Opin.Nephrol.Hypertens.,21(1),pp.66-71 See (2012), Nakamura, et al., Nephron, Vo See also l.72, pp.454-460 (1996). ETA receptor antagonist This increases sodium and water retention in the kidneys, but this is usually clinically manageable. It is possible. For example, Saleh, et al., J. Pharm. Exp. Ther., See 338(1), pp.263-270(2011). Atracentan is a sugar. In patients with urinary tract disease (DKD), doubling of serum creatinine or end-stage renal disease It has been shown to significantly reduce the risk of kidney events as defined by He erspink,et al.,The Lancet,393,pp1937-194 See 7(2019). DKD is called secondary glomerular disease and is a specific systemic disease. The underlying cause can lead to secondary kidney disease, and in the case of DKD, microvascular complications arise from long-term diabetes. It develops as a result of [unclear]. For example, Dattani and McAdoo, Medicine, See 47(10), pp.644-648(2019). The etiology of DKD is multifactorial. It is complicated. Diabetes causes glucose toxicity in renal cells, especially renal endothelial cells. Sexually elevated blood glucose levels, and hypertension associated with shear stress being transmitted to resident glomerular cells. Systemic and renal hemodynamic factors are major contributing factors to the development of DKD. For example, Thom as et al.,Nat.Rev.Disease Primers.1,pp.1 See 5018-15026 (2015). Hyperglycemia, dyslipidemia, and oxidative stress Metabolic components such as thresholds, as well as hemodynamic factors such as vasoactive substances associated with hypertension. All of the dysregulatory factors in a diabetic environment, including several others, stimulate renal ET-1 formation. In addition, since DKD usually requires long-term diabetes before the onset of DKD, This is primarily observed in the elderly population, and aging is also associated with increased ET-1 production in the kidneys. For example, Kohan, Kidney Int., 86(5), pp.896-904. See (2014). When combined, this is all ETA receptor blockers. Obtain solid scientific evidence for the treatment of DKD with tracentan. Dhaun, et al. See Hypertension, Vol. 57, pp. 772-779 (2011). thing.

[0005] In contrast to DKD, IgA nephropathy is a primary kidney disease characterized by the presence of focal or endogenous kidney lesions. It is thought to be a bulbar disease. The peak incidence of IgA nephropathy is in young individuals aged 20 or 30 years. It is seen in humans and, unlike DKD, is an autoimmune disease. IgA nephropathy is a glomerular mesanitis. This is due to the deposition of pathogenic IgA / immune complexes in Gyum. For example, Lai, et al. l.,Nature Reviews Disease Primers,2,pp.1 See 6001,2016. A definitive diagnosis is made by performing a kidney biopsy and immunofluorescence microscopy to identify mesan The deposition of gynecomastia (IgA) needs to be confirmed. This is important for understanding the causative events that cause IgA nephropathy. Recent advances in this field have shown that abnormal mucosal immune responses are caused by circulating anti-glycan autoantibodies. It has been revealed that this stimulates the production of galactose-deficient IgA1, which is recognized as an autoantigen. The immune recognition involved nephritis-induced immune complexes that deposited in the kidneys and activated mesangial cells. This leads to the formation of activating mesangial cells, which proliferate and produce excess extracellular matri It produces oxalic components, cytokines, and chemokines. For example, Suzuki, et al. al., J. Am. Soc. Nephrol., Vol. 22, pp. 1795-180 See 3 (2011). Up to 40% of patients with IgA nephropathy confirmed by biopsy have long-term During follow-up, the patient progresses to end-stage renal failure at some point. Mesangial cell activity The role of ET-1 or ETA receptors in transformation has not been reported to date, and Sentan has not been tested in IgA nephropathy. As further described herein... Atrasentan can be administered in an effective dose with acceptable toxicity, if desired. The goal is to treat the underlying IgAN while minimizing undesirable side effects and improving the patient's quality of life. It has appropriate selectivity to improve. Some embodiments are for subjects with IgA nephropathy. A method for inhibiting the activation of mesangial cells in a target, wherein the target is given a therapeutically effective amount of Atra The treatment involves administering sentan or a pharmaceutically acceptable salt thereof, and the subject is diabetic nephropathy. If you have ever been diagnosed with one or more of the following: HIV / AIDS, or acute renal failure No, we provide a method.

[0006] Some embodiments describe P in mesangial cells in subjects with IgA nephropathy. Inhibits DGF (e.g., PIK3R1, PDGFRA, NFKBIA, PIK3CG) Among PLA2G4A, TIAM1, PDGFB, NFKB1, and MAP3K1 A method for reducing one or more activities and / or expressions, wherein a therapeutically effective amount of The treatment involves administering tracentan or a pharmaceutically acceptable salt thereof, and the subjects are diabetic patients. If you have ever been diagnosed with one or more of the following: nephropathy, HIV / AIDS, or acute renal failure To provide a method that avoids mistakes.

[0007] Some embodiments are methods for treating IgA nephropathy, which are used in subjects who require it. , including administering a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof, The target group includes 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 before.

[0008] Some embodiments are methods for treating IgA nephropathy, which are used in subjects who require it. , including administering a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof, The target group consists of individuals with one or more of the following conditions: diabetic nephropathy, HIV / AIDS, or acute renal failure. If there isn't one, we'll provide a way.

[0009] Some embodiments are methods for treating IgA nephropathy, which are used in subjects who require it. , including administering a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof, The target group includes individuals suffering from one or more of the following conditions: diabetic nephropathy, HIV / AIDS, or acute renal failure. To provide a method that does not currently exist.

[0010] Some embodiments are methods for treating IgA nephropathy, which are used in subjects who require it. , including administering a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof, The target group is one of the following: diabetic nephropathy, HIV / AIDS, prostate cancer, or acute renal failure. This provides a method for diagnosing the above and other conditions that have not been diagnosed before.

[0011] Some embodiments are methods for treating IgA nephropathy, which are used in subjects who require it. , including administering a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof, The target group includes those with one or more of the following conditions: diabetic nephropathy, HIV-related nephropathy, prostate cancer, or acute renal failure. This provides a method for diagnosis that has never been made before.

[0012] Some embodiments are methods for treating IgA nephropathy, which are used in subjects who require it. , including administering a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof, The target group includes those with one or more of the following conditions: diabetic nephropathy, HIV-related nephropathy, or acute renal failure. It provides a method for those who have never been diagnosed with it.

[0013] Some embodiments are methods for treating IgA nephropathy, which are used in subjects who require it. , including administering a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof, The target group is those receiving treatment for one or more of the following conditions: diabetic nephropathy, HIV-related nephropathy, or acute renal failure. To provide a method that has not been implemented.

[0014] Some embodiments are methods for treating IgA nephropathy, which are used in subjects who require it. , including administering a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof, The subjects were determined to have controlled serum glucose levels, and the subjects were HIV-related. This method provides information for individuals who have never been diagnosed with one or more of the following: septal kidney disease or acute renal failure.

[0015] Some embodiments describe renal inflammation and / or lines in subjects with IgA nephropathy. A method to reduce fibrosis, which involves administering a therapeutically effective dose of atrasentan to a subject who needs it. The present invention provides a method comprising administering a pharmaceutically acceptable salt thereof.

[0016] Some embodiments describe methods for reducing the incidence of hematuria in subjects with IgA nephropathy. Therefore, to those who need it, a therapeutically effective amount of atrasentan or its pharmaceutically acceptable dose. The present invention provides a method comprising administering a tolerable salt.

[0017] Some embodiments describe methods for stabilizing eGFR in subjects with IgA nephropathy. Therefore, to those who need it, a therapeutically effective amount of atrasentan or its pharmaceutically acceptable dose. The present invention provides a method comprising administering a tolerable salt.

[0018] Some embodiments describe the IgA nephropathy-related disease flare in subjects with IgA nephropathy. A method to reduce the number of people, and to provide a therapeutically effective amount of atrasentan to those who need it. The present invention provides a method comprising administering a pharmaceutically acceptable salt thereof.

[0019] Some embodiments delay the onset of ESRD in subjects with IgA nephropathy. A method for providing a therapeutically effective amount of atrasentan or its pharmaceutical ingredients to a subject that requires it. The present invention provides a method comprising administering a salt that is acceptable to the substance.

[0020] Some embodiments describe a method for reducing proteinuria in subjects with IgA nephropathy. Therefore, to those who need it, a therapeutically effective amount of atrasentan or its pharmaceutically acceptable dose. The present invention provides a method comprising administering a tolerable salt.

[0021] Some embodiments are methods for reducing fatigue in subjects with IgA nephropathy, For those who require it, a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof. This includes administering a drug, and the target population is those with diabetic nephropathy, HIV-related nephropathy, prostate cancer, or acute cancer. This method provides a way to determine that a person does not have one or more of the conditions of renal failure.

[0022] Some embodiments are methods for inhibiting the activation of sangium cells, and mesangium The cells are brought into contact with an effective amount of atrasentan or a pharmaceutically acceptable salt thereof. Includes, provides methods.

[0023] Some embodiments describe the activation of mesangial cells in contact with IgA immune complexes. A method of reducing mesangial cells by an effective amount of atrasentan or its pharmaceutically effective The present invention provides a method that includes contacting the salt with an acceptable salt.

[0024] Some embodiments treat IgA nephropathy in subjects requiring treatment for IgA nephropathy. A method comprising: a) determining that the subject has elevated serum Gd-IgA1 levels. b) administer a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof to the subject. To provide a method that includes giving in.

[0025] Some embodiments treat IgA nephropathy in subjects requiring treatment for IgA nephropathy. A method comprising: a) determining that the subject has an elevated level of mesangial activation. b) administer a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof to the subject. To provide a method that includes giving in.

[0026] Some embodiments treat IgA nephropathy in subjects requiring treatment for IgA nephropathy. A method wherein a) the subject has elevated levels of IgA immune complexes in the kidney. a) to determine that the subject has received a therapeutically effective dose of atrasentan or a pharmaceutically acceptable dose. The present invention provides a method comprising administering a salt. [Brief explanation of the drawing]

[0027] [Figure 1A] Treatment with atrasentan reduces the proliferation of primary human mesangial cells exposed to immune complexes derived from IgAN-containing subjects. [Figure 1B] This shows the content of galactose-deficient (Gd)-IgA and total IgA after purifying immune complexes from IgAN or healthy control serum. [Figure 2A] The image shows a decrease in the proliferation of endothelin 1 (ET-1)-stimulated primary human mesangium cells (after 48 hours) when treated with increasing concentrations of atrasentan, as shown on a logarithmic scale, and exhibits an IC50 of approximately 5.1 nM. [Figure 2B] The image shows a decrease in the proliferation of endothelin 1 (ET-1)-stimulated primary human mesangium cells (after 72 hours) when treated with increasing concentrations of atrasentan, as shown on a logarithmic scale, and exhibits an IC50 of approximately 50.8 nM. [Figure 3A] The study shows increased IL-6 production (approximately a 6-fold increase) in primary human mesangium cells exposed to ET-1 for 48 hours, and decreased IL-6 levels when treated with increasing concentrations of atrasentan (shown on a logarithmic scale), exhibiting an IC50 of approximately 1 nM. [Figure 3B]The study shows increased IL-6 production (approximately a 2.2-fold increase) in primary human mesangium cells exposed to ET-1 for 72 hours, and decreased IL-6 levels when treated with increasing concentrations of atrasentan (shown on a logarithmic scale), exhibiting an IC50 of approximately 1 nM. [Figure 4] UACR levels in g-ddY mice are shown at baseline, before atrasentan administration, and after treatment with atrasentan in drinking water at 0 (control), 10, 20, or 30 mg / kg / day for approximately 5 days. (*P<0.05, compared to baseline level, paired with t-test). [Figure 5] This shows the change in UACR levels (percentage of baseline) in g-ddY mice after administration of atrasentan in drinking water at 0 (control), 10, 20, or 30 mg / kg / day for approximately 5 days. (*P<0.05, compared to the control group (0 mg / kg / day), unpaired t-test). [Figure 6] This shows the top 100 differentially expressed genes in kidney tissue of g-ddY mice after treatment with 0 (control), 10, 20, or 30 mg / kg / day of atrasentan. The heatmap shows row-type z-shifted counts per million (CPM) values ​​for each of the top 100 differentially expressed genes. [Figure 7A] This graph shows differential gene expression in kidney tissue after treatment with 0 mg / kg / day of atrasentan in g-ddY mice (control) and 10 mg / kg / day. Black dots indicate genes that are not significantly differentially expressed. Gray dots with a change greater than 0 logarithmically indicate upregulated genes. Gray dots with a change less than 0 logarithmically indicate downregulated genes. [Figure 7B] This graph shows differential gene expression in kidney tissue after treatment with 0 mg / kg / day of atrasentan in g-ddY mice (control) and 20 mg / kg / day. Black dots indicate genes that are not significantly differentially expressed. Gray dots with a change greater than 0 logarithmically indicate upregulated genes. Gray dots with a change less than 0 logarithmically indicate downregulated genes. [Figure 7C]This graph shows differential gene expression in kidney tissue after treatment with 0 mg / kg / day of atrasentan in g-ddY mice (control) and 30 mg / kg / day. Black dots indicate genes that are not significantly differentially expressed. Gray dots with a change greater than 0 logarithmically indicate upregulated genes. Gray dots with a change less than 0 logarithmically indicate downregulated genes. [Figure 8A] This shows differentially expressed genes in the kidney tissue of g-ddY mice after treatment with 0 (control) and 10 mg / kg / day of atrasentan, along with the ET1 gene signature and a subset of related genes. [Figure 8B] This shows differentially expressed genes in the kidney tissue of g-ddY mice after treatment with 0 (control) and 20 mg / kg / day of atrasentan, along with the ET1 gene signature and a subset of related genes. [Figure 8C] This shows differentially expressed genes in the kidney tissue of g-ddY mice after treatment with 0 (control) and 30 mg / kg / day of atrasentan, along with the ET1 gene signature and a subset of related genes. [Figure 9A] This shows the significantly enriched (FDR < 0.05) characteristic gene sets after treatment with 10 mg / kg / day of atrasentan in g-ddY mice, compared to treatment with 0 mg / kg / day (control) of atrasentan. A negative normalized enrichment score (NES) indicates under-expression, and a positive NES indicates overexpression. [Figure 9B] This shows the significantly enriched (FDR < 0.05) characteristic gene sets after treatment with 20 mg / kg / day of atrasentan in g-ddY mice, compared to treatment with 0 mg / kg / day (control) of atrasentan. A negative normalized enrichment score (NES) indicates under-expression, and a positive NES indicates overexpression. [Figure 9C]This shows the significantly enriched (FDR < 0.05) characteristic gene sets after treatment with 30 mg / kg / day of atrasentan in g-ddY mice, compared to treatment with 0 mg / kg / day (control) of atrasentan. A negative normalized enrichment score (NES) indicates under-expression, and a positive NES indicates overexpression. [Figure 10] The study shows significant enrichment (FDR < 0.05) of characteristic gene set pathways after treatment of ET-1-stimulated HRMCs with 1 nM and 25 nM atrasentan, and after treatment of g-ddY mice with 10, 20, or 30 mg / kg / day atrasentan compared to 0 mg (control) of atrasentan, compared to untreated HRMCs (control). [Figure 11A] This shows the overlap of gene signatures between the published human mesangium 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 mesangium), differentially expressed genes after treatment of g-ddY mice with 30 mg / kg / day of atrasentan (labeled as g-ddY), and differentially expressed genes after treatment of HRMCs with 25 nM atrasentan in the presence of ET1 (labeled as HRMC). [Figure 11B] After treatment of g-ddY mice with 30 mg / kg / day of atrasentan, the expression levels of 44 genes that overlapped between the single-cell signature of the human mesangium and differentially expressed genes (logarithmic z-transformed values, 2 counts per million) were observed. [Figure 12A] This table shows comparisons between potential biomarkers based on human and mouse populations, where 'x' indicates translationability and whether the potential biomarker is present in plasma / serum and / or urine. In particular, each of the relevant markers is found in both human and mouse populations (e.g., g-ddY mice). [Figure 12B] The log-2 (CPM) values ​​of each potential biomarker are shown for g-ddY mice after treatment with 0 (control), 10, 20, or 30 mg / kg / day of atrasentan. [Modes for carrying out the invention]

[0028] Table 1: Comparison of 10 mg / kg / day atrasentan compared to 0 mg / kg / day (control) Top 40 DEGs (25 superior) in the treatment of g-ddY mice with atrasentan (The 15 is controlled downwards).

[0029] Table 2: Comparison of 20 mg / kg / day atrasentan compared to 0 mg / kg / day (control) Top 50 DEGs (25 superior) in the treatment of g-ddY mice with atrasentan (The 25 and 25 are controlled downwards).

[0030] Table 3: Comparison of 30 mg / kg / day atrasentan compared to 0 mg / kg / day (control) Top 50 DEGs (25 superior) in the treatment of g-ddY mice with atrasentan (The 25 and 25 are controlled downwards).

[0031] Table 4 Comparison of 10, 20, or 3 mg / kg / day of atrasentan with 0 mg / kg / day (control) Concentrated signaling after treatment of g-ddY mice with 0 mg / kg / day of atrasentan. Transmission pathway. The Z-score indicates the magnitude of the effect observed at each dosage.

[0032] Table 5: 10, 20, or 3 mg / kg / day of atrasentan compared to 0 mg / kg / day (control). Characteristic gene sequences after treatment of g-ddY mice with 0 mg / kg / day of atrasentan Gene set enrichment analysis shows the enrichment of a gene set. NES shows the expression of DEG within the gene set. This is a normalized enrichment score that takes into account the size of the gene set. <-1.5 or An NES of >1.5 is considered biologically significant. The adj p-value is given for a given concentration. The calculated NES for the selected gene set is the estimated probability that the result is a false positive.

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

[0034] Table 7 Molecular data of transmembrane receptors, G protein-coupled receptors, and protein complexes A list of upstream regulators classified by IP. P-values ​​for overlaps are derived from the dataset and IPKB. The significance of enrichment is shown based on the number of overlapping genes with the genetic target. <-2 The p-values ​​for activation z-score thresholds >2 and overlap thresholds <0.05 are considered significant. It was done.

[0035] Table 8 Upstream classification by transcription regulator and ligand-dependent nuclear receptor molecular type List of regulatory factors. The p-values ​​for overlaps indicate overlap between the dataset and the IPKB gene targets. Significant enrichment based on the number of duplicate genes. Activation z-score threshold <-2 or >2. The p-values ​​for the values ​​and the overlapping threshold of <0.05 were considered significant.

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

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

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

[0039] Table 12 Compared to atrasentan at 0 mg / kg / day (control), 10, 20, or Cell proliferation signals after treatment with 30 mg / kg / day of atrasentan in g-ddY mice The inheritance of components of the signaling pathway (mitotic spindle and G2M cell cycle checkpoint) Child expression.

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

[0041] Table 14 Comparison of 10, 20, or atrasentan at 0 mg / kg / day (control) Mesangial cells in g-ddY mice after treatment with 30 mg / kg / day of atrasentan. Gene expression of 44 genes associated with the spore signature. [Modes for carrying out the invention]

[0042] A.Definition To make this disclosure easier to understand, certain terms are defined first. When used in this application, unless otherwise expressly provided herein, the following Each term shall have the meaning set forth below. Additional definitions shall be provided throughout the application. It will be explained in its entirety.

[0043] Unless otherwise defined, all technical and scientific terms used herein are defined in this document. The disclosure has the same meaning as it would be generally understood by those skilled in the art. For example, Conc 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. This provides to those skilled in the art. For the purposes of this disclosure, the following terms are defined:

[0044] Units, prefixes, and symbols are from the Systeme International de It is shown in a format recognized by Unites (SI). The numerical range defines the range. Numerical values ​​are included. The headings provided herein are referenced throughout this specification. This does not limit the various forms of this disclosure that may be possessed. Therefore, the use defined immediately below The term is more fully defined by referring to the entire specification.

[0045] As used herein, the terms "a," "an," or "the" refer to one. This includes not only embodiments having a member, but also embodiments having two or more members. When used in writing, the singular forms "a," "an," and "the" are clearly distinguishable by context. Unless otherwise specified, it includes multiple referents. Therefore, for example, a reference to "cell" is The reference to "drugs" includes multiple such cells and refers to one or more drugs known to those skilled in the art. This includes mentions of such things.

[0046] As used herein, the term "or" is generally interpreted non-exclusively. It should. For example, a claim against "a composition containing A or B" is typically A and The present invention will describe a composition having both B and B. However, "or" is , cannot be combined without contradiction (for example, compositions with a pH of 9-10 or 7-8) ) This should be interpreted to exclude the presented aspects.

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

[0048] As used herein, the term "and / or" means whether or not the other is present. It should be interpreted as a specific disclosure of each of two specific features or components. Therefore, when used in phrases such as "A and / or B" in this specification, it means "and / or The term "and / or" is used in the context of "A and B", "A or B", "A" (only), and It is intended to include only "B". Similarly, "A, B, and / or C", etc. When used in the phrase, the term "and / or" is used in the following forms: 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) each include. That is the intention.

[0049] As used herein, the terms “about” and “approximately” generally refer to the nature of measurement. This refers to the acceptable degree of error in a measured quantity, taking into account quality or precision. Typical example The degree of symbolic error is within 20 percent (%) of a given value or range of values, or within 10 percent. , within 5%. References to "approximately X" are at least the values ​​X, 0.95X, 0.96X, 0 .97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X , and specifically show 1.05X. Therefore, "approximately X" is, for example, "0.98X". This is intended to provide supplementary written explanations regarding limitations on the scope of the patent claims. The terms "about" and "approximately" encompass the given quantity itself, especially with respect to a given quantity. explain.

[0050] When "approximately" is applied to the beginning of a numerical range, it is applied to both ends of the range. Therefore, "approximately" "5-20%" is equivalent to "approximately 5% to approximately 20%". The "approximately" is applied to the first value in the set of values. If applicable, it will be applied to all values ​​in that set. Therefore, "approximately 0.5, 0.75, "or 1.0 mg" is equivalent to "approximately 0.5, approximately 0.75, or approximately 1.0 mg."

[0051] As used herein, the term "about" refers to a series of peak positions in X-ray powder diffraction. For example, if it precedes the 2θ value, all peaks in the preceding group will have a variation of ±0.1°. This means that it is reported with respect to the angular position it has. Therefore, for example, about 8.3°, 9.7°, 10.0°, 13.0°, 15.6°, 17.2°, or 19.5° The phrases are 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° It means...

[0052] The "treatment" or "therapy" in question refers to symptoms, complications, conditions, or biochemical conditions associated with the disease. Reversing, alleviating, improving, inhibiting, or slowing the onset, progression, development, severity, or relapse of the symptoms. Any type of intervention or process carried out on a subject with the aim of doing so, This refers to the administration of an activator to the target.

[0053] "Administering" or "administering" refers to any of the various methods and delivery systems known to those skilled in the art. This refers to the physical introduction of a therapeutic agent into a target using a device. Routes of administration include oral and intravenous. Internal, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral administration routes, such as injection or injection This may include administration (e.g., intravenous infusion). Administration may also be, for example, once, multiple times, and / or Alternatively, it can be carried out over a period of time longer than one.

[0054] The terms "preventive" or "preventive" refer to the development of a disease or side effects. To prevent or inhibit the development of a condition, or at least prevent it from developing completely (e.g.) For example, with the aim of reducing the symptoms or severity of a disease or condition, This refers to any type of intervention or process carried out by, or the administration of an activator to a subject. .

[0055] The term "subject" includes any human or non-human animal. This includes non-human primates, sheep, dogs, and animals such as mice, rats, and guinea pigs. This includes, but is not limited to, vertebrates such as rodents. The subject is human. The terms "subject," "patient," and "individual" are used in this specification. It is used interchangeably in writing.

[0056] The “effective dose,” “therapeutic effective dose,” or “therapeutic effective dosage” of a drug or therapeutic agent is, When used alone or in combination with other medications, it may delay the onset of the disease or cause it to worsen. A decrease in the severity of the patient's symptoms, an increase in the frequency and duration of asymptomatic periods, or a decrease in the severity of the disease. Anything that promotes disease regression as demonstrated by improvement of functional impairment or disability due to pain This refers to the amount of the drug. The ability of a therapeutic agent to promote disease regression is, for example, in human trials. In elephants, in animal model systems that predict effectiveness in humans, or in vitro By evaluating the activity of drugs in assays, various methods known to experienced practitioners can be used. It can be used and evaluated.

[0057] The phrase "pharmaceutically acceptable" means that a substance or composition is not chemically and / or toxic. Scientifically, the formulation must be compatible with other components and / or the mammals being treated with them. It indicates that something must be done.

[0058] As used herein, "polymorph" refers to distinct solids that share the same molecular formula, Each polymorph may possess distinct physical properties in a different solid state. A single compound can exist in various polymorphic forms. Each form may have a different solubility profile, melting point temperature, fluidity, dissolution rate, and / Alternatively, they may have different physical properties of distinct solid states, such as different X-ray diffraction peaks. Actual physical characteristics are the three-dimensional structure of molecules within a unit cell that defines a particular polymorphic form of a substance. It is affected by orientation. The polymorphism of a compound can be determined in the laboratory by X-ray powder diffraction ("XRP"). Distinguishing by X-ray diffraction spectroscopy (D) and other methods such as infrared spectroscopy. This is possible. Additionally, polymorphic forms of the same active pharmaceutical ingredient or drug component can be administered on their own. It can be dissolved or formulated as a pharmaceutical (pharmaceutical composition), for example, the active pharmaceutical ingredient Degree, stability, fluidity, ease of handling, and compressibility, as well as the safety and efficacy of pharmaceuticals. It is well known in the pharmaceutical field that this can affect efficacy. For more details, 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 that is not crystalline. It means a solid. Amorphous solids generally have short-range molecular arrangements like crystals, but crystalline solids It does not possess the long-range ordered molecular packing seen in the human body. The form of the solid state of a solid is observed under polarized light. Microscopy, X-ray powder diffraction ("XRPD"), differential scanning calorimetry ("DSC"), or the same as above. This can be determined by other standard techniques known to the individual.

[0060] As used herein, the term "crystalline" refers to a regular pattern of molecules or external surfaces. This refers to a solid state having a repeating arrangement. The form of the solid state of a solid is observed under a polarized light microscope. Microscopy, X-ray powder diffraction ("XRPD"), differential scanning calorimetry ("DSC"), or those skilled in the art. This can be determined by other known standard techniques. Therefore, the method used herein The term "crystalline purity" refers to amorphous atracentane or its pharmaceutically acceptable purity. Specific results of atracentan or pharmaceutically acceptable salts thereof in a sample that may contain salts Crystalline polymorphs, atracentane or pharmaceutically acceptable salts thereof, or mixtures thereof This refers to the percentage of one or more additional crystalline polymorphs. Atracentane or In the context where the pharmaceutically acceptable crystalline polymorphism of the salt is described as having "substantial crystalline purity" In other words, it means that the polymorph does not substantially contain other polymorphs (amorphous and / or crystalline). (For example, less than 10%, less than 5%, less than 2%, less than 1%, less than 0.5%, less than 0.1%) This means less than 0.05%.

[0061] As used herein, the term "chemical purity" refers to a specific compound in a sample (for example, This refers to the percentage of atracentan or its pharmaceutically acceptable salt. That is, atrasentan or a pharmaceutically acceptable salt thereof, and containing or containing it The composition prepared is 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)aminosaccharide) Contains, but is not limited to, rubonylmethyl)pyrrolidine-3-carboxylate. It may contain one or more impurities. A sample of atracentan or a pharmaceutically acceptable salt thereof When it is stated that a sample has "substantial purity," 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%, and (Contains less than 0.05%).

[0062] As used herein, the term “diastereomer excess” refers to the same compound present in a mixture. Compounds in a mixture that may have other diastereomers of the substance (e.g., atracentane or This refers to the amount of one diastereomer (of the pharmaceutically acceptable salts) specified herein. The term "substantial diastereomer purity" used in this context refers to approximately 90%, 95%, and 99%. This refers to a diastereomer excess rate exceeding %, 99.5%, 99.9%, or 100%. ru.

[0063] As used herein, the term “pharmaceutically acceptable carrier” means a cell, organism, Alternatively, it refers to a substance that assists in the administration of an activator to a target. "Pharmacologically acceptable carrier" means, It may be included in the compositions of this disclosure and does not cause any seriously harmful toxicological effects on the subject. This refers to a carrier or excipient. Non-limiting examples of pharmaceutically acceptable carriers include water, NaCl, Standard saline solution, Ringer's lactate solution, standard sucrose, standard glucose, binder, filler Disintegrants, lubricants, coatings, sweeteners, flavorings and colorings, liposomes, dispersion media Examples include microcapsules, cationic lipid carriers, isotonic agents, and absorption retarders. The carrier also provides stability, sterility, and isotonicity to the formulation (for example, antimicrobial properties). (Preservatives, antioxidants, chelating agents, and buffering agents), to prevent the action of microorganisms (for example) For example, antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, and sorbic acid. ), or a substance for providing food flavorings, etc., to a formulation. Several embodiments In this context, the carrier facilitates the delivery of small molecule drugs or antibodies to target cells or tissues. It is a pharmaceutical agent. Those skilled in the art will recognize that other pharmaceutical carriers are useful in this disclosure. .

[0064] As used herein, the term “expression” refers to a protein or in a mammalian cell. This 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 This refers to one or more protein activities, such as one or more of the activity of binding to a partner.

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

[0067] As used herein, the term "NF-κB signaling" refers to IKKα, IKKβ , IκB, and one or more NF-κB, and / or the activity of NF-κB One or more genes that regulate (e.g., TNF-α, IL-1, CAM, COX-2, etc.) This refers to the expression and / or activity of one or more of the iNOS.

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

[0069] As used herein, the term "SGLT-2 inhibitor" refers to sodium-glucose inhibitors. This refers to compounds that inhibit transporter-2 (SGLT-2). SGLT-2 inhibitors affect the kidneys. It inhibits glucose reabsorption and therefore exerts a glucose-lowering effect. SGLT-2 Inhibitors treat type 2 diabetes by enhancing diabetes independently of insulin, and cardiac 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. , not limited to compounds that inhibit only SGLT-2, therefore, SGLT-2 inhibition (e.g.) For example, it includes compounds that have other activities in addition to SGLT-1 inhibition.

[0070] In some embodiments, SGLT-2 inhibitors are drugs known as gliflozin. It includes compounds of the class of substances. In some embodiments, SGLT-2 inhibitors are FD Compounds approved as SGLT-2 inhibitors by regulatory authorities such as the A or EMA. This includes non-exclusive examples of SGLT-2 inhibitors such as bexagliflozin and canagliflozin. INVOKANA (registered trademark), dapagliflozin (FARXIGA (registered trademark)) ), empagliflozin (JARDIANCE®), erzgliflozin (S TEGLATRO (trademark), Ipragliflozin (SUGLAT (registered trademark)), Luce Ogliflozin (LUSEFI® registered trademark), remogliflozin, cergliflozin, Licogliflozin, sotagliflozin (ZYNQUISTA®), and tohogliflozin This includes, but is not limited to, Flozin.

[0071] In some embodiments, the SGLT-2 inhibitor is dapagliflozin, canagliflozin, etc. Flozin, Ipragliflozin, Empaglifodin, Bexagliflozin, Licogliflozin Zin, Janagliflozin (XZP-5695), Tofogliflozin, Erzgliflozin N, Henagliflozin (SHR-3824), Enabogliflozin (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), so Tagliflozin, Luseogliflozin, Cergliflozin etabonate (ethyl carbonate), Lemogliflozin, Lemogliflozin etavonate, and T-1095(((2R,3 S,4S,5R,6S)-6-(2-(3-(benzofuran-5-yl)propanoyl) (-3-hydroxy-5-methylphenoxy)-3,4,5-trihydroxytetrahydro This includes, but is not limited to, 2H-pyran-2-yl ethanolate.

[0072] In some embodiments, the SGLT-2 inhibitor is dapagliflozin, canaglyph Rosin, Ipragliflozin, Empaglifodin, Bexagliflozin, Licogliflozin Janagliflozin (XZP-5695), Tofogliflozin, Erzgliflozin , Henagliflozin (SHR-3824), Enabogliflozin (DWP-16001) It contains C-glycosides such as the following. In some embodiments, the SGLT-2 inhibitor is Fogliflozin, erzgliflozin, and henagliflozin (SHR-3824) The following embodiments include C-glycosides having a bicyclic or spiropyran group. In this context, SGLT-2 inhibitors include dapagliflozin, canagliflozin, and ipraglyph. Rosin, empagliflozin, besagliflozin, licoglyflozin, janagliflozin Zin (XZP-5695) and enabogliflozin (DWP-16001), It contains bicyclic or C-glycosides that do not have a spiropyran group.

[0073] In some embodiments, SGLT-2 inhibitors are TA-1887(3-(4-S Clopropylbenzyl)-4-fluoro-1-(β-D-glucopyranosyl)-1H- Indole) and indole-N-glycoside 18(3-(4-ethylbenzyl)-1- It contains N-glycosides such as (β-D-glucopyranosyl)-1H-indole.

[0074] In some embodiments, SGLT-2 inhibitors include 2-methyl Contains tilthio-C-glycoside.

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

[0076] In some embodiments, the SGLT-2 inhibitor is cergliflozin etabonate. (Ethyl carbonate), remogliflozin, remogliflozin ethanolate, 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 oxytetrahydro-2H-pyran-2-yl(ethanol)(ethanol) It contains O-glycoside prodrugs.

[0077] In some embodiments, the SGLT-2 inhibitors defined herein are SGLT This includes any compound that exhibits SGLT-2 inhibitory activity. In some embodiments, SGLT-2 inhibitory activity is expressed. For example, a harmful agent exhibits 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 possessing this property, it is more selective to SGLT-2 than to SGLT-1. (Example) When measured by the assay described herein, SGLT-2 inhibitors showed approximately 1000 nM of unintended SGLT-2 inhibitors. Full, less than approximately 500 nM, less than approximately 200 nM, less than approximately 100 nM, less than approximately 50 nM, approximately 25 Inhibitory activity (IC) against SGLT-2 at nM, less than approximately 10 nM, or less than approximately 1 nM 50 ) can be shown. In some embodiments, SGLT-2 inhibitors are specified herein. When measured using the assay provided, the levels were approximately less than 25 nM, less than 10 nM, and less than 5 nM. , or inhibitory activity against SGLT-2 of less than approximately 1 nM (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 It is described in 94). In short, CHO cells are human SGLT-2 (GenBan It is stably transfected with cDNA encoding kM95549. Cells are washed. Next, 10 μM [ 14 [C]α-methylglucopyranoside (AMG) and 10μ Incubate using an inhibitor of M. 14 C]AMG's incorporation of phloridine Quench with a cold buffer containing the cells to lyse them. Then, using a suitable reagent, 14 C Quantify the incorporation of AMG.

[0078] SGLT-2 inhibitors include pharmaceutically acceptable salts, solvates, complexes, and their It contains salts of solvates, for example, "dapagliflozin" contains salts of dapagliflozin (salts) This includes salts (such as acid salts) and solvates (such as propylene glycol hydrate), and similarly, "Canagliflozin" includes solvates (such as canagliflozin hemihydrate) and solvates It contains salts (such as hydrochloride of hydrates). Similarly, henagliflozin (SHR-3824) And dapagliflozin contains a complex (each containing henagliflozin proline and It contains dapagliflozin and proline, among others.

[0079] As used herein, the subject is described as having “controlled serum glucose levels”. If included, it means the subject has serum glucose levels within the normal or healthy range. This means that in some embodiments, the target is approximately 70 mg / dL to approximately 130 mg / dL. The subject has a fasting serum glucose level of g / dL. For example, the subject has a level of approximately 130 mg / dL. , 125mg / dL, 120mg / dL, 115mg / dL, 110mg / dL, 105 mg / dL, 100mg / dL, 95mg / dL, 90mg / dL, 85mg / dL, 8 The patient was determined to have a fasting serum glucose level of 0 mg / dL or less than 75 mg / dL. It is being done.

[0080] When used in the methods described herein, the term “reduce” refers to atracentan or the same parameters in subjects before the initiation of administration of the pharmaceutically acceptable salt. The reduction of the parameter shown compared to the baseline measurement (or multiple measurement), or the baseline of the same parameters in healthy subjects (e.g., subjects without IgA nephropathy) This refers to a reduction in the indicated parameter compared to a line measurement (or multiple measurements). The term "increase" as used herein refers to atrasentan or its pharmaceutically active ingredients. Baseline measurements of the same parameters in subjects taken before the initiation of administration of the acceptable salts An increase in the parameter shown compared to a constant value (or multiple measurements), or in a healthy subject ( For example, baseline measurements of the same parameter in subjects without IgA nephropathy ( This refers to an increase in the parameter shown compared to multiple measurements.

[0081] The term "glomerular filtration rate (GFR)" refers to the amount of blood drawn from the glomerular capillaries of the kidney per unit time. It is defined as the volume of fluid filtered into Bowman's capsule. It is related to overall kidney function. This indicates that the glomerular filtration rate (GFR) is a constant level of blood that is freely released by the kidneys. Calculated by measuring any chemical substance that is filtered and neither reabsorbed nor secreted. This is possible. Therefore, the ratio measured is the amount of substance in the urine derived from the calculated amount of blood. GFR is generally recorded in units of volume per hour, for example, milliliters / minute. Therefore, the following formula can be used: GFR = (urinary concentration × urine volume) / plasma concentration. GF R can be measured by injecting inulin into plasma. Inulin is a thread. Since it is neither reabsorbed nor secreted by the kidney after glomerular filtration, its excretion rate is determined by glomerular filtration. It is directly proportional to the filtration rate of water and solute passing through it. Normal values ​​are GFR = 90-125 m³. L / min / 1.73m 2 In particular, GFR = 100-125 mL / min / 1.73 m 2 G Other principles for measuring FR include 51Cr-EDTA, [125I]iotamart. This includes the measurement of iohexol. "Estimated glomerular filtration rate (eGFR)" is defined by Chroni c Kidney Disease Epidemiology Collaborat ion(CKD-EPI) formula, Cockcroft-Gault formula, or Modifi Based on the Diet in Renal Disease (MDRD) formula These are defined as being derived from screening based on serum creatinine levels, and these All of the above is publicly known in the art. The term "stabilizing eGFR" as used herein is used to mean stabilizing eGFR. " reduces the rate of decrease in eGFR and / or attenuates the rate of decrease in eGFR This means that. In some embodiments, the rate of decrease of the target eGFR is atrase After treatment with anthan or a pharmaceutically acceptable salt thereof, at least about 20%, at least Approximately 30%, at least approximately 40%, at least approximately 50%, at least approximately 60%, at least Approximately 70%, at least approximately 80%, at least approximately 90%, or at least approximately 95%, Or it can be attenuated to any value between them. This attenuation can be, for example, about 1 week, about 2 weeks, about 3 weeks, approximately 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, approximately 40 weeks, approximately 50 weeks, approximately 60 weeks, approximately 70 weeks, approximately 80 weeks Between approximately 90 weeks, 100 weeks, 110 weeks, 120 weeks, 130 weeks, and 140 weeks, the interval is approximately 90 weeks, 100 weeks, 110 weeks, 120 weeks, 130 weeks, and 140 weeks. Weeks, approximately 150 weeks, approximately 160 weeks, approximately 170 weeks, approximately 180 weeks, approximately 190 weeks, if This can be approximately 200 weeks, or any value of treatment during that period. Some implementations In this state, the subjects receive atrasentan or a pharmaceutically acceptable substance for approximately 15 to 30 days. They are being treated with salts. In some embodiments, the subjects are treated for about 6 months to about 1 year. The patient is being treated with atrasentan or a pharmaceutically acceptable salt thereof.

[0082] "ESRD" is an abbreviation for End-Stage Renal Disease. When used herein, the term ESRD is used in reference to the development of ESRD. The disease is characterized by a target of approximately 15 mL / min / 1.73 m². 2At any point in time when the eGFR is less than, and / or This is defined as the point at which the subject begins chronic dialysis. The subject is at risk of progressing to ESRD. If defined as "high," the subject is atrasentan or its pharmaceutically acceptable Prior to the first dose of salt, the patient had been excreting more than 1 g / day of protein in the urine for at least approximately 3 months. / or have an eGFR of less than 60.

[0083] As used herein, "IgA nephropathy-related disease flare" refers to hematuria, worsening proteinuria, and overall This refers to a disease flare associated with physical symptoms and a decrease in eGFR. Other symptoms associated with a disease flare Symptoms include increased edema, fatigue, increased hematuria, gross hematuria, and generally progression of the disease. This includes other symptoms that have adverse effects.

[0084] When used herein, the subject is defined as "maintaining potassium levels within a normal physiological range." When it is written as "ru", the target is blood potassium levels of approximately 3.5 mEq / L to approximately 5.2 mEq / L. It has a level.

[0085] When used herein, the subject is defined as "maintaining sodium levels within a normal physiological range." When it says "do," the target is a blood sodium level of approximately 135 to 145 mEq / L. It has a .

[0086] As used herein, the term "proteinuria" refers to the presence of protein in the urine at levels exceeding normal levels. This refers to the presence of protein. "Proteinuria" includes "albuminuria" and "microalbuminuria." It contains "urine." Normal human protein levels in urine range from approximately 0 to 30 mg / L. While this can be observed, in any given urine sample, the level can reach approximately 80 mg / L. (24 hours) In the case of urine collection, normal human urine protein levels range from approximately 0 to 150 mg. Tan Proteinuria can be indicated by the total protein / creatinine ratio in urine (UPCR) or by the ratio of specific proteins such as albumin / creatinine ratio (ACR) in urine exceeding approximately 30 m g / g. Typically, the UACR value in urine in mg / g is approximately equal to the albumin excretion rate by the subject in mg / day. Proteinuria, including albuminuria and microalbuminuria, often causes or indicates a disease, but is not limited to the occurrence of the disease. Proteinuria encompasses all forms of proteinuria, including but not limited to physiological proteinuria, functional proteinuria, and exercise-induced proteinuria associated with one form of functional proteinuria after excessive muscle work. Furthermore, proteinuria encompasses benign proteinuria (also known as "essential" proteinuria), which refers to types or proteinuria that are not the result of pathological changes in the kidneys. Proteinuria also encompasses pathological proteinuria, e.g., protein levels in urine higher than normal physiological levels. When used herein, the term "albuminuria" (also known as "macroalbuminuria") refers to the presence of albumin in urine exceeding normal levels. Since urinary proteins are mainly albumin, normal human urinary UACR levels range from approximately 0 to 30 mg / mmol. When used herein, the term "microalbuminuria" refers to the presence of albumin in urine excreted at a rate of approximately 20 to 200 μg / min or at a level of approximately 30 to 300 mg / L in humans. When defined by urinary ACR, "microalbuminuria" refers to the presence of albumin in urine excreted at a rate of approximately 20 to 200 μg / min or at a level of approximately 30 to 300 mg / L in humans. When defined by urinary ACR, "microalbuminuria" refers to the presence of albumin in urine excreted at a rate of approximately 20 to 200 μg / min or at a level of approximately 30 to 300 mg / L in humans. When defined by urinary ACR, "microalbuminuria" refers to the presence of albumin in urine excreted at a rate of approximately 20 to 200 μg / min or at a level of approximately 30 to 300 mg / L in humans. When defined by urinary ACR, "microalbuminuria"

[0087] As used herein, the term "albuminuria" (also known as "macroalbuminuria") refers to the presence of albumin in urine exceeding normal levels. Since urinary proteins are mainly albumin, normal human urinary UACR levels range from approximately 0 to 30 mg / mmol. As used herein, the term "microalbuminuria" refers to the presence of albumin in urine excreted at a rate of approximately 20 to 200 μg / min or at a level of approximately 30 to 300 mg / L in humans. When defined by urinary ACR, "microalbuminuria" refers to the presence of albumin in urine excreted at a rate of approximately 20 to 200 μg / min or at a level of approximately 30 to 300 mg / L in humans. When defined by urinary ACR, "microalbuminuria" mmol. As used herein, the term "microalbuminuria" refers to the presence of albumin in urine excreted at a rate of approximately 20 to 200 μg / min or at a level of approximately 30 to 300 mg / L in humans. When defined by urinary ACR, "microalbuminuria" refers to the presence of albumin in urine excreted at a rate of approximately 20 to 200 μg / min or at a level of approximately 30 to 300 mg / L in humans. When defined by urinary ACR, "microalbuminuria" refers to the presence of albumin in urine excreted at a rate of approximately 20 to 200 μg / min or at a level of approximately 30 to 300 mg / L in humans. When defined by urinary ACR, "microalbuminuria" Lubuminuria is defined as a urinary UACR level exceeding approximately 30 mg / g, or approximately 3.5 mg / g in women. This refers to urinary UACR of g / mmol or higher, or approximately 2.5 mg / mmol or higher in men. While high albuminuria is often an early warning sign of kidney disease, other causes can also be present.

[0088] As used herein, the term “hematuria” refers to the presence of blood in the urine. As macroscopic hematuria (visible traces of blood cells) or microscopic hematuria (microscopic traces of blood) It can appear. Confirmed signs of microscopic hematuria are present in at least three properly collected urine samples. It is defined as three or more red blood cells present in each high-magnification microscopic field of view (HPF). Microscopic hematuria can also be detected in the clinic using the dipstick test (colorimetric estimation). Hematuria (either microscopic or macroscopic) may be asymptomatic (associated with hematuria). The condition may be symptomatic (without additional symptoms) or symptomatic. Additional symptoms may include urinary dysfunction (painful urination). Symptoms include: a feeling of needing to empty the bladder completely, increased frequency or frequency of urination, or flank pain. .

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

[0090] The terms “synergistic” or “synergistic” are used herein to describe a combination of two therapeutic agents. This means that the combined effect is greater than the combined effect of each drug when administered individually. It is used in this way. For example, Chou and Talalay, Advances i See Enzyme Regulation (1984), 22, 27-55. "Synergistic effective quantity" is a quantity that has a synergistic effect (as "synergistic" is defined herein). This refers to the amount of a combination of two or more therapeutic agents. In some embodiments, synergistically An effective combination of compounds is one in which one or more compounds in the combination are administered when the compound is administered alone. Even when administered at doses that may be below the therapeutic dose, it can still be therapeutically effective.

[0091] Various factors recognized in the relevant technical field, such as the patient's height, weight, sex, and age, It will be understood that different concentrations of each compound can be used depending on the patient's medical history. Examples of synergistic effects include enhanced therapeutic effect and reduced dosage at an equivalent or increased level of potency. Reduced or delayed development of drug resistance, and simultaneous enhancement or equivalent therapeutic effect (e.g.) (at least one therapeutic agent with the same therapeutic effect) and at least one desirable therapeutic agent This includes, but is not limited to, the reduction of drug effects (e.g., side effects and adverse events). stomach.

[0092] In some embodiments, the term "synergistic effect" as used herein refers to an effect, for example, Atrasentan or a pharmaceutically acceptable salt thereof, and SGLT-2 inhibitors administered alone The clinical results described herein, including those greater than the sum of the effects observed when administered Atrasentan or its pharmaceutically beneficial or desired results A combination of acceptable salts and one or more additional therapeutic agents (e.g., SGLT-2 inhibitors) This refers to the treatment of IgA nephropathy, kidney inflammation and / or line To reduce vascular disease, reduce hematuria, and reduce proteinuria (e.g., albuminuria) Reducing, stabilizing eGFR, reducing the number of disease flares associated with IgA nephropathy Reducing, delaying the onset of ESRD, reducing fatigue, reducing the activation of mesangial cells, which includes but is not limited to these.

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

[0094] In some embodiments, as used herein, "synergistic effect" refers to a combination of atrasentan or a pharmaceutically acceptable salt thereof, and an SGLT-2 inhibitor that results in a desired therapeutic effect and a reduction in the occurrence and / or severity of an undesired drug effect, side effect, or adverse event. In some embodiments, the undesired drug effect, side effect, or adverse event is associated with or observed in monotherapy with atrasentan or a pharmaceutically acceptable salt thereof, and an SGLT-2 inhibitor. In some embodiments, the undesired drug effect, side effect, or adverse event is one or more of fluid retention, anemia, nausea, constipation, thirst, fracture, increased urination, urinary tract infection, yeast infection, vaginal itching, increased LDL cholesterol level, increased brain natriuretic peptide (BNP) level, acute sodium retention, and a rapid increase in creatinine level. ​​​​​​​In some embodiments, fluid retention is associated with a weight gain exceeding approximately 3 kg. In some embodiments, the increased BNP level was greater than approximately 300 pg / mL. stomach.

[0095] As described herein, any concentration range, percentage range, ratio range, and The integer range is any integer value within the enumerated range, unless otherwise specified, and appropriate In such cases, it should be understood that the fraction (such as one-tenth and one-hundredth of an integer) is included. It is.

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

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

[0098] B. Introduction Most cases of IgAN present with single or transient macroscopic hematuria, or routine urine. It first appears after microscopic hematuria and / or proteinuria are detected during the examination. Therefore, the target group includes those with crescent-shaped IgAN or macroscopic hematuria causing tubular obstruction, etc. It presents with acute kidney injury. The definitive diagnosis of IgAN is typically established by renal biopsy. Immunofluorescence and / or immunoperoxidase studies of IgA deposits are performed. Inconspicuous, prominent spherical deposits of IgA within the um and along the glomerular capillary walls (C IgAN is characterized by (sometimes accompanied by IgG) specific factors that correlate with long-term outcomes. The histopathological features include mesangial proliferation, intracapillary proliferation, segmental scarring, and urinary This includes tubular atrophy.

[0099] C. Treatment Methods In normal, healthy human kidneys, ET-1 and ET-RA expression is stronger in vascular tissue. However, it is not very strong in the glomerular structure. In contrast, the target of IgAN is ET in the kidney. -1 and ET-RA show increased expression. In that population, ET-1 expression is associated with protein It is positively correlated with cucumber and is at least partially improved by the administration of ACE inhibitors. In the present day, the treatment for IgAN involves antihypertensive drugs and antiproteinuria drugs (e.g., angiotensin). Corticosteroids (angiotensin-converting enzyme inhibitors and / or angiotensin II receptor blockers) Optimize along with the course of the disease to suppress disease progression. For example, Penfold e t al.,Int.J.Nephrol.and Renovascular Dis See .11, pp.137-148 (2017). However, combinations of these drugs Combinations may cause serious dose-limiting side effects such as hyperkalemia, and in more severe cases... Further immunosuppression may be necessary.

[0100] Clinically, IgAN is diagnosed by renal biopsy, showing proliferation of mesangial cells and / Alternatively, it may indicate the presence of matrix expansion (or advanced focal segmental glomerulosclerosis), and immunity Epidemiography shows predominant mesangial granule deposition of IgA (2+ or higher). This condition is associated with diabetes. Unlike other progressive kidney diseases such as nephropathy, diabetic nephropathy typically involves peripheral fire ants Diffuse capillary basement membrane thickening with PAS-positive nodules, progressive segmental or overall filaments. It presents with globular sclerosis and thickened arteries accompanied by hyaline deposition. For example, Zanatta, et al. al.,Renal Failure,34(3),pp.308-315(2012 See ().

[0101] Therefore, in one embodiment, a method for treating IgA nephropathy, which is necessary for the target This includes administering a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof. A method is provided herein.

[0102] In some embodiments, the target is diabetic nephropathy, HIV / AIDS, and HIV-related conditions. If you have never been diagnosed with one or more of the following: nephropathy, prostate cancer, or acute renal failure In some embodiments, the target is diabetic nephropathy, HIV / AIDS, HIV-related diseases. Have you ever been diagnosed with any of the following: septal kidney disease, prostate cancer, or acute renal failure? No. In some embodiments, the subject has never been diagnosed with diabetic nephropathy. In some embodiments, the subjects are those who have been previously diagnosed with HIV / AIDS. In some embodiments, the subjects are those who have been diagnosed with HIV-related nephropathy. Never. In some embodiments, subjects have been diagnosed with prostate cancer to date. Never. In some embodiments, subjects have been diagnosed with acute renal failure. I have never done so. In some embodiments, the subjects are diabetic nephropathy, HIV / AIDS If you have previously been diagnosed with one or more of the following: HIV-related nephropathy, cancer, or acute renal failure In some embodiments, the subjects are those with diabetes (i.e., type 1 or type 2 diabetes). They have never been diagnosed with diabetes. In some embodiments, the subjects are diabetes I have been diagnosed with a disease (i.e., type 1 or type 2 diabetes) in the past. In this embodiment, the subjects are individuals who have previously been diagnosed with diabetes and have diabetic nephropathy. It has never been diagnosed before. In some embodiments, the subjects have type 2 diabetes and It has never been diagnosed before. In some embodiments, the subjects have type 2 diabetes and They have been diagnosed before. In some embodiments, the subjects have type 2 diabetes and I have been diagnosed with this condition before, but I have never been diagnosed with diabetic nephropathy.

[0103] In some embodiments, the subjects have not currently been diagnosed with cancer. In some embodiments, the subject is not currently receiving cancer treatment. In this case, the cancer is either lung cancer or prostate cancer.

[0104] In some embodiments, the target is diabetic nephropathy, HIV / AIDS, and HIV-related conditions. Not having one or more of the following: nephropathy, prostate cancer, or acute renal failure. (Several embodiments) In this study, the subjects include diabetic nephropathy, HIV / AIDS, HIV-related nephropathy, prostate cancer, and or does not have any of the following acute renal failures. In some embodiments, the subject is diabetes The subject does not have pathological nephropathy. In some embodiments, the subject does not have HIV / AIDS. i. In some embodiments, the subjects do not have HIV-related nephropathy. Morphologically, the subject does not have cancer. In some embodiments, cancer is present in the prostate. It is cancer. In some embodiments, the cancer is lung cancer. In this case, the subjects do not have acute renal failure. In some embodiments, the subjects have diabetes. One or more of the following: diseased nephropathy, HIV / AIDS, HIV-related nephropathy, cancer, or acute renal failure It does not have the above. In some embodiments, the cancer is lung cancer or prostate cancer. In some embodiments, the subjects have diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject is diabetes (i.e., type 1 or type 2 diabetes). ) does not have. In some embodiments, the subject has diabetes and diabetic nephropathy No. In some embodiments, the subject has type 2 diabetes. In this state, the subject does not have type 2 diabetes. In some embodiments, the subject is He has type 2 diabetes but does not have diabetic nephropathy.

[0105] In some embodiments, the target is diabetic nephropathy, HIV / AIDS, and HIV-related conditions. Not suffering from one or more of the following: nephropathy, prostate cancer, or acute renal failure. In terms of administration methods, the target patients are those with diabetic nephropathy, HIV / AIDS, HIV-related nephropathy, and prostate problems. Neither of the above, nor acute renal failure. In some embodiments The subjects do not suffer from diabetic nephropathy. In some embodiments, the subjects are HI Not suffering from V / AIDS. In some embodiments, the subjects are HIV-related nephropathy. They are not suffering from it. In some embodiments, the subjects are not suffering from cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, The cancer is lung cancer. In some embodiments, the subjects are not suffering from acute renal failure. In some embodiments, the target is diabetic nephropathy, HIV / AIDS, HIV-related diseases. Not suffering from one or more of the following: septal kidney disease, cancer, or acute renal failure. Several implementations In this context, the cancer is either lung cancer or prostate cancer. In some embodiments, Elephants do not suffer from diabetes (i.e., type 1 or type 2 diabetes). Several implementations In this state, the subject suffers from diabetes (i.e., type 1 or type 2 diabetes). In several embodiments, the subjects are patients suffering from diabetes such as type 1 diabetes or type 2 diabetes. However, they do not suffer from diabetic nephropathy. In some embodiments, the subjects are type 2 The subject does not have diabetes. In some embodiments, the subject has type 2 diabetes. In some embodiments, the subjects have type 2 diabetes, but also diabetic nephropathy. I do not have the disease.

[0106] In some embodiments, the target is diabetic nephropathy, HIV / AIDS, and HIV-related conditions. Not receiving treatment for one or more of the following: nephropathy, prostate cancer, or acute renal failure. In this embodiment, the target is diabetic nephropathy, HIV / AIDS, HIV-related nephropathy, prostate The patient is not receiving treatment for either adenocarcinoma or acute renal failure. In some embodiments, In this case, the subject is not receiving treatment for diabetic nephropathy. In some embodiments, The elephants are not receiving treatment for HIV / AIDS. In some embodiments, the subjects are He has not received treatment for HIV-related nephropathy. In some embodiments, the subject is the prostate gland. They have not received treatment for it. In some embodiments, the subjects are receiving treatment for acute renal failure. Not included. In some embodiments, the target is diabetic nephropathy, HIV / AIDS, You are not receiving treatment for one or more of the following: HIV-related nephropathy, cancer, or acute renal failure. In some embodiments, the cancer is lung cancer or prostate cancer. In this study, the subjects were not receiving treatment for diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject is the treatment of diabetes (i.e., type 1 or type 2 diabetes). They are receiving treatment. In some embodiments, the subjects are type 1 diabetes or type 2 diabetes. They are receiving treatment for diabetes but not for diabetic nephropathy. Several implementations In terms of morphology, the subjects are not receiving treatment for type 2 diabetes. In some embodiments, The subjects are receiving treatment for type 2 diabetes. In some embodiments, the subjects are type 2 I am receiving treatment for diabetes, but not for diabetic nephropathy.

[0107] In certain embodiments, subjects are determined to have controlled serum glucose levels. In some embodiments, subjects having controlled serum glucose levels He is not receiving treatment for diabetes. In some embodiments, controlled serum glucose Subjects with a certain level of diabetes are receiving treatment for diabetes. In some embodiments, Subjects with controlled serum glucose levels are not receiving treatment for type 2 diabetes. In some embodiments, subjects with controlled serum glucose levels have type 2 diabetes. The patient is receiving treatment for an illness. In some embodiments, the subject has controlled serum glucose The patient has been diagnosed with a level, and the target group is those with HIV-related nephropathy or acute renal failure. Never diagnosed with one or more conditions. For example, the subjects were approximately 130 mg / dL and approximately 125 mg / dL. / 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 Approximately 80 mg / dL, or less than approximately 75 mg / dL, or any value in between. It is determined that the patient has a fasting serum glucose level. In certain embodiments, the subject is Never having been diagnosed with one or more of the following: HIV-related nephropathy or acute renal failure. In the application method, the subject is controlled serum glucose as described elsewhere in this specification. The patient has been determined to have a course level, and the target group is those with HIV-related nephropathy or acute renal failure. Never diagnosed with one or more blood disorders. In certain embodiments, the subject is controlled blood The subjects are those who have been determined to have clear glucose levels and who have HIV-related nephropathy or acute renal failure. I have never been diagnosed with one or more of the above conditions.

[0108] In another embodiment, reducing renal inflammation and / or fibrosis in subjects with IgA nephropathy. A method to reduce the amount of atrasentan or other substances that are effective in treating the target that needs it. A method comprising administering a pharmaceutically acceptable salt of is provided herein.

[0109] In some embodiments, renal inflammation in subjects with IgA nephropathy is atra 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 Approximately 20 weeks, approximately 30 weeks, approximately 40 weeks, approximately 50 weeks, approximately 60 weeks, approximately 70 weeks, approximately 80 weeks Weeks, approximately 90 weeks, approximately 100 weeks, approximately 110 weeks, approximately 120 weeks, approximately 130 weeks, approximately 14 0 weeks, approximately 150 weeks, approximately 160 weeks, approximately 170 weeks, approximately 180 weeks, approximately 190 weeks, also After approximately 200 weeks of treatment (or any value within that period), there is a reduction of at least about 10%. In certain embodiments, kidney inflammation in the subjects is at least about 20%, about 3%. 0%, approximately 40%, approximately 50%, approximately 60%, approximately 70%, approximately 80%, approximately 90%, or approximately 95% The value decreases by %, or any value in between. In some of the embodiments described above, the subject is Treatment with atrasentan or a pharmaceutically acceptable salt for approximately 15 to 30 days. Yes, they are.

[0110] In some embodiments, renal fibrosis in subjects with IgA nephropathy is atrace After treatment with anthan or a pharmaceutically acceptable salt thereof (e.g., about 1 week, about 2 weeks, about 3 weeks, approximately 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, approximately 40 weeks, approximately 50 weeks, approximately 60 weeks, approximately 70 weeks, approximately 80 weeks Between approximately 90 weeks, 100 weeks, 110 weeks, 120 weeks, 130 weeks, and 140 weeks, the interval is approximately 90 weeks, 100 weeks, 110 weeks, 120 weeks, 130 weeks, and 140 weeks. Weeks, approximately 150 weeks, approximately 160 weeks, approximately 170 weeks, approximately 180 weeks, approximately 190 weeks, if After approximately 200 weeks of treatment (or any value within that time), the levels should decrease by at least about 10%. In certain embodiments, renal fibrosis in the subjects is at least about 20%, about 30%. Approximately 40%, 50%, 60%, 70%, 80%, 90%, or 95% Or any value between them decreases. In some of the embodiments described above, the subject is about Treatment with atrasentan or a pharmaceutically acceptable salt for 15 to approximately 30 days. .

[0111] In some embodiments, renal fibrosis in subjects with IgA nephropathy is atrace After treatment with anthan or a pharmaceutically acceptable salt thereof (e.g., about 1 week, about 2 weeks, about 3 weeks, approximately 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, approximately 40 weeks, approximately 50 weeks, approximately 60 weeks, approximately 70 weeks, approximately 80 weeks Between approximately 90 weeks, 100 weeks, 110 weeks, 120 weeks, 130 weeks, and 140 weeks, the interval is approximately 90 weeks, 100 weeks, 110 weeks, 120 weeks, 130 weeks, and 140 weeks. Weeks, approximately 150 weeks, approximately 160 weeks, approximately 170 weeks, approximately 180 weeks, approximately 190 weeks, if After approximately 200 weeks of treatment, or any value during that time, the affected cortical region of the kidney It decreases to less than approximately 50%. In certain embodiments, renal fibrosis in the subject , it decreases to less than 40% of the cortical area. For example, in some embodiments, the target Renal fibrosis in the cortical region occurs in approximately 35%, 30%, 25%, 20%, and 15% of the cortical region, respectively. It decreases to less than approximately 10%, or any value in between. In this case, the subjects were given atrasentan or a pharmaceutically acceptable substance for approximately 15 to 30 days. It is being treated with salt.

[0112] In another embodiment, a method for reducing the incidence of hematuria in subjects with IgA nephropathy, to those who need it, a therapeutically effective dose of atrasentan or a pharmaceutically acceptable dose thereof. A method comprising administering salt is provided herein.

[0113] In some embodiments, high-magnification (microscope) field of view in subjects with IgA nephropathy The number of urinary red blood cells per (rbc / hpf) is determined by atrasentan or its pharmaceutically acceptable After treatment with salt (for example, 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 Approximately 110 weeks, approximately 120 weeks, approximately 130 weeks, approximately 140 weeks, approximately 150 weeks, approximately 160 weeks Weeks, approximately 170 weeks, approximately 180 weeks, approximately 190 weeks, or approximately 200 weeks, or that After treatment of any value between them, it decreases by at least about 10%. In certain embodiments, The urinary RBC / HPF ratio in the subjects was at least approximately 20%, approximately 30%, approximately 40%, and approximately 50%. %, approximately 60%, approximately 70%, approximately 80%, approximately 90%, or approximately 95%, or somewhere in between. The value decreases. In some of the embodiments described above, the subject is for about 15 to about 30 days. The patient is being treated with atrasentan or a pharmaceutically acceptable salt thereof.

[0114] In another embodiment, a method for stabilizing eGFR in a subject with IgA nephropathy, to those who need it, a therapeutically effective dose of atrasentan or a pharmaceutically acceptable dose thereof. A method comprising administering salt is provided herein.

[0115] In some embodiments, the rate of decrease in eGFR in subjects with IgA nephropathy is reduced. A method to reduce, which involves administering a therapeutically effective dose of atrasentan or other substances to the target that requires it. A method comprising administering a pharmaceutically acceptable salt of is provided herein. In that embodiment, the rate of reduction of the target eGFR is determined by atrasentan or its pharmaceutically After treatment with acceptable salts (e.g., 1 week, approximately 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, 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 between, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 16 0 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value between them), is reduced by at least about 10%. In some embodiments, the reduction rate of 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 any value between them. In some of the foregoing embodiments, the subject is treated with atrasentan or a pharmaceutically acceptable salt thereof for about 15 days to about 30 days. In some of the foregoing embodiments, the subject is treated with atrasentan or a pharmaceutically acceptable salt thereof for about 6 months to about 1 year.

[0116] In some embodiments, the reduction rate of the eGFR of a subject having IgA nephropathy is reduced by less than about 10 mL / min / 1.73m 2 after treatment with atrasentan 2 or a pharmaceutically acceptable salt thereof. 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, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value between them) after treatment. In certain embodiments, the After treatment with 1 or a pharmaceutically acceptable salt for approximately 6 months to 1 year, approximately 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 , Alternatively, approximately 0.75 mL / min / 1.73 m 2 Reduce to less than or any value between them. The typical age-related decline in eGFR is, for example, approximately 20 to 30 years old per year. 1mL / min / 1.73m 2 That is the case.

[0117] In another embodiment, the number of IgA nephropathy-related disease flares in subjects with IgA nephropathy is reduced. A method for causing this, which involves delivering a therapeutically effective amount of atrasentan or Methods comprising administering pharmaceutically acceptable salts are provided herein. In some embodiments, this method reduces the flare of diseases associated with hematuria. In embodiments, this method reduces the flare of diseases associated with proteinuria. In one embodiment, the method is used to treat diseases associated with IgA nephropathy related to systemic symptoms. A is reduced. In some embodiments, this method is described elsewhere in this specification. To reduce the decrease in eGFR, in some embodiments, this method reduces the floating To reduce one or more of the following: swelling, fatigue, hematuria, or gross hematuria. Several implementation forms In this context, this method has a positive effect on the progression of the disease.

[0118] In another embodiment, a method for delaying the onset of ESRD in subjects with IgA nephropathy. Therefore, to those who need it, a therapeutically effective amount of atrasentan or a pharmaceutically acceptable amount A method comprising administering a salt is provided herein.

[0119] In some embodiments, this method is used to diagnose IgA nephropathy in subjects and to e GFR of 15 mL / min / 1.73 m 2 Increase the time between the specified time and the time below that. In terms of application, this method diagnoses IgA nephropathy in the subject and assesses the subject's eGFR when it is 15m L / min / 1.73m 2 Increase the time between the time below and the time below by at least approximately 10%. For example In some embodiments, this method is used to diagnose IgA nephropathy in subjects and to assess the subjects eGFR of 15 mL / min / 1.73 m² 2 The time between the above and below should be at least approximately 20% Approximately 30%, 40%, 50%, 60%, 70%, 80%, 90%, and 100% %, approximately 150%, approximately 200%, approximately 250%, approximately 300%, approximately 350%, approximately 400%, approximately 4 Increase by 50%, or approximately 500%, or any value in between.

[0120] In a specific embodiment, this method diagnoses IgA nephropathy in a subject and eGF in the subject. R is 15 mL / min / 1.73 m 2 Increase the time between the current time and the time below by at least approximately one year. For example, this method is used when the target eGFR is 15 mL / min / 1.73 m 2 For a period of time less than, At least approximately 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 could cause a delay of a year.

[0121] In another embodiment, a method for reducing proteinuria in a subject having IgA nephropathy, For those in need, administer a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof. Methods including giving are provided herein.

[0122] In some embodiments, proteins in the urine of subjects with IgA nephropathy (e.g., The amount of albumin) after treatment with atrasentan or a pharmaceutically acceptable salt (e.g.) For example, 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 5 weeks, approximately 6 weeks, approximately 7 weeks, approximately 8 weeks Between approximately 9 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, 50 weeks, and 60 weeks... Weeks, approximately 70 weeks, approximately 80 weeks, approximately 90 weeks, approximately 100 weeks, approximately 110 weeks, approximately 120 weeks Between approximately 130 weeks, 140 weeks, 150 weeks, 160 weeks, 170 weeks, and 18 weeks, the intervals are approximately 18 weeks, 14 weeks, 15 weeks, 160 weeks, 170 weeks, and 18 weeks. (After 0 weeks, approximately 190 weeks, or approximately 200 weeks of treatment, or any value in between) , reducing by at least about 10%. In some embodiments, the protein in the urine of the subject The amounts are at least about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately Reduce by 90%, or approximately 95%, or any value in between. In some cases, the subjects received atrasentan or a pharmaceutically acceptable substance for approximately 15 to 30 days. It is being treated with salt.

[0123] In certain embodiments, proteins in the urine of subjects with IgA nephropathy (e.g., alpha) The amount of bumin) is approximately 2 days after treatment with atrasentan or a pharmaceutically acceptable salt. After approximately 30 days, the level is reduced by approximately 20% to 80%. In certain embodiments, IgA nephropathy The amount of protein (e.g., albumin) in the urine of the target is determined by atrasentan or Approximately 15 to 30 days after treatment with pharmaceutically acceptable salts, the levels are reduced by approximately 20% to 80%. In some of these embodiments, the amount of protein in the urine of the subject is approximately 25%. ~Reduces by approximately 80%. In some of these embodiments, the amount of protein in the target urine The amount is reduced by approximately 30% to approximately 80%. In some of these embodiments, the urine of the subject The amount of protein is reduced by approximately 35% to approximately 80%. In some of these embodiments, The amount of protein in the target urine is reduced by approximately 40% to approximately 80%. In some cases, the amount of protein in the urine of the subject is reduced by approximately 45% to approximately 80%. In some of these embodiments, the amount of protein in the urine of the subject was approximately 50% to approximately 80%. Reduce. In the above embodiment, the amount of protein in the urine of a subject with IgA nephropathy (for example) The reduction in albumin levels 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 the start of treatment.

[0124] In some embodiments, proteins in the urine of subjects with IgA nephropathy (e.g., The amount of albumin) after treatment with atrasentan or a pharmaceutically acceptable salt (e.g.) For example, 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 5 weeks, approximately 6 weeks, approximately 7 weeks, approximately 8 weeks Between approximately 9 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, 50 weeks, and 60 weeks... Weeks, approximately 70 weeks, approximately 80 weeks, approximately 90 weeks, approximately 100 weeks, approximately 110 weeks, approximately 120 weeks Between approximately 130 weeks, 140 weeks, 150 weeks, 160 weeks, 170 weeks, and 18 weeks, the intervals are approximately 18 weeks, 14 weeks, 15 weeks, 160 weeks, 170 weeks, and 18 weeks. (After 0 weeks, approximately 190 weeks, or approximately 200 weeks of treatment, or any value in between) This reduces the level by approximately 100 mg / dL to approximately 3,000 mg / dL. In a specific embodiment, The amount of protein in elephant urine is reduced by approximately 100 mg / dL to 2,500 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is approximately 100 mg / dL to approximately 2, Reduces by 000 mg / dL. In a particular embodiment, the amount of protein in the target urine is It reduces the level by approximately 100 mg / dL to approximately 1,500 mg / dL. In a specific embodiment, the target The amount of protein in the urine is reduced by approximately 100 mg / dL to approximately 1,000 mg / dL. In a specific embodiment, the amount of protein in the target urine is approximately 100 mg / dL to approximately 500 mg / dL. Reduces the amount of protein in the target urine by approximately 10 mg / dL. In a particular embodiment, the amount of protein in the target urine is approximately 10 mg / dL. Reduces the level from 0 mg / dL to approximately 400 mg / dL. In a specific embodiment, the amount of the target substance in urine is reduced. The amount of protein is reduced by approximately 100 mg / dL to approximately 300 mg / dL. In this study, the amount of protein in the target urine was reduced by approximately 100 mg / dL to approximately 200 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is approximately 500 mg / dL. It reduces the protein in the urine of the subject by approximately 2,500 mg / dL. In certain embodiments, the protein in the urine of the subject The amount is reduced by approximately 500 mg / dL to approximately 2,000 mg / dL. The amount of protein in the target urine was reduced by approximately 500 mg / dL to approximately 1,500 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is approximately 500 mg / dL to approximately Reduces by 1,000 mg / dL. In a specific embodiment, the amount of protein in the target urine. This reduces the level by approximately 500 mg / dL to approximately 900 mg / dL. In certain embodiments, the target The amount of protein in the urine is reduced by approximately 500 mg / dL to approximately 800 mg / dL. In one embodiment, the amount of protein in the target urine is approximately 600 mg / dL to approximately 900 mg Reduces by / dL. In a particular embodiment, the amount of protein in the target urine is approximately 700m Reduces the protein content by approximately 900 mg / dL. In a specific embodiment, the protein in the target urine... The amount of chlorine is reduced by approximately 1,000 mg / dL to approximately 2,000 mg / dL. In some cases, the subjects were given atrasentan or its pharmacology for approximately 15 to 30 days. The treatment is with a moderately tolerable salt. In the embodiments described above, subjects having IgA nephropathy The reduction in the amount of protein (e.g., albumin) in the urine is due to atrasentan or the drug The amount of urinary protein (e.g., albumin) before the initiation of scientifically acceptable salt treatment. It is related to this.

[0125] In certain embodiments, proteins in the urine of subjects with IgA nephropathy (e.g., alpha) The amount of bumin is approximately 15% of the amount obtained from treatment with atrasentan or a pharmaceutically acceptable salt. After approximately 30 days, the level decreases by approximately 100 mg / dL to 500 mg / dL. (Specific embodiment) In this study, the amount of protein in the subject's urine was determined to be atrasentan or a pharmaceutically acceptable amount. Approximately 15 to 30 days after treatment with salt, the dose is approximately 200 mg / dL to 500 mg / dL. Reduce. In a specific embodiment, the amount of protein in the target urine is reduced by atrasentan. Or, approximately 15 to 30 days after treatment with the pharmaceutically acceptable salt, approximately 300 mg / d The L level is reduced by approximately 500 mg / dL. In the above embodiment, the target of a person with IgA nephropathy The reduction in the amount of protein (e.g., albumin) in urine is due to atrasentan or its pharmaceutical The amount of protein (e.g., albumin) in the urine before the start of treatment with a moderately tolerable salt is They are related.

[0126] In certain embodiments, proteins in the urine of subjects with IgA nephropathy (e.g., alpha) The amount of bumin is approximately 15% of the amount obtained from treatment with atrasentan or a pharmaceutically acceptable salt. After approximately 30 days, the level decreases by approximately 500 mg / dL to 900 mg / dL. In this case, the amount of protein in the urine of the subject is atrasentan or pharmaceutically acceptable Approximately 15 to 30 days after salt treatment, the blood sugar level decreased by approximately 600 mg / dL to 900 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is determined to be atrasentan or Approximately 15 to 30 days after treatment with the pharmacopoeia-acceptable salt, approximately 700 mg / dL~ It reduces by approximately 900 mg / dL. In the above embodiment, the urine of a subject with IgA nephropathy The reduction in the amount of protein (e.g., albumin) is due to atrasentan or its pharmaceutically Related to the amount of protein (e.g., albumin) in the urine before the initiation of treatment with acceptable salts. They are doing it.

[0127] In some embodiments, subjects with IgA nephropathy are given atrasentan or After treatment with pharmaceutically acceptable salts (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 During the course of treatment, or after 200 weeks, the amount of protein in the urine is less than approximately 1.0 gram / day (for example, It has a reduced level of albumin. In certain embodiments, the subject has about 0.9g It has reduced levels of urinary protein of less than lamb / day. In certain embodiments, The subjects have reduced levels of urinary protein of less than approximately 0.8 grams / day. In this embodiment, the subject is a reduced level of urinary protein of less than approximately 0.7 grams / day. It has a certain property. In certain embodiments, the subject has less than approximately 0.6 grams of protein in the urine. It has a reduced level of quality. In certain embodiments, the subject is approximately 0.5 grams / day It has reduced levels of protein in the urine. In certain embodiments, the subject is It has a reduced level of protein in urine of less than approximately 0.4 grams / day. Specific embodiments In this study, the subjects were those with reduced levels of urinary protein of less than approximately 0.3 grams / day. In certain embodiments, the subject has a low urinary protein level of less than about 0.2 grams / day. It has a reduced level. In some of the embodiments described above, the subject is about 15 days to about 30 days For several days, the patient is treated with atrasentan or a pharmaceutically acceptable salt thereof. In this state, the amount of protein (e.g., albumin) in the urine of a subject with IgA nephropathy The reduction was observed in the urine before the initiation of treatment with atrasentan or a pharmaceutically acceptable salt thereof. It is related to the amount of protein (e.g., albumin).

[0128] In another embodiment, a method for reducing fatigue in a subject with IgA nephropathy, which does not require The target population is administered a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof. Methods including the following are provided herein. In some embodiments, the subject is Having one or more of the following conditions: diabetic nephropathy, HIV-associated nephropathy, prostate cancer, or acute renal failure. It has been determined that it has not been done. In a particular embodiment, the subject suffers from diabetic nephropathy. It has been determined that it is not. In certain embodiments, the subject is HIV-related neurological disorder He has been determined not to have the disease. In a particular embodiment, the subject has prostate cancer. It has been determined that it has not occurred. In a particular embodiment, the subject suffers from acute renal failure. It has been determined that there is no one present.

[0129] In some embodiments, fatigue in subjects with IgA nephropathy is treated with atrasentan. or after treatment with the pharmaceutically acceptable salt (for example, 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, approximately 40 weeks, approximately 50 weeks, approximately 60 weeks, approximately 70 weeks, approximately 80 weeks, approximately 90 weeks Weeks, approximately 100 weeks, approximately 110 weeks, approximately 120 weeks, approximately 130 weeks, approximately 140 weeks, approximately 1 50 weeks, approximately 160 weeks, approximately 170 weeks, approximately 180 weeks, approximately 190 weeks, or approximately 20 After 0 weeks (or any value of treatment during those weeks), the level is reduced by approximately 5% to approximately 80%. In the application method, fatigue is reduced by approximately 10% to approximately 75%. In a specific embodiment, Fatigue is reduced by approximately 10% to 70%. In certain embodiments, fatigue is reduced by approximately 10% to 70%. It is reduced by approximately 65%. In certain embodiments, fatigue is reduced by approximately 10% to approximately 60%. In certain embodiments, fatigue is reduced by approximately 10% to approximately 55%. And fatigue is reduced by approximately 10% to approximately 50%. In a particular embodiment, fatigue is approximately It is reduced by 10% to approximately 45%. In certain embodiments, fatigue is reduced by approximately 10% to approximately 40%. Reduce. In certain embodiments, fatigue is reduced by approximately 10% to approximately 35%. Morphologically, fatigue is reduced by approximately 10% to approximately 30%. In a particular embodiment, fatigue The feeling is reduced by approximately 10% to approximately 25%. In certain embodiments, fatigue is reduced by approximately 10% to approximately Reduced by 20%. In certain embodiments, fatigue is reduced by approximately 10% to approximately 15%. In certain embodiments, fatigue is reduced by approximately 20% to approximately 75%. As a result, fatigue is reduced by approximately 20% to approximately 70%. In a particular embodiment, fatigue is reduced by approximately 2 It is reduced by 0% to approximately 65%. In certain embodiments, fatigue is reduced by approximately 20% to approximately 60%. In certain embodiments, fatigue is reduced by approximately 20% to 55%. In this state, fatigue is reduced by approximately 20% to approximately 50%. In a specific embodiment, fatigue It is reduced by approximately 20% to approximately 45%. In certain embodiments, fatigue is reduced by approximately 20% to approximately 4 Reduced by 0%. In certain embodiments, fatigue is reduced by approximately 20% to approximately 35%. In one embodiment, fatigue is reduced by approximately 20% to 30%. In a specific embodiment... Fatigue is reduced by approximately 30% to approximately 75%. In certain embodiments, fatigue is reduced by approximately 30% It is reduced by approximately 70%. In certain embodiments, fatigue is reduced by approximately 30% to 65%. In certain embodiments, fatigue is reduced by approximately 30% to approximately 60%. In this case, fatigue is reduced by approximately 30% to approximately 55%. In a particular embodiment, fatigue is It reduces fatigue by approximately 30% to 50%. In certain embodiments, fatigue is reduced by approximately 30% to 45%. Reduced by %. In certain embodiments, fatigue is reduced by approximately 30% to approximately 40%. In some embodiments, fatigue is reduced by approximately 40% to approximately 75%. In certain embodiments, Fatigue is reduced by approximately 40% to 70%. In a particular embodiment, fatigue is reduced by approximately 40% It reduces fatigue by approximately 65%. In certain embodiments, fatigue is reduced by approximately 40% to 60%. In certain embodiments, fatigue is reduced by approximately 40% to approximately 55%. In this case, fatigue is reduced by approximately 40% to approximately 50%. In a particular embodiment, fatigue is It is reduced by approximately 50% to approximately 75%. In certain embodiments, fatigue is reduced by approximately 50% to approximately 70%. Reduced. In certain embodiments, fatigue is reduced by approximately 50% to approximately 65%. In the application method, fatigue is reduced by approximately 50% to approximately 60%. In this case, the subjects were given atrasentan or a pharmaceutically acceptable substance for approximately 15 to 30 days. It is being treated with salt. In certain embodiments, the reduction of fatigue is measured on the fatigue severity scale. Chaldor fatigue scale, FACIT fatigue scale, simplified fatigue chart, FA CT-F subscale, overall vitality and impact, May and Kline adjectives Checklist, Pearson-Byars fatigue and emotional checklist, Rhoten fatigue Fatigue scale, fatigue and anergy schedule, visual analog scale, and This includes a decrease in the score of one or more of the individual strengths on the checklist. In this context, the reduction of fatigue experienced by subjects with IgA nephropathy is attributed to atrasentan or This is related to the fatigue experienced by the subject before the initiation of treatment with the pharmacologically acceptable salt. In some embodiments, a reduction in fatigue includes a decrease in the score on a simplified fatigue chart. .

[0130] Selection of target Subjects with IgA nephropathy as described elsewhere in this specification are known in the art. Diagnosis can be made using one or more methods. In non-limiting cases, renal biopsy, gas Detecting lactose-deficient IgA (e.g., Gd-IgA1), detecting anti-glycan antibodies To excrete, to detect the deposition of IgA immune complexes in the kidneys, or one of the above Any combination is included. In some embodiments, the diagnosis of IgA nephropathy is This includes detecting the deposition of IgA immune complexes in the kidney. In certain embodiments, The diagnosis of IgA nephropathy includes a renal biopsy. In certain embodiments, the diagnosis of IgA nephropathy is made by a renal biopsy. This includes detecting lactose-deficient IgA. In certain embodiments, it is used in the diagnosis of IgA nephropathy. The determination includes detecting an anti-glycan antibody (e.g., KM55). In certain embodiments, The diagnosis of IgA nephropathy is made by renal biopsy and subsequent (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 presence of a specific protein in the subject Bell is determined before administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, serum levels of Gd-IgA1, serum levels of autoantibodies specific to Gd-IgA1, Serum and / or urine levels of IgA1-containing immune complexes. For example, Kn oppova,et al.,Front.Immunol.,Vol.17,Art. See 117(2016), which is incorporated herein in its entirety by reference. In some embodiments, the subject is atrasentan or a pharmaceutically acceptable substance. Prior to administration of the salt, the patient had a Gd-IgA level of 90th percentile or higher. In the administration method, the subject is subjected to the administration of atrasentan or a pharmaceutically acceptable salt thereof before administration. It has a Gd-IgA level of 95th percentile or higher. In some embodiments, The target Gd-IgA level is determined over approximately 6 months to 1 year using atrasentan or other pharmaceutically acceptable substances. After treatment with the appropriate salt, the level decreases to below the 90th percentile.

[0132] In certain embodiments, the target is approximately 50% or more of the glomeruli (for example, approximately 60% or more, approximately More than 70%, or approximately 80%, 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 hyp (Cercellularity) is present in the target, and intravascular cytosis is present in the glomerular capillary tubules. It is defined as cytogenesis due to an increase in the number of cells in the lumen. In certain embodiments, segmentation Segmental sclerosis is present in the whole, while segmental sclerosis is present in only a part of the glomerular tuft, not the entire tuft. It is defined as sclerosis (occlusion of capillary tubular lumen by matrix). Specific implementation forms In this state, the target is approximately 50% or more of the cortical region (for example, approximately 60% or more, approximately 65% ​​or more, Approximately 70% or more, approximately 75% or more, or approximately 80% or more have tubular atrophy / interstitial fibrosis. Tubular atrophy / interstitial fibrosis is a presumptive pattern of cortical regions showing tubular atrophy or interstitial fibrosis. - Defined as a centroid. In certain embodiments, the object is crescent-shaped on the glomerulus. Such exist. In some of these embodiments, the target is less than approximately 25% of the glomeruli (e.g., For example, crescent shapes exist in approximately 20%, 15%, 10%, or less than 5%. In this embodiment, the subjects are classified as M1, E1 under the Oxford MEST-C classification system. , have a MEST-C score of S1, T1 or T2, and / or C0 or C1. The Oxford MEST-C classification system is based on the Kidney International classification. al(2009)76,546-556 and Nature Reviews Neph Defined in rology(2017)13,385-386, each of these references The whole of these is incorporated herein by Kidney Research and d Clinical Practice (2016) 35, 197-203; and I gA Nephropathy in Medscape (Actual on November 4, 2019) See also (which are referred to herein), and each of these is incorporated into this specification by reference. (It gets inserted).

[0133] In some embodiments, the subjects are at high risk of progressing to ESRD. In some application methods, the target is atrasentan or a pharmaceutically acceptable salt thereof. Prior to the first dose, consume an average of at least 1 gram of protein per day for at least approximately 3 months. It is excreted in the urine. In certain embodiments, the subject is atrasentan or the drug Prior to the first dose of a scientifically acceptable salt, administer 60 mL / min / 1.7 for at least approximately 3 months. 3m2 The following (for example, approximately 55 or less, approximately 50 or less, approximately 45 or less, approximately 40 or less, approximately 35 or less) It has an average eGFR. In some of these embodiments, the subject is atrium Before the first dose of 0.73 ml or a pharmaceutically acceptable salt thereof, 30 mL / min / 1.73 ml 2 super It has eGFR.

[0134] In some embodiments, the subject is atrasentan or a pharmaceutically acceptable substance. Before the first dose of salt, at least approximately 3 months (for example, at least approximately 4 months, less For approximately 5 months, at least approximately 6 months, at least approximately 7 months, at least approximately 8 months. , for at least approximately 9 months, at least approximately 10 months, at least approximately 11 months, and at least (Also approximately 1 year, at least approximately 1.5 years, or at least approximately 2 years), on average approximately per day They excrete more than 1 gram of protein in their urine. For example, the subject is atrasentan or Prior to the first dose of the pharmaceutically acceptable salt, a normal daily dose should be administered for at least approximately three months. Approximately 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 Lamb, 3.4 grams, 3.5 grams, 5 grams, 7.5 grams, or 10 grams, Alternatively, any value of protein between those levels can be excreted in the urine.

[0135] In some embodiments, the subject is atrasentan or a pharmaceutically acceptable substance. Before the first dose of salt, at least approximately 3 months (for example, at least approximately 4 months, less For approximately 5 months, at least approximately 6 months, at least approximately 7 months, at least approximately 8 months. , for at least approximately 9 months, at least approximately 10 months, at least approximately 11 months, and at least (Also approximately 1 year, at least approximately 1.5 years, or at least approximately 2 years), on average approximately per day They excrete 0.3 grams to approximately 2 grams of protein in their urine. For example, the subjects are small. For approximately 3 months, the daily intake was about 0.3 to 0.5 grams, and 0.5 to 1 gram. Approximately 0.5 to 1.5 grams, approximately 1 to 1.5 grams, or approximately 1.5 to 2 grams Grams of protein can be excreted in the urine.

[0136] In some embodiments, the subject is atrasentan or a pharmaceutically acceptable substance. Prior to the first dose of salt, at least two of three consecutive measurements over one year, the daily dose They excrete at least about 1 gram of protein in their urine. For example, the subject is Atra. Prior to the first dose of sentan or a pharmaceutically acceptable salt thereof, three consecutive doses over a one-year period In at least two of the measurements, the daily intake was approximately 1.1 grams, 1.2 grams, and 1.3 grams. 1.4 grams, 1.5 grams, 1.6 grams, 1.7 grams, 1.8 grams, 1.9 gram, 2.0 gram, 2.1 gram, 2.2 gram, 2.3 gram, 2.4 gram, 2 0.5 grams, 2.6 grams, 2.7 grams, 2.8 grams, 2.9 grams, 3.0 grams 3.1 grams, 3.2 grams, 3.3 grams, 3.4 grams, 3.5 grams, 5 grams 7.5 grams, or 10 grams of protein, or any value in between. Proteins are excreted in the urine.

[0137] In some embodiments, the subject is atrasentan or a pharmaceutically acceptable substance. Prior to the first dose of salt, at least approximately 300 mg / g for at least 3 months, for example, 3 It has a UACR value of 00 mg / g to approximately 5,000 mg / g. In some embodiments, The subjects were those who, prior to the first dose of atrasentan or a pharmaceutically acceptable salt thereof, had a small amount of... For at least three months, approximately 800 mg / g, for example, 800 mg / g to approximately 5,000 mg / g It has a UACR value of . In some embodiments, the subject is atracentane or so Prior to the first dose of the pharmaceutically acceptable salt, at least approximately 3 months, at least approximately 50 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 approximately 5,000 mg / g, or any value in between. It has a CR value.

[0138] In some embodiments, the subject is atrasentan or a pharmaceutically acceptable substance. Prior to the first dose of salt, for at least 3 months, compared to the mean UACR value of the subjects, In both cases, there is a decrease of approximately 30% in UACR values, for example, atrasentan or its pharmaceutically acceptable value. Prior to the first dose of the salt, the subject's UACR value was compared to approximately 3 for at least 3 months. It has a decrease of 0% to approximately 100%. In some embodiments, the target is the atrium Prior to the first administration of the substance or a pharmaceutically acceptable salt thereof, the subject should be treated for at least three months. Compared to the average UACR value, it is at least approximately 30%, approximately 40%, approximately 50%, approximately 60%, and approximately 70%. UACR values ​​of %, approximately 80%, approximately 90%, or approximately 100%, or any value in between. It has a decrease. In some embodiments, subjects having a decrease in UACR value also have No significant sodium retention and / or significant fluid retention is experienced. (Several embodiments) In this study, significant fluid retention occurred over a 6-week period of approximately 1 kg to 4 kg, for example, approximately 4 kg. g, approximately 3.5kg, approximately 3kg, approximately 2.5kg, approximately 2kg, approximately 1.5kg, or approximately 1kg g, or any value over 6 weeks or more. In some embodiments, Subjects with significant fluid retention exhibit clinical symptoms of edema.

[0139] In certain embodiments, the subject is atrasentan or a pharmaceutically acceptable salt thereof. Before the first dose, at least 3 months (for example, about 3 months, about 4 months, about 5 months) Approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately (For 12 months, approximately 1.5 years, or approximately 2 years), approximately 20-90 mL / min / 1.73 m³ 2 It has an average eGFR. For example, the number of atrasentan or pharmaceutically acceptable salts Prior to administering dose 1, administer approximately 20-50 mL / min / 1.73 m³ for at least 3 months. 2 , about 30 ~Approx. 60mL / min / 1.73m 2 , about 40~70mL / min / 1.73m 2 Approximately 50 to 80mL / min / 1.73m 2 , or approximately 60-90 mL / min / 1.73 m 2 .some In the embodiment, the subject is atrasentan or a pharmaceutically acceptable salt thereof Prior to administration, administer at least 60 mL / min / 1.73 m² for approximately 3 months. 2 The average eGFR below It has. In a particular embodiment, the subject is subjected to 55 mL / min / 1 for at least about 3 months. 73m 2 The following average eGFRs are observed. In certain embodiments, the subject has at least approximately For 3 months, 50 mL / min / 1.73 m 2 The following average eGFR is observed in specific embodiments. In this context, the subjects were required to consume 45 mL / min / 1.73 m³ for at least approximately 3 months. 2 The following average eGF It has R. In a particular embodiment, the subject is 40 mL / min / for at least about 3 months. 1.73m 2 The following average eGFRs are observed. In certain embodiments, the subjects are at least For approximately 3 months, 35 mL / min / 1.73 m³ 2 The following average eGFRs are observed in specific implementations. In this scenario, the subjects consumed 25 mL / min / 1.73 m³ for at least approximately 3 months. 2 The following average e The subject has a GFR. In a specific embodiment, the subject receives 20 mL / for at least about 3 months. min / 1.73m 2 The following average eGFR is observed. In some of the embodiments described above, Elephants should be given at least three months prior to administration of atrasentan or a pharmaceutically acceptable salt thereof. Approximately 30mL / min / 1.73m 2 ~Approx. 60mL / min / 1.73m 2 The average eGFR For example, the target 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 0.73m 2 ~About 45mL / min / 1.73m 2 , or approximately 30 mL / min / 1.73 m 2 ~about 40 mL / min / 1.73 m 2 It may have an average eGFR of [value missing].

[0140] In certain embodiments, the subject is atrasentan or a pharmaceutically acceptable salt thereof. Before the first dose, at least 3 months (for example, at least about 4 months, at least about For 5 months, at least about 6 months, at least about 7 months, at least about 8 months, less At least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year During the period of at least approximately 1.5 years, or at least approximately 2 years, approximately 30 mL / min / 1.73 m 2 ~About 45mL / min / 1.73m 2 For example, approximately 45 or less, approximately 40 or less, approximately 35 or less, or having an average eGFR of approximately 30 or less. In some embodiments, the subject is at Prior to the first dose of spiralan or a pharmaceutically acceptable salt thereof, at least approximately 3 months , about 25mL / min / 1.73m 2 ~Approx. 75mL / min / 1.73m 2 It has an average eGFR. For example, before the first dose of atrasentan or a pharmaceutically acceptable salt thereof, a small amount For at least 3 months, approximately 25 mL / min / 1.73 m 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 between them.

[0141] In some embodiments, the subject is atrasentan or a pharmaceutically acceptable substance. Before the first dose of salt, at least 3 months (for example, at least about 4 months, and less) For approximately 5 months, at least approximately 6 months, at least approximately 7 months, at least approximately 8 months, For at least about 9 months, at least about 10 months, at least about 11 months, at Approximately 1 year, at least approximately 1.5 years, or at least approximately 2 years, with an average growth rate of approximately 4% to approximately 6%. They have an average HbA1c level. For example, the subjects were approximately 4.2%, 4.4%, 4.6%, and 4. 8%, approximately 5.0%, approximately 5.2%, approximately 5.4%, approximately 5.6%, approximately 5.8%, or approximately 6. Alternatively, it may have an average HbA1c of any value between those two.

[0142] In some embodiments, the subject is atrasentan or a pharmaceutically acceptable substance. Before the first dose of salt, at least 3 months (for example, at least about 4 months, and less) For approximately 5 months, at least approximately 6 months, at least approximately 7 months, at least approximately 8 months, For at least about 9 months, at least about 10 months, at least about 11 months, at Approximately 125 mg / dL (for about 1 year, at least about 1.5 years, or at least about 2 years) The subjects had the following average fasting blood glucose levels. For example, the subjects had levels of approximately 120 mg / dL and approximately 115 mg / dL. / 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 average fasting blood glucose level may be in dL, or any value between those two.

[0143] In some embodiments, the subject maintains potassium levels within a normal physiological range. In certain embodiments, the subject is atrasentan or a pharmaceutically acceptable substance. Before the first dose of salt, at least 3 months (for example, at least about 4 months, and less) For approximately 5 months, at least approximately 6 months, at least approximately 7 months, at least approximately 8 months, For at least about 9 months, at least about 10 months, at least about 11 months, at For approximately one year, at least about 1.5 years, or at least about 2 years, correct potassium levels. Maintain within a normal physiological range. In certain embodiments, the subject maintains potassium levels within 3 Maintain the level within 0.5-5.2 mEq / L. For example, the target level is approximately 3.5 mEq / L, approximately 3. 6 mEq / L, approximately 3.7 mEq / L, approximately 3.8 mEq / 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. 4.8 mEq / L, approximately 4.9 mEq / L, approximately 5.0 mEq / L, approximately 5.1 mEq / L, also Maintain an average potassium level of approximately 5.2 mEq / L, or any value in between. ru.

[0144] In some embodiments, the subject maintains sodium levels within a normal physiological range. To hold. In certain embodiments, the subject is atrasentan or pharmaceutically acceptable Before the first dose of the salt, at least 3 months (for example, at least about 4 months, less For approximately 5 months, at least approximately 6 months, at least approximately 7 months, at least approximately 8 months. , for at least approximately 9 months, at least approximately 10 months, at least approximately 11 months, and at least Potassium levels (for about 1 year, at least about 1.5 years, or at least about 2 years) Maintain within a normal physiological range. In certain embodiments, the subject is sodium level Maintain the concentration within 135-145 mEq / L. For example, the target is approximately 135 mEq / L, approximately 136mEq / L, approx. 137mEq / L, approx. 138mEq / L, approx. 139mEq / L, approx. 140mEq / L, approx. 141mEq / L, approx. 142mEq / L, approx. 143mEq / L, approx. The average of 144 mEq / L, approximately 145 mEq / L, or any value in between. Maintain thorium levels.

[0145] In some embodiments, the subject is atrasentan or a pharmaceutically acceptable substance. Before the first dose of salt, the ALT / AST level should be approximately the same as the ALT / AST level. , during administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the subject is Before the first dose of atrasentan or a pharmaceutically acceptable salt thereof, reduce the level by approximately 25%. Approximately 20%, approximately 15%, approximately 10%, approximately 5%, approximately or 2.5%, or whatever in between. ALT / AST levels within the range of acceptable values ​​can be controlled with atrasentan or other pharmaceutically acceptable drugs. It is present during salt administration.

[0146] In some embodiments, the subject is atrasentan or a pharmaceutically acceptable substance. Before the first dose of salt, the bilirubin level should be approximately the same as the bilirubin level, This is present during administration of sentan or a pharmaceutically acceptable salt thereof. For example, the subject is atrace Before the first dose of thontan or a pharmaceutically acceptable salt thereof, take about 25% of the level, about 20 %, approximately 15%, approximately 10%, approximately 5%, or approximately 2.5%, or any value in between. Bilirubin levels within the range during administration of atrasentan or a pharmaceutically acceptable salt thereof. To possess.

[0147] In some embodiments, fluid retention in the subject is (for example, atrasentan) Or during treatment with a pharmaceutically acceptable salt thereof, and / or atrasentan or It can be managed with a diuretic (before the first dose of the pharmaceutically acceptable salt). For example, fluid retention. The weight gain over a 6-week period may be less than approximately 3 kilograms (kg). In the embodiment, fluid retention lasted for more than 6 weeks, with amounts of approximately 4 kg, 3.5 kg, and 3 kg respectively. kg, approximately 2.5 kg, approximately 2 kg, approximately 1.5 kg, or less than approximately 1 kg, or those It is any value in between.

[0148] In some embodiments, the subject is atracentan as disclosed herein. or before, substantially simultaneously with, or after the administration of a pharmaceutically acceptable salt thereof, The subject undergoes surgery and / or other regimens. In some embodiments, the subject is described in this specification. As disclosed in the book, before administering atrasentan or a pharmaceutically acceptable salt thereof, Substantially, or after administration, other chemical and / or biological therapeutic agents are administered. It can be done.

[0149] In some embodiments, the subject is atrasentan or a pharmaceutically acceptable substance. Prior to the first dose of salt, at least approximately 60 weeks, one of the renin-angiotensin systems The subject is receiving one or more inhibitors. For example, in some embodiments, the subject is receiving atrase Before the first dose of thontan or a pharmaceutically acceptable salt thereof, at least approximately 12 weeks, approximately For 24 weeks, approximately 48 weeks, or approximately 60 weeks, or any value in between, renin - The patient is receiving an inhibitor of one or more components of the angiotensin system.

[0150] In some embodiments, the subject is one or more renin-angiotensin system inhibitors. The subject is receiving the maximum tolerated stable dose. For example, the subject is receiving atrasentan or Before the first dose of the pharmaceutically acceptable salt, at least approximately 12 weeks, approximately 14 weeks, approximately 16 weeks, approximately 18 weeks, approximately 20 weeks, approximately 25 weeks, approximately 30 weeks, approximately 35 weeks, approximately 40 weeks For approximately 45 weeks, or approximately 50 weeks, or any value in between, one or more Lenny They can receive the maximum tolerated stable dose of an angiotensin system inhibitor. In the embodiment, one or more inhibitors of the renin-angiotensin system are used in the angiotensin Tensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), The group is selected from nin inhibitors and aldosterone antagonists. For example, Inhibitors of one or more of the renin-angiotensin system include ACE inhibitors, ARBs, and These may be combinations thereof, and ACE inhibitors or ARBs are also mentioned elsewhere in this specification. It may be listed. For example, ACE inhibitors include quinapril, fosinopril, and perindopril. Captopril, Enalapril, Enalaprilat, Ramipril, Cilazapril, Derap Lil, Fosenopril, Zophenopril, Indrapril, Benazepril, Lysinopril Spirapril, Trandolapril, Perindep, Pentopril, Moexipril, Reci You can choose from Namin and Pivopril. For example, ARBs include Candesalta. Candesartan cilexetil, eprosartan, irbesartan, losartan, ol Mesartan, olmesartan medoxomil, telmisartan, valsartan, azilsal You can choose between tammedoxomil and BRA-657.

[0151] In some embodiments, the subjects are also administered one or more additional drugs. In some embodiments, one or more additional agents include calcineurin inhibitors, pro Theasomal inhibitors, aminoquinolines, complement inhibitors, B cell inhibitors, cytotoxic agents, mTOR Inhibitors and steroids are selected. In some embodiments, one or more additional The dosage of the additional drug is approximately the same as the treatment with atrasentan or a pharmaceutically acceptable salt. After 15 to approximately 30 days, the levels decrease. In some embodiments, one or more additional drugs are used. It is an immunosuppressant.

[0152] In some embodiments, the subjects are not currently receiving one or more additional medications. In certain embodiments, the subject is atrasentan or a pharmaceutically acceptable salt thereof. Prior to administering drug 1, the patient had not used one or more additional medications for more than two weeks within the past six months.

[0153] In some embodiments, one or more additional agents include calcineurin inhibitors, p Loteasome inhibitors, aminoquinolines, complement inhibitors, B cell inhibitors, cytotoxic agents, mTO The choice is made from R inhibitors and steroids.

[0154] In certain embodiments, one or more additional agents are steroids. For example, one The additional medications listed above are prednisone, dexamethasone, hydrocortisone, and cyclosporine. You can choose from a group consisting of n and any of the aforementioned combinations.

[0155] In certain embodiments, one or more additional agents are aminoquinolines. For example, One or more additional drugs may be hydroxychloroquine.

[0156] In some embodiments, the subject is one or more additional treatments with atrasentan. The patient is receiving the medication. In certain embodiments, the dosage of one or more additional medications is at After treatment with spiralan 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 Between 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, The levels decrease after 180 weeks, 190 weeks, or 200 weeks of treatment. In some cases, the dosage of one or more additional drugs is atrasentan or its pharmaceutical The decrease occurs approximately 15 to 30 days after treatment with a moderately acceptable salt. In some cases, the dosage of additional medication is reduced by approximately 10% to 100%. Specific implementation In this morphology, the dosage of additional drugs is reduced by approximately 15% to approximately 100%. Specific Embodiments In this case, the dosage of additional drugs is reduced by approximately 20% to approximately 100%. In addition, the dosage of additional medication is reduced by approximately 25% to approximately 100%. In certain embodiments, The dosage of additional drugs is reduced by approximately 30% to approximately 100%. In certain embodiments, The dosage of the additional drug is reduced by approximately 35% to approximately 100%. In certain embodiments, additional The dosage of the drug is reduced by approximately 40% to approximately 100%. In certain embodiments, additional drugs The dosage is reduced by approximately 45% to approximately 100%. In certain embodiments, the administration of additional drugs The dosage is reduced by approximately 50% to 100%. In certain embodiments, the dosage of additional drugs This decreases by approximately 55% to approximately 100%. In certain embodiments, the dosage of additional drugs is It decreases by approximately 60% to approximately 100%. In certain embodiments, the dosage of the additional drug is approximately 6 The dose decreases by 5% to approximately 100%. In certain embodiments, the dose of additional drugs decreases by approximately 70%. ~Decreases by approximately 100%. In certain embodiments, the dosage of additional drugs is reduced by approximately 75% ~ It decreases by 100%. In certain embodiments, the dosage of the additional drug is approximately 80% to approximately 10%. It decreases by 0%. In certain embodiments, the dosage of the additional drug is approximately 85% to approximately 100%. The dosage decreases. In certain embodiments, the dosage of the additional drug decreases by approximately 90% to approximately 100%. In some of the embodiments described above, the dosage of one or more additional drugs is determined by the atrace Treatment with anthan or a pharmaceutically acceptable salt takes approximately 15 to 30 days (for example, approximately It decreases after 15 days, approximately 20 days, approximately 25 days, or approximately 30 days. When the dosage of additional medication is reduced by 100%, the subject no longer needs additional medication. do not have.

[0157] In certain embodiments, the dosage of one or more steroids is atrasentan or so After treatment with a pharmaceutically acceptable salt of, for example, atrasentan or its pharmaceutically acceptable The decrease occurs approximately 15 to 30 days after treatment with the salt. Therefore, the steroid dosage is reduced by approximately 10% to approximately 100%, as described herein. In some embodiments, prednisone, dexamethasone, hydrocortisone, The dosage of cyclosporine, or any combination of the above, is equivalent to that of atrasentan. Alternatively, after treatment with a pharmaceutically acceptable salt thereof, the risk is reduced by approximately 10% to 100%.

[0158] In certain embodiments, the dosage of one or more aminoquinolines is equal to that of atrasentan or After treatment with its pharmaceutically acceptable salt, for example, atrasentan or its pharmaceutically acceptable The decrease occurs approximately 15 to 30 days after treatment with acceptable salts. In this specification, the dosage of aminoquinoline is approximately 10% to approximately 100% The % decreases. In some embodiments, the dose of hydroxychloroquine is reduced. After treatment with thontan or its pharmaceutically acceptable salts, the symptoms are reduced by approximately 10% to 100%. .

[0159] In some embodiments, the subject receives one or more additional therapeutic agents simultaneously. One or more additional therapeutic agents are described herein. For example, the subject is renin-an The patient is simultaneously receiving an inhibitor of one or more elements of the giotensin-aldosterone system. In certain embodiments, the subjects are SGLT-2 inhibitors, ACE inhibitors, ARBs, and stats. Diuretics, calcium channel blockers, beta-blockers, aldosterone antagonists , fish oil, hydroxychloroquine, or any combination of the above simultaneously In some of these embodiments, the subjects are simultaneously receiving an SGLT-2 inhibitor. In some of these embodiments, the subject is an ACE inhibitor, an ARB, or a similar. These combinations are being received simultaneously. In a particular embodiment, the target is Atorbastachi Fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin , and simultaneously receiving one or more statins such as pitavastatin. Specific Embodiments In this study, the subjects were hydrochlorothiazide, trichlormethiazide, and hydroflumethiazide. D, Kinetazon, Methrazon, Chlorthiazide, Chlorthalidone, Indapamide, Methic Rothiazidobemetanide, torsemide, pyretanide, ethacrine, bumetanide, furosemide One of the following: diuretic, triamterene, spironolactone, eplerenone, and amyloride The above diuretics are being taken simultaneously. In certain embodiments, the subject is canagliflozin, SGLT-2 such as dapagliflozin, empagliflozin, or erzgliflozin The patient is receiving the inhibitor simultaneously. In certain embodiments, the subject is quinapril, fosinop Lil Perindopril, Captopril, Enalapril, Enalaprilat, Ramipril Cilazapril, Delapril, Fosenopril, Zofenopril, Indolapril, Benazepam Prill, Lysinopril, Spirapril, Trandolapril, Perindep, Pentopril, One or more ACE inhibitors such as moexipril, resinamin, and pivopril are used simultaneously. It is being received. In a particular embodiment, the subject is candesartan, candesartan silec. Cetyl, eprosartan, irbesartan, losartan, olmesartan, olmesartan Medoxomil, telmisartan, valsartan, azilsartan medoxomil, and They are also receiving ARBs such as BRA-657. In certain embodiments, the subject is The patient is receiving both a urinary drug and an ACE inhibitor or ARB simultaneously. In certain embodiments, The elephant is receiving diuretics, ACE inhibitors, and ARBs simultaneously. In certain embodiments, The subjects are diuretics and SGLT-2 inhibitors, as well as ACE inhibitors or ARBs. It is sometimes received. In certain embodiments, the subjects are diuretics, SGLT-2 inhibitors, AC The patient is simultaneously receiving an E inhibitor and an ARB. In certain embodiments, one or more additional Patients receiving these medications simultaneously have not previously received one or more of these medications. For example, SGLT-2 inhibitors that have never been administered before Those receiving both treatments simultaneously.

[0160] In some embodiments, the subject is one or more additional subjects, such as those described herein. I have received other treatments before, but not simultaneously. For example, the subject is Honmei As detailed in the manual, SGLT-2 inhibitors, ACE inhibitors, ARBs, statins, diuretics Drugs, calcium channel blockers, beta-blockers, aldosterone antagonists, fish oil, hydrochloride I have previously received cycloloquine, or any of the aforementioned combinations, Sometimes not. In some of these embodiments, the subject is an SGLT-2 inhibitor. I have received this treatment before, but not at the same time.

[0161] In some embodiments, the subject is atrasentan or a pharmaceutically acceptable substance. Prior to the first dose of salt, cellular glomerular crescents present in less than 25% of glomeruli within 6 months. It has a body. For example, the subject is approximately 25%, 20%, 15%, 10%, and 5% of the glomerulus. It has cellular glomerular crescents present in %, or about 1%, or any value in between. Obtain. In some embodiments, the subject has cellular glomerular crescents present in the glomerulus. No. In certain embodiments, the subject is a clinically diagnosed patient with rapidly progressive glomerulonephritis (RPGN). It is not under suspicion.

[0162] In some embodiments, the subject is atrasentan or a pharmaceutically acceptable substance. Prior to the first administration of salt, the patient had not received an organ transplant.

[0163] In some embodiments, the subject is atrasentan or a pharmaceutically acceptable substance. Prior to the first dose of salt, the patient has a systolic blood pressure of less than approximately 160 mmHg. For example, the subject is: Approximately less than 155 mmHg, approximately less than 150 mmHg, approximately less than 145 mmHg, or approximately 140 mmHg The systolic blood pressure may be less than mmHg. In some embodiments, the subject is atrase Before the first dose of thontan or a pharmaceutically acceptable salt thereof, reduce blood glucose levels to less than approximately 100 mmHg. They have tonic blood pressure. For example, the subjects are those with a blood pressure of less than approximately 100 mmHg, less than approximately 95 mmHg, and The subject may have a diastolic blood pressure of less than approximately 90 mmHg. In some embodiments, the subject is Systolic blood pressure of approximately 100 mmHg to 130 mmHg and approximately 70 mmHg to 90 mmHg He has a diastolic blood pressure of g.

[0164] In some embodiments, the subject is atrasentan or a pharmaceutically acceptable substance. Prior to the first administration of salt, the patient had never been diagnosed with heart failure. In some embodiments, The subjects were those with fluid overload prior to the first dose of atrasentan or a pharmaceutically acceptable salt thereof. I have never been hospitalized before for a condition related to this. Non-specific examples of the condition include control This includes peripheral edema, pleural effusion, or ascites that have not been observed. In some embodiments, The elephants were clinically severe before the first dose of atrasentan or a pharmaceutically acceptable salt thereof. He has never been diagnosed with a serious liver disease. In some embodiments, the target transamina The enzyme or bilirubin level is the first of the atracentan or pharmaceutically acceptable salts. Before administration, the ALT level should be no more than twice the normal upper limit. For example, the target ALT level is approximately 110 U. Less than / L (for example, less than approximately 100U / L, less than 90U / L, less than approximately 80U / L, approximately 70U) Less than / L, less than approximately 60U / L, less than approximately 50U / L, or less than approximately 40U / L, or (Any value between these). As another example, the target AST level is less than 100 U / L. (For example, less than 90 U / L, less than approximately 80 U / L, less than approximately 70 U / L, less than approximately 60 U / L, (less than approximately 50 U / L, or less than approximately 40 U / L, or any value in between). As yet another example, the bilirubin level in question is less than approximately 2.5 mg / dL (for example, approximately Less than 2 mg / dL, less than approximately 1.5 mg / dL, less than approximately 1.4 mg / dL, approximately 1.3 mg / Less than dL, less than approximately 1.2 mg / dL, less than approximately 1.1 mg / dL, less than approximately 1.0 mg / dL (or less than approximately 0.9 mg / dL, or any value in between).

[0165] In some embodiments, the subject is atrasentan or a pharmaceutically acceptable substance. Before the first dose of salt, if the concentration is greater than approximately 9 g / dL (for example, approximately 10 g / dL, approximately 11 g / dL, approximately Hemoglobin (12 g / dL, or approximately 13 g / dL or any value in between) It has a certain level. In some embodiments, the subject is atrasentan or its drug Before the first dose of a scientifically acceptable salt, at least approximately 3 months (for example, approximately 4 months) I have not received a blood transfusion for anemia for approximately 5 months, 6 months, or 1 year. In some embodiments, the subject is atrasentan or a pharmaceutically acceptable salt thereof. Prior to the first dose, the patient had not been diagnosed with cancer for at least five years. Several implementations In this state, the subject is before the first administration of atrasentan or a pharmaceutically acceptable salt thereof. Furthermore, you must not have been diagnosed with cancer (for example, lung cancer or prostate cancer) in the past five years. i. In some embodiments, non-melanoma skin cancer that does not require treatment and is progressing. Otherwise, the subject should be present before the first dose of atrasentan or a pharmaceutically acceptable salt thereof. They have not been diagnosed with cancer for at least five years. In some embodiments, Unless it is an ongoing non-melanoma skin cancer that does not require treatment, the target is atrasentan. or the person does not have cancer prior to the first dose of the pharmaceutically acceptable salt thereof. Several implementations Morphologically, the subjects are not non-melanoma skin cancers that are progressing and do not require treatment. Prior to the first dose of atrasentan or a pharmaceutically acceptable salt thereof, patients who have cancer No. In some embodiments, non-melanoma skin cancer that does not require treatment. Unless it is cancer, the subject is given the first dose of atrasentan or a pharmaceutically acceptable salt thereof. Prior to this, he had not received cancer treatment for at least five years.

[0166] In some embodiments of the methods, uses, or products for use described herein, the subject This includes having one or more of the following conditions: diabetic nephropathy, HIV / AIDS, or acute renal failure. Never diagnosed. Some actual methods, uses, or uses of the product described herein. In terms of treatment methods, the target population includes those with diabetic nephropathy, HIV / AIDS, and cancer (e.g., prostate cancer). You have never been diagnosed with one or more of the following: lung cancer or acute renal failure. In some embodiments, the target is diabetic nephropathy, HIV / AIDS, prostate cancer. They have never been diagnosed with one or more of the following conditions: or acute renal failure. In terms of administration methods, the target patients are those with diabetic nephropathy, HIV-related nephropathy, prostate cancer, or acute renal failure. One or more of the above have never been diagnosed before. In some embodiments, The target patients include those with diabetic nephropathy, HIV-related nephropathy, and cancer (e.g., lung cancer or prostate cancer). Or, never having been previously diagnosed with one or more of the following acute renal failures. Morphologically, the target is one of the following: diabetic nephropathy, HIV-related nephropathy, or acute renal failure. The above has never been diagnosed before. In a specific embodiment, the subject is diabetic nephropathy. The subject has never been diagnosed with the disease. In certain embodiments, the subject is HIV / AI The patient has never been diagnosed with DS. In certain embodiments, the subject is acute renal failure. This has never been diagnosed before. In certain embodiments, the subject is HIV-related nephropathy. It has never been diagnosed as such before. In a particular embodiment, the subject has been diagnosed with cancer. Never. In a specific embodiment, the subject has never been diagnosed with prostate cancer. In certain embodiments, the subject has never been diagnosed with lung cancer. The target group includes one of the following: diabetic nephropathy, HIV / AIDS, and acute renal failure. It has never been diagnosed before. In a particular embodiment, the subject is diabetic nephropathy. , HIV / AIDS, prostate cancer, and acute renal failure (all of the above) Never diagnosed. In certain embodiments, the subjects are diabetic nephropathy, HIV-related kidney disease. If you have ever been diagnosed with any one of the following: prostate cancer, or acute renal failure No. In certain embodiments, the subjects are diabetic nephropathy, HIV-related nephropathy, and acute kidney disease. Never previously diagnosed with any of the following deficiencies. The methods and uses described herein. Alternatively, in some embodiments of the product for use, the subject is diabetes and previously diagnosed Never been dismissed. Any implementation of the methods, uses, or products for use described herein. Morphologically, the subjects have never been diagnosed with type 2 diabetes. In some cases, the subjects are controlled serum as described elsewhere in this specification. It has been determined that it has glucose levels.

[0167] In some embodiments, the target is diabetic nephropathy, HIV / AIDS, or acute The patient does not have one or more of the following conditions of renal failure. In some embodiments, the subject is diabetic nephropathy. Not having one or more of the following: disease, HIV / AIDS, prostate cancer, or acute renal failure. In some embodiments, the target is diabetic nephropathy, HIV-related nephropathy, prostate cancer, and The subject does not have one or more of the acute renal failures. In some embodiments, the subject has diabetes Not having one or more of the following: diseased nephropathy, HIV-associated nephropathy, or acute renal failure. Specific implementation Morphologically, the subject does not have diabetic nephropathy. In a particular embodiment, the subject is , not having HIV / AIDS. In certain embodiments, the subject has acute renal failure. Not done. In certain embodiments, the subject does not have HIV-related nephropathy. In one embodiment, the subject does not have prostate cancer. In a specific embodiment, the subject This includes having one or more of the following conditions: diabetic nephropathy, HIV / AIDS, and acute renal failure. No. In certain embodiments, the subjects are diabetic nephropathy, HIV / AIDS, and prostate problems. Neither of the above, nor acute renal failure. In certain embodiments, The target group includes any of the following conditions: diabetic nephropathy, HIV-related nephropathy, prostate cancer, and acute renal failure. It does not have any of the above. In certain embodiments, the subject is diabetic nephropathy, HIV-related kidney The patient does not have any of the following conditions: The subjects do not have diabetes. In some embodiments, the subjects have type 2 diabetes. It does not have. In some of the embodiments described above, the subject is described elsewhere in this specification. As indicated, the patient has been determined to have controlled serum glucose levels.

[0168] In some embodiments, the target is diabetic nephropathy, HIV / AIDS, or acute Not suffering from one or more of the conditions of renal failure. In some embodiments, the subjects are diabetes If you have one or more of the following conditions: diseased nephropathy, HIV / AIDS, prostate cancer, or acute renal failure Not applicable. In some embodiments, the subjects are diabetic nephropathy, HIV-related nephropathy, prostate Not suffering from one or more of the following: adenocarcinoma or acute renal failure. In some embodiments The target group includes those suffering from one or more of the following conditions: diabetic nephropathy, HIV-related nephropathy, or acute renal failure. Not suffering from the disease. In certain embodiments, the subject does not suffer from diabetic nephropathy. In this embodiment, the subjects are not HIV / AIDS. The subjects are not suffering from acute renal failure. In certain embodiments, the subjects have HIV. The subject is not suffering from related nephropathy. In certain embodiments, the subject is suffering from prostate cancer. No. In certain embodiments, the subjects are diabetic nephropathy, HIV / AIDS, and acute The subject does not have any of the conditions of renal failure. In certain embodiments, the subject has diabetes. Having one of the following conditions: diseased nephropathy, HIV / AIDS, prostate cancer, or acute renal failure. Not affected. In certain embodiments, the subjects are diabetic nephropathy, HIV-related nephropathy, prostate The patient is not suffering from either adenocarcinoma or acute renal failure. In certain embodiments, The target group is one of the following: diabetic nephropathy, HIV-related nephropathy, and acute renal failure. They are also not suffering from diabetes. In some embodiments, the subjects are not suffering from diabetes. In some embodiments, the subjects do not have type 2 diabetes. In some cases, the subjects are controlled serum glucose as described elsewhere in this specification. It has been determined to have a course level.

[0169] In some embodiments, the target is diabetic nephropathy, HIV / AIDS, or acute The subject is not receiving treatment for one or more conditions of renal failure. In some embodiments, the subject is Treatment for one or more of the following: diabetic nephropathy, HIV / AIDS, prostate cancer, or acute renal failure. Not receiving treatment. In some embodiments, the subjects are diabetic nephropathy, HIV-related kidney Not receiving treatment for one or more of the following: disease, prostate cancer, or acute renal failure. In this embodiment, the target is one of the following conditions: diabetic nephropathy, HIV-related nephropathy, or acute renal failure. Not receiving one or more treatments. In certain embodiments, the subject is the treatment of diabetic nephropathy. Not receiving. In certain embodiments, subjects are receiving treatment for HIV / AIDS. No. In certain embodiments, the subjects are not receiving treatment for acute renal failure. Morphologically, the subjects are not receiving treatment for HIV-related nephropathy. In a specific embodiment, The subjects are not receiving treatment for prostate cancer. In certain embodiments, the subjects have diabetes. Not receiving treatment for any one of the following: sexually transmitted nephropathy, HIV / AIDS, or acute renal failure. i. In certain embodiments, the target is diabetic nephropathy, HIV / AIDS, prostate cancer, and not receiving treatment for any of the following acute renal failures. In certain embodiments The target group includes diabetic nephropathy, HIV-related nephropathy, prostate cancer, and acute renal failure. None of the treatments have been received. In certain embodiments, the subjects are diabetic nephropathy, HI They are not receiving treatment for either V-related nephropathy or acute renal failure. In some embodiments, the subjects are not receiving treatment for diabetes. The subjects are not receiving treatment for type 2 diabetes. In some of the embodiments described above, the subjects This has controlled serum glucose levels, as described elsewhere in this specification. It has been determined that...

[0170] In some embodiments, the subject is found to have controlled serum glucose levels. The patient is diagnosed with one or more of the following conditions: HIV-related nephropathy or acute renal failure. It has never been interrupted. In certain embodiments, the subject is controlled serum glucose level It has been determined that it has the flu. For example, the subjects were approximately 130 mg / dL and approximately 125 mg / dL. 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 approximately 75 mg / dL, or any value in between. It is determined that the serum glucose level is present. In certain embodiments, the subject is H Never having been diagnosed with one or more of the following: IV-related nephropathy or acute renal failure. Specific implementation In this state, the subject is controlled serum glucose as described elsewhere in this specification. The patient has been diagnosed with a level, and the target group is those with HIV-related nephropathy or acute renal failure. I have never been diagnosed with more than one condition.

[0171] In some embodiments, the subjects are those with chronic kidney disease other than IgA nephropathy and those who have not previously been diagnosed with it. It has never been done. Non-specific examples include diabetic nephropathy, hypertensive nephropathy, or IgA This includes primary glomerulostomies that are not associated with nephropathy. In certain mechanisms, The elephant has never been diagnosed with diabetic kidney disease. In certain embodiments, The elephant has never been diagnosed with hypertensive kidney disease. In certain embodiments, Elephants have never been diagnosed with primary glomerulopathy that is not associated with IgA nephropathy.

[0172] In some embodiments, the subjects do not have chronic kidney disease other than IgA nephropathy. Typical cases are those determined not to be associated with diabetic nephropathy, hypertensive nephropathy, or IgA nephropathy. This includes primary glomerulosis. In certain embodiments, the subject is diabetic nephropathy. Not present. In certain embodiments, the subject does not have hypertensive nephropathy. In this context, the subjects do not have primary glomerulopathy that is determined to be unrelated to IgA nephropathy.

[0173] In some embodiments, the subjects are not suffering from chronic kidney disease other than IgA nephropathy. Non-limiting examples include those not associated with diabetic nephropathy, hypertensive nephropathy, or IgA nephropathy. This includes primary glomerulosis that is diagnosed as such. In certain embodiments, the subject is diabetic nephropathy. The subject is not suffering from the disease. In certain embodiments, the subject is suffering from hypertensive nephropathy. No. In certain embodiments, the subject is primary filaments that are determined not to be associated with IgA nephropathy. I do not have bulbar dysplasia.

[0174] In some embodiments, the subjects are those receiving treatment for chronic kidney disease other than IgA nephropathy. No. Non-limiting examples include those associated with diabetic nephropathy, hypertensive nephropathy, or IgA nephropathy. This includes primary glomerulosis that is determined to be absent. In certain embodiments, the subject is diabetes. The subject is not receiving treatment for hypertensive kidney disease. In certain embodiments, the subject is not receiving treatment for hypertensive kidney disease. Not receiving treatment. In certain embodiments, the subject is determined not to be associated with IgA nephropathy. He is not receiving treatment for primary glomerulosis.

[0175] Treatment outcome In some embodiments of the methods, uses, or products for use described herein, nephritis The symptoms decrease after treatment with atrasentan or a pharmaceutically acceptable salt thereof. In that embodiment, renal inflammation in the subject is treated with atrasentan or pharmaceutically effective After treatment with acceptable salts (e.g., 1 week, approximately 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, 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 Between approximately 110 weeks, 120 weeks, 130 weeks, 140 weeks, 150 weeks, and 16 weeks, the intervals are approximately 110 weeks, 120 weeks, 130 weeks, 140 weeks, 150 weeks, and 16 weeks. 0 weeks, approximately 170 weeks, approximately 180 weeks, approximately 190 weeks, or approximately 200 weeks, or After treatment of any value between these, the decrease is at least about 10%. In some embodiments And, in the subjects, kidney inflammation was at least about 20%, about 30%, about 40%, and about 50%. Approximately 60%, 70%, 80%, 90%, or 95%, or somewhere in between. The value decreases. In some of the embodiments described above, the subject is for about 15 to about 30 days. The patient is being treated with atrasentan or a pharmaceutically acceptable salt thereof.

[0176] In some embodiments, renal fibrosis is treated with atrasentan or a pharmaceutically acceptable drug. It decreases after treatment with salts. In some embodiments, renal fibrosis in subjects , after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., 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 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 (After treatment for at least 10 weeks, or approximately 200 weeks, or any value in between), It decreases by %. In certain embodiments, renal fibrosis in the subject decreases by at least about 20%. Approximately 30%, approximately 40%, approximately 50%, approximately 60%, approximately 70%, approximately 80%, approximately 90%, or approximately It decreases by 95%, or any value in between. In some of the embodiments described above, The elephants were treated with atrasentan or a pharmaceutically acceptable salt thereof for approximately 15 to 30 days. It is being done.

[0177] In some embodiments, renal fibrosis in a subject is treated with atrasentan or the drug After treatment with a scientifically acceptable salt (e.g., 1 week, approximately 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, approximately 20 weeks, approximately 30 weeks Between approximately 40 weeks, 50 weeks, 60 weeks, 70 weeks, 80 weeks, 90 weeks, and 1 0 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, After treatment of any value between those, the cortical area decreases by less than 50%. Specific implementation In this state, renal fibrosis in the subject is reduced by less than 40% in the cortical region. For example, In several embodiments, renal fibrosis in the subjects was present in approximately 35%, approximately 30%, and approximately in the cortical region. Up to 25%, approximately 20%, approximately 15%, or less than approximately 10%, or any value in between. It decreases. In some of the embodiments described above, the subject is at a rate of approximately 15 to 30 days. It is being treated with sentan or a pharmaceutically acceptable salt thereof.

[0178] In some embodiments, the occurrence of hematuria is due to atrasentan or its pharmaceutically acceptable After treatment with the salt, the amount decreases in the subject. In some embodiments, the subject The number of red blood cells in urine per high-magnification (microscope) field of view (rbc / hpf) is atracenta After treatment with o or a pharmaceutically acceptable salt thereof (e.g., 1 week, about 2 weeks, about 3 weeks) Approximately 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, 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 approximately 2 After 0 weeks of treatment, it decreases by at least about 10%. In certain embodiments, the subject The urinary RBC / HPF is reduced by at least about 20%. For example, in some embodiments In this study, the urinary RBC / HPF ratio in the subjects was at least approximately 30%, approximately 40%, and approximately 50%. %, approximately 60%, approximately 70%, approximately 80%, approximately 90%, or approximately 95%, or somewhere in between. An arbitrary value is decreased. In some of the embodiments described above, the subject is approximately 15 to 30 days. They are being treated with atrasentan or a pharmaceutically acceptable salt thereof.

[0179] In some embodiments, the rate of decrease of the target eGFR is determined by atracentan or After treatment with pharmaceutically acceptable salts (e.g., 1 week, 2 weeks, 3 weeks, approximately 4 weeks, approximately 5 weeks) 1 week, approximately 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 10 0 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, After treatment of any value between those, the levels are reduced by at least about 10%. And the rate of decrease in the target eGFR is reduced by at least about 20%. For example, several actual In the application method, the reduction rate of the target eGFR was at least approximately 30%, approximately 40%, and approximately 50%. Approximately 60%, 70%, 80%, 90%, or 95%, or somewhere in between. The value of intent is reduced. In some of the embodiments described above, the subject is for about 15 to about 30 days. The patient is treated with atrasentan or a pharmaceutically acceptable salt thereof. In some cases, the subjects were given atrasentan or a pharmaceutically acceptable substance for approximately 6 months to 1 year. It is being treated with salt.

[0180] In some embodiments, the rate of decrease of the target eGFR is determined by atracentan or After treatment with pharmaceutically acceptable salts (e.g., approximately 1 week, 2 weeks, 3 weeks, 4 weeks) Approximately 5 weeks, approximately 6 weeks, approximately 7 weeks, approximately 8 weeks, approximately 9 weeks, approximately 10 weeks, approximately 20 weeks, approximately 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 Between approximately 160 weeks, 170 weeks, 180 weeks, 190 weeks, or 200 weeks After treatment (or any value in between), the reduction is less than approximately 10 mL / min per year. In this embodiment, the rate of decrease in the target eGFR is reduced to less than approximately 9 mL / min per year. However, in some embodiments, the rate of decrease in the target eGFR is less than approximately 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, approximately 4 mL / min per year Less than one minute, less than approximately 3 mL / min per year, less than approximately 2 mL / min per year, or less than approximately 1 mL / min per year. or any value between them. In some of the embodiments described above, the subject is Treatment with atrasentan or a pharmaceutically acceptable salt for approximately 15 to 30 days. In some of the embodiments described above, the subject is atracentan for about 6 months to about 1 year. or it is being treated with a pharmaceutically acceptable salt thereof.

[0181] In some mechanisms, the risk of developing ESRD in subjects is reduced by atracentan. or after treatment with the pharmaceutically acceptable salt (for example, 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, approximately 40 weeks, approximately 50 weeks, approximately 60 weeks, approximately 70 weeks, approximately 80 weeks, approximately 90 weeks Weeks, approximately 100 weeks, approximately 110 weeks, approximately 120 weeks, approximately 130 weeks, approximately 140 weeks, approximately 1 50 weeks, approximately 160 weeks, approximately 170 weeks, approximately 180 weeks, approximately 190 weeks, or approximately 20 After 0 weeks (or any value of treatment during those weeks), the reduction is approximately 20% to 99%. For example The risk of developing ESRD in the target group is approximately 20%, 25%, 30%, 35%, and 4%. 0%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 8 It can be reduced to 0%, approximately 85%, approximately 90%, or approximately 99%, or any value in between. In some of the embodiments described above, the subjects received treatment for approximately 90 to 180 days. In certain embodiments, the risk of developing ESRD in individuals is increased by atrasentan. Approximately 90 to 180 days after treatment with the pharmaceutically acceptable salt, about 20% to 9 It reduces by 9%. In some of the embodiments described above, the target is approximately 6 months to approximately 1 year. The patient is being treated with spiralan or a pharmaceutically acceptable salt thereof.

[0182] In some embodiments, this method is used to diagnose IgA nephropathy in subjects and to e GFR is approximately 15 mL / min / 1.73 m² 2 Increase the time between the time below a certain limit. In terms of application, this method diagnoses IgA nephropathy in the subject and assesses the subject's eGFR when it is 15m L / min / 1.73m 2 Increase the time between the time below and the time below by at least approximately 10%. For example In some embodiments, this method is used to diagnose IgA nephropathy in subjects and to assess the subjects eGFR of 15 mL / min / 1.73 m² 2 The time between the above and below should be at least approximately 20% Approximately 30%, 40%, 50%, 60%, 70%, 80%, 90%, and 95% Approximately 100%, approximately 150%, approximately 200%, approximately 250%, approximately 300%, approximately 350%, approximately 40 Increase by 0%, approximately 450%, approximately 500%, or any value in between.

[0183] In some embodiments, this method is used to diagnose IgA nephropathy in subjects and to e GFR of 15 mL / min / 1.73 m 2 Increase the time between the above and below by at least approximately one year. For example, this method is used when the target eGFR is 15 mL / min / 1.73 m 2 time less than This will take at least approximately 1.5 years, approximately 2 years, approximately 2.5 years, approximately 3 years, approximately 3.5 years, approximately 4 years, and approximately 4 years. 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 in between. It can be delayed by any value.

[0184] In some embodiments, the method involves atrasentan or a pharmaceutically acceptable substance. Before the first dose of the salt, at least approximately 3 months (for example, at least approximately 4 months) At least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months Between, for at least approximately 9 months, at least approximately 10 months, at least approximately 11 months, less (For both approximately 1 year, at least approximately 1.5 years, or at least approximately 2 years), the average eGFR The rate of decrease is reduced from approximately 0.75 mL / min / year to approximately 6 mL / min / year. For example, this method is e The average rate of decrease in GFR is approximately 0.75 mL / min / year, approximately 1 mL / min / year, and approximately 1.5 mL / min / year. / 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 This reduces the flow rate by approximately 6 mL / year or about 6 mL / min / year. In some embodiments, this method reduces the flow rate by approximately 6 mL / year. Prior to the first dose of lusentan or a pharmaceutically acceptable salt, e Reduce the average rate of decline in GFR by approximately 4 mL / min / year to approximately 5 mL / min / year. Several implementation methods In this procedure, before the first administration of atrasentan or a pharmaceutically acceptable salt, For at least about 3 months, the average rate of decrease in eGFR was approximately 3 mL / min / year to approximately 6 mL / min / year. Reduce. In some embodiments, this method uses atracentane or pharmaceutically acceptable Prior to the first dose of the salt, the mean rate of decrease in eGFR was reduced by approximately 4 mL for at least about 3 months. This reduces the amount by approximately 5 mL / min / year. In some embodiments, the mL / min / year The decrease in eGFR was 1.73 m 2 It refers to the unit per serving.

[0185] In some embodiments, the method involves atrasentan or a pharmaceutically acceptable substance. Approximately 6 to 24 months after treatment with salt, the average rate of decrease in eGFR was approximately 15% to 3%. It reduces by 0%. Through several mechanisms, the average rate of decrease in eGFR is atlasentan or approximately 6 months, 9 months, 12 months, and 15 months after treatment with a pharmaceutically acceptable salt thereof. After 18 months, 21 months, or 24 months, it may be reduced by approximately 15%. (Several embodiments) In this context, the mean rate of eGFR decline is determined by atrasentan or its pharmaceutically acceptable salt. Approximately 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months after treatment. After several months, it can be reduced by approximately 20%. In some embodiments, the average rate of decrease in eGFR is Approximately 6 months, 9 months, 1 month after treatment with atrasentan or a pharmaceutically acceptable salt. It can be reduced by approximately 25% after 2 months, 15 months, 18 months, 21 months, or 24 months. In several embodiments, the mean rate of eGFR reduction is determined by atrasentan or its pharmaceutically acceptable properties. Treatment with tolerable salts began approximately 6 months, 9 months, 12 months, 15 months, 18 months, and 21 months later. It can be reduced by approximately 30% after 1 month or 24 months.

[0186] In another embodiment, a method for reducing proteinuria, which is used in treatment for a person in need. 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 (for example, 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, 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 After weeks, or approximately 200 weeks, or any value of treatment in between, at least approximately 1 Reduced by 0%. In some embodiments, the amount of protein in the target urine is reduced to as little as It is also reduced by about 15%. For example, in some embodiments, the amount of protein in the target urine The amounts are at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, and about 8%. Reduce by 0%, approximately 90%, approximately 95%, or any value in between. (See above implementation) In some forms, the subject is atrasentan or drug for approximately 15 to 30 days. It is being treated with scientifically acceptable salts.

[0188] In a particular embodiment, the amount of protein (e.g., albumin) in the urine of the subject is A Approximately 15 to 30 days after treatment with tracentan or a pharmaceutically acceptable salt thereof, It reduces the amount of phlegm in the urine of the subject by approximately 20% to 80%. In some of these embodiments, The amount of protein is reduced by approximately 25% to approximately 80%. In some of these embodiments, The amount of protein in elephant urine is reduced by approximately 30% to 80%. In this case, the amount of protein in the urine of the subject is reduced by approximately 35% to approximately 80%. In some application methods, the amount of protein in the target urine was reduced by approximately 40% to 80%. In some of these embodiments, the amount of protein in the urine of the subject is approximately 45%~ It reduces by approximately 80%. In some of these embodiments, the amount of protein in the urine of the subject This reduces emissions by approximately 50% to 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 (for example, 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, 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 Approximately 100 mg / (after treatment for weeks, or approximately 200 weeks, or any value in between) Reduces protein levels by approximately 3,000 mg / dL. In a specific embodiment, the protein in the urine of the subject The amount of chlorine is reduced by approximately 100 mg / dL to approximately 2500 mg / dL. The amount of protein in the urine of the subjects ranged from approximately 100 mg / dL to approximately 2,000 mg / dL. Reduce. In certain embodiments, the amount of protein in the urine of the subject is approximately 100 mg / dL. Reduces by approximately 1,500 mg / dL. In certain embodiments, the protein in the urine of the subject is reduced. The amount is reduced by approximately 100 mg / dL to approximately 1,000 mg / dL. In a specific embodiment, As a result, the amount of protein in the target urine is reduced by approximately 100 mg / dL to approximately 500 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is approximately 100 mg / dL to approximately 4 Reduces by 00 mg / dL. In a particular embodiment, the amount of protein in the target urine is approximately It reduces the level by 100 mg / dL to approximately 300 mg / dL. In a specific embodiment, the urine of the target The amount of protein is reduced by approximately 100 mg / dL to approximately 200 mg / dL. Specific implementations In this state, the amount of protein in the subject's urine is approximately 500 mg / dL to approximately 2,500 mg / dL. It reduces by dL. In a particular embodiment, the amount of protein in the target urine is approximately 500 mg. Reduces sputum levels in the urine of the subject by approximately 2,000 mg / dL. In a specific embodiment, sputum levels in the urine of the subject are reduced by approximately 2,000 mg / dL. The amount of protein is reduced by approximately 500 mg / dL to approximately 1,500 mg / dL. Specific embodiment In this study, the amount of protein in the urine of the subject ranged from approximately 500 mg / dL to approximately 1,000 mg / dL. L is reduced. In a particular embodiment, the amount of protein in the target urine is approximately 500 mg / Reduces dL to approximately 900 mg / dL. In a specific embodiment, the protein in the urine of the target subject is reduced. The amount is reduced by approximately 500 mg / dL to approximately 800 mg / dL. In certain embodiments, The amount of protein in the target urine will be reduced by approximately 600 mg / dL to approximately 900 mg / dL. In a specific embodiment, the amount of protein in the target urine is approximately 700 mg / dL to approximately 900 mg / dL Reduces mg / dL. In a particular embodiment, the amount of protein in the target urine is approximately 1 mg. It reduces the odor from 000 mg / dL to approximately 2,000 mg / dL. The subjects were given atrasentan or a pharmaceutically acceptable salt thereof for approximately 15 to 30 days. He is receiving treatment.

[0190] In a particular embodiment, the amount of protein (e.g., albumin) in the urine of the subject is A Approximately 15 to 30 days after treatment with tracentan or a pharmaceutically acceptable salt thereof, It reduces the level by 100 mg / dL to approximately 500 mg / dL. In a specific embodiment, the urine of the subject The amount of protein is approximately [amount missing] from treatment with atrasentan or a pharmaceutically acceptable salt. After 15 to approximately 30 days, the level will decrease by approximately 200 mg / dL to approximately 500 mg / dL. Specific implementation Morphologically, the amount of protein in the subject's urine is determined by atrasentan or its pharmaceutically acceptable Approximately 15 to 30 days after treatment with the salt, the dose is approximately 300 mg / dL to 500 mg / dL. Reduce L.

[0191] In a particular embodiment, the amount of protein (e.g., albumin) in the urine of the subject is A Approximately 15 to 30 days after treatment with tracentan or a pharmaceutically acceptable salt thereof, It reduces the level by approximately 500 mg / dL to approximately 900 mg / dL. In a specific embodiment, the target urine The amount of protein inside is derived from treatment with atrasentan or a pharmaceutically acceptable salt thereof. After approximately 15 to 30 days, the level will decrease by approximately 600 mg / dL to 900 mg / dL. Specific implementation Morphologically, the amount of protein in the subject's urine is determined by atrasentan or its pharmaceutically acceptable Approximately 15 to 30 days after treatment with salt, the dose is approximately 700 mg / dL to 900 mg / dL. Reduce L.

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

[0193] In some embodiments, the target age group is approximately 15 to 40 years old. In terms of age groups, the target groups are approximately 15-25 years old, 20-30 years old, 25-35 years old, and 30 years old. ~Approximately 40 years old, or any age in between. In some embodiments, the target This is approximately 20 to 30 years old, or any age in between. In some embodiments The target age groups are approximately 20, 21, 22, 23, 24, 25, and 26 years old. They are approximately 27, 28, 29, or 30 years old.

[0194] In some embodiments, the level of fatigue in the patient is related to atrasentan or the drug. It is reduced after treatment with a scientifically acceptable salt. In some embodiments, fatigue is After treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., about 1 week, about 2 weeks) Weeks, approximately 3 weeks, approximately 4 weeks, approximately 5 weeks, approximately 6 weeks, approximately 7 weeks, approximately 8 weeks, approximately 9 weeks, approximately 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 Between approximately 200 weeks, or after any value of treatment in between, approximately 5% to approximately 80% Reduced. In certain embodiments, fatigue is reduced by approximately 10% to approximately 75%. In the application method, fatigue is reduced by approximately 10% to approximately 70%. In a specific embodiment, Fatigue is reduced by approximately 10% to 65%. In certain embodiments, fatigue is reduced by approximately 10% to 65%. It is reduced by approximately 60%. In certain embodiments, fatigue is reduced by approximately 10% to approximately 55%. In certain embodiments, fatigue is reduced by approximately 10% to approximately 50%. And fatigue is reduced by approximately 10% to approximately 45%. In a particular embodiment, fatigue is approximately It is reduced by 10% to approximately 40%. In certain embodiments, fatigue is reduced by approximately 10% to approximately 35%. Reduce. In certain embodiments, fatigue is reduced by approximately 10% to approximately 30%. In terms of form, fatigue is reduced by approximately 10% to approximately 25%. In certain embodiments, fatigue The feeling is reduced by approximately 10% to approximately 20%. In certain embodiments, fatigue is reduced by approximately 10% to approximately Reduced by 15%. In some of the embodiments described above, the subject is approximately 15 to 30 days. The patient is treated with atrasentan or a pharmaceutically acceptable salt thereof. In certain embodiments, Furthermore, the reduction in fatigue was measured using the Fatigue Severity Scale, the Chaldor Fatigue Scale, and FAC. IT fatigue scale, simplified fatigue list, FACT-F subscale, overall vitality and Influence, May and Kline Adjective Checklist, Pearson-Byar Fatigue Emotion Checklist, Rhoten Fatigue Scale, Fatigue and Anergy A decrease in the score of one or more of the following: the schedule or the individual strengths of the checklist. include.

[0195] Some embodiments describe the activation of mesangial cells in subjects with IgA nephropathy. A method of inhibition, wherein the target is given a therapeutically effective amount of atrasentan or a pharmaceutically acceptable amount This includes administering salts, and the target population is those with diabetic nephropathy, HIV / AIDS, or acute kidney disease. This method provides a way for those who have not previously been diagnosed with one or more of the following deficiencies.

[0196] Some embodiments describe 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 A method for reducing the expression and / or activity of one or more P3K1s, and for the target , including administering a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof, The target group includes 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 before.

[0197] Some embodiments are methods for inhibiting the activation of sangium cells, and mesangium The cells are brought into contact with an effective amount of atrasentan or a pharmaceutically acceptable salt thereof. Includes, provides methods.

[0198] In some embodiments, mesangial activation is induced by IgA immune complexes. In some embodiments, mesangial activation occurs in the presence of IgA immune complexes. It is related to the presence and / or amount of IgA immune complexes, which can be detected by various methods. It is possible that the complex may be detected in serum or urine, and may also be detected in kidney biopsy samples. ru.

[0199] In some mechanisms, inhibiting the activation of mesangial cells is possible. Reduce the expression and / or activity of one or more biomarkers indicating the proliferation of um cells. This includes inhibiting the activation of mesangial cells in some embodiments. This includes reducing inflammation in mesangial cells. In some embodiments, the mesa Reducing inflammation in mesangial cells involves IL6, MCP1, or mesangial cells. Reduces the expression and / or activity of one or more other biomarkers indicating inflammation. This includes reducing inflammation in mesangial cells. This includes reducing the expression and / or activity of IL-6. In some embodiments, Furthermore, the expression and / or activation of one or more biomarkers indicating inflammation in mesangial cells. Sexual activity occurs after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., about one week later). Approximately 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, approximately 20 weeks, approximately 30 weeks, approximately 40 weeks, approximately 50 weeks, approximately 60 weeks, approximately 70 weeks 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 1 After 90 weeks, or approximately 200 weeks, or any value in between, approximately 25% It reduces by approximately 99%. In some embodiments, one or more mesangial cells exhibit inflammation. The expression and / or activity of the above biomarkers were approximately 25% to 50%, and approximately 40% to 6%. 0%, approximately 50% to approximately 75%, approximately 60% to approximately 80%, approximately 75% to approximately 90%, approximately 85% to approximately 90% Reduce by 9%, or any value in between. For example, in some such embodiments In this case, one or more biomarkers could be IL-6.

[0200] In some mechanisms, inhibiting the activation of mesangial cells is possible. This includes reducing inflammation in mesangial cells. In some embodiments, mesangial cells Reducing inflammation in cells reduces IL-6 signaling (for example, IL- 6. Expression and / or activity of one or more proteins involved in signaling pathways To reduce, for example, Cntfr, Il1b, Csf1, Il2ra, Map3k8 This includes a reduction of one or more of the following: , and Il1r1. In some embodiments, Reducing inflammation in sanital cells involves Cntfr, Il1b, Csf1, and Il2ra. , Map3k8, Il1r1, or one or more of these (for example, one, two, three, four, and This includes reducing the expression and / or activity of five of the following:

[0201] In some mechanisms, inhibiting the activation of mesangial cells is possible. This includes reducing the fibrous response in um cells. In some embodiments, Reducing fibrous reactions in sangium cells is achieved by NF-κB, TGF, and PDGF. , CTGF, MMP, TIMPS, or other biomeridians exhibiting mesangial cell fibrosis This includes reducing the expression and / or activity of one or more of the kerrs. In the application method, NF-κB, TGF, PDGF, CTGF, MMP, and TIMPS The expression and / or activity of one or more of the following is pharmaceutically acceptable. Compared to the expression and / or activity before administration of the salt, atrasentan or the drug After treatment with a scientifically acceptable salt (e.g., approximately 1 week, 2 weeks, 3 weeks, 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, 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 approximately 200 weeks, After treatment (or any value between those), the reduction is approximately 25% to approximately 99%. Morphologically, NF-κB, TGF, PDGF, CTGF, MMP, and TIMPS The expression and / or activity of one or more of these is approximately 25% to 50%, and approximately 40% to 60%. Approximately 50% to 75%, approximately 60% to 80%, approximately 75% to 90%, approximately 85% to 99% or any value between them.

[0202] In some mechanisms, inhibiting the activation of mesangial cells is possible. This includes reducing the fibrous reaction in um cells. In some embodiments, Reducing fibrous responses includes reducing NF-κB signaling. In that embodiment, reducing the fibrous reaction is achieved by 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 raf1 (for example, 1, 2, 3, 4, or 5) to reduce the activity of Ehd1, Snn, Tnfaip 8, Ackr3, Id2, Ccn1, Efna1, Ccnd1, Cdkn1a, Pnrc 1 (If the component inhibits NF-κB signaling) One or more of these (for example, 1 This includes increasing the expression and / or activity of (one, two, three, four, or five) .

[0203] In some embodiments, reducing the fibrous response is related to PDGF signaling. This includes reducing the fibrous reaction. In some embodiments, reducing the fibrous reaction is , Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tia One or more of m1, Pdgfb, Nfkb1 (for example, 1, 2, 3, 4, ...) To reduce the expression and / or activity of (5) and / or Hras( If the components inhibit PDGF signaling, one or more of them (for example, one, two) This includes increasing the expression and / or activity of (one, three, four, or five) cells.

[0204] In some embodiments, the expression of NF-κB and / or PDGF and / or The expression of activity and / or activity is due to atrasentan or a pharmaceutically acceptable salt thereof. Compared to the expression and / or activity prior to administration, atrasentan or its pharmaceutically acceptable After treatment with salt (for example, 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 Approximately 110 weeks, approximately 120 weeks, approximately 130 weeks, approximately 140 weeks, approximately 150 weeks, approximately 160 weeks Weeks, approximately 170 weeks, approximately 180 weeks, approximately 190 weeks, or approximately 200 weeks, or that After treatment of any value between these, the levels are reduced by approximately 25% to approximately 99%. In some embodiments, Therefore, the expression and / or activity of NF-κB and / or PDGF are approximately 25% to approximately 50%. %, approximately 40% to 60%, approximately 50% to 75%, approximately 60% to 80%, approximately 75% to 90% Reduce by a percentage, approximately 85% to 99%, or any value in between.

[0205] In some mechanisms, reducing the fibrous response in mesangial cells This includes reducing matrix secretion by mesangial cells. Several implementations Morphologically, reducing matrix secretion by mesangial cells is important for mesangial cells. Reduce the expression and / or activity of one or more excessive matrix secretions by Um cells. This includes doing so.

[0206] Some embodiments describe the activation of mesangial cells in contact with IgA immune complexes. A method to reduce mesangial cells with an effective amount of atrasentan or its pharmaceutical The present invention provides a method for activating mesangial cells, which involves contacting them with a suitably acceptable salt. Reducing the expression of one or more biomarkers indicating mesangial cell proliferation This includes reducing activity and / or activity.

[0207] In some embodiments, reducing the activation of mesangial cells is possible. This includes reducing inflammation in mesangial cells. In some embodiments, mesangial cells Reducing cellular inflammation indicates inflammation of IL6, MCP1, or mesangial cells. This includes reducing the expression and / or activity of one or more other biomarkers. nothing.

[0208] In some embodiments, reducing the activation of mesangial cells is possible. This includes reducing the fibrous response in Gyum cells. In some embodiments, Reducing fibrous reactions in mesangial cells is achieved through TGF, PDGF, and CTGF. Among MMP, TIMPS, or other biomarkers indicating mesangial cell fibrosis This includes reducing the expression and / or activity of one or more of the following:

[0209] In some mechanisms, reducing the fibrous response in mesangial cells This includes reducing matrix secretion by mesangial cells. Several implementations Morphologically, reducing matrix secretion by mesangial cells is important for mesangial cells. Expression of one or more biomarkers indicating excessive matrix secretion by Um cells and / or including reducing activity.

[0210] In some embodiments, reducing mesangial cell activation is desirable. This includes reducing the migration of mesangial cells. In some embodiments, Reducing undesirable mesangial cell migration is possible with atrasentan or its pharmaceuticals. It occurs approximately 15 to 30 days after treatment with a moderately acceptable salt. In some embodiments In reducing undesirable mesangial cell migration, atrasentan or It occurs approximately 3 to 6 months after treatment with the pharmacologically acceptable salt.

[0211] In some embodiments, reducing mesangial cell activation is desirable. This includes reducing the proliferation of mesangial cells. In some embodiments, Reducing the proliferation of undesirable mesangial cells is possible with atrasentan or other drugs. It occurs approximately 15 to 30 days after treatment with scientifically acceptable salts. Several implementations In this state, reducing the proliferation of undesirable mesangial cells is possible with atracentan. It occurs approximately 3 to 6 months after treatment with a pharmaceutically acceptable salt thereof.

[0212] In some embodiments, the proliferation of undesirable mesangial cells is caused by atracenta After treatment with ointment or a pharmaceutically acceptable salt thereof (for example, about 1 week, about 2 weeks, about 3 weeks) Between approximately 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, and 2 weeks, the interval is approximately 2 weeks. 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 (or any value of treatment during that time), the level is reduced by approximately 25% to 99%. In some embodiments, the proliferation of undesirable mesangial cells is approximately 25% to 5%. 0%, approximately 40% to 60%, approximately 50% to 75%, approximately 60% to 80%, approximately 75% to 9% Reduce by 0%, approximately 85% to approximately 99%, or any value in between.

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

[0214] In some embodiments, contact occurs in vitro. And contact occurs in vivo.

[0215] Some embodiments treat IgA nephropathy in subjects requiring treatment for IgA nephropathy. A method comprising: a) determining that the subject has elevated serum Gd-IgA1 levels. b) administer a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof to the subject. The present invention provides a method that includes giving [something]. In some embodiments, the subject is diabetes. You have been previously diagnosed with one or more of the following: sexually transmitted nephropathy, HIV / AIDS, or acute renal failure. This does not happen. In some embodiments, the subjects are those who have been diagnosed with HIV-related nephropathy. It has never been done. In some embodiments, the subjects have been previously diagnosed with cancer. No. In some embodiments, cancer is lung cancer or prostate cancer.

[0216] Some embodiments treat IgA nephropathy in subjects requiring treatment for IgA nephropathy. A method comprising: a) determining that the subject has an elevated level of mesangial activity. a) administer a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to the subject. The present invention provides a method that includes administering a drug.

[0217] In some embodiments, the determination of elevated levels of mesangial activation is based on the target or To obtain samples and to evaluate the level of mesangial activation in the same samples, Includes. In some embodiments, the sample is a kidney biopsy sample. In this context, the sample may be a blood sample, a urine sample, a kidney biopsy sample, or a combination of two or three of the above. Selected from the combinations.

[0218] In some embodiments, the sample was found to have elevated levels of mesangial cells. Trix secretion, IgA immune complex deposition, mesangial cell proliferation, and capillary endothelial cell It shows one or more of the cell proliferations. In some embodiments, the sample is elevated level This shows IgA immune complex deposition.

[0219] In some embodiments, the subject is a therapeutically effective amount of atrasentan or its pharmaceutically effective Before administering the acceptable salt, over a one-year period, the least of three consecutive measurements Both tests, conducted twice, determined that the patient had at least approximately 1 g / day of proteinuria. For example, approximately 1g / day, approximately 1.2g / day, approximately 1.4g / day, approximately 1.6g / day, approximately 1.8g / day, or At least about 2g / day.

[0220] In some embodiments, the subject is a therapeutically effective amount of atrasentan or its pharmaceutically effective Prior to administering the acceptable salt, administer a stable dose of RAS inhibitors at maximum tolerance for at least 12 weeks. The harmful agent is administered. In some embodiments, the subject is given a stable dose at maximum tolerance. The RAS inhibitor and a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof It is administered at times. In some embodiments, RAS inhibitors are used to convert angiotensin. It is an enzyme inhibitor. In some embodiments, the RAS inhibitor is an enzyme inhibitor of angiotensin receptor It is an anti-inflammatory drug (ARB).

[0221] In some embodiments, the subject is a therapeutically effective amount of atrasentan or its pharmaceutically effective The patient is determined to have hematuria before administering the acceptable salt. In some embodiments, In some embodiments, hematuria is microscopic hematuria. That is the case.

[0222] In some embodiments, the subject is a therapeutically effective amount of atrasentan or its pharmaceutically effective Before administering the acceptable salt, at least 30 mL / min / 1.73 m 2 It has eGFR It has been determined that... In some embodiments, the subject is a therapeutically effective amount of atracenta Before administering the na or a pharmaceutically acceptable salt, ingest approximately 30 mL / min / 1.73 m 2 ~about 6 0mL / min / 1.73m 2 It has been determined that it has eGFR.

[0223] In some embodiments, the target is diabetic nephropathy, HIV / AIDS, or acute They have never been diagnosed with one or more types of renal failure. The subjects have never been diagnosed with HIV-related nephropathy. In some embodiments... In this case, the subjects have not been diagnosed with cancer to date. In some embodiments, The symptoms are either lung cancer or prostate cancer.

[0224] Some embodiments treat IgA nephropathy in subjects requiring treatment for IgA nephropathy. A method wherein a) the subject has elevated levels of IgA immune complexes in the kidney. a) to determine that the subject has received a therapeutically effective dose of atrasentan or a pharmaceutically acceptable dose. The present invention provides a method comprising administering a salt.

[0225] In some embodiments, elevated levels of IgA immune complexes in the kidney are determined. This involves obtaining a sample from the target and evaluating the level of IgA immune complexes in the same sample. This includes the following. In some embodiments, the sample is a kidney biopsy sample. In the embodiment, the sample is a blood sample, a urine sample, a kidney biopsy sample, or one of the two or Three combinations are selected. In some embodiments, the IgA immune complex is It deposits on mesangium.

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

[0227] In some embodiments, the sample was found to have elevated levels of mesangial cells. Trix secretion, IgA immune complex deposition in the mesangium, and activation of mesangial cells. It exhibits one or more of the following: proliferation of mesangial cells, and proliferation of intracapillary cells.

[0228] In some embodiments, the subject is a therapeutically effective amount of atrasentan or its pharmaceutically effective Before administering the acceptable salt, over a one-year period, the least of three consecutive measurements Both tests, conducted twice, determined that the patient had at least approximately 1 g / day of proteinuria. For example, approximately 1g / day, approximately 1.2g / day, approximately 1.4g / day, approximately 1.6g / day, approximately 1.8g / day, or At least about 2g / day.

[0229] In some embodiments, the subject is a therapeutically effective amount of atrasentan or its pharmaceutically effective Prior to administering the acceptable salt, administer a stable dose of RAS inhibitors at maximum tolerance for at least 12 weeks. The harmful agent is administered. In some embodiments, the subject is given a stable dose at maximum tolerance. The RAS inhibitor and a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof It is administered at times. In some embodiments, RAS inhibitors are used to convert angiotensin. It is an enzyme inhibitor. In some embodiments, the RAS inhibitor is an enzyme inhibitor of angiotensin receptor It is an anti-inflammatory drug (ARB).

[0230] In some embodiments, the subject is a therapeutically effective amount of atrasentan or its pharmaceutically effective The patient is determined to have hematuria before administering the acceptable salt. In some embodiments, In some embodiments, hematuria is microscopic hematuria. That is the case.

[0231] In some embodiments, the subject is a therapeutically effective amount of atrasentan or its pharmaceutically effective Before administering the acceptable salt, at least 30 mL / min / 1.73 m 2 It has eGFR It has been determined that... In some embodiments, the subject is a therapeutically effective amount of atracenta Before administering the na or a pharmaceutically acceptable salt, ingest approximately 30 mL / min / 1.73 m 2 ~about 6 0mL / min / 1.73m 2 It has been determined that it has eGFR.

[0232] In some embodiments, the target is diabetic nephropathy, HIV / AIDS, or acute They have never been diagnosed with one or more types of renal failure. The subjects have never been diagnosed with HIV-related nephropathy. In some embodiments... In this case, the subjects have not been diagnosed with cancer to date. In some embodiments, The symptoms are either lung cancer or prostate cancer.

[0233] In some embodiments, this method involves ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, S Expression and / or activity of one or more of LC6A19, IL-6, and NF-κB. This includes determining the expression and / or activity of the therapeutic agent. This is determined before administration of an effective dose of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, expression and / or activity are controlled by therapeutically effective amounts of atrasentan. Alternatively, this is determined after administration of a pharmaceutically acceptable salt thereof.

[0234] In some embodiments, determining expression and / or activity is the therapeutically effective dose. This is done before the administration of atrasentan or a pharmaceutically acceptable salt thereof. In the application method, determining the expression and / or activity of atracenta is necessary. After administration of o or a pharmaceutically acceptable salt thereof, for example, for about 1 week, about 2 weeks, about 3 weeks, Approximately 4 weeks, approximately 5 weeks, approximately 6 weeks, approximately 7 weeks, approximately 8 weeks, approximately 9 weeks, approximately 10 weeks, approximately 20 weeks Between approximately 30 weeks, 40 weeks, 50 weeks, 60 weeks, 70 weeks, 80 weeks, and 9 weeks, the interval is approximately 9 weeks. 0 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 It is performed after 0 weeks, or any value of treatment during those weeks.

[0235] In some embodiments, the target is 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, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Expression of one or more of the following: Pik3cg, Pla2g4a, Tiam1, and Pdgfb and / or determined to have activity. In some embodiments, the subject is 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 oxy Dase, MAPK, cPLA2, TNF-α, IL-1, CAM, COX-2, iNOS , JAK, STAT3, PI3K, Akt / PKB, IKKs, IkBs, NF-kB, Elevated one or more of MAPK, Ras, Raf, MEK, ERK, and MCP1 It is determined to have expression and / or activity. In some embodiments, The elephants are Cntfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1, 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, Serpine1, Ccl20, Per1, Cx cl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pi Elevated k3cg, Pla2g4a, Tiam1, and Pdgfb It is determined to have expression and / or activity. In some embodiments, the target These include ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, and DPEP1. , one of ASL, AMN, ALPL, SLC6A19, IL-6, and NF-kB It has been determined to have one or more elevated expressions and / or activity. Several implementations In this context, the targets are ET1, TGF, PDGF, CTGF, MMP, TIMPS, and IG. One or more of F1, DPEP1, ASL, AMN, ALPL, and SLC6A19 It has been determined to have elevated expression and / or activity of [the substance].

[0236] Some embodiments are methods for treating IgA nephropathy in subjects, wherein (a) subjects 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 one or more Pdgfb have elevated expression and / or activity. (b) The subject is determined to have received a therapeutically effective amount of atrasentan or a pharmaceutically acceptable dose. The present invention provides a method comprising administering a salt to which the present is contained.

[0237] Some embodiments include ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, NF- kB, PKC, PI3K, Src, Ras, ERK1 / 2, Rho, Rac, Akt, 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 / or a method for treating IgA nephropathy in a subject determined to be active, This includes administering a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof to elephants. Hmm, I will provide a method.

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

[0239] Atracentane and its preparation method are protected by U.S. Patent No. 7,208,517 and International Patent No. As described in Patent Application Publication No. 1997 / 030045 (see, for example, Example 501) Each of these is incorporated herein by reference in whole.

[0240] In some embodiments, atrasentan is administered as a free base. In other embodiments, atracentane is used as described elsewhere in this specification. It is administered as a pharmaceutically acceptable salt.

[0241] Atracentan is ET A It is an inhibitor, ET B Compared to ET A Approximately 1.86 It is 0 times selective. When used herein, "ET A " is the 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, atracentan is in the form of a pharmaceutically acceptable salt. The phrase “pharmaceutically acceptable salt” as used herein refers to the compounds of this disclosure (e.g., This refers to pharmaceutically acceptable organic or inorganic salts of atracentan. Examples of salts include: Acids formed by the reaction between atracentane and an acid (e.g., organic or inorganic acid) This includes addition salts. Non-limiting examples include sulfates, citrates, acetates, oxalates, and chlorides. Substances, bromides, iodides, nitrates, hydrogen sulfates, phosphates, acidic phosphates, isonicotinates Lactates, salicylates, acidic citrates, tartrates, oleates, tannates, Calcium tartrate, hydrogen tartrate, ascorbate, succinate, maleate, mandelion (e.g., (S)-mandelate or (R)-mandelate), gentisinate, Fumarate, gluconate, glucuronate, sugarate, formate, benzoate, glutamine Salts, methanesulfonates "mesylate", ethanesulfonates, benzenesulfonates , and p-toluenesulfonate, pamoate (i.e., 4,4'-methylene-bis- (2-hydroxy-3-naphthoate) salts are included. An example salt is also atracene. This also includes base addition salts formed by the reaction between tan and a base. Non-limiting examples include alb. Potassium metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) This includes sodium (sodium) salts and ammonium salts. The pharmaceutically acceptable salt is acetate ion. , may involve the inclusion of another molecule such as succinate ions or other counterions. The counterion is, It can be any organic or inorganic part that stabilizes the charge of the parent compound. Furthermore, pharmaceutical A salt that is generally acceptable may have two or more charged atoms in its structure. If it is part of a scientifically acceptable salt, it may have multiple counterions. Therefore, Therefore, a pharmaceutically acceptable salt is one or more charged atoms and / or one or more counterions. It can have. When referring to atracentan, the term "salt(s)" is used. A salt of atracentane that may exist alone or in a mixture with free atracentane. It will be understood.

[0243] In some embodiments, atracentan is in the form of a hydrochloride salt. Atrasentan hydrochloride, also known as atrasentan hydrochloride (CAS number: 195733-43-8); Atrasentan hydrochloride; atrasentan chloride salt; atrasentan HCl; atrasentan monohydrochloride; (2R,3R,4S)-4-(1,3-benzodioxide) Sole-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4- 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-pyllone Din carboxylic acid, monohydrochloride; 3-pyrrolidine carboxylic acid, 4-(1,3-benzodioxate (Il-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methyl) Toxyphenyl)-, monohydrochloride, [2R-(2α,3β,4α)]; ABT-627; A -147627.1; Abbott-147627.1 has the following structure: [ka] The molar ratio of atracentane to chloride is 1:1. Atracentane hydrochloride and its preparation The manufacturing method is described in U.S. Patent No. 7,208,517 and International Patent Application Publication No. 1997 / 030. Further details are provided in No. 045 (see, for example, Example 501), each of which is referenced. By reference, the entirety of these elements is incorporated herein.

[0244] In some embodiments, atracentan is in the form of a mandelate salt. In some embodiments, atracentan is in the form of (S)-mandelate. Specific implementation In terms of form, atracentane is in the form of (R)-mandelate. Specific Embodiments In atracentane mandelate, atracentane and mandelate are , having a molar ratio of 1:1. In certain embodiments, atracentane mandelate is used. Furthermore, atracentan and mandelate have a molar ratio of 2:1. Mandelate salt and its preparation method are U.S. Patent Nos. 8,962,675 and 9,6. Further details are provided in issue 37,476, and each of these is referred to in whole. It will be included in the specifications.

[0245] In some embodiments, atracentane is in the form of a hemisulfate. Salt and its preparation method are protected by U.S. Patent Nos. 8,962,675 and 9,637,47 Further details are provided in section 6, and each of these is incorporated herein by reference as a whole. To be absorbed.

[0246] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof is free of It is in the form of aqueous gypsum. In certain embodiments, atracentane or pharmaceutically acceptable The salt is in the form of a hydrate. In certain embodiments, atracentane or Pharmacologically acceptable salts are in the form of solvates.

[0247] stereochemistry Atracentane has three asymmetric centers and is registered under U.S. Patent No. 7,208,517 and As described in International Patent Application Publication No. 1997 / 030045, each stereoisomer ( For example, produced as an enantiomer or diastereomer, or a mixture thereof. It is possible. In some embodiments, the atracentane described herein is (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2- (Dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine- It is a 3-carboxylic acid, and includes (2R,3R,4S)-stereoisomers. In certain embodiments... Furthermore, atracentane contains virtually no other stereoisomers (2R,3R,4S)-12R. They are isomers (for example, <10%, <5%, <2%, <1%, <0% of the other stereoisomer). (Containing 5%, <0.1%, <0.05%).

[0248] polymorph As described herein, atrasentan or a pharmaceutically acceptable salt thereof is 1 It may be in more than one polymorphic form. In some embodiments, atracentane or so The pharmaceutically acceptable salts are substantially amorphous (e.g., >75%, >80%, >85%). It is amorphous (>90%, >95%, >98%, >99%, or >99.5%). In several embodiments, atrasentan or a pharmaceutically acceptable salt thereof is substantially Crystallinity (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >9 It has 9% or >99.5% crystallinity.

[0249] In certain embodiments, atracentan or a pharmaceutically acceptable salt thereof is atra Contains sentan hydrochloride crystalline form 1. In certain embodiments, atrasentan or Pharmaceutically acceptable salts are essentially atracentane hydrochloride crystalline form 1 (e.g., >75%). >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% This is form 1). Atracentane hydrochloride crystal form 1 and the method for producing it are internationally recognized. Patent Application Publication No. 2006 / 034094 (the entirety of which is incorporated herein by reference) It is described in (ru).

[0250] In some embodiments, atracentane hydrochloride crystalline form 1 is Cu-Kα radiation When measured at approximately 25°C using [a specific method / tool], the values ​​were approximately 8.3°, 9.7°, 10.0°, and 13°, respectively. At least three 2θ values ​​having 0°, 15.6°, 17.2°, or 19.5° (e.g.) For example, an X-ray powder diffraction pattern having 3, 4, 5, 6, or 7 peaks Thus, it is characterized. In a particular embodiment, the crystalline form 1 of atracentane hydrochloride is When measured at approximately 25°C using Cu-Kα radiation, the values ​​were approximately 8.3°, 9.7°, and 1°, respectively. Small 2θ values ​​of 0.0°, 13.0°, 15.6°, 17.2°, or 19.5° It has at least three peaks, and is essentially less than approximately 6.2° and / or about 6.6°~8°. Characterized by an X-ray powder diffraction pattern that lacks a peak with a 2θ value of 0°.

[0251] In some embodiments, the crystal form 1 of atracentane hydrochloride is orthorhombic and P 2 l 2 l 2 lIn the space group, when measured using Cu-Kα radiation at approximately 25°C, These are 17.663 Å ± 0.005 Å, 21.24 Å ± 0.01 Å, and 8.005 Å ± It is characterized by lattice constants a, b, and c of 0.002 Å.

[0252] In some embodiments, the atracentane hydrochloride crystalline form 1 has substantial crystalline purity It has. In some embodiments, the atracentane hydrochloride crystalline form 1 is substantially It has chemical purity. In some embodiments, the crystalline form 1 of atracentane hydrochloride is It has substantial diastereomer purity.

[0253] Representative characteristic peak positions of the X-ray powder diffraction pattern of atracentane hydrochloride crystal morphology I The position is expressed as an angle with respect to 2θ, and when measured with Cu-Ka radiation at approximately 25°C, it 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 defined by its associated Miller index (hkl) value and its integrated intensity (peak height). It is shown together with ( ). Peak height can vary, depending on temperature, crystal size or morphology. , sample preparation, or high sample density in the analysis wells of the Scintag×2 diffraction pattern system It is understood that this depends on variables such as [variable name]. When measured with different radiation sources, It should be understood that the peak position may change. For example, 1.5406 each. 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 are measured using Cu-Kα radiation. This can provide a different peak position than the one obtained.

[0254] In certain embodiments, atracentan or a pharmaceutically acceptable salt thereof is atra Contains sentan hydrochloride crystalline form 2. In certain embodiments, atrasentan or Pharmaceutically acceptable salts are essentially atracentane hydrochloride crystalline form 2 (e.g., >75%). >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% This is form 2). Atracentane hydrochloride crystal form 2 and the method for producing it are internationally recognized. Patent Application Publication No. 2006 / 034094 (the entirety of which is incorporated herein by reference) It is described in (ru).

[0255] In a specific embodiment, the atracentane hydrochloride crystalline form 2 is subjected to Cu-Kα radiation. When measured at approximately 25°C, the 2θ values ​​are approximately 6.7° and 22.05°, respectively. Peaks 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° Characterized by n.

[0256] In certain embodiments, the atracentane hydrochloride crystalline form 2 has substantial crystalline purity. Furthermore, when measured at approximately 25°C using Cu-Kα radiation, the values ​​were approximately 6.7° and 22°, respectively. The peak has a 2θ value of 0.05° and others at approximately 8.4°, 15.6°, and 18.0°, respectively. At least one peak having a 2θ value of 18.5°, 19.8°, or 20.6° It is characterized by the X-ray powder diffraction pattern it possesses.

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

[0258] In certain embodiments, the atracentane hydrochloride crystalline form 2 has substantial crystalline purity, actual The atracentane salt possesses qualitative chemical purity and substantial diastereomer purity. The acid salt crystal form 2, when measured using Cu-Kα radiation at approximately 25°C, was approximately 6. Peaks with 2θ values ​​of 7° and 22.05°, and approximately 8.4° and 15.6° respectively. , having 2θ values ​​of 18.0°, 18.5°, 19.8°, or 20.6° at least It is characterized by an X-ray powder diffraction pattern with a single peak.

[0259] In certain embodiments, atracentan or a pharmaceutically acceptable salt thereof is atra Contains sentan hydrochloride crystalline form 3. In certain embodiments, atrasentan or Pharmaceutically acceptable salts are essentially atracentane hydrochloride crystalline form 3 (e.g., >75%). >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% This is form 3). Atracentane hydrochloride crystal form 3 and the method for producing it are internationally recognized. Patent application publication No. 2006 / 034234 and U.S. Patent No. 9,051,301 (this Each of these is described (the whole of which is incorporated herein by reference).

[0260] In a specific embodiment, the atracentane hydrochloride crystalline form 3 is subjected to Cu-Kα radiation. When measured at approximately 25°C, they have 2θ values ​​of approximately 6.7° and 21.95°, respectively. Peaks 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° Characterized by n.

[0261] In certain embodiments, the atracentane hydrochloride crystalline form 3 has substantial crystalline purity. Furthermore, when measured at approximately 25°C using Cu-Kα radiation, the values ​​were approximately 6.7° and 21°, respectively. The peak has a 2θ value of 0.95° and others at approximately 8.4°, 15.6°, and 18.0°, respectively. At least one peak having a 2θ value of 18.5°, 19.8°, or 20.6° It is characterized by the X-ray powder diffraction pattern it possesses.

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

[0263] In certain embodiments, the atracentane hydrochloride crystalline form 3 has substantial crystalline purity, actual The atracentane salt possesses qualitative chemical purity and substantial diastereomer purity. The acid salt crystal morphology 3, when measured using Cu-Kα radiation at approximately 25°C, yielded approximately 6 units each. Peaks with 2θ values ​​of 7° and 21.95°, and approximately 8.4° and 15.6° respectively. , having 2θ values ​​of 18.0°, 18.5°, 19.8°, or 20.6° at least It is characterized by an X-ray powder diffraction pattern with a single peak.

[0264] In certain embodiments, atracentane or a pharmaceutically acceptable salt thereof is amorphous. Contains atracentane hydrochloride. In certain embodiments, atracentane hydrochloride is substantially Specifically amorphous (for example, >75%, >80%, >85%, >90%, >95%, >98%) It is amorphous (>99% or >99.5%). Amorphous atracentane hydrochloride and The method for producing this is described in International Patent Application Publication No. 2006 / 034085 (see reference for the full details). The body is incorporated herein (as described).

[0265] In certain embodiments, amorphous atracentane hydrochloride has substantial chemical purity. In certain embodiments, amorphous atracentane hydrochloride is substantially diastereoma - Possesses purity.

[0266] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof is used. Contains crystalline atracentane mandelate. In certain embodiments, atracentane and Its pharmaceutically acceptable salt is substantially crystalline atracentamandelate (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >9 It is 9.5% crystalline atracentane mandelate.

[0267] In certain embodiments, crystalline atracenta mandelate is crystalline atracenta It is atracentan(S)-mandelate. In certain embodiments, it is atracentan(S)-mandelate. The delate salt is an anhydrous salt. In certain embodiments, atracentane(S)-mandel Acid salts are solvated salts. In certain embodiments, atracentane(S)-mandelic acid The salt consists of acetonitrile solvate, ethanol solvate, and pyridine solvate. A solvating salt selected from the group. In certain embodiments, atracentane(S)-ma Ndel salts are hydrated salts. (a) (S)-mandelate (1:1 stoichiometry)

[0268] In certain embodiments, crystalline atracentan(S)-mandelate is crystalline atracentan(S)-mandelate. It is spiralan (S)-mandelate, and the molar ratio of atracentan to (S)-mandelate The ratio is approximately 1:1. In certain embodiments, atracentane(S)-mandelate It is an anhydrous salt. In certain embodiments, atracentan(S)-mandelate is It is a solvated salt. In certain embodiments, atracentan(S)-mandelate is a Selected from the group consisting of cetonitrile solvate, ethanol solvate, and pyridine solvate. The selected solvating salt is atracentane(S)-mandelic acid. In certain embodiments, atracentane(S)-mandelic acid The salt is a hydrated salt. In certain embodiments, atracentane or a pharmaceutically acceptable salt thereof. The salts that are processed are effectively (for example, >75%, >80%, >85%, >90%, >95%) Crystalline atracentane(S)-mandelic acid with >98%, >99%, or >99.5% content. It is a salt, and the molar ratio of atracentane to (S)-mandelate is approximately 1:1.

[0269] In certain embodiments, crystalline (S)-mandelate is used with monochromatic Kα1 radiation. When measured at approximately 25°C, the values ​​were 5.5±0.2, 9.7±0.2, and 19.4±0.2 degrees. It has an X-ray powder diffraction pattern that includes a peak at 2θ. In certain embodiments, crystalline ( S)-Mandelate was measured at approximately 25°C using monochromatic Kα1 radiation and yielded a value of 5.5±0 Includes peaks at 0.2, 9.7±0.2, 12.1±0.2, and 19.4±0.2 degrees 2θ. It has an X-ray powder diffraction pattern. Radiation. In certain embodiments, crystalline (S)-ma When measured using monochromatic Kα1 radiation at approximately 25°C, ndelate salts were found to be 5.5±0.2, 9 0.7±0.2, 12.1±0.2, 18.0±0.2, 18.4±0.2, and 19. It has an X-ray powder diffraction pattern that includes a peak at 4±0.2 degrees 2θ. In a particular embodiment, Therefore, the experimental errors associated with the X-ray powder diffraction peak values ​​listed in the various embodiments above are ± The degree is 0.1 degrees 2θ. In certain embodiments, the crystalline (S)-mandelate is an anhydrous salt In certain embodiments, the molar ratio of atracentane to (S)-mandelate is It is approximately 1:1.

[0270] In certain embodiments, the crystalline (S)-mandelate has an orthorhombic lattice structure. In certain embodiments, crystalline (S)-mandelates have the P212121 space group. In certain embodiments, the crystalline (S)-mandelates are each approximately 9.95 It has unit cell a, b, and c values ​​of 4 Å, approximately 11.049 Å, and approximately 30.861 Å. In certain embodiments, the crystalline (S)-mandelates are approximately 90° and approximately It has unit cell α, β, and γ values ​​of 90° and approximately 90°. In certain embodiments Crystalline (S)-mandelate has the following properties: (a) orthorhombic lattice type, (b) P21212 1. Space group, (c) approximately 9.954 Å, approximately 11.049 Å, and approximately 30.861 Å, respectively. The values ​​of the unit cell a, b, and c in Å, and / or (d), respectively, are approximately 90° and approximately 9°. At least three of the unit cell values ​​α, β, and γ for 0° and approximately 90° It possesses. In certain embodiments, the crystalline (S)-mandelate is (a) an orthorhombic lattice. (b) P212121 space group, (c) approximately 9.954 Å and 11.049 Å, respectively. , and the unit cell values ​​a, b, and c of approximately 30.861 Å, as well as / or (d) the The unit cell values ​​α, β, and γ are approximately 90°, approximately 90°, and approximately 90°, respectively. In certain embodiments, the crystalline (S)-mandelate is an anhydrous salt. In the application form, the molar ratio of atracentane to (S)-mandelate is approximately 1:1. (b) (S)-mandelate (2:1 stoichiometry)

[0271] In certain embodiments, crystalline (S)-mandelate is crystalline atracentane (S It is atracentane to (S)-mandelate, and the molar ratio of atracentane to (S)-mandelate is approximately 2:1 In certain embodiments, crystalline atracentane(S)-mandelate is anhydrous. It is a salt. In certain embodiments, crystalline atracentane(S)-mandelate is soluble. It is a pharmacochemical salt. In certain embodiments, crystalline atracentane(S)-mandelate is , a hydrated salt. In certain embodiments, atrasentan or pharmaceutically acceptable The salt is effectively (for example, >75%, >80%, >85%, >90%, >95%, >9 In crystalline atracentane(S)-mandelates of 8%, >99%, or >99.5% Yes, the molar ratio of atracentane to (S)-mandelate is approximately 2:1.

[0272] In certain embodiments, crystalline (S)-mandelate is used with monochromatic Kα1 radiation. When measured at approximately 25°C, the values ​​were 4.5±0.2, 8.6±0.2, and 18.1±0.2 degrees. It has an X-ray powder diffraction pattern that includes a peak at 2θ. In certain embodiments, crystalline ( S)-Mandelate was measured at approximately 25°C using monochromatic Kα1 radiation and yielded a value of 4.5±0 Includes peaks at 0.2, 8.6±0.2, 18.1±0.2, and 18.7±0.2 degrees 2θ. It has an X-ray powder diffraction pattern. In a specific embodiment, crystalline (S)-mandelic acid When measured using monochromatic Kα1 radiation at approximately 25°C, the salt values ​​were 4.5±0.2 and 8.6±0. Includes peaks at 0.2, 9.1±0.2, 18.1±0.2, and 18.7±0.2 degrees 2θ. It has an X-ray powder diffraction pattern. In a particular embodiment, the various embodiments described above are arranged in rows. The experimental error associated with the X-ray powder diffraction peak values ​​cited is ±0.1 degrees 2θ. In the application form, the crystalline (S)-mandelate is an anhydrous salt. In a specific embodiment, Crystalline (S)-mandelate salts are hydrated salts.

[0273] In certain embodiments, crystalline atracenta mandelate is crystalline atracenta It is a n(R)-mandelate salt. In certain embodiments, crystalline atracentane(R) - Mandelates are anhydrous salts. In certain embodiments, crystalline atracentane (R )-Mandelate salts are solvated salts. In certain embodiments, crystalline atracentane (R)-Mandelate is a hydrated salt. (c)(R)-Mandelate (1:1 stoichiometry)

[0274] In certain embodiments, crystalline atracentan(R)-mandelate is crystalline atracentan(R)-mandelate. It is spiralan(R)-mandelate, and the molar ratio of atracentan to(R)-mandelate The ratio is approximately 1:1. In certain embodiments, crystalline atracentane(R)-mande The ruate is an anhydrous salt. In certain embodiments, crystalline atracentane(R)-mann Delate salts are solvated salts. In certain embodiments, crystalline atracentane(R)- Mandelate salts are hydrated salts. In certain embodiments, atrasentan or its drug Scientifically acceptable salts are practically (e.g., >75%, >80%, >85%, >90%) Crystalline atracentane(R)- It is a mandelate salt, and the molar ratio of atracentane to (R)-mandelate is approximately 1:1. ru.

[0275] In certain embodiments, crystalline atracentane(R)-mandelate is monochromatic Kα1 When measured using radiation at approximately 25°C, the values ​​were 5.7±0.2, 11.8±0.2, and 2 It has an X-ray powder diffraction pattern that includes a peak at 0.9 ± 0.2 degrees 2θ. In a specific embodiment, In this case, crystalline atracentane(R)-mandelate was found to be approximately 2 using monochromatic Kα1 radiation. When measured at 5℃, the values ​​were 5.7±0.2, 8.2±0.2, 11.8±0.2, and 20 It has an X-ray powder diffraction pattern that includes a peak at 0.9 ± 0.2 degrees 2θ. In a specific embodiment, Furthermore, crystalline atracentane(R)-mandelate was measured using monochromatic Kα1 radiation for approximately 25 When measured at °C, the values ​​were 5.7±0.2, 8.2±0.2, 8.6±0.2, and 11.8±0. It has an X-ray powder diffraction pattern that includes peaks at 2 and 20.9 ± 0.2 degrees 2θ. In this embodiment, the X-ray powder diffraction peak values ​​listed in the various embodiments described above are related to The experimental error is ±0.1 degrees 2θ. In a specific embodiment, crystalline atracentane (R)-Mandelate is an anhydrous salt.

[0276] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof is non Contains crystalline atracentane mandelate. In certain embodiments, atracentane and Its pharmaceutically acceptable salt is substantially amorphous atracentane mandelate (for example, >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >9 It is 9.5% amorphous atracentane mandelate.

[0277] In certain embodiments, amorphous atracenta mandelate is amorphous atracenta It is a(S)-mandelate. In certain embodiments, amorphous atracentane(S) - Mandelates are anhydrous salts. In certain embodiments, amorphous atracentane (S )-Mandelate salts are solvated salts. In certain embodiments, amorphous atracentane (S)-Mandelates are acetonitrile solvate, ethanol solvate, and pyridium It is a solvated salt selected from the group consisting of solvates. In certain embodiments, amorphous Atracentan(S)-mandelate is a hydrated salt. In certain embodiments, amorphous. In the atracentan (S)-mandelate salt, atracentan and (S)-mande The molar ratio of the lute acid salt is approximately 1:1. In certain embodiments, amorphous atracentane ( In (S)-mandelate, the molar ratio of atracentane to (S)-mandelate is: The ratio is approximately 2:1.

[0278] In certain embodiments, amorphous atracenta mandelate is amorphous atracenta It is a(R)-mandelate. In certain embodiments, amorphous atracentane(R) - Mandelates are anhydrous salts. In certain embodiments, amorphous atracentane (R )-Mandelate salts are solvated salts. In certain embodiments, amorphous atracentane (R)-Mandelates are acetonitrile solvate, ethanol solvate, and pyridium It is a solvated salt selected from the group consisting of solvates. In certain embodiments, amorphous Atracentan(R)-mandelate is a hydrated salt. In certain embodiments, amorphous In the atracentan(R)-mandelate salt, atracentan and (R)-mande The molar ratio of the lute acid salt is approximately 1:1. In certain embodiments, amorphous atracentane ( In (R)-mandelate, the molar ratio of atracentane to (R)-mandelate is: The ratio is approximately 2:1.

[0279] Crystalline and amorphous atracentane mandelates are patented by the U.S. Patent No. 8,962,675. And further described in No. 9,637,476, each of which is by reference All of these are incorporated herein.

[0280] E. Pharmaceuticals As used herein, the term “pharmaceutical composition” refers to the active ingredient and the carrier that constitute the composition. Products containing inert components, as well as any combination of two or more components, complexation, This is due to aggregation, or dissociation of one or more components, or other types of one or more components. A reaction or interaction of which includes any products obtained directly or indirectly. Therefore, the pharmaceutical compositions of this disclosure are compounds of this disclosure, or pharmaceutically acceptable compounds. A mixture of a salt, or a solvate or solvate of that salt, and a pharmaceutically acceptable carrier. This includes any composition produced by doing so.

[0281] The amount administered varies depending on the compound formulation, administration route, etc., and is generally determined experimentally. The active unit dose of the formulation is fixed and inevitably varies depending on the target, host, and route of administration. The amount of the compound varies depending on the specific application, ranging from approximately 0.1 milligrams (mg) to approximately 10 mg or The dose may vary or be adjusted to approximately 0.5 mg to approximately 2 mg. For convenience, the total daily dose may be divided into multiple doses. It can be administered in divided doses throughout the day.

[0282] The pharmaceutical compositions of this disclosure for injection are pharmaceutically acceptable sterile aqueous or non-aqueous solutions, Powders, suspensions, or emulsions, as well as sterile injectable solutions or dispersions immediately before use. Contains sterile powder for reconstitution. Suitable aqueous and non-aqueous carriers, diluents, solvents, and Examples of vehicles include water, ethanol, and polyols (glycerol, propylene glycol). (e.g., polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oil (olive oil) This includes injectable organic esters such as ethyl oleate (e.g., ethyl oleate). Fluidity is essential in the case of dispersions, for example, by using coating materials such as lecithin. This can be maintained by maintaining the required particle size and by using surfactants. .

[0283] These pharmaceutical compositions also contain adjuvants such as preservatives, humectants, emulsifiers, and dispersants. It may contain . Prevention of microbial action is achieved by various antimicrobial and antifungal agents, for example, para This can be ensured by including ben, chlorobutanol, phenolsorbic acid, etc. It may also be desirable to include isotonic agents such as sugar and sodium chloride. In an injectable dosage form. Long-term absorption is caused by drugs that delay absorption, such as aluminum monostearate and gelatin. This can be achieved by including the compound, polymer matrix, liposome, It can also be incorporated into sustained-release or targeted delivery systems such as microspheres. Lighter formulations can provide a more effective distribution of compounds.

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

[0285] Solid dosage forms of immediate pharmaceutical compositions for oral administration include capsules, tablets, pills, powders, and It contains granules. In such a solid dosage form, the active compound is at least one inactive drug Scientifically acceptable excipients or carriers, such as sodium citrate or doxyphosphate. Calcium, and / or a) starch, lactose, sucrose, glucose, ma b) Carboxylmethylcellulose, and fillers or bulking agents such as silicic acid, Sucrose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia, etc. Binder, c) humectant such as glycerol, d) agar, calcium carbonate, potato or It contains tapioca starch, alginic acid, certain silicates, and disintegrants such as sodium carbonate. e) Solution retarders such as paraffin, f) Absorption enhancers such as quaternary ammonium compounds, g) Humectants, e.g., cetyl alcohol and glycerol monostearate, h) kaolin and adsorbents such as bentonite clay, as well as i) talc, calcium stearate Magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and can be optionally mixed with lubricants such as mixtures thereof. Capsules, tablets, and In the case of bi-piles, the dosage form may also include a buffering agent.

[0286] Similar types of solid pharmaceutical compositions also include lactose and high molecular weight polysaccharides. 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 immediate pharmaceutical compositions, such as tablets, sugar-coated tablets, capsules, pills, and granules, are enteric-coated. Prepared using coatings and shells such as coatings and other pharmaceutical coatings. They may optionally contain an opacifying agent, and they may be active ingredients In a specific part of the intestinal tract, either by a delay of only a few minutes, or preferentially, or optionally, It may be a formulation. Examples of embedding pharmaceutical compositions that can be used include polymeric substances and It contains wax.

[0288] The active compound may also, where appropriate, contain one or more of the above excipients in a microcapsule. It may be a modified form.

[0289] Liquid dosage forms of immediate pharmaceutical compositions for oral administration include pharmaceutically acceptable emulsions, solutions, and suspensions. This includes turbidities, syrups, and elixirs. In addition to the active compound, liquid dosage forms include, for example, For example, water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol. Pyryl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, p Ppropylene glycol, 1,3-butylene glycol, dimethylformamide, oil (especially, Cottonseed oil, peanut oil, corn oil, wheat germ oil, olive oil, castor oil, and sesame oil ), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and Sorbitan fatty acid esters and mixtures thereof are commonly used in the art. It may contain the inert diluent used.

[0290] In addition to inert diluents, oral pharmaceutical compositions also contain wetting agents, emulsifiers, and suspending agents, as well as sweeteners. This may also include adjuvants such as flavoring agents, aromatherapy agents, and fragrances.

[0291] In addition to the active compound, the suspension of this compound contains, for example, ethoxylated isostearyl alcohol. Coal, polyoxyethylene sorbitol, and sorbitan ester, microcrystalline cellulose Sugars such as hydroxyaluminum metahydroxyaluminum, bentonite, agar, and tragacanth. It may contain turbidants, as well as mixtures thereof.

[0292] The compounds and compositions described herein can be administered, for example, orally or parenterally, for 4 to 120 Every hour, or depending on the needs of the specific drug, dosage form, and / or route of administration, The dosage ranges from approximately 0.01 milligrams (mg / kg) to approximately 0.05 mg / kg per gram. It can be administered in drug doses. Interrelationship between drug doses in animals and humans (square meters of body surface) (Based on milligrams per tor) Freireich et al., Can As described by r Chemother. Rep. 50, 219-244 (1966) Body surface area can generally be determined from the patient's height and weight. For example, Scien tific Tables,Geigy Pharmaceuticals,Ardsl See ey, NY, 537 (1970). In certain embodiments, the composition It is administered orally or by injection. The methods described herein are as desired or described. The aim is to administer an effective amount of the compound or compound composition in order to achieve the desired effect. In general, the pharmaceutical compositions of this disclosure are administered approximately 1 to 6 times per day, or as continuous infusions. It will be administered. Such administration can be used as a treatment for chronic or acute conditions.

[0293] Lower or higher doses than those listed above may be required. The specific dosage and treatment regimen for the patient depends on the activity of the specific compound used, and the year Age, weight, general health status, sex, diet, administration time, excretion rate, drug combinations, disease The severity and course of the illness, condition, or symptoms, the patient's predisposition to the disease, and the treatment being provided. It depends on various factors, including the judgment of the attending 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 Atrasentan compounds or their pharmaceuticals (containing g, or approximately 0.6 mg to approximately 1 mg) Contains a moderately acceptable salt. In some embodiments, the dosage form is 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 mg, approximately 0.8 mg, approximately 0.85 mg, 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, Approximately 1.7 mg, approximately 1.8 mg, approximately 1.9 mg, approximately 2 mg, or any value in between. , comprising atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, The dosage form is approximately 0.75 mg of atrasentan compound or a pharmaceutically acceptable salt thereof. include.

[0295] The dosage form may further contain a pharmaceutically acceptable carrier and / or additional therapeutic agent. ru.

[0296] A suitable dosage level can be determined by any appropriate method. Preferably, the active ingredient The drug is administered either as a topical injection 1 to 4 times a day, or via a drug delivery system. If used, it is administered less frequently. Nevertheless, the pharmaceutical combination of the present disclosure The actual dosage levels and time course of administration of the active ingredients in the product may be unbearable for the patient. Achieving the desired therapeutic response for specific patients, compositions, and administration methods without toxicity. The amount of active ingredient can be changed to obtain an effective amount for that purpose. In some cases, the dosage In particular, age, sex, weight, diet, and the patient's general health condition, route of administration, and active ingredients. Depending on the individual response, the nature of the formulation, and the time or interval at which administration is performed, as described. It may deviate from the specified amount. Therefore, in some cases, using less than the minimum amount specified above may be necessary. While this is quite possible, in other cases it may exceed the specified limit. When administered, it may be recommended to divide these into several individual doses over a day. .

[0297] Exemplary dosage forms of atrasentan In some embodiments, (a) about 0.25 mg to about 1.25 mg of atracenta atrasentan or an equivalent amount of its pharmaceutically acceptable salt (atrasentan or its pharmaceutically acceptable salt in the dosage form) The weight percentage of salt that is generally acceptable is approximately 0.05 on atracentan free base equivalent basis. (b) a pharmaceutically acceptable diluent (which is approximately 2.0% by weight) A stable solid pharmaceutical dosage form containing the above is provided herein.

[0298] In some embodiments, (a) about 0.25 mg to about 1.25 mg of atracenta atrasentan or an equivalent amount of its pharmaceutically acceptable salt (atrasentan or its pharmaceutically acceptable salt in the dosage form) The weight percentage of salt that is generally acceptable is approximately 0.05 on atracentan free base equivalent basis. (b) a pharmaceutically acceptable antioxidant (which is approximately 2.0% by weight) The molar ratio of the antioxidant to atracentan or its pharmaceutically acceptable salt is approximately 10: (c) a pharmaceutically acceptable diluent, comprising (c) a stable solid drug (c) a pharmaceutically acceptable diluent. Scientific 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 approximately 4 When stored at 0°C and approximately 75% relative humidity for a period of 6 months, other antioxidants are lacking. In terms of degradation, it is less than that of atrasentan in the same dosage form.

[0300] In some embodiments, the dosage form is stored in a semipermeable or substantially impermeable container during the storage period. It is stored in a container. In some embodiments, the dosage form is sealed during storage. It is stored in HDPE bottles or blister packaging in some embodiments. The dosage form is stored in a sealed HDPE bottle during the storage period. In some embodiments The dosage form is stored in blister packaging during the storage period.

[0301] (i) Atracentan The dosage form is the free base of atrasentan, a pharmaceutically acceptable salt of atrasentan, or These combinations may be included. In some embodiments, the dosage form is Atra Contains the free base of sentan. In some embodiments, the dosage form is a drug of atrasentan. Contains scientifically acceptable salts. In some embodiments, the dosage form is atracentane hydrochloride. Contains salt. In some embodiments, the dosage form is amorphous atracentane hydrochloride, atracentane hydrochloride. Centane hydrochloride crystal form 1, atracentane hydrochloride crystal form 2, and atracentane salt Contains atracentane hydrochloride having a polymorph selected from the group consisting of three acid salt crystal forms. In some embodiments, the dosage form comprises amorphous atracentane hydrochloride. In some embodiments, the dosage form comprises atracentane hydrochloride crystalline form 1. In terms of form, the dosage form includes atracentane hydrochloride crystalline form 2. In some embodiments... In some embodiments, the dosage form includes atracentane hydrochloride crystalline form 3. The dosage form contains atracentane mandelate. In certain embodiments, the dosage form is crystalline. Atracentane mandelate (for example, crystalline atracentane(S)-mandelate) Contains and / or crystalline atracentane(R)-mandelate. In certain embodiments The dosage form is amorphous atracentane mandelate (for example, amorphous atracentane (S Contains )-mandelate and / or amorphous atracentan(R)-mandelate. In some of the embodiments described above, (the dosage form is crystalline and / or amorphous atracenta (If it contains n(S)- and / or (R)-mandelate), atracentan and mande The molar ratio with ruate is 1:1. In certain other embodiments, atracentane and ma The molar ratio with nderate is 2:1.

[0302] In certain embodiments, the dosage form comprises amorphous atracentane hydrochloride, and atracentane It substantially does not contain other forms of (e.g., other salts and / or other polymorphs) (e.g., (Containing <10%, <5%, <1%, <0.5%, <0.1%, <0.05%). Specific In the embodiment, the dosage form comprises atrasentan hydrochloride crystalline form 1, and atrasentan It substantially does not contain other forms of (e.g., other salts and / or other polymorphs) (e.g., (Containing <10%, <5%, <1%, <0.5%, <0.1%, <0.05%). Specific In the embodiment, the dosage form comprises atrasentan hydrochloride crystalline form 2, and atrasentan Substantially does not include other forms (e.g., other salts and / or other polymorphs). Specific implementation In terms of form, the dosage form includes atrasentan hydrochloride crystalline form 3, and other forms of atrasentan. Substantially free of other forms (e.g., other salts and / or other polymorphs) (e.g., <10) (Containing %, <5%, <1%, <0.5%, <0.1%, <0.05%). Specific implementation forms In this state, the dosage form contains crystalline atracentan (S)-mandelate, and atracentan It substantially does not contain other forms of (e.g., other salts and / or other polymorphs) (e.g., (Containing <10%, <5%, <1%, <0.5%, <0.1%, <0.05%). Specific In one embodiment, the dosage form comprises crystalline atrasentan(R)-mandelate, and Substantially contains no other forms of spiralan (e.g., other salts and / or other polymorphs). (For example, containing <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) In certain embodiments, the dosage form comprises amorphous atracentan(S)-mandelate. Furthermore, other forms of atracentan (e.g., other salts and / or other polymorphs) are substantially Excluding (for example, <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) (Contains). In certain embodiments, the dosage form is amorphous atracentane(R)-mandel. It contains salts and other forms of atracentan (e.g., other salts and / or other polymorphs) Effectively does not include (for example, <10%, <5%, <1%, <0.5%, <0.1%, <0 (Contains 0.05%).

[0303] In some embodiments, atrasentan or its pharmaceutically acceptable dosage form The weight percentage of salt is approximately 0.1 weight percent on atracentan free base equivalent basis. It is approximately 2.0 weight percent. In some embodiments, atrasentan in the dosage form Or the weight percentage of the pharmaceutically acceptable salt thereof is the amount of atracentan free base equivalent base In some embodiments, the amount is approximately 0.2% to 1.0% by weight. Furthermore, the weight percentage of atrasentan or its pharmaceutically acceptable salt in the dosage form is A Tracentan is present in approximately 0.3% to 0.8% by weight on a free base equivalent basis. Yes. In some embodiments, atrasentan or its pharmaceutically acceptable content in the dosage form The weight percentage of the salt is approximately 0.40 weight percent on an atracentan free base equivalent basis. The amount is approximately 0.45% by weight. In some embodiments, the amount in the dosage form is approximately 0.45% by weight. The weight percentage of sentan or its pharmaceutically acceptable salt is the free base of atrasentan. This is approximately 0.60% to 0.65% by weight on an equivalent basis.

[0304] In some embodiments, the dosage form is approximately 0.40 mg to approximately 1.00 mg of atracene. The agent comprises tan, or an equivalent amount thereof of a pharmaceutically acceptable salt. In some embodiments, the agent The form is approximately 0.40 mg to 0.85 mg of atrasentan, or an equivalent amount of its pharmaceutically acceptable dosage. Contains a salt that is tolerated. In some embodiments, the dosage form is about 0.50 mg of atracene The agent comprises tan, or an equivalent amount thereof of a pharmaceutically acceptable salt. In some embodiments, the agent The form contains approximately 0.75 mg of atrasentan, or an equivalent amount of its pharmaceutically acceptable salt. .

[0305] (ii) Diluent Suitable diluents for use in the disclosed dosage form include lactose (lactose monohydrate, Lactose anhydrous, and PHARMATOSE® DCL21, etc., scrofula cellulose, glucose, mannitol, sorbitol, isomalt, microcrystalline cellulose (A (e.g., VICEL® PH101 and VICEL® PH102), Silicified microcrystalline cellulose (PROSOLV® SMCC50 and SMCC This includes 90, dicalcium phosphate, starch, and combinations thereof. , but not limited to these. In some embodiments, the diluent is lactose, mannitol Toll, isomalt, microcrystalline cellulose, dicalcium phosphate, and combinations thereof Selected from the group consisting of combinations. In some embodiments, the diluent is lactose That is the case.

[0306] In some embodiments, the weight percentage of the diluent in the dosage form is about 70% by weight. The weight of the diluent in the dosage form is approximately 99% by weight. In some embodiments, the weight of the diluent in the dosage form The weight percentage is approximately 80% to 99% by weight. In terms of form, the weight percentage of the diluent in the dosage form is approximately 85% to 99% by weight. It is a percentage. In some of the embodiments described above, the diluent is lactose, mannidine Selected from the group consisting of tor, isomalt, and combinations thereof. Non-restrictive For example, the diluent could be lactose.

[0307] (iii) Binder In some embodiments, the dosage form is a pharmaceutically acceptable binder (e.g., polymer). Further includes a binder. Suitable binders for use in the disclosed dosage forms include hydroxypropyl Ropil methylcellulose (e.g., hypromellose E5 (premium LV)), hydroxyl Celluloses such as cypropylethylcellulose and hydroxypropylcellulose, This includes, but is not limited to, other pharmaceutically acceptable substances having aggregation properties. No. In some embodiments, the binder is hydroxymethylpropylcellulose. Hydroxyethylpropylcellulose and the group consisting of hydroxypropylcellulose Selected from. In some embodiments, the binder is hydroxypropylmethyl methyl ester. The binder is lurose. In some embodiments, the binder is hydroxypropylcellulose. In some embodiments, the binder is hydroxyethylpropylcellulose. It is S.

[0308] In some embodiments, the dosage form further comprises a pharmaceutically acceptable binder. The weight percentage of the binder inside is approximately 1.0 weight percent to approximately 10.0 weight percent. Yes. In some embodiments, the weight percentage of the binder in the dosage form is about 1.0 by weight. The amount is approximately 8.0% by weight. In some embodiments, the amount in the dosage form is The weight percentage of the combination is approximately 1.0 weight percent to approximately 5.0 weight percent. In some of the embodiments described above, the binder is hydroxymethylpropylcellulose, A group consisting of hydroxyethylpropylcellulose and hydroxypropylcellulose. It is a polymer binder that is selected from among others.

[0309] In some embodiments, the dosage form further comprises a pharmaceutically acceptable binder, and binds The weight-to-weight ratio of the agent to atracentan or a pharmaceutically acceptable salt is atracentan The ratio is approximately 2:1 to approximately 25:1 on a free base equivalent basis. In some embodiments, the ratio The weight-to-weight ratio of the combination to atracentan or a pharmaceutically acceptable salt is atracentan The ratio is approximately 1:1 to approximately 20:1 on a free base equivalent basis. In some embodiments, The weight-to-weight ratio of the binder to atracentan or a pharmaceutically acceptable salt thereof is atracentan The ratio is approximately 1:1 to approximately 15:1 on a nitrate free base equivalent basis. In certain embodiments, The combination contains hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, A polymer binder selected from the group consisting of and hydroxypropylcellulose.

[0310] (iv) Disintegrant In some embodiments, the dosage form optionally includes a pharmaceutically acceptable disintegrant. Hmm. Suitable disintegrants for use in the disclosed dosage forms include cross-linked polyvinylpyrrolidone (PO LYPLASDONE (trademark) XL, etc., cornstarch, potato starch, sugar Sorghum starch, and modified starch (containing sodium starch glycolate), cold Natural alginate, microcrystalline cellulose, croscarmellose sodium, and combinations thereof This includes, but is not limited to, combinations. In some embodiments, the disintegrant Crospovidone, sodium starch glycolate, and croscarmellose sodium Selected from the group consisting of um. In some embodiments, the disintegrant is cross-linked polyvinyl The disintegrant is lupyrolidone. In some embodiments, the disintegrant is crospovidone.

[0311] In some embodiments, the dosage form further comprises a pharmaceutically acceptable disintegrant. In this embodiment, the weight percentage of the disintegrant in the dosage form is about 1.0 weight percent to about It is 10.0 weight percent. In some embodiments, the weight of the disintegrant in the dosage form - Cent is approximately 1.0 weight percent to approximately 6.0 weight percent. Several implementations In terms of form, the weight percentage of the disintegrant in the dosage form is approximately 1.0 weight percent to approximately 4.0 weight percent. It is expressed as a weight percentage. In some of the embodiments described above, the disintegrant is crospovidone. That is the case.

[0312] In some embodiments, the dosage form further comprises a pharmaceutically acceptable disintegrant, and disintegrates Agents and antioxidants (e.g., L-cysteine) or their pharmaceutically acceptable salts or es The weight-to-weight ratio with Tel is approximately 60:1 to approximately 3:1. In some embodiments, Disintegrants and antioxidants (e.g., L-cysteine) or their pharmaceutically acceptable salts or The weight-to-weight ratio with ester is approximately 50:1 to approximately 4:1. In some embodiments, Furthermore, disintegrants and antioxidants (e.g., L-cysteine) or their pharmaceutically acceptable salts are also used. The weight-to-weight ratio of esters is approximately 35:1 to 5:1.

[0313] (v) Additional excipients In further embodiments, the dosage form is optionally a pharmaceutically acceptable lubricant and / or containing a flow promoter. Lubricants and flow promoters suitable for use in the disclosed dosage forms. The agent contains silicon dioxide (SYLOID(registered trademark) 244FP and AEROSIL(registered trademark) (Registered trademark) 200, etc., Glyceryl behenate (COMPRITOL (registered trademark), etc.) Talc, stearic acid, solid polyethylene glycol, silica gel, and mixtures thereof This includes, but is not limited to, other substances that have lubricating or sliding properties. In certain embodiments, the lubricant is glyceryl behenate (COMPRITOL (registered trademark) (Standard) etc. In certain embodiments, the flow promoter is silicon dioxide (SYLOI D(registered trademark)244FP, etc. In certain embodiments, the lubricant is behenic acid The active ingredient is glyceryl, and the flow enhancer is silicon dioxide.

[0314] In some embodiments, the dosage form further comprises a pharmaceutically acceptable flow enhancer. In another embodiment, the weight percentage of the flow accelerator in the dosage form is approximately 0.1% by weight to approximately 1% by weight. It is 0.5 by weight percent. In some embodiments, the weight of the flow promoter in the dosage form - Cent is approximately 0.1% by weight to approximately 1.0% by weight. Some implementations In terms of form, the weight percentage of the flow accelerator in the dosage form is approximately 0.1% by weight to approximately 0% by weight. It is 0.8 weight percent. In some embodiments, the flow promoter is silicon dioxide That is the case.

[0315] In some embodiments, the dosage form further comprises a pharmaceutically acceptable lubricant. In several embodiments, the dosage form further comprises a pharmaceutically acceptable hydrophobic lubricant. In several embodiments, the weight percentage of lubricant in the formulation is about 0.05% by weight. It is approximately 5.0 weight percent. In some embodiments, the weight of the lubricant in the formulation The weight percentage is approximately 0.2% to 3.0% by weight. In embodiments, the weight percentage of lubricant in the formulation is about 0.5% by weight to about 2% by weight. It is 0.0 weight percent. In certain embodiments, the lubricant is glyceryl behenate. be.

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

[0317] (vi) Antioxidants Antioxidants suitable for use in the disclosed dosage form include those that function as reducing agents and are pharmacy-grade in dosage form. The reduction products that are generally acceptable include antioxidants that are oxidized. In some embodiments, Therefore, the antioxidant has a lower oxidation-reduction potential than atracentane (i.e., approximately 900mV less). It has a redox potential of 100mV and a redox potential greater than approximately 550mV. In some embodiments, the antioxidant has a redox potential of less than approximately 550 mV. In this embodiment, the antioxidant has an oxidation-reduction potential of approximately 1 mV to approximately 550 mV. In some embodiments, the solubility of the antioxidant in water at approximately 25°C is approximately 24 mg / mL. Larger than. In some embodiments, the antioxidant is an amino acid, or its pharmaceutically acceptable properties. It is a salt or ester that is permissible. In some embodiments, the antioxidant is a salt or ester. It is a stain. In some embodiments, the antioxidant is L-cysteine, or so It is a pharmaceutically acceptable salt or ester of [the substance]. In some embodiments, it is an antioxidant. The agents are L-cysteine ​​hydrochloride monohydrate, L-cysteine ​​hydrochloride anhydrous, and L-cysteine Selected from the group consisting of ethyl isoethyl esters. In some embodiments, the dosage form is, Contains L-cysteine ​​hydrochloride monohydrate.

[0318] In some embodiments, the weight percentage of the antioxidant in the dosage form is about 0.05 by weight. The amount is approximately 1.0% by weight. In some embodiments, the amount of antimicrobial activity in the dosage form is approximately 1.0% by weight. The weight percentage of the oxidizing agent is approximately 0.07% to 0.7%. In some embodiments, the weight percentage of the antioxidant in the dosage form is about 0.09 by weight. It is approximately 0.5% by weight.

[0319] In some embodiments, an antioxidant and atracentan or a pharmaceutically acceptable The molar ratio of the salt is approximately 10:1 to approximately 1:10. In some embodiments, the agent The molar ratio of the antioxidant in the form to atracentane or a pharmaceutically acceptable salt thereof is approximately 5 The ratio is approximately 1 to 1.5. In some embodiments, the antioxidant and atracentan or The molar ratio of its pharmaceutically acceptable salt is approximately 2:1 to approximately 1:2. In terms of form, the molar ratio of antioxidant to atracentan or a pharmaceutically acceptable salt thereof. The ratio is approximately 1:1.

[0320] In some embodiments, the antioxidant is L-cysteine ​​or a pharmaceutically acceptable It is a salt that is pharmaceutically acceptable. In certain embodiments, L-cysteine ​​or its pharmaceutically acceptable salt in the dosage form The acceptable weight percentage of salt or ester is approximately 0.05% to 1.0%. This is a weight percentage. In certain embodiments, L-cysteine ​​or the drug in the dosage form The scientifically acceptable weight percentage of salts or esters is approximately 0.07 weight percent. It is approximately 0.7 weight percent. In certain embodiments, L-cysteine ​​in the dosage form and The pharmaceutically acceptable weight percentage of the salt or ester is approximately 0.09% by weight. Cent is approximately 0.5 weight percent.

[0321] In certain embodiments, L-cysteine ​​or a pharmaceutically acceptable salt thereof in the dosage form is also included. The molar ratio of the ester to atracentane or a pharmaceutically acceptable salt is approximately 1 The ratio is approximately 0:1 to 1:10. In certain embodiments, L-cysteine ​​or other compounds in the dosage form. A pharmaceutically acceptable salt or ester of and atracentan or a pharmaceutically acceptable The molar ratio of the salt is approximately 5:1 to approximately 1:5. In certain embodiments, L-system Yin or a pharmaceutically acceptable salt or ester thereof, and atrasentan or drug The scientifically acceptable molar ratio with salt is approximately 2:1 to approximately 1:2. In certain embodiments, L-cysteine ​​or a pharmaceutically acceptable salt or ester thereof, and atracentan The molar ratio with its pharmaceutically acceptable salt is approximately 1:1.

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

[0323] (Vii) Additional embodiments In some embodiments, the dosage form is atrasentan or a pharmaceutically acceptable one. The salt and antioxidants are included. In some of these embodiments, the antioxidant is L-cis Theine, or a pharmaceutically acceptable salt or ester thereof. Several embodiments In this, antioxidants (e.g., L-cysteine, or its pharmaceutically acceptable salts or The molar ratio of the ester is approximately 5:1 to approximately 1:5. The dosage form is hydroxymethylpropylcellulose, hydroxyethylpropylcellulose A pharmaceutically acceptable substance selected from the group consisting of s and hydroxypropylcellulose. It further contains a polymer binder and an antioxidant (e.g., L-cysteine, or its pharmaceutically appropriate properties). (acceptable salts or esters) and atracentane or a pharmaceutically acceptable salt thereof The molar ratio is approximately 5:1 to 1:5, and the binder and atrasentan or its pharmaceutically acceptable properties The acceptable weight-to-weight ratio with salt is approximately 1:1 to approximately 2 on atracentan free base equivalent basis. The ratio is 0:1. In some embodiments, this dosage form further comprises a disintegrant, and the disintegrant and antioxidants (e.g., L-cysteine, or its pharmaceutically acceptable salt or es) The weight-to-weight ratio of (Tel) is approximately 60:1 to approximately 3:1. In some embodiments, The weight percentage of atrasentan or a pharmaceutically acceptable salt in this dosage form is A Tracentan is present in approximately 0.2% to 1.0% by weight on a free base equivalent basis. Yes. In some embodiments, this dosage form is approximately 0.40 mg to approximately 0.85 mg. Contains tranentan, or an equivalent amount of its pharmaceutically acceptable salt.

[0324] In some embodiments, the dosage form is hydroxymethylpropylcellulose, hydro Selected from the group consisting of hydroxyethylpropylcellulose and hydroxypropylcellulose. It contains a selected pharmaceutically acceptable polymer binder and an antioxidant (e.g., L-cysteine) or a pharmaceutically acceptable salt or ester thereof) and atrasentan or drug The scientifically acceptable molar ratio of salt is approximately 2:1 to 1:2, with the binder and atracenta The weight-to-weight ratio of atracentane free base equivalent to that of atracentane free base equivalent is The ratio is approximately 1:1 to approximately 15:1. In some embodiments, the dosage form contains a disintegrant. It also contains a disintegrant and an antioxidant (e.g., L-cysteine, or its pharmaceutically acceptable form). The weight-to-weight ratio of salts or esters is approximately 50:1 to 4:1. In embodiments, the weight of atrasentan or a pharmaceutically acceptable salt thereof in this dosage form The percentage is approximately 0.2% by weight to approximately 1.0% by weight of atracentan on a free base equivalent basis. This is a weight percentage. In some embodiments, this dosage form is approximately 0.40 mg to approximately Contains 0.85 mg of atrasentan, or an equivalent amount of its pharmaceutically acceptable salt.

[0325] In some embodiments, the dosage form is hydroxymethylpropylcellulose, hydro Selected from the group consisting of hydroxyethylpropylcellulose and hydroxypropylcellulose. It contains a selected pharmaceutically acceptable polymer binder and an antioxidant (e.g., L-cysteine) or a pharmaceutically acceptable salt or ester thereof) and atrasentan or drug The scientifically acceptable molar ratio of salt to binder is approximately 1:1, with atracentane or so The weight-to-weight ratio of the pharmaceutically acceptable salt is approximately 1 on atracentan free base equivalent basis. The ratio is approximately 1 to 15:1. In some embodiments, this dosage form further contains a disintegrant. Furthermore, disintegrants and antioxidants (e.g., L-cysteine ​​or its pharmaceutically acceptable salts) are also included. The weight-to-weight ratio (or ester) is approximately 35:1 to 5:1. Several implementations In this dosage form, the weight portion of atrasentan or a pharmaceutically acceptable salt thereof The nut is approximately 0.3% to 0.8% by weight in terms of atracentan free base equivalents. It is -cent. In some embodiments, this dosage form is about 0.40 mg to about 0.8 Contains 5 mg of atrasentan, or an equivalent amount of its pharmaceutically acceptable salt.

[0326] In some embodiments, the dosage form is hydroxymethylpropylcellulose, hydro Selected from the group consisting of hydroxyethylpropylcellulose and hydroxypropylcellulose. It contains a selected pharmaceutically acceptable polymer binder, and the dosage form is approximately 0.05% by weight. ~Approximately 1.0 weight percent of antioxidants (e.g., L-cysteine, or its pharmaceutically acceptable content) It contains (a salt or ester) and the dosage form is approximately 1.0% by weight to approximately 10.0% by weight Contains a percentage of the binder. In some embodiments, this dosage form further contains the disintegrant. The weight percentage of the disintegrant in the dosage form is approximately 1.0% by weight to approximately 10.0% by weight. It is a percent. In some embodiments, atrasentan or so in this dosage form The pharmaceutically acceptable weight percentage of the salt is approximately 0 on atracentan free base equivalent basis. It is between 0.1% by weight and approximately 2.0% by weight. In some embodiments, The dosage form is approximately 0.40 mg to 0.85 mg of atrasentan, or an equivalent amount of its pharmaceutical formula. Contains salts that are permissible.

[0327] In some embodiments, the dosage form is hydroxymethylpropylcellulose, hydro Selected from the group consisting of hydroxyethylpropylcellulose and hydroxypropylcellulose. It contains a selected pharmaceutically acceptable polymer binder, and the dosage form is approximately 0.07% by weight. ~Approximately 0.70 weight percent antioxidant (e.g., L-cysteine, or its pharmaceutically effective Contains (acceptable salts or esters), and the dosage form is approximately 1.0 weight percent of the binder. It contains 8.0 weight percent. In some embodiments, this dosage form further contains the disintegrant. The weight percentage of the disintegrant in the dosage form is approximately 1.0% by weight to approximately 6.0% by weight. -cent. In some embodiments, atracentan or The pharmaceutically acceptable weight percentage of salt is approximately 0 on atracentane free base equivalent basis. This is 2% by weight to about 1.0% by weight. In some embodiments, this The dosage form is approximately 0.40 mg to 0.85 mg of atrasentan, or an equivalent amount of the pharmaceutically appropriate dosage form. Contains acceptable salts.

[0328] In some embodiments, the dosage form is hydroxymethylpropylcellulose, hydro Selected from the group consisting of hydroxyethylpropylcellulose and hydroxypropylcellulose. It contains a selected pharmaceutically acceptable polymer binder, and the dosage form is approximately 0.09 weight percent. ~Approximately 0.80 weight percent antioxidant (e.g., L-cysteine, or its pharmaceutically effective Contains (acceptable salts or esters), and the dosage form is approximately 1.0 weight percent of the binder. It contains 5.0 weight percent. In some embodiments, this dosage form further contains the disintegrant. The weight percentage of the disintegrant in the dosage form is approximately 1.0% by weight to approximately 4.0% by weight. -cent. In some embodiments, atracentan or The pharmaceutically acceptable weight percentage of salt is approximately 0 on atracentane free base equivalent basis. This is 3% by weight to about 0.8% by weight. In some embodiments, this The dosage form is approximately 0.40 mg to 0.85 mg of atrasentan, or an equivalent amount of the pharmaceutically appropriate dosage form. Contains acceptable salts.

[0329] In some embodiments, the dosage form is (a) Atracentan, on a free base equivalent basis, approximately 0.1% by weight to approximately 2.0% by weight - Centatracentane or a pharmaceutically acceptable salt thereof, (b) Approximately 0.05% to 1.0% by weight of antioxidants (e.g., L-sulfamethoxazole) Stain, or a pharmaceutically acceptable salt or ester thereof), (c) Diluent of approximately 75% to 99% by weight, (d) A pharmaceutically acceptable binder in an amount of approximately 1.0 weight percent to approximately 10.0 weight percent. , (e) Optionally, approximately 1.0 weight percent to approximately 10.0 weight percent of a pharmaceutically acceptable amount. Disintegrants that are used (f) Optionally, a pharmaceutically acceptable amount of approximately 0% to 1.5% by weight. A flow promoter, and (g) Optionally, approximately 0% to 5.0% by weight of pharmaceutically acceptable A lubricant, The cumulative weight percentage of all components in the dosage form is equal to 100 percent.

[0330] In some embodiments, the dosage form is (a) Atracentan, on a free base equivalent basis, approximately 0.1% by weight to approximately 2.0% by weight - Centatracentane or a pharmaceutically acceptable salt thereof, (b) Approximately 0.05% to 1.0% by weight of antioxidants (L-cysteine or its pharmaceutically acceptable salt or ester), (c) Diluent of approximately 75% to 99% by weight, (d) A pharmaceutically acceptable binder in an amount of approximately 1.0 weight percent to approximately 10.0 weight percent. , (e) Approximately 1.0 weight percent to approximately 10.0 weight percent of a pharmaceutically acceptable disintegrant , (f) Optionally, a pharmaceutically acceptable amount of approximately 0% to 1.5% by weight. A flow promoter, and (g) Optionally, approximately 0% to 5.0% by weight of pharmaceutically acceptable A lubricant, The cumulative weight percentage of all components in the dosage form is equal to 100 percent.

[0331] In some embodiments, the dosage form is (a) Atracentan, on a free base equivalent basis, approximately 0.2% by weight to approximately 1.0% by weight - Centatracentane or a pharmaceutically acceptable salt thereof, (b) Approximately 0.07% to 0.7% by weight of antioxidants (L-cysteine) or its pharmaceutically acceptable salt or ester), (c) Diluent of approximately 82% to 99% by weight, (d) A pharmaceutically acceptable binder in an amount of approximately 1.0 weight percent to approximately 8.0 weight percent. (e) Optionally, a pharmaceutically acceptable amount of approximately 1.0 weight percent to approximately 6.0 weight percent. Disintegrants that are used (f) Optionally, a pharmaceutically acceptable amount of approximately 0% to 1.0% by weight. A flow promoter, and (g) Optionally, approximately 0% to 3.0% by weight of pharmaceutically acceptable A lubricant, The cumulative weight percentage of all components in the dosage form is equal to 100 percent.

[0332] In some embodiments, the dosage form is (a) Atracentan, on a free base equivalent basis, approximately 0.2% by weight to approximately 1.0% by weight - Centatracentane or a pharmaceutically acceptable salt thereof, (b) L-cysteine ​​in an amount of approximately 0.07% to approximately 0.70% by weight, or The pharmaceutically acceptable salt or ester thereof, (c) Diluent of approximately 82% to 99% by weight, (d) A pharmaceutically accep...

Claims

1. A method for inhibiting mesangial cell activation in subjects with IgA nephropathy, The subjects are administered a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof. and The aforementioned subject has one or more of the following conditions: diabetic nephropathy, HIV / AIDS, or acute renal failure. A method that has never been used for diagnosis before.

2. A method for treating IgA nephropathy, wherein a therapeutically effective amount of atras is administered to a patient in need. This includes administering thontan or a pharmaceutically acceptable salt thereof. The aforementioned subject has one or more of the following conditions: diabetic nephropathy, HIV / AIDS, or acute renal failure. A method that has never been used for diagnosis before.

3. A method for treating IgA nephropathy, wherein a therapeutically effective amount of atras is administered to a patient in need. This includes administering thontan or a pharmaceutically acceptable salt thereof. The aforementioned subject has one or more of the following conditions: diabetic nephropathy, HIV / AIDS, or acute renal failure. No method.

4. A method for treating IgA nephropathy, wherein a therapeutically effective amount of atras is administered to a patient in need. This includes administering thontan or a pharmaceutically acceptable salt thereof. The aforementioned subject has one or more of the following conditions: diabetic nephropathy, HIV / AIDS, or acute renal failure. A method that does not involve infection.

5. A method for treating IgA nephropathy, wherein a therapeutically effective amount of atras is administered to a patient in need. This includes administering thontan or a pharmaceutically acceptable salt thereof. The aforementioned subjects are those with diabetic nephropathy, HIV / AIDS, prostate cancer, or acute renal failure. A method for which one or more of the following conditions have not been previously diagnosed.

6. A method for treating IgA nephropathy, wherein a therapeutically effective amount of atras is administered to a patient in need. This includes administering thontan or a pharmaceutically acceptable salt thereof. The aforementioned subjects are those with diabetic nephropathy, HIV-related nephropathy, prostate cancer, or acute renal failure. Methods that have not been diagnosed with one or more conditions in the past.

7. A method for treating IgA nephropathy, wherein a therapeutically effective amount of atras is administered to a patient in need. This includes administering thontan or a pharmaceutically acceptable salt thereof. The subject has one or more of the following conditions: diabetic nephropathy, HIV-related nephropathy, or acute renal failure. A method that has never been used to diagnose before.

8. A method for treating IgA nephropathy, wherein a therapeutically effective amount of atras is administered to a patient in need. This includes administering thontan or a pharmaceutically acceptable salt thereof. The aforementioned subject has one or more of the following conditions: diabetic nephropathy, HIV-related nephropathy, or acute renal failure. A method that does not involve receiving treatment.

9. A method for treating IgA nephropathy, wherein a therapeutically effective amount of atras is administered to a patient in need. This includes administering thontan or a pharmaceutically acceptable salt thereof. The subject has been determined to have controlled serum glucose levels, The aforementioned subjects have been diagnosed with one or more of the following: HIV-related nephropathy or acute renal failure. A method I've never tried before.

10. A method for reducing renal inflammation and / or fibrosis in subjects with IgA nephropathy If available, and to those who need it, a therapeutically effective amount of atrasentan or its pharmaceutically acceptable dose. A method comprising administering a salt.

11. A method for reducing the incidence of hematuria in subjects with IgA nephropathy, which requires The patient is given a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof. A method that includes [this].

12. A method for stabilizing eGFR in subjects with IgA nephropathy, which requires The patient is given a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof. A method that includes [this].

13. A method to reduce the number of IgA nephropathy-related disease flares in subjects with IgA nephropathy. Therefore, to those who need it, a therapeutically effective amount of atrasentan or a pharmaceutically acceptable amount A method comprising administering a salt.

14. A method for delaying the onset of ESRD in subjects with IgA nephropathy, which is necessary The target population is administered a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof. A method that includes doing so.

15. A method for reducing proteinuria in subjects with IgA nephropathy, which requires The patient is given a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof. A method that includes [this].

16. The mesangial activation is induced by an IgA immune complex, as described in claim 1. method.

17. The mesangial activation is associated with the presence of IgA immune complexes, as described in claim 1. The method.

18. Inhibiting the activation of mesangial cells leads to one or more indications of mesangial cell proliferation. The method according to claim 1, comprising reducing the expression and / or activity of a biomarker. method.

19. Inhibiting the activation of mesangial cells reduces inflammation of mesangial cells. The method according to claim 1, comprising the following:

20. Reducing inflammation in mesangial cells is important because it reduces IL-6, which is an indicator of inflammation in mesangial cells. Reduce the expression and / or activity of MCP1 or one or more other biomarkers. The method according to claim 19, which includes causing to do so.

21. Reducing inflammation in mesangial cells reduces IL-6 signaling. The method according to claim 19 or 20, including the method described in claim 19 or 20.

22. Inhibiting the activation of mesangial cells leads to fibrous reactions in the mesangial cells. The method according to claim 1, comprising reducing the amount of.

23. Reducing the fibrous reaction in the aforementioned mesangial cells is achieved by TGF, PDGF, C TGF, MMP, TIMPS, or other biomarkers indicating mesangial cell fibrosis Claim 22, comprising reducing the expression and / or activity of one or more of the following The method.

24. Reducing the fibrous reaction in the aforementioned mesangial cells is related to ET1, TGF, and PD. GF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALP L, SLC6A19, IL-6, NF-kB, PKC, PI3K, Src, Ras, ER K1 / 2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, c (A ２ . , PI3K, Akt / PKB, IKKs, IkBs, MAPK, Ras, Raf, MEK , ERK, MCP1, Cntfr, Il1b, Csf1, Il2ra, Map3k8, I l1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkb ia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Sps b1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob Nfat5, Edn1, Rel, Nr4a3, Nfkb1, Serpin1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nf One of the following: kbia, Pik3cg, Pla2g4a, Tiam1, and Pdgfb The method according to claim 22 or 23, which includes reducing the expression and / or activity described above. method.

25. Reducing the fibrous reaction in the aforementioned mesangial cells is related to ET1, TGF, and PD. GF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALP L, SLC6A19, IL-6, PKC, PI3K, Src, Ras, ERK1 / 2, R ho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA ２ , T NF-α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt / PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK To reduce the expression and / or activity of one or more of ERK and MCP1. The method according to any one of claims 22 to 24, including the method described in any one of claims 22 to 24.

26. Reducing the fibrous reaction in the aforementioned mesangial cells is possible with Cntfr, Il1b , Csf1, Il2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Ge m, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Tr ib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a 3, Nfkb1, Serpin1, Ccl20, Per1, Cxcl2, Map3k8, Tr af1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Reduce the expression and / or activity of one or more of TiaM1 and Pdgfb. The method according to any one of claims 22 to 25, including the act of

27. Reducing the fibrous response in the aforementioned mesangial cells is linked to the transmission of NF-κB signals. Claims 22 to 25 include reducing the transmission and / or PDGF signaling. The method described in either of the above terms.

28. Reducing the fibrous reaction in the aforementioned mesangial cells is possible in mesangial cells The method according to any one of claims 23 to 27, which includes reducing matrix secretion. method.

29. Reducing matrix secretion by mesangial cells is possible because mesangial cells This includes reducing the expression and / or activity of one or more excessive matrix secretions. The method according to claim 28.

30. A method for reducing fatigue in subjects with IgA nephropathy, which requires The subjects were given a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof. Including, The aforementioned subject is one of the following: diabetic nephropathy, HIV-related nephropathy, prostate cancer, or acute renal failure. A method used to determine that the patient was not infected with more than one disease.

31. A method for treating IgA nephropathy in subjects requiring treatment for IgA nephropathy, a) Determining that the subject has IgA immune complex deposition in the kidney, b) Administer to the subject a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof. A method that includes doing something.

32. A method for treating IgA nephropathy in subjects requiring treatment for IgA nephropathy, a) Determining that the subject has an elevated level of mesangial activity, b) Administer to the subject a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof. A method that includes doing something.

33. A method for treating IgA nephropathy in subjects requiring treatment for IgA nephropathy, a) The subject is determined to have elevated levels of IgA immune complexes in the kidney. to, b) Administer to the subject a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof. A method that includes doing something.

34. The atrasentan is administered as a pharmaceutically acceptable salt according to claims 1 to 33. The method described in either of the above terms.

35. The atrasentan is defined as atrasentan hydrochloride or atrasentan mandelate. The method according to any one of claims 1 to 34, which is administered by [method].

36. The atrasentan is administered as atrasentan hydrochloride, according to claims 1 to 35. The method described in either of the above terms.

37. The atrasentan is administered as a free base, according to any one of claims 1 to 33. Method of description.

38. Any one of claims 1 to 37, wherein the subject is also administered one or more additional drugs. Methods used.

39. The one or more additional drugs mentioned above are calcineurin inhibitors, proteasome inhibitors, and ami. Noquinoline, complement inhibitors, B cell inhibitors, cytotoxic agents, mTOR inhibitors, and steroids The method according to claim 38, selected from D.

40. The aforementioned subjects are ACE inhibitors, ARBs, statins, diuretics, calcium channel blockers, Beta-blockers, aldosterone antagonists, fish oil, hydroxychloroquine, or pre- The person described in any one of claims 1 to 39 who simultaneously receives any of the combinations described above. Law.

41. The subject is simultaneously receiving an ACE inhibitor, an ARB, or a combination thereof. The method according to any one of claims 1 to 40.

42. Any of claims 1 to 41 further comprises administering a therapeutically effective dose of an SGLT-2 inhibitor. The method described in any one of the items.

43. A method for inhibiting the activation of mesangial cells, wherein mesangial cells are subjected to an effective amount of ato A method comprising contacting with spiralan or a pharmaceutically acceptable salt thereof.

44. A method for reducing the activation of mesangial cells in contact with IgA immune complexes. Mesangial cells are brought into contact with an effective amount of atrasentan or a pharmaceutically acceptable salt thereof. A method that includes the act of doing so.

Images