Methods for treating focal segmental glomerulosclerosis with atrasentan

Abstract

Provided herein is a method for treating focal segmental glomerulosclerosis (FSGS), comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Also provided herein is a method for reducing nephritis and / or fibrosis, reducing the rate of decline in eGFR, delaying the onset of ESKD, reducing proteinuria, and reducing fatigue in a subject with FSGS, comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to the subject.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 343,574, filed May 19, 2022, the contents and disclosures of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Focal segmental glomerulosclerosis (FSGS) is a glomerular disease characterized by proteinuria, frequent progression to end-stage kidney disease (ESKD), and recurrence after kidney transplantation in approximately 25% of patients, adversely affecting long-term allograft survival (Cravedi, 2013). It is a heterogeneous disorder resulting from podocyte injury and depletion due to diverse initiating causes. Primary (idiopathic) FSGS is the most common form of the disease and is presumed to be the result of unknown circulating factors. Secondary FSGS includes virus-associated or drug-induced FSGS. Maladaptive forms of secondary FSGS result from an adaptive structural-functional response to excessive single-nephron workload (Rosenberg, 2017). FSGS can be caused by a number of genetic mutations in genes that code for proteins expressed primarily in podocytes and their slit diaphragms. Genetic causes of FSGS can exist as sporadic or familial diseases with autosomal dominant, autosomal recessive, X-linked, or mitochondrial inheritance patterns (Rood, 2012; Jefferson, 2014; Dummer, 2015; De Vriese, 2018). Apolipoprotein L1 (APOL1) gene variants increase the risk of ESKD in FSGS patients of African descent (Dummer, 2015). The annual incidence of FSGS ranges from 0.2 to 1.8 cases per 100,000 per year (McGrogan, 2011). Conservative management of FSGS includes blood pressure control, especially with RAS inhibitors and dietary sodium restriction. Further treatment is individualized based on the specific form of FSGS, taking into account patient-specific factors such as age and comorbidities. Treatment of primary FSGS also includes the use of drugs that are immunosuppressive and may also have a direct effect on podocytes, including prednisone, calcineurin inhibitors, cyclophosphamide, and mycophenolate mofetil plus high-dose dexamethasone (Korbet, 2012; Rosenberg, 2017).

[0003] There are no approved treatments for FSGS, and for patients who have failed conservative management with agents that block the renin-angiotensin-aldosterone system, there are no established safe and effective treatment options. As a result, there is a significant unmet medical need to develop therapies for patients with FSGS who remain at risk for progressive renal failure. Summary of the Invention

[0004] Atrasentan is a selective endothelin A (ETA) receptor antagonist (ETA Ki approx. 34 pM; ETB Ki approx. 63 nM, ETA selectivity approx. 1800x). See, e.g., Wu-Wong et al., Clin. Sci. (Lond.), 103(48), pp. 107s-111s (2002). Selective ETA receptor antagonists block ETA function while having minimal effect on ETB receptors, providing beneficial renal effects including vasodilation and reduced inflammation while still allowing ET-1 clearance. See, e.g., Jandellet-Dahm and Watson, Curr. Opin. Nephrol. Hypertens., 21(1), pp. 66-71 (2012); see also Nakamura, et al., Nephron, Vol. 72, pp. 454-460 (1996). ETA receptor antagonists increase sodium and water retention by the kidney, which is typically clinically manageable. See, e.g., Saleh, et al., J. Pharm. Exp. Ther., 338(1), pp. 263-270 (2011).

[0005] Atrasentan has been extensively studied as a once-daily treatment for diabetic kidney disease (DKD) in individuals with type 2 diabetes in addition to optimal doses of renin-angiotensin system (RAS) inhibitors. ETA activation is associated with the progression of many kidney diseases as measured by proteinuria, renal inflammation, or fibrosis. (Dhaun, 2012; Vignon-Zellweger, 2012).

[0006] Atrasentan has been shown to be effective in patients with diabetic kidney disease, significantly reducing the risk of renal events defined as a doubling of serum creatinine or end-stage renal disease. See, e.g., Heerspink, et al., The Lancet, 393, pp 1937-1947 (2019). DKD is considered a secondary glomerular disease, and kidney disease is secondary to identified systemic causes in the case of DKD, as a microvascular complication to long-standing diabetes. See, e.g., Dattani and McAdoo, Medicine, 47(10), pp. 644-648 (2019). The pathogenesis of DKD is multifactorial and complex. Systemic and renal hemodynamic factors related to chronically elevated blood glucose levels due to diabetes, which cause glucose toxicity to renal cells, particularly renal endothelial cells, as well as hypertension, which results in shear stress transmitted to resident glomerular cells, are important pathogenic drivers of DKD. See, e.g., Thomas et al., Nat. Rev. Disease Primers. 1, pp. 15018-15026 (2015). Multiple factors that are dysregulated in the diabetic environment, including metabolic components such as hyperglycemia, dyslipidemia, and oxidative stress, as well as hemodynamic factors such as vasoactive substances associated with hypertension, all stimulate renal ET-1 formation. In addition, DKD is typically observed in older populations due to the need for many years of diabetes before the onset of DKD, and aging is also associated with increased ET-1 production in the kidney. See, e.g., Kohan, Kidney Int., 86(5), pp. 896-904 (2014). Together, all of these provide a sound scientific basis for the treatment of DKD with the ETA receptor blocker atrasentan. See, e.g., Dhaun, et al., Hypertension, Vol. 57, pp. 772-779 (2011).

[0007] Some embodiments provide a method of treating focal segmental glomerulosclerosis (FSGS) in a subject with FSGS, the method comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof.

[0008] Some embodiments provide a method of reducing nephritis and / or fibrosis in a subject with FSGS, the method comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof.

[0009] Some embodiments provide a method of reducing the rate of decline in estimated glomerular filtration rate (eGFR) in a subject with FSGS, the method comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof.

[0010] Some embodiments provide a method of delaying the onset of ESKD in a subject with FSGS, the method comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof.

[0011] Some embodiments provide a method of reducing proteinuria in a subject with FSGS, the method comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof.

[0012] Some embodiments provide a method of reducing fatigue in a subject with FSGS, the method comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof.

[0013] Some embodiments provide a method of stabilizing functional podocyte mass in a subject with FSGS, the method comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof.

[0014] Some embodiments provide a method of stabilizing or reducing nephritis and / or fibrosis. In some cases, the nephritis and / or fibrosis is tubulointerstitial inflammation. Some embodiments provide that the nephritis and / or fibrosis is tubulointerstitial fibrosis. Some embodiments provide that the nephritis and / or fibrosis comprises glomerular inflammation and / or glomerulosclerosis. Some embodiments provide that the nephritis and / or fibrosis comprises one or more of tubulointerstitial inflammation, tubulointerstitial fibrosis, glomerular inflammation, or glomerulosclerosis.

[0015] Some embodiments provide that the subject has biopsy-confirmed FSGS. Some embodiments provide that the subject has been diagnosed with biopsy-confirmed FSGS. Some embodiments provide that the subject has a genetic diagnosis of FSGS due to a known podocyte protein mutation. Additional embodiments include subjects with a mutation in APOL1.

[0016] Some embodiments provide that the FSGS comprises nephrotic syndrome. Some embodiments provide that the nephrotic syndrome is selected from proteinuria, hypoalbuminemia, hypercholesterolemia, peripheral edema, or any combination of the foregoing.

[0017] Some embodiments provide that the FSGS is perihilar FSGS. Some embodiments provide that the FSGS is apical FSGS. Some embodiments provide that the FSGS is cellular FSGS. Some embodiments provide that the FSGS is collapsing FSGS. Some embodiments provide that the FSGS is primary FSGS. Some embodiments provide that the FSGS is non-specific (NOS) FSGS.

[0018] Some embodiments provide that the FSGS is virus-associated FSGS. Some embodiments provide that the virus-associated FSGS is not HIV-associated FSGS. Some embodiments provide that the FSGS is toxin-associated FSGS. Some embodiments provide that the FSGS is adaptive FSGS.

[0019] Some embodiments provide that the subject is also administered one or more additional agents. Some embodiments provide that the one or more additional agents are selected from a calcineurin inhibitor, a proteasome inhibitor, an aminoquinoline, a complement inhibitor, a B cell inhibitor, a cytotoxic agent, an mTOR inhibitor, a steroid, and combinations thereof. Some embodiments provide that the one or more additional agents include a calcineurin inhibitor. Some embodiments provide that the calcineurin inhibitor is a cyclosporine. Some embodiments provide that the one or more additional agents include an immunosuppressant. Some embodiments provide that the immunosuppressant is mycophenolate mofetil (MMF), cyclophosphamide, or chlorambucil. Some embodiments provide that the one or more additional agents include a steroid. Some embodiments provide that the steroid is selected from the group consisting of prednisone, dexamethasone, hydrocortisone, cyclosporine, adrenocorticotropic hormone (ACTH), and any combination of the foregoing. Some embodiments provide that the one or more additional agents include an aminoquinoline. Some embodiments provide that the one or more additional agents is hydroxychloroquine.Some embodiments provide that the subject is not currently receiving one or more immunosuppressive agents.

[0020] Some embodiments provide that the one or more additional agents are administered at a stable dosage for at least 12 weeks prior to administration of a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof. Some embodiments provide that the dosage of the one or more additional agents is decreased after about 15 days to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0021] Some embodiments provide for the dosage of one or more additional agents to be reduced by about 25% to about 100% (about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%). Some embodiments provide for the dosage of one or more additional agents to be reduced by about 50% to about 100%. Some embodiments provide for the dosage of one or more additional agents to be reduced by about 75% to about 100%.

[0022] Some embodiments provide that the subject is concurrently receiving an ACE inhibitor, an ARB, a statin, a diuretic, a calcium channel blocker, a beta blocker, an aldosterone antagonist, fish oil, hydroxychloroquine, an SGLT2i, or any combination of the foregoing.

[0023] Some embodiments provide that the subject is concurrently receiving an ACE inhibitor, an ARB, or a combination thereof.Some embodiments provide that the statin is selected from the following: atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin.Some embodiments provide that the diuretic is selected from the following: hydrochlorothiazide, trichlormethiazide, hydroflumethiazide, quinethazone, metolazone, chlorothiazide, chlorthalidone, indapamide, methyclothiazide bumetanide, torsemide, piretanide, ethacrynic acid, bumetanide, furosemide, triamterene, spironolactone, eplerenone, and amiloride. Some embodiments provide that the ACE inhibitor is selected from the following: quinapril, fosinopril perindopril, captopril, enalapril, enalaprilat, ramipril, cilazapril, delapril, fosinopril, zofenopril, indolapril, benazepril, lisinopril, spirapril, trandolapril, perindep, pentopril, moexipril, rescinnamine, and pivopril.Some embodiments provide that the ARB is selected from the following: candesartan, candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan, olmesartan medoxomil, telmisartan, valsartan, azilsartan medoxomil, and BRA-657.

[0024] Some embodiments provide that atrasentan is administered as a pharma- ceutically acceptable salt.Some embodiments provide that atrasentan is administered as atrasentan hydrochloride or atrasentan mandelate.Some embodiments provide that atrasentan is administered as atrasentan hydrochloride.Some embodiments provide that atrasentan is administered as the free base.

[0025] Some embodiments provide that the subject is at high risk of progressing to end stage kidney disease (ESKD). Some embodiments provide that the subject has been diagnosed with FSGS. Some embodiments provide that the diagnosis of FSGS comprises a kidney biopsy, a genetic test for a mutation in a podocyte protein associated with FSGS, or a combination of any of the foregoing. Some embodiments provide that the diagnosis of FSGS comprises a kidney biopsy.

[0026] Some embodiments provide that the subject excretes an average of about 0.75 g / g or more of protein in the urine per day for at least about 3 months prior to the first administration of atrasentan, or a pharma- ceutically acceptable salt thereof. Some embodiments provide that the subject excretes an average of about 1.5 g / g or more of protein in the urine per day for at least about 3 months prior to the first administration of atrasentan, or a pharma-ceutically acceptable salt thereof. Some embodiments provide that the subject excretes an average of about 3.5 g / g or more of protein in the urine per day for at least about 3 months prior to the first administration of atrasentan, or a pharma-ceutically acceptable salt thereof. Some embodiments provide that the subject excretes an average of about 3.5 g / g to about 10 g / g of protein in the urine per day for at least about 3 months prior to the first administration of atrasentan, or a pharma-ceutically acceptable salt thereof.

[0027] Some embodiments provide that the subject is excreting an average of about 0.75 grams to 1.5 grams of protein in the urine per day for at least about three months prior to the first administration of atrasentan, or a pharma- ceutically acceptable salt thereof.

[0028] Some embodiments provide that the subject is excreting an average of about 1 gram or more of protein in the urine per day for at least about 3 months prior to the first administration of atrasentan, or a pharma- ceutically acceptable salt thereof.

[0029] In some embodiments, the subject receives between about 20 and about 120 mL / min / 1.73 m for at least about 3 months prior to the first administration of atrasentan, or a pharma- ceutical acceptable salt thereof. 2 The mean eGFR of

[0030] In some embodiments, the subject receives between about 30 and about 90 mL / min / 1.73 m for at least about 3 months prior to the first administration of atrasentan, or a pharma- ceutical acceptable salt thereof. 2 The mean eGFR of

[0031] In some embodiments, the subject receives between about 20 and about 60 mL / min / 1.73 m for at least about 3 months prior to the first administration of atrasentan, or a pharma- ceutical acceptable salt thereof. 2 The mean eGFR of

[0032] Some embodiments provide that the subject has a urinary protein-to-creatinine ratio (UPCR) of greater than about 1.5 g / g to about 11 g / g (e.g., about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 g / g) for at least about 3 months prior to the first administration of atrasentan, or a pharma- ceutical acceptable salt thereof.

[0033] Some embodiments provide that the subject has an average HbA1c of about 4% to about 6% for at least about 3 months prior to the first dose of atrasentan, or a pharma- ceutically acceptable salt thereof.

[0034] Some embodiments provide that the subject has an average fasting blood glucose level of about 125 mg / dL or less for at least about three months prior to the first administration of atrasentan, or a pharma- ceutically acceptable salt thereof.

[0035] Some embodiments provide that a subject maintains potassium levels within the normal physiological range.

[0036] Some embodiments provide that a subject maintains sodium levels within the normal physiological range.

[0037] Some embodiments provide that the subject has an alanine transaminase / aspartate transaminase (ALT / AST) level during administration of atrasentan, or a pharmaceutically acceptable salt thereof, that is about the same as the ALT / AST level before the first administration of atrasentan, or a pharmaceutically acceptable salt thereof.

[0038] Some embodiments provide that the subject has a bilirubin level during administration of atrasentan, or a pharma- ceutically acceptable salt thereof, that is about the same as the bilirubin level prior to the first administration of atrasentan, or a pharma- ceutically acceptable salt thereof. Thus, in some embodiments, the bilirubin level can be used to assess liver function or the effect of administration of one or more agents described herein.

[0039] Some embodiments provide that the subject's fluid retention is manageable with a diuretic.

[0040] Some embodiments provide that the amount of protein in a subject's urine is reduced by about 20% to about 80% after about 15 to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0041] Some embodiments provide that the amount of protein in a subject's urine is reduced by about 20% to about 80% after about 4 weeks to about 10 weeks of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0042] Some embodiments provide that the amount of protein in the subject's urine is reduced by about 20% to about 80% after about 10 weeks of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. Some embodiments provide that the amount of protein in the subject's urine is reduced by about 20% to about 80% after about 12 weeks of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. Some embodiments provide that the amount of protein in the subject's urine is reduced by about 20% to about 80% after about 12 weeks to about 24 weeks of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0043] Some embodiments provide for a reduction in the amount of protein in a subject's urine by about 35% to about 80% (about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80%).

[0044] Some embodiments provide that the amount of protein in a subject's urine is reduced by about 100 mg / dL to about 900 mg / dL after about 15 to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0045] Some embodiments provide that protein in a subject's urine is reduced by about 100 mg / dL to about 500 mg / dL after about 15 to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0046] Some embodiments provide that the amount of protein in a subject's urine is reduced by about 500 mg / dL to about 900 mg / dL after about 15 to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0047] Some embodiments provide that the subject's UPCR is reduced to about 1.5 g / g to less than about 11 g / g after about 15 to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. Some embodiments provide that the subject's UPCR is reduced to about 1.5 g / g, about 2 g / g, about 3 g / g, about 4 g / g, about 5 g / g, about 6 g / g, about 7 g / g, about 8 g / g, about 9 g / g, about 10 g / g, or less than about 11 g / g after about 15 to about 30 days of treatment with atrasentan, or a pharma-ceutically acceptable salt thereof. Some embodiments provide that the subject's UPCR is reduced to about 1.5 g / g to less than about 11 g / g after about 12 to about 24 weeks of treatment with atrasentan, or a pharma-ceutically acceptable salt thereof. Some embodiments provide that the subject's UPCR is reduced to less than about 1.5 g / g, about 2 g / g, about 3 g / g, about 4 g / g, about 5 g / g, about 6 g / g, about 7 g / g, about 8 g / g, about 9 g / g, about 10 g / g, or about 11 g / g after about 12 weeks to about 24 weeks of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0048] Some embodiments provide that a subject's risk of developing ESKD is reduced by about 20% to about 99% after about 6 months to about 24 months of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0049] Some embodiments provide that a subject's risk of developing ESKD is reduced by about 20% to about 99% after about 12 months to about 60 months (about 6 months, about 9 months, about 12, months, about 15 months, about 18 months, about 21 months, about 24 months, about 27 months, about 30 months, about 33 months, about 36 months, about 39 months, about 42, months, about 45 months, about 48 months, about 51 months, about 54 months, about 57 months, or about 60 months) of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0050] Some embodiments provide that the average rate of decline in eGFR is from about 0.75 mL / min / year to about 75 mL / min / year for at least about 3 months prior to the first administration of atrasentan, or a pharma- ceutical acceptable salt thereof.

[0051] Some embodiments provide that the average rate of decline in eGFR is from about 3 mL / min / year to about 6 mL / min / year for at least about 3 months prior to the first administration of atrasentan, or a pharma- ceutical acceptable salt thereof.

[0052] Some embodiments provide that the average rate of decline in eGFR is about 4 mL / min / year to about 5 mL / min / year for at least about 3 months prior to the first administration of atrasentan, or a pharma- ceutical acceptable salt thereof.

[0053] Some embodiments provide that the mean decline in eGFR is about 15% to about 70% after about 6 months to about 24 months of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0054] Some embodiments provide that the therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, is from about 0.20 mg to about 1.5 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0055] Some embodiments provide that the therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, is from about 0.25 mg to about 1.25 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0056] Some embodiments provide that the therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, is from about 0.40 mg to about 0.85 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0057] Some embodiments provide that the therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, is about 0.75 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0058] Some embodiments provide that the therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, is from about 0.75 mg to about 1.5 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0059] Some embodiments provide that the therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, is from about 0.80 mg to about 1.5 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0060] Some embodiments provide that the therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, is from about 1.0 mg to about 1.5 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0061] Some embodiments provide that the therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, is from about 1.25 mg to about 1.5 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0062] Some embodiments provide that the therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, is about 1.5 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0063] Some embodiments provide that the method further comprises administering a therapeutically effective amount of an SGLT-2 inhibitor. Some embodiments provide that the SGLT-2 inhibitor is selected from bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin, sergliflozin, licogliflozin, sotagliflozin, and tofogliflozin.

[0064] Some embodiments provide that the SGLT-2 inhibitor is canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin.

[0065] Some embodiments provide that the subject has been determined to have proteinuria of at least 1 g / day in at least two of three consecutive readings over a one-year period prior to administration of a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof.

[0066] Some embodiments provide that the subject has been administered a maximally tolerated stable dose of a RAS inhibitor for at least 12 weeks prior to administration of a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof.

[0067] Some embodiments provide that the subject is administered a maximum tolerated stable dose of a RAS inhibitor and a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, simultaneously.

[0068] Some embodiments provide that the subject has an endothelial flow rate of at least 30 mL / min / 1.73 m prior to administration of a therapeutically effective amount of atrasentan, or a pharma- ceutical acceptable salt thereof. 2 The present invention provides that the patient has been determined to have an eGFR of

[0069] Some embodiments provide that the FSGS comprises non-nephrotic range proteinuria of less than 3.5 grams of protein in the urine per day for at least about three months prior to administration of a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof.

[0070] Some embodiments provide that FSGS is associated with one or more genetic mutations. Some embodiments provide that the one or more genetic mutations are in a gene encoding a podocyte protein associated with FSGS. Some embodiments provide that the one or more genetic mutations are selected from one or more mutations in a gene selected from the group consisting of: NPHS1, NPHS2, CD2AP, TRPC6, ACTN4, INF2, MYO1E, ARHGAP24, ARHGDIA, PLCE1, PTPRO, WT1, LXMB1, tRNAleu, COQ2, COQ6, ITGB4, PDSS2, CD151, CUBN, LAMB2, APOL1, and any combination of the foregoing. Some embodiments provide that the one or more genetic mutations are in APOL1.

[0071] Some embodiments provide that the subject has been administered a previous therapy for FSGS and has failed to respond to the previous therapy.

[0072] Some embodiments provide that the previous therapy is a standard of care therapy for FSGS. Some embodiments provide that the previous therapy is selected from the following: actar, sparsentan, rituximab with plasma exchange, vorcosporine, 10-nitro-9(E)-octadec-9-enoic acid (CXA-10), PF-06730512, 4-chloro-N-[5-methyl-2-[7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl]-3-pyridyl]-3-(trifluoromethyl)benzenesulfonamide (CCX140-B), abatacept, bardoxolone, or any combination of the foregoing.

[0073] Some embodiments provide that the subject has not been or is not being treated with a sodium glucose cotransporter 2 (SGLT2) inhibitor.

[0074] Some embodiments provide that the subject has not been or is not being treated with antiretroviral therapy, examples of which include, but are not limited to, protease inhibitors, reverse transcription inhibitors, integrase inhibitors, and combinations thereof, such as HAART (highly active antiretroviral therapy).

[0075] Some embodiments provide that the subject has not been previously diagnosed with one or more of acute kidney injury (e.g., due to hypoxia), diabetic nephropathy (also called diabetic kidney disease or "DKD"), IgA nephropathy, sickle cell nephropathy, HIV / AIDS, or acute renal failure.

[0076] Some embodiments provide that the subject has not been previously diagnosed with HIV-associated nephropathy.

[0077] Some embodiments provide that the subject has not been previously diagnosed with HIV.

[0078] Some embodiments provide that the subject is not currently diagnosed with HIV.

[0079] Some embodiments provide that the subject is not currently being treated for HIV.

[0080] Some embodiments provide that the subject has not been previously diagnosed with renal vascular hypertension.

[0081] Some embodiments provide that the subject is not currently being treated for renal vascular hypertension. [Brief description of the drawings]

[0082] [Figure 1]FIG. 1 shows the overall study scheme (all cohorts) of the Phase 2 study disclosed herein. Abbreviations: DKD = diabetic kidney disease; FSGS = focal segmental glomerulosclerosis; IgAN = immunoglobulin A nephropathy; PK = pharmacokinetics; QD = once daily. a; Subjects in cohort 2 (FSGS) have the option to escalate dose at or after week 12. These subjects will move on to cohort 2b. [Diagram 2] 1 shows dose escalation for cohorts 2 (2b) and 5 of the Phase 2 study disclosed herein. [Diagram 3] 1 shows baseline characteristics of patients with FSGS included in the Phase 2 study disclosed herein. [Figure 4] 1 shows urinary protein to creatinine ratios (UPCR) measured at weeks 0, 6, 12, and 24 of the Phase 2 study disclosed herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0083] Brief explanation of the table Table 1: Objectives and endpoints for each cohort in the Phase 2 study disclosed herein. Table 2: Information regarding atrasentan used in the Phase 2 study disclosed herein. Table 3: Laboratory evaluations required for the protocol in the Phase 2 study disclosed herein.

[0084] I. Definition In order that this disclosure may be more readily understood, certain terms are first defined. As used in this application, unless otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Further definitions are set forth throughout this application.

[0085] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains. For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary Of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press provide those skilled in the art with a general dictionary of many of the terms used in this disclosure. For purposes of this disclosure, the following terms are defined.

[0086] Units, prefixes, and symbols are denoted in the accepted format of the Systeme International de Unites (SI). Numerical ranges are inclusive of the numerical values ​​defining the range. The headings provided herein are not intended to limit the various aspects of the disclosure, which can be had by reference to the specification in its entirety. Thus, the terms defined immediately below are more fully defined by reference to the specification in its entirety.

[0087] As used herein, the terms "a," "an," or "the" include not only embodiments having one member, but also embodiments having two or more members. The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "cell" includes a plurality of such cells, reference to an "agent" includes reference to one or more agents known to those of skill in the art, and so forth.

[0088] The term "or" as used herein should generally be construed as non-exclusive. For example, a claim to "a composition comprising A or B" typically presents embodiments that include a composition that contains both A and B. However, "or" should be construed to exclude presented embodiments that cannot be consistently combined (e.g., a composition pH of 9-10 or 7-8).

[0089] The group "A or B" is typically equivalent to the group "selected from the group consisting of A and B."

[0090] The term "and / or" as used herein should be interpreted as a specific disclosure of each of two specified features or components, with or without the other. Thus, the term "and / or" used herein in phrases such as "A and / or B" is intended to include "A and B", "A or B", "A" (single), and "B" (single). Similarly, the term "and / or" used in phrases such as "A, B, and / or C" is intended to encompass each of the following embodiments: 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 (single); B (single); and C (single).

[0091] The terms "about" and "approximately" as used herein are generally intended to mean an acceptable degree of error for the measured quantity, given the nature or precision of the measurement. Typical exemplary degrees of error are within 20 percent (%), within 10%, or within 5% of a given value or range of values. Any reference to "about X" specifically denotes at least the values ​​X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, "about X" is intended to provide written description support for a claim limitation, for example, "0.98X". The terms "about" and "approximately" include and describe the given quantity itself, especially in relation to the given quantity.

[0092] When "about" is applied to the beginning of a numerical range, it applies to both ends of the range. Thus, "about 5 to 20%" is equivalent to "about 5% to about 20%." When "about" is applied to the first value in a set of values, it applies to every value in that set. Thus, "about 0.5, 0.75, or 1.0 mg" is equivalent to "about 0.5, about 0.75, or about 1.0 mg."

[0093] As used herein, the term "about," when preceding a set of X-ray powder diffraction peak positions (e.g., 2θ values), means that all of the peaks in the group it precedes are reported with respect to angular positions having a variability of ±0.1°. Thus, for example, the phrase about 8.3°, 9.7°, 10.0°, 13.0°, 15.6°, 17.2°, or 19.5° means 8.3°±0.1°, 9.7°±0.1°, 10.0°±0.1°, 13.0°±0.1°, 15.6°±0.1°, 17.2°±0.1°, or 19.5°+0.1°.

[0094] "Treatment" or "therapy" of a subject refers to any type of intervention or process performed on a subject, or administration of an active agent to a subject, for the purpose of reversing, alleviating, ameliorating, inhibiting, or slowing the onset, progression, occurrence, severity, or recurrence of a symptom, complication, condition, or biochemical sign associated with a disease.

[0095] "Administering" or "administration" refers to the physical introduction of a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those of skill in the art. Routes of administration can include oral, intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as injection or infusion (e.g., intravenous infusion). Administration can be, for example, once, multiple times, and / or over one or more extended periods of time.

[0096] The terms "prophylactic" or "prophylactically" refer to any type of intervention or process performed on a subject, or administration of an active agent to a subject, with the purpose of protecting against or preventing the onset of a disease or condition, or at least preventing it from developing altogether (e.g., reducing the symptoms or severity of the disease or condition) (e.g., in the occurrence of side effects, etc.).

[0097] A "subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In some embodiments, the subject is a human. The terms "subject" and "patient" and "individual" are used interchangeably herein.

[0098] In some cases, a subject with FSGS has one or more genetic mutations associated with FSGS. Genetic mutations described herein include a deletion, insertion, or substitution of at least one amino acid compared to the wild-type protein (e.g., contributing to the onset of FSGS); a mutation in a gene resulting in the expression of a protein with one or more point mutations compared to the wild-type protein (e.g., contributing to the onset of FSGS), a mutation in a gene resulting in the expression of a protein with at least one deletion, insertion, or substitution of at least one amino acid compared to the wild-type protein, a gene duplication resulting in an increased level of the protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) resulting in an increased level of transcription or translation in a cell), an alternatively spliced ​​version of an mRNA molecule resulting in a protein with a deletion of at least one amino acid compared to the wild-type version of the protein), or an increased expression (e.g., increased levels) of the wild-type version in a mammalian cell due to - for example - aberrant cell signaling and / or dysregulated signaling (e.g., compared to a control cell) (e.g., contributing to the onset of FSGS). As another example, the dysregulation of a gene, protein, or expression or activity, or any level thereof, can be a mutation in a gene that encodes a protein that is constitutively active or has increased activity compared to a protein encoded by a gene that does not contain the mutation.

[0099] The term "wild-type" refers to a nucleic acid (eg, a DNA or mRNA sequence) or protein sequence that is typically found in subjects that do not have a disease or disorder (eg, FSGS) associated with the reference nucleic acid or protein.

[0100] An "effective amount" or "therapeutically effective amount" or "therapeutically effective dosage" of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, delays the onset of the disease or promotes disease regression as evidenced by a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or an improvement in the impairment or disability due to the disease affliction. The ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to those of skill in the art, such as by assaying the activity of the agent during clinical trials in human subjects, in animal model systems predictive of efficacy in humans, or in in vitro assays.

[0101] The phrase "pharmacologically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation, and / or the mammal being treated therewith.

[0102] As used herein, "polymorph" refers to distinct solids that share the same molecular formula, but each polymorph may have distinct solid properties. A single compound may occur in a variety of polymorphic forms, each with different distinct solid properties, such as different solubility profiles, melting point temperatures, flow properties, dissolution rates, and / or different X-ray diffraction peaks. These practical physical properties are influenced by the conformation and orientation of the molecules within the unit cell that defines a particular polymorphic form of a substance. Polymorphic forms of a compound can be distinguished in the laboratory by X-ray diffraction spectroscopy, such as X-ray powder diffraction ("XRPD"), and by other methods, such as infrared spectroscopy. Furthermore, polymorphic forms of the same drug substance or active pharmaceutical ingredient can be administered by themselves or formulated as a formulation (pharmaceutical composition), and are well known in the pharmaceutical arts to affect, for example, the solubility, stability, flow properties, ease of handling, and compressibility of the drug substance, as well as the safety and efficacy of the formulation. For further details see Hilfiker, Rolf (ed.), Polymorphism in the Pharmaceutical Industry. Weinheim, Germany: Wiley-VCH 2006.

[0103] As used herein, the term "non-crystalline" refers to a solid in a solid state that is in a non-crystalline state. Amorphous solids generally have crystal-like short-range molecular arrangements, but do not have the long-range order of molecular packing seen in crystalline solids. The solid state form of a solid can be determined by polarized light microscopy, X-ray powder diffraction ("XRPD"), differential scanning calorimetry ("DSC"), or other standard techniques known to those skilled in the art.

[0104] As used herein, the term "crystalline" refers to a solid in the solid state having a regularly repeating arrangement of molecules or external surface planes. The solid state form of a solid may be determined by polarized light microscopy, X-ray powder diffraction ("XRPD"), differential scanning calorimetry ("DSC"), or other standard techniques known to those skilled in the art. Thus, as used herein, the term "crystalline purity" refers to the percentage of a particular crystalline polymorph of atrasentan or a pharma- ceutically acceptable salt thereof in a sample that may contain amorphous atrasentan or a pharma- ceutically acceptable salt thereof, one or more additional crystalline polymorphs of atrasentan or a pharma- ceutically acceptable salt thereof, or a mixture thereof. When a crystalline polymorph of atrasentan or a pharma- ceutically acceptable salt thereof is described as having "substantial crystalline purity," it means that the polymorph is substantially free (e.g., including <10%, <5%, <2%, <1%, <0.5%, <0.1%, or <0.05%) of other polymorphs (amorphous and / or crystalline).

[0105] The term "chemical purity" as used herein refers to the percentage of a particular compound (e.g., atrasentan or a pharma- ceutically acceptable salt thereof) in a sample. Thus, atrasentan or a pharma- ceutically acceptable salt thereof and compositions comprising or made therefrom may contain one or more impurities, including, but not limited to, water, ethyl acetate, ethanol, (2R,3R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-l-(N-(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid ... (2R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid, (2R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-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)aminocarbonylmethyl)pyrrolidine-3-carboxylate. When a sample of atrasentan or a pharma- ceutically acceptable salt thereof is described as having "substantial purity," the sample is substantially free of impurities (e.g., including <10%, <5%, <2%, <1%, <0.5%, <0.1%, or <0.05%).

[0106] The term "diastereomeric excess" as used herein means the amount of one diastereomer of a compound (e.g., atrasentan or a pharma- ceutically acceptable salt thereof) in a mixture that may have other diastereomers of the same compound in the mixture. The term "substantial diastereomeric purity" as used herein means a diastereomeric excess of greater than about 90%, 95%, 99%, 99.5%, 99.9%, or 100%.

[0107] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance that aids in the administration of an active agent to a cell, organism, or subject. "Pharmaceutically acceptable carrier" refers to a carrier or excipient that may be included in the compositions of the present disclosure and does not cause significant adverse toxicological effects to the subject. Non-limiting examples of pharmaceutically acceptable carriers include water, NaCl, saline solution, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings and colorants, liposomes, dispersion media, microcapsules, cationic lipid carriers, isotonicity and absorption delaying agents, and the like. Carriers may also be substances that provide stability, sterility, and isotonicity to the formulation (e.g., antimicrobial preservatives, antioxidants, chelating agents, and buffers), prevent the action of microorganisms (e.g., antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like), or provide edible flavors to the formulation, and the like. In some cases, the carrier is an agent that facilitates delivery of a small molecule drug or antibody to a target cell or tissue. One of skill in the art will recognize that other pharmaceutical carriers are useful in the present disclosure.

[0108] As used herein, the term "expression" refers to the level of protein or mRNA in a mammalian cell.

[0109] The term "activity" as used herein refers to one or more activities of a protein, such as binding or enzymatic activity (e.g., one or more of phosphorylation, dephosphorylation, nuclear import, transcriptional activation, transcriptional repression, and / or binding activity to a substrate or binding partner).

[0110] As used herein, the term "IL-6 signaling" refers to the expression and / or activity of one or more proteins in a signaling pathway that begins with activation of the IL-6 receptor and ends with gene expression. Non-limiting examples of proteins in a signaling pathway that begins with activation of the IL-6 receptor and ends with gene expression include IL-6 receptor, JAK, STAT3, PI3K, Akt / PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, and ERK.

[0111] As used herein, the term "NF-kB signaling" refers to the expression and / or activity of one or more of IKKα, IKKβ, IkB, and NF-kB, and / or one or more genes upregulated by NF-kB (e.g., one or more of TNF-α, IL-1, CAM, COX-2, and iNOS).

[0112] As used herein, the term "PDGF signaling" refers to the signaling pathways involved in the regulation of PDGF receptor, PKC, PI3K, Src, Ras, ERK1 / 2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, and cPLA. 2 By this is meant the expression and / or activity of one or more of:

[0113] The term "SGLT-2 inhibitor" as used herein refers to a compound that inhibits sodium glucose cotransporter-2 (SGLT-2). SGLT-2 inhibitors disrupt glucose reabsorption by the kidney, thus exerting a glucose-lowering effect. By enhancing glycosuria independent of insulin, SGLT-2 inhibitors have been shown to treat type 2 diabetes and improve cardiovascular outcomes. See Wright, 2001, Am. J. Physiol. Renal Physiol. 280:F10; and Scheen, 2018, Circ. Res. 122:1439. In some embodiments, the term "SGLT-2 inhibitor" refers to a compound whose primary effect is the inhibition of SGLT-2, but is not limited to compounds that only inhibit SGLT-2, and thus includes compounds that have other activities in addition to SGLT-2 inhibition (e.g., SGLT-1 inhibition).

[0114] In some embodiments, the SGLT-2 inhibitor includes compounds from the class of drugs known as gliflozins. In some embodiments, the SGLT-2 inhibitor includes compounds approved as SGLT-2 inhibitors by a regulatory agency such as the FDA or EMA. Non-limiting examples of SGLT-2 inhibitors include bexagliflozin, canagliflozin (INVOKANA®), dapagliflozin (FARXIGA®), empagliflozin (JARDIANCE®), ertugliflozin (STEGLATRO™), ipragliflozin (SUGLAT®), luseogliflozin (LUSEFI®), remogliflozin, sergliflozin, licogliflozin, sotagliflozin (ZYNQUISTA™), and tofogliflozin.

[0115] In some embodiments, the SGLT-2 inhibitor is selected from the group consisting of dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, bexagliflozin, licogliflozin, janagliflozin (XZP-5695), tofogliflozin, ertugliflozin, henagliflozin (SHR-3824), enavogliflozin (DWP-16001), TA-1887 (3-(4-cyclopropylbenzyl)-4-fluoro-1-(β-D-glucopyranosyl)-1H-indole), indole-N-glycoside 18 ( 3-(4-ethylbenzyl)-1-(β-D-glucopyranosyl)-1H-indole), sotagliflozin, luseogliflozin, sergliflozin etabonate (ethyl carbonate), remogliflozin, remogliflozin etabonate, and T-1095 (((2R,3S,4S,5R,6S)-6-(2-(3-(benzofuran-5-yl)propanoyl)-3-hydroxy-5-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)etabonate).

[0116] In some embodiments, the SGLT-2 inhibitor comprises a C-glycoside such as dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, bexagliflozin, licogliflozin, janagliflozin (XZP-5695), tofogliflozin, ertugliflozin, henagliflozin (SHR-3824), enavogliflozin (DWP-16001), etc. In some embodiments, the SGLT-2 inhibitor comprises a C-glycoside having a bicyclic or spiropyran group, such as tofogliflozin, ertugliflozin, and henagliflozin (SHR-3824). In some embodiments, the SGLT-2 inhibitor comprises a C-glycoside that does not have a bicyclic or spiropyran group, such as dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, bexagliflozin, licogliflozin, janagliflozin (XZP-5695), and enavogliflozin (DWP-16001).

[0117] In some embodiments, the SGLT-2 inhibitor comprises an N-glycoside such as TA-1887 (3-(4-cyclopropylbenzyl)-4-fluoro-1-(β-D-glucopyranosyl)-1H-indole) and indole-N-glycoside 18 (3-(4-ethylbenzyl)-1-(β-D-glucopyranosyl)-1H-indole).

[0118] In some embodiments, the SGLT-2 inhibitor comprises a 2-methylthio-C-glycoside, such as sotagliflozin.

[0119] In some embodiments, the SGLT-2 inhibitor comprises a thiopyran-C-glycoside, such as luseogliflozin.

[0120] In some embodiments, SGLT-2 inhibitors include O-glycosides and O-glycoside prodrugs, such as sergliflozin etabonate (ethyl carbonate), remogliflozin, remogliflozin etabonate, and T-1095 (((2R,3S,4S,5R,6S)-6-(2-(3-(benzofuran-5-yl)propanoyl)-3-hydroxy-5-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)etabonate).

[0121] In some embodiments, an SGLT-2 inhibitor, as defined herein, includes any compound that exhibits SGLT-2 inhibitory activity. In some embodiments, an SGLT-2 inhibitor is selective for SGLT-2 over SGLT-1, for example, by having about 2-fold, about 5-fold, about 10-fold, about 20-fold, about 50-fold, about 100-fold, about 200-fold, about 300-fold, about 400-fold, about 500-fold, about 750-fold, about 1,000-fold, about 1,250-fold, about 1,500-fold, about 1,750-fold, about 2,000-fold, about 2,500-fold, or any value therebetween, greater activity for SGLT-2 than for SGLT-1. Exemplary SGLT-2 inhibitors have an inhibitory activity against SGLT-2 (IC) of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM, as measured in the assays described herein. 50 In some embodiments, the SGLT-2 inhibitor may exhibit an inhibitory activity against SGLT-2 (IC) of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM, as measured in an assay described herein. 50 An exemplary assay for determining SGLT-2 inhibitory activity is described in Ryan, et al., Kidney International, Vol. 45, pp. 48-57 (1994). Briefly, CHO cells are stably transfected with a cDNA encoding human SGLT-2 (GenBank #M95549). The cells are washed and then incubated with 10 μM [ 14C] α-methylglucopyranoside (AMG) and incubated with 10 μM inhibitor. 14 The uptake of [C]AMG is quenched with cold buffer containing phlorizin and the cells are lysed. 14 C]AMG uptake is quantified.

[0122] SGLT-2 inhibitors include pharma- ceutically acceptable salts, solvates, complexes, and salts of solvates thereof, e.g., "dapagliflozin" includes salts of dapagliflozin (such as the hydrochloride salt), as well as solvates (such as propylene glycol hydrate); similarly, "canagliflozin" includes solvates (such as canagliflozin hemihydrate) and salts of solvates (such as the hydrochloride salt of the hydrate). Similarly, henagliflozin (SHR-3824) and dapagliflozin include complexes (such as the complexes henagliflozin proline and dapagliflozin proline, respectively).

[0123] As used herein, when a subject is described as having a "controlled serum glucose level", it means that the subject has a serum glucose level within a normal or healthy range. In some embodiments, the subject has a fasting serum glucose level of about 70 mg / dL to about 130 mg / dL. For example, the subject has been determined to have a fasting serum glucose level of less than about 130 mg / dL, 125 mg / dL, 120 mg / dL, 115 mg / dL, 110 mg / dL, 105 mg / dL, 100 mg / dL, 95 mg / dL, 90 mg / dL, 85 mg / dL, 80 mg / dL, or 75 mg / dL.

[0124] As used in the methods described herein, the term "reducing" refers to a decrease in the indicated parameter relative to a baseline measurement of the same parameter in a subject obtained before the start of administration of atrasentan or a pharma- ceutically acceptable salt thereof, or a decrease in the indicated parameter relative to a baseline measurement of the same parameter in a healthy subject (e.g., a subject not having FSGS). Similarly, the term "increasing" as used herein refers to an increase in the indicated parameter relative to a baseline measurement of the same parameter in a subject obtained before the start of administration of atrasentan or a pharma- ceutically acceptable salt thereof, or an increase in the indicated parameter relative to a baseline measurement of the same parameter in a healthy subject (e.g., a subject not having FSGS).

[0125] The term "glomerular filtration rate" (GFR) is defined as the volume of fluid filtered from the renal (kidney) glomerular capillaries into Bowman's capsule per unit time. It indicates overall kidney function. Glomerular filtration rate (GFR) can be calculated by measuring any chemical that has a steady level in the blood and is freely filtered but is neither reabsorbed nor secreted by the kidney. Thus, the rate measured is the amount of substance in the urine derived from a volume of blood that can be calculated. GFR is typically recorded in units of volume per time, e.g., milliliters per minute, and the following formula can be used: GFR = (urine concentration x urine volume) / plasma concentration. GFR can be determined by injecting inulin into the plasma. Since inulin is neither reabsorbed nor secreted by the kidney after glomerular filtration, its excretion rate is directly proportional to the filtration rate of water and solutes passing through the glomerular filter. Normal values ​​are: GFR = 90-125 mL / min / 1.73 m 2 , especially GFR = 100-125 mL / min / 1.73 m 2Other principles for determining GFR include measuring 51Cr-EDTA, [125I] iothalamate or iohexol. "Estimated glomerular filtration rate (eGFR)" is defined as derived from serum creatinine value at screening, for example, based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Cockcroft-Gault or Modification of Diet in Renal Disease (MDRD) formulas, all of which are known in the art. As used herein, "reducing the rate of decline of eGFR" means reducing the rate of decline of eGFR and / or attenuating the rate of decline of eGFR. As shown herein, eGFR is an art-recognized measurement of disease or disease progression. For example, the rate of decline in eGFR may be attenuated by at least about 20%; at least about 30%; at least about 40%; at least about 50%; at least about 60%; at least about 70%; at least about 80%; at least about 90%; or at least about 95%; or any value therebetween, following treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. This attenuation can be, for example, after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks of treatment, or any value therebetween. In some embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days. In some embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 6 months to about 1 year.

[0126] "ESKD" is an abbreviation for end stage kidney disease. As used herein, the onset of ESKD occurs when a subject has a kidney failure rate of approximately 15 mL / min / 1.73 m 2The term "ESRD" is defined as the time point at which a subject has an eGFR of less than 1 g / day and / or the time point at which the subject begins chronic dialysis. If a subject is defined as being "at high risk of progression to ESKD", the subject has >1 g / day urinary protein and / or an eGFR<60 for at least about 3 months prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. As used herein, and as will be recognized by those of skill in the art, any historical or incidental reference to ESRD (end stage renal disease) is used interchangeably in the art to refer to ESKD (end stage renal disease), the more recent term for the condition.

[0127] As used herein, when a subject is described as "maintaining potassium levels within the normal physiological range," the subject has a blood potassium level of about 3.5 mEq / L to about 5.2 mEq / L.

[0128] As used herein, when a subject is described as "maintaining sodium levels within the normal physiological range," the subject has a blood sodium level of about 135 to about 145 mEq / L.

[0129] As used herein, the term "proteinuria" refers to the presence of protein in urine above normal levels. "Proteinuria" includes "albuminuria" and "microalbuminuria". Normal human protein levels appear in urine in the range of about 0-30 mg / L, but for any given urine sample, levels can reach about 80 mg / L. For a 24-hour urine collection, normal human urinary protein levels range from about 0-150 mg. Proteinuria can be indicated by the urinary total protein / creatinine ratio (UPCR) or by the ratio of specific proteins, such as a urinary albumin / creatinine ratio (ACR) of greater than about 30 mg / g. Typically, the urinary UACR value (mg / g) is approximately equal to the albumin excretion (mg / day) by the subject. Proteinuria, including albuminuria and microalbuminuria, often results in or is indicative of disease, but is not limited to the production of disease. Proteinuria is intended to include all forms of proteinuria, including but not limited to physiological proteinuria; functional proteinuria; and exercise proteinuria, which is related to the form of functional proteinuria after excessive muscle exertion.In addition, proteinuria includes benign proteinuria (also known as "essential" proteinuria), which refers to the type or proteinuria that is not the result of pathological changes in the kidney.Proteinuria also covers pathological proteinuria, for example, the level of protein in urine that is higher than normal physiological levels.

[0130] As used herein, the term "albuminuria" (also known as macroalbuminuria) refers to the presence of albumin in urine above normal levels. As urinary protein is primarily albumin, normal human urinary UACR levels range from about 0 to 30 mg / mmol. As used herein, the term "microalbuminuria" refers to the presence of albumin in urine, which is excreted at a rate of about 20 to 200 μg / min in humans, or at levels of about 30 to 300 mg / L. When defined by urinary ACR, "microalbuminuria" refers to a urinary UACR of more than about 30 mg / g, or a urinary UACR of about 3.5 mg / mmol or more in women and about 2.5 mg / mmol or more in men. Microalbuminuria is often an early warning of kidney disease, but may also be present for other reasons.

[0131] As used herein, "ALT" refers to alanine transaminase. As used herein, "AST" refers to aspartate transaminase.

[0132] The term "synergism" or "synergistic" is used herein to mean that the effect of the combination of two or more therapeutic agents is greater than the sum of the effects of each agent when administered alone. See, e.g., Chou and Talalay, Advances in Enzyme Regulation (1984), 22, 27-55. A "synergistically effective amount" is the amount of a combination of two or more therapeutic agents that results in a synergistic effect (as "synergistic" is defined herein). In some embodiments, a synergistically effective amount of a combination can be therapeutically effective even when one or more compounds in the combination are administered at a dose that is sub-therapeutic when that compound is administered alone.

[0133] It will be understood that different concentrations of each compound may be used depending on various factors recognized in the art, such as the patient's height, weight, sex, age, and medical history. Exemplary synergistic effects include, but are not limited to, enhanced therapeutic efficacy, reduced dosage at equivalent or increased efficacy levels, reduced or delayed development of drug resistance, and simultaneous enhanced or equivalent therapeutic effects (e.g., the same therapeutic effect of at least one of the therapeutic agents), and reduced undesirable drug effects (e.g., side effects and adverse events) of at least one of the therapeutic agents.

[0134] In some embodiments, "synergistic effect" as used herein refers to a combination of atrasentan or a pharma- ceutically acceptable salt thereof with one or more additional therapeutic agents (e.g., an SGLT-2 inhibitor) that results in a beneficial or desired outcome, including any of the clinical outcomes described herein, that is greater than the sum of the effects observed when atrasentan or a pharma- ceutically acceptable salt thereof and an SGLT-2 inhibitor are administered alone. Such clinical outcomes include, but are not limited to, treatment of FSGS, reduction in renal inflammation and / or fibrosis, reduction in proteinuria (e.g., albuminuria), reduction in fatigue, reduction in the rate of decline of eGFR, delay in the onset of ESKD, reduction in fatigue, and reduction in mesangial cell activation.

[0135] In some embodiments, "synergistic effect" as used herein refers to a combination of atrasentan, or a pharma- ceutically acceptable salt thereof, and an SGLT-2 inhibitor that results in a greater reduction in proteinuria, such as albuminuria, than the sum of the effects observed when atrasentan, or a pharma- ceutically acceptable salt thereof, and an SGLT-2 inhibitor are administered alone.

[0136] In some embodiments, "synergy" as used herein refers to a combination of atrasentan, or a pharma- ceutically acceptable salt thereof, and an SGLT-2 inhibitor that results in a desired therapeutic effect and a reduced incidence and / or severity of undesired drug effects, side effects, or adverse events. In some embodiments, the undesired drug effects, side effects, or adverse events are associated with or observed in atrasentan, or a pharma- ceutically acceptable salt thereof, or an SGLT-2 inhibitor monotherapy. In some embodiments, the undesired drug effects, side effects, or adverse events are one or more of fluid retention, anemia, nausea, constipation, dry mouth, bone fractures, increased urination, urinary tract infection, yeast infection, vaginal pruritus, increased LDL cholesterol levels, increased brain natriuretic peptide (BNP) levels, acute sodium retention, and acute increase in creatinine levels. In some embodiments, the fluid retention is associated with a weight gain of more than about 3 kg. In some embodiments, the increased BNP level is more than about 300 pg / mL.

[0137] An adverse event (AE) is any undesirable or untoward medical occurrence in a human subject, including any abnormal sign (e.g., abnormal physical examination or laboratory findings), symptom, or disease that is temporally related to the subject's participation in the study, whether or not considered related to the subject's participation in the study. Any medical condition or clinically significant laboratory abnormality that has an onset date before the first dose is a pre-existing condition that must be taken as part of the medical history and should not be considered an AE unless it worsens in intensity or frequency after enrollment. Events that meet the definition of an AE include one or more of the events in the following paragraphs.

[0138] An AE may be any abnormal laboratory result (hematology, clinical chemistry, or urinalysis) that requires intervention or other safety assessment (e.g., ECG, vital sign measurements), including any worsening from baseline that is considered clinically significant (i.e., unrelated to progression of the underlying disease) in the investigator's medical and scientific judgment. An AE may include an exacerbation of a chronic or intermittent pre-existing condition, including either an increase in the frequency and / or intensity of the condition. A new condition is detected or diagnosed after administration of the study drug, although it may have been present before the start of the study. Signs, symptoms, or clinical sequelae that are suspicious of a drug-drug interaction. Signs, symptoms, or clinical sequelae that are suspicious of an overdose of the study drug or a concomitant medication. An overdose itself is not considered an AE / SAE unless it is an intentional overdose with the potential for suicide / self-harm. Such overdoses should be reported regardless of sequelae.

[0139] A "serious adverse event" (SAE) is any AE that results in: death; a life-threatening condition (putting the subject at immediate risk of death); hospitalization of the subject or prolongation of an existing hospitalization; persistent or significant disability / incapacity; congenital anomaly / birth defect; or any other AE that, based on the medical judgment of the investigator, may require medical or surgical intervention to prevent one of the outcomes listed above (examples of such events include allergic bronchospasm requiring intensive care in the emergency room or at home, blood disorders or convulsions that do not result in hospitalization of the subject, or the development of drug dependence or abuse).

[0140] "Adverse events of special concern" (AESI) included dilutional anemia, vasodilation / hypotension / acute kidney injury, or cardiac failure.

[0141] As described herein, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the recited range, and, where appropriate, fractions thereof (such as tenths and hundredths of integers), unless otherwise stated.

[0142] Unless otherwise specified, references to amounts of atrasentan in this disclosure are based on the free equivalent amount of atrasentan. For example, 0.75 mg of atrasentan refers to 0.75 mg of atrasentan in the free form, or the equivalent amount of a salt form of atrasentan.

[0143] Various aspects of the disclosure are described in further detail in the following subsections.

[0144] II. Treatment method In normal and healthy human kidneys, the expression of endothelin-1 (ET-1) and endothelin A receptor (ET-RA) is stronger in vascular tissues and weaker in glomerular structures. In contrast, subjects with FSGS show increased expression of ET-1 and ET-RA in the kidney. In that population, ET-1 expression positively correlates with proteinuria, which is at least partially ameliorated by administration of ACE inhibitors. In fact, the current treatment for FSGS is the optimization of antihypertensive and antiproteinuric agents (e.g., angiotensin-converting enzyme inhibitors and / or angiotensin II receptor blockers) along with a course of corticosteroids to inhibit disease progression. See, for example, Penfold et al., Int. J. Nephrol. and Renovascular Dis. 11, Pp. 137-148 (2017). However, these combinations of drugs can exhibit significant dose-limiting side effects, such as hyperkalemia, and in more severe cases, further immunosuppression may be required.

[0145] Clinically, FSGS is diagnosed by kidney biopsy showing the presence of mesangial cell proliferation and / or matrix proliferation (or focal segmental glomerulosclerosis in advanced stages) with predominant mesangial granular deposits of IgA (2+ or higher) by immunofluorescence. This pathology differs from other progressive kidney diseases such as diabetic nephropathy, which typically presents with diffuse capillary basement membrane thickening with peripheral hyaline PAS-positive nodules, segmental or global glomerulosclerosis in advanced stages, and thickened arterioles with hyaline deposits. See, e.g., Zanatta, et al., Renal Failure, 34(3), pp.308-315 (2012).

[0146] Thus, in one aspect, provided herein is a method for treating FSGS, comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. In another aspect, provided herein is a method for reducing nephritis and / or fibrosis in a subject with FSGS, comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. In another aspect, provided herein is a method for reducing the rate of decline of eGFR in a subject with FSGS, comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. In another aspect, provided herein is a method for delaying the onset of ESKD in a subject with FSGS, comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. In another aspect, provided herein is a method for reducing proteinuria in a subject with FSGS, comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. In another aspect, provided herein is a method of reducing fatigue in a subject with FSGS, comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. In another aspect, provided herein is a method of stabilizing functional podocyte mass in a subject with FSGS, comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. As provided herein, in some embodiments, disease progression is stabilized, reduced, or delayed according to certain methods disclosed herein, including as measured by art-recognized parameters, examples of which are provided herein.

[0147] In some cases, FSGS is diagnosed by biopsy-confirmed FSGS. Some embodiments provide that the subject has a genetic diagnosis of FSGS due to a known podocyte protein mutation. Additional embodiments include subjects with a mutation in APOL1. In some cases, FSGS includes nephrotic syndrome. In some cases, nephrotic syndrome is selected from proteinuria, hypoalbuminemia, hypercholesterolemia, peripheral edema, or any combination of the foregoing. In some cases, FSGS is perihilar FSGS, apical FSGS, cellular FSGS, collapsing FSGS, primary FSGS, virus-associated FSGS, non-HIV-associated FSGS, toxin-associated FSGS, adaptive FSGS, or a combination thereof. In some cases, FSGS is non-specific (NOS) FSGS.

[0148] In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject has not been previously diagnosed with any of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject has not been previously diagnosed with diabetic nephropathy. In some embodiments, the subject has not been previously diagnosed with HIV / AIDS. In some embodiments, the subject has not been previously diagnosed with HIV-associated nephropathy. In some embodiments, the subject has not been previously diagnosed with prostate cancer. In some embodiments, the subject has not been previously diagnosed with acute renal failure. In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, cancer, or acute renal failure. In some embodiments, the subject has not been previously diagnosed with diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject has been previously diagnosed with diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject has been previously diagnosed with diabetes and has not been previously diagnosed with diabetic nephropathy. In some embodiments, the subject has not been previously diagnosed with type 2 diabetes. In some embodiments, the subject has been previously diagnosed with type 2 diabetes. In some embodiments, the subject has been previously diagnosed with type 2 diabetes and has not been previously diagnosed with diabetic nephropathy.

[0149] In some embodiments, the subject is not currently diagnosed with cancer. In some embodiments, the subject is not currently being treated for cancer. In some embodiments, the cancer is lung cancer or prostate cancer.

[0150] In some embodiments, the subject does not have one or more of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject does not have any of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject does not have diabetic nephropathy. In some embodiments, the subject does not have HIV / AIDS. In some embodiments, the subject does not have HIV-associated nephropathy. In some embodiments, the subject does not have cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the subject does not have acute renal failure. In some embodiments, the subject does not have one or more of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, cancer, or acute renal failure. In some embodiments, the cancer is lung cancer or prostate cancer. In some embodiments, the subject has diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject does not have diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject has diabetes and does not have diabetic nephropathy. In some embodiments, the subject has type 2 diabetes. In some embodiments, the subject does not have type 2 diabetes. In some embodiments, the subject has type 2 diabetes and does not have diabetic nephropathy.

[0151] In some embodiments, the subject does not suffer from one or more of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject does not suffer from any of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject does not suffer from diabetic nephropathy. In some embodiments, the subject does not suffer from HIV / AIDS. In some embodiments, the subject does not suffer from HIV-associated nephropathy. In some embodiments, the subject does not suffer from cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the subject does not suffer from acute renal failure. In some embodiments, the subject does not suffer from one or more of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, cancer, or acute renal failure. In some embodiments, the cancer is lung cancer or prostate cancer. In some embodiments, the subject does not suffer from diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject does not have diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject has diabetes, such as type 1 diabetes or type 2 diabetes, but does not have diabetic nephropathy. In some embodiments, the subject does not have type 2 diabetes. In some embodiments, the subject has type 2 diabetes. In some embodiments, the subject has type 2 diabetes, but does not have diabetic nephropathy.

[0152] In some embodiments, the subject is not being treated for one or more of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject is not being treated for any of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject is not being treated for diabetic nephropathy. In some embodiments, the subject is not being treated for HIV / AIDS. In some embodiments, the subject is not being treated for HIV-associated nephropathy. In some embodiments, the subject is not being treated for prostate cancer. In some embodiments, the subject is not being treated for acute renal failure. In some embodiments, the subject is not being treated for one or more of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, cancer, or acute renal failure. In some embodiments, the cancer is lung cancer or prostate cancer. In some embodiments, the subject is not being treated for diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject is being treated for diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject is being treated for diabetes, such as type 1 diabetes or type 2 diabetes, but is not being treated for diabetic nephropathy. In some embodiments, the subject is not being treated for type 2 diabetes. In some embodiments, the subject is being treated for type 2 diabetes. In some embodiments, the subject is being treated for type 2 diabetes, but is not being treated for diabetic nephropathy.

[0153] In certain embodiments, the subject has been determined to have a controlled serum glucose level. In some embodiments, the subject with the controlled serum glucose level is not being treated for diabetes. In some embodiments, the subject with the controlled serum glucose level is being treated for diabetes. In some embodiments, the subject with the controlled serum glucose level is not being treated for type 2 diabetes. In some embodiments, the subject with the controlled serum glucose level is being treated for type 2 diabetes. In some embodiments, the subject has been determined to have a controlled serum glucose level; and the subject has not been diagnosed with one or more of HIV-associated nephropathy or acute renal failure. For example, the subject is determined to have a fasting serum glucose level of less than about 130 mg / dL, about 125 mg / dL, about 120 mg / dL, about 115 mg / dL, about 110 mg / dL, about 105 mg / dL, about 100 mg / dL, about 95 mg / dL, about 90 mg / dL, about 85 mg / dL, about 80 mg / dL, or about 75 mg / dL, or any value therebetween. In certain embodiments, the subject has not been diagnosed with one or more of HIV-associated nephropathy or acute renal failure. In certain embodiments, the subject has been determined to have a controlled serum glucose level as described elsewhere herein; and the subject has not been diagnosed with one or more of HIV-associated nephropathy or acute renal failure. In certain embodiments, the subject has been determined to have a controlled serum glucose level; and the subject has not been diagnosed with one or more of HIV-associated nephropathy or acute renal failure.

[0154] In another aspect, provided herein is a method of stabilizing or reducing nephritis and / or fibrosis in a subject with FSGS, comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. In some cases, the nephritis and / or fibrosis is tubulointerstitial inflammation. In some cases, the nephritis and / or fibrosis is tubulointerstitial fibrosis. In some cases, the nephritis and / or fibrosis comprises glomerular inflammation and / or glomerulosclerosis. In some cases, the nephritis and / or fibrosis comprises tubulointerstitial inflammation, tubulointerstitial fibrosis, glomerular inflammation, and / or glomerulosclerosis.

[0155] In some embodiments, nephritis in a subject with FSGS is reduced by at least about 10% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In certain embodiments, the subject's nephritis is reduced by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%, or any value therebetween. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days.

[0156] In some embodiments, renal fibrosis in a subject with FSGS is reduced by at least about 10% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In certain embodiments, the subject's renal fibrosis is reduced by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%, or any value therebetween. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days.

[0157] In some embodiments, renal fibrosis in a subject with FSGS is reduced to less than about 50% of the cortical area of ​​the affected kidney after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween).In certain embodiments, renal fibrosis in a subject is reduced to less than about 40% of the cortical area. For example, in some embodiments, the subject's renal fibrosis is reduced to less than about 35%, about 30%, about 25%, about 20%, about 15%, or about 10% of the cortical area, or any value therebetween. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days.

[0158] In some embodiments, the number of urinary red blood cells per high power (microscopic) field (rbc / hpf) in a subject with FSGS is reduced by at least about 10% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In certain embodiments, the urinary rbc / hpf in the subject is reduced by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%, or any value therebetween. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days.

[0159] In another aspect, provided herein is a method of reducing the rate of decline of eGFR in a subject with FSGS, the method comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof.

[0160] In some embodiments, provided herein is a method of reducing the rate of decline of eGFR in a subject with FSGS, the method comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the rate of decline of the subject's eGFR is reduced by at least about 10% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In some embodiments, the subject's eGFR declines by at least about 20%; at least about 30%; at least about 40%; at least about 50%; at least about 60%; at least about 70%; at least about 80%; at least about 90%; or at least about 95%; or any value therebetween. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 6 months to about 1 year.

[0161] In some embodiments, the rate of decline in eGFR in a subject with FSGS after treatment with atrasentan or a pharma- ceutical acceptable salt thereof is about 10 mL / min / 1.73 m 2For example, after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween. In certain embodiments, the subject's rate of decline in eGFR is about 9 mL / min / 1.73 m after about 6 months to about 1 year of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. 2 , approx. 8mL / min / 1.73m 2 , about 7mL / min / 1.73m 2 , approx. 6mL / min / 1.73m 2 , about 5mL / min / 1.73m 2 , approx. 4mL / min / 1.73m 2 , about 3mL / min / 1.73m 2 , about 2mL / min / 1.73m 2 , about 1mL / min / 1.73m 2 , or about 0.75 mL / min / 1.73 m 2 For example, in subjects about 20 to about 30 years of age, the typical decline in eGFR with age is about 1 mL / min / 1.73 m 2 / year.

[0162] In another aspect, provided herein is a method of delaying the onset of ESKD in a subject with FSGS, the method comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof.

[0163] In some embodiments, the method includes a diagnosis of FSGS in a subject and a determination of whether the subject's eGFR is 15 mL / min / 1.73 m 2 In certain embodiments, the method increases the time between a diagnosis of FSGS in a subject and the time the subject's eGFR drops below 15 mL / min / 1.73 m. 2For example, in some embodiments, the method increases the time between a diagnosis of FSGS in a subject and the time the subject's eGFR drops below 15 mL / min / 1.73 m by at least about 10%. 2 The time between the time when the serum albumin level drops below 100%, ...

[0164] In certain embodiments, the method includes determining whether a patient has a diagnosis of FSGS in a subject and whether the subject's eGFR is greater than or equal to 15 mL / min / 1.73 m 2 For example, the method may increase the time between when the subject's eGFR drops below 15 mL / min / 1.73 m by at least about 1 year. 2 The time for the decline to below 1.5 years can be delayed by at least about 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, 5 years, 5.5 years, 6 years, 6.5 years, 7 years, 7.5 years, 8 years, 8.5 years, 9 years, 9.5 years, 10 years, 11 years, 12 years, 13 years, 15 years, 15 years, 16 years, 17 years, 18 years, 19 years, or 20 years.

[0165] In another aspect, provided herein is a method of reducing proteinuria in a subject with FSGS, comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof.As used throughout this specification, proteinuria is understood to measure protein in urine.Typically, albumin is the major protein in urine, but other and multiple proteins can be tested as part of one or more of the methods described herein.Reference to "protein" may refer to albumin or one or more other proteins that are typically detected in urine in some embodiments described herein, as will be understood by those skilled in the art.

[0166] In some embodiments, the amount of protein (e.g., albumin) in the urine of a subject with FSGS is reduced by at least about 10% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In some embodiments, the amount of protein in the subject's urine is reduced by at least about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%, or any value therebetween. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days.

[0167] In certain embodiments, the amount of protein (e.g., albumin) in the urine of a subject with FSGS is reduced by about 20% to about 80% after about 2 to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In certain embodiments, the amount of protein (e.g., albumin) in the urine of a subject with FSGS is reduced by about 20% to about 80% after about 15 to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In certain of these embodiments, the amount of protein in the urine of the subject is reduced by about 25% to about 80%. In certain of these embodiments, the amount of protein in the urine of the subject is reduced by about 30% to about 80%. In certain of these embodiments, the amount of protein in the urine of the subject is reduced by about 35% to about 80%. In certain of these embodiments, the amount of protein in the urine of the subject is reduced by about 40% to about 80%. In certain of these embodiments, the amount of protein in the urine of the subject is reduced by about 45% to about 80%. In certain of these embodiments, the amount of protein in the subject's urine is reduced by about 50% to about 80%. In the foregoing embodiments, the reduction in the amount of protein (e.g., albumin) in the urine of a subject with FSGS is relative to the amount of protein (e.g., albumin) in the urine before initiation of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0168] In some embodiments, the amount of protein (e.g., albumin) in the urine of a subject with FSGS is reduced by about 100 mg / dL to about 3,000 mg / dL after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 2,500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 2,000 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 1,500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 1,000 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 400 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 300 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 200 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 2,500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 2,000 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 1,500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 1,000 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 900 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 800 mg / dL.In certain embodiments, the amount of protein in the subject's urine is reduced by about 600 mg / dL to about 900 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 700 mg / dL to about 900 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 1,000 mg / dL to about 2,000 mg / dL. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days. In the foregoing embodiments, the reduction in the amount of protein (e.g., albumin) in the subject's urine is relative to the amount of protein (e.g., albumin) in the urine of the subject with FSGS prior to the initiation of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0169] In certain embodiments, the amount of protein (e.g., albumin) in the urine of a subject with FSGS is reduced by about 100 mg / dL to about 500 mg / dL after about 15 to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In certain embodiments, the amount of protein in the urine of a subject with FSGS is reduced by about 200 mg / dL to about 500 mg / dL after about 15 to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In certain embodiments, the amount of protein in the urine of a subject with FSGS is reduced by about 300 mg / dL to about 500 mg / dL after about 15 to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In the foregoing embodiments, the reduction in the amount of protein (e.g., albumin) in the urine of a subject with FSGS is relative to the amount of protein (e.g., albumin) in the urine before the initiation of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0170] In certain embodiments, the amount of protein (e.g., albumin) in the urine of a subject with FSGS is reduced by about 500 mg / dL to about 900 mg / dL after about 15 to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In certain embodiments, the amount of protein in the urine of a subject with FSGS is reduced by about 600 mg / dL to about 900 mg / dL after about 15 to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In certain embodiments, the amount of protein in the urine of a subject with FSGS is reduced by about 700 mg / dL to about 900 mg / dL after about 15 to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In the foregoing embodiments, the reduction in the amount of protein (e.g., albumin) in the urine of a subject with FSGS is relative to the amount of protein (e.g., albumin) in the urine before the initiation of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0171] In some embodiments, a subject with FSGS has a reduction in urinary protein (e.g., albumin) levels of less than about 1.0 gram / day after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, 50 weeks, 60 weeks, 70 weeks, 80 weeks, 90 weeks, 100 weeks, 110 weeks, 120 weeks, 130 weeks, 140 weeks, 150 weeks, 160 weeks, 170 weeks, 180 weeks, 190 weeks, or 200 weeks of treatment). In certain embodiments, a subject has a reduction in urinary protein levels of less than about 0.9 gram / day. In certain embodiments, a subject has a reduction in urinary protein levels of less than about 0.8 gram / day. In certain embodiments, a subject has a reduction in urinary protein levels of less than about 0.7 gram / day. In certain embodiments, the subject has a reduced level of protein in the urine of less than about 0.6 grams / day. In certain embodiments, the subject has a reduced level of protein in the urine of less than about 0.5 grams / day. In certain embodiments, the subject has a reduced level of protein in the urine of less than about 0.4 grams / day. In certain embodiments, the subject has a reduced level of protein in the urine of less than about 0.3 grams / day. In certain embodiments, the subject has a reduced level of protein in the urine of less than about 0.2 grams / day. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days. In the foregoing embodiments, the reduction in the amount of protein (e.g., albumin) in the urine of the subject with FSGS is relative to the amount of protein (e.g., albumin) in the urine before the initiation of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0172] In another aspect, provided herein is a method of reducing fatigue in a subject with FSGS, comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the subject is determined not to have one or more of diabetic nephropathy, HIV-associated nephropathy, prostate cancer, or acute renal failure. In certain embodiments, the subject is determined not to have diabetic nephropathy. In certain embodiments, the subject is determined not to have HIV-associated neuropathy. In certain embodiments, the subject is determined not to have prostate cancer. In certain embodiments, the subject is determined not to have acute renal failure.

[0173] In some embodiments, fatigue in a subject with FSGS is reduced by about 5% to about 80% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In certain embodiments, fatigue is reduced by about 10% to about 75%. In certain embodiments, fatigue is reduced by about 10% to about 70%. In certain embodiments, fatigue is reduced by about 10% to about 65%. In certain embodiments, fatigue is reduced by about 10% to about 60%. In certain embodiments, fatigue is reduced by about 10% to about 55%. In certain embodiments, fatigue is reduced by about 10% to about 50%. In certain embodiments, fatigue is reduced by about 10% to about 45%. In certain embodiments, fatigue is reduced by about 10% to about 40%. In certain embodiments, fatigue is reduced by about 10% to about 35%. In certain embodiments, fatigue is reduced by about 10% to about 30%. In certain embodiments, fatigue is reduced by about 10% to about 25%. In certain embodiments, fatigue is reduced by about 10% to about 20%. In certain embodiments, fatigue is reduced by about 10% to about 15%. In certain embodiments, fatigue is reduced by about 20% to about 75%. In certain embodiments, fatigue is reduced by about 20% to about 70%. In certain embodiments, fatigue is reduced by about 20% to about 65%. In certain embodiments, fatigue is reduced by about 20% to about 60%. In certain embodiments, fatigue is reduced by about 20% to about 55%. In certain embodiments, fatigue is reduced by about 20% to about 50%. In certain embodiments, fatigue is reduced by about 20% to about 45%. In certain embodiments, fatigue is reduced by about 20% to about 40%. In certain embodiments, fatigue is reduced by about 20% to about 35%. In certain embodiments, fatigue is reduced by about 20% to about 30%. In certain embodiments, fatigue is reduced by about 30% to about 75%. In certain embodiments, fatigue is reduced by about 30% to about 70%. In certain embodiments, fatigue is reduced by about 30% to about 65%.In certain embodiments, fatigue is reduced by about 30% to about 60%. In certain embodiments, fatigue is reduced by about 30% to about 55%. In certain embodiments, fatigue is reduced by about 30% to about 50%. In certain embodiments, fatigue is reduced by about 30% to about 45%. In certain embodiments, fatigue is reduced by about 30% to about 40%. In certain embodiments, fatigue is reduced by about 40% to about 75%. In certain embodiments, fatigue is reduced by about 40% to about 70%. In certain embodiments, fatigue is reduced by about 40% to about 65%. In certain embodiments, fatigue is reduced by about 40% to about 60%. In certain embodiments, fatigue is reduced by about 40% to about 55%. In certain embodiments, fatigue is reduced by about 40% to about 50%. In certain embodiments, fatigue is reduced by about 50% to about 75%. In certain embodiments, fatigue is reduced by about 50% to about 70%. In certain embodiments, fatigue is reduced by about 50% to about 65%. In certain embodiments, fatigue is reduced by about 50% to about 60%. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days. In certain embodiments, the reduction in fatigue comprises a reduction in the score on one or more of the Fatigue Severity Scale, the Chalder Fatigue Scale, the FACIT Fatigue Scale, the Brief Fatigue Inventory, the FACT-F subscale, General Energy and Impact, the May and Kline Adjective Checklist, the Pearson-Byars Fatigue Checklist, the Rhoten Fatigue Scale, the Schedule for Fatigue and Anergy, the Visual Analog Scale, or the Personal Physical Fitness Checklist. In the foregoing embodiments, the reduction in fatigue experienced by the subject with FSGS is relative to the fatigue experienced by the subject prior to the initiation of treatment with atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the reduction in fatigue comprises a reduction in the score on the Brief Fatigue Inventory.

[0174] III. Target Selection Subjects with FSGS as described elsewhere herein can be diagnosed using one or more methods known in the art, including, but not limited to: kidney biopsy, detection of anti-glycan antibodies, detection of fibrotic deposits in the kidney, or any combination of the foregoing.

[0175] In some embodiments, the presence and / or level of a particular protein in a subject is determined prior to administration of atrasentan or a pharma- ceutically acceptable salt thereof. For example, serum levels of Gd-IgA1, serum levels of autoantibodies specific to Gd-IgA1, and / or serum and / or urinary levels of IgA1-containing immune complexes. See, for example, Knoppova, et al., Front. Immunol., Vol. 17, Art. 117 (2016), which is incorporated herein by reference in its entirety. In some embodiments, a subject has a Gd-IgA level within the 90th percentile or higher prior to administration of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, a subject has a Gd-IgA level within the 95th percentile or higher prior to administration of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject's Gd-IgA levels fall below the 90th percentile after about 6 months to 1 year of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0176] In certain embodiments, the subject has mesangial cellularity in about ≧50% (e.g., about ≧60%, about ≧70%, or about ≧80%) of the glomerulus, where mesangial cellularity is defined as more than four mesangial cells in any mesangial region of the glomerulus. In certain embodiments, the subject has intratubular hypercellularity, where intratubular hypercellularity is defined as hypercellularity resulting from an increased number of cells in the lumen of the glomerular capillaries. In certain embodiments, the subject has segmental sclerosis, where segmental sclerosis is defined as adhesions or sclerosis (obstruction of the capillary lumen by matrix) in some but not all of the glomerular tuft. In certain embodiments, the subject has tubular atrophy / interstitial fibrosis in about ≧50% (e.g., about ≧60%, about ≧65%, about ≧70%, about ≧75%, or about ≧80%) of the cortical area, where tubular atrophy / interstitial fibrosis is defined as the estimated percentage of the cortical area that exhibits tubular atrophy or interstitial fibrosis. In certain embodiments, the subject has crescents present on the glomeruli. In certain of these embodiments, the subject has crescents present in less than about 25% (e.g., less than about 20%, about 15%, about 10%, or about 5%) of the glomeruli. In certain embodiments, the subject has a MEST-C score of M1; E1; S1; T1 or T2; and / or C0 or C1 under the Oxford MEST-C classification system. The Oxford MEST-C classification system is defined in Kidney International (2009) 76, 546-556 and Nature Reviews Nephrology (2017) 13, 385-386, each of which is incorporated by reference in its entirety. (See also Kidney Research and Clinical Practice (2016) 35, 197-203, each of which is incorporated by reference in its entirety.)

[0177] In some embodiments, the subject is at high risk of progressing to ESKD. In certain of these embodiments, the subject excretes an average of about 1 gram or more of protein in the urine per day for at least about 3 months prior to the first administration of atrasentan, or a pharma- ceutically acceptable salt thereof. In certain of these embodiments, the subject excretes an average of about 0.75 grams or more of protein in the urine per day for at least about 3 months prior to the first administration of atrasentan, or a pharma-ceutically acceptable salt thereof. In certain of these embodiments, the subject excretes an average of about 0.75 grams to about 1.5 grams of protein in the urine per day for at least about 3 months prior to the first administration of atrasentan, or a pharma-ceutically acceptable salt thereof. In certain of these embodiments, the subject excretes an average of about 1 gram or more of protein in the urine per day for at least about 3 months prior to the first administration of atrasentan, or a pharma-ceutically acceptable salt thereof.

[0178] In certain embodiments, the subject is administered about 20 to about 120 mL / min / 1.73 m for at least about 3 months prior to the first administration of atrasentan, or a pharma- ceutical acceptable salt thereof. 2 (about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or 120). In certain embodiments, the subject has an average eGFR of about 20 to about 90 mL / min / 1.73 m for at least about 3 months prior to the first administration of atrasentan, or a pharmacologic salt thereof. 2 In certain embodiments, the subject has a mean eGFR of about 20 to about 60 mL / min / 1.73 m for at least about 3 months prior to the first administration of atrasentan, or a pharmacologic salt thereof. 2 have a mean eGFR of

[0179] In certain embodiments, the subject has a blood glucose level of ≦60 mL / min / 1.73 m for at least about 3 months prior to the first administration of atrasentan, or a pharmacologic acceptable salt thereof. 2(e.g., about ≦55, about ≦50, about ≦45, about ≦40, about ≦35). In certain of these embodiments, the subject has an eGFR>30 mL / min / 1.73 m prior to the first administration of atrasentan or a pharma- ceutical acceptable salt thereof. 2 has.

[0180] In some embodiments, the subject is excreting an average of about 1 gram or more of protein in the urine per day for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years) prior to the first administration of atrasentan, or a pharma- ceutical acceptable salt thereof. For example, a subject may be excreting an average of about 1.1 grams, 1.2 grams, 1.3 grams, 1.4 grams, 1.5 grams, 1.6 grams, 1.7 grams, 1.8 grams, 1.9 grams, 2.0 grams, 2.1 grams, 2.2 grams, 2.3 grams, 2.4 grams, 2.5 grams, 2.6 grams, 2.7 grams, 2.8 grams, 2.9 grams, 3.0 grams, 3.1 grams, 3.2 grams, 3.3 grams, 3.4 grams, 3.5 grams, 5 grams, or 7.5 grams, or 10 grams of protein per day, or any value therebetween, in the urine for at least three months prior to the first administration of atrasentan, or a pharma- ceutically acceptable salt thereof.

[0181] In some embodiments, the subject is excreting an average of about 0.3 grams to about 2 grams of protein in the urine per day for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years) prior to the first administration of atrasentan, or a pharma- ceutically acceptable salt thereof. For example, the subject may be excreting about 0.3 grams to 0.5 grams, 0.5 grams to 1 gram, about 0.5 grams to 1.5 grams, about 1 gram to 1.5 grams, or about 1.5 grams to 2 grams of protein per day in the urine for at least 3 months.

[0182] In some embodiments, the subject excretes at least about 1 gram of protein in the urine per day in at least two of three consecutive measurements one year prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. For example, the subject may excrete about 1.1 grams, 1.2 grams, 1.3 grams, 1.4 grams, 1.5 grams, 1.6 grams, 1.7 grams, 1.8 grams, 1.9 grams, 2.0 grams, 2.1 grams, 2.2 grams, 2.3 grams, 2.4 grams, 2.5 grams, 2.6 grams, 2.7 grams, 2.8 grams, 2.9 grams, 3.0 grams, 3.1 grams, 3.2 grams, 3.3 grams, 3.4 grams, 3.5 grams, 5 grams, 7.5 grams, or 10 grams of protein in the urine per day in at least two of three consecutive measurements one year prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof, or any value therebetween.

[0183] In some embodiments, the subject has a UACR value of at least about 300 mg / g, e.g., 300 mg / g to about 5,000 mg / g, for at least 3 months prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject has a UACR value of about 800 mg / g, e.g., 800 mg / g to about 5,000 mg / g, for at least 3 months prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject has a UACR value of at least about 500 mg / g, about 600 mg / g, about 700 mg / g, about 800 mg / g, about 900 mg / g, about 1,000 mg / g, about 1,500 mg / g, about 2,000 mg / g, about 2,500 mg / g, about 3,000 mg / g, about 3,500 mg / g, about 4,000 mg / g, about 4,500 mg / g, or about 5,000 mg / g, or any value therebetween, for at least 3 months prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof.

[0184] In some embodiments, the subject has a reduction in UACR value of at least about 30% relative to the subject's average UACR value for at least 3 months prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof, for example, a reduction of about 30% to about 100% relative to the subject's average UACR value for at least 3 months prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject has a reduction in UACR value of at least about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%, or any value therebetween, relative to the subject's average UACR value for at least 3 months prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject having a reduction in UACR value also does not experience significant sodium retention and / or significant fluid retention. In some embodiments, significant fluid retention can be from about 1 kg to about 4 kg over a 6 week period, for example, about 4 kg, about 3.5 kg, about 3 kg, about 2.5 kg, about 2 kg, about 1.5 kg, or about 1 kg over a 6 week period, or any value therebetween. In some embodiments, subjects with significant fluid retention exhibit clinical symptoms of edema.

[0185] In certain embodiments, the subject is administered about 20 to about 90 mL / min / 1.73 m for at least about 3 months (e.g., about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 1.5 years, or about 2 years) prior to the first administration of atrasentan, or a pharma- ceutical acceptable salt thereof. 2 For example, for at least about 3 months prior to the first administration of atrasentan, or a pharma- ceutical acceptable salt thereof, the patient has a mean eGFR of about 20 to about 50 mL / min / 1.73 m 2 ;Approx. 30~60mL / min / 1.73m 2 ;Approx. 40~70mL / min / 1.73m 2 ;Approx. 50~80mL / min / 1.73m 2 or about 60 to about 90 mL / min / 1.73 m 2 In some embodiments, the subject has a mean eGFR ≦60 mL / min / 1.73 m for at least about 3 months prior to the first administration of atrasentan, or a pharma- ceutical acceptable salt thereof. 2 In certain embodiments, the subject has a mean eGFR ≦55 mL / min / 1.73 m for at least about three months. 2 In certain embodiments, the subject has a mean eGFR≦50 mL / min / 1.73 m for at least about 3 months. 2 In certain embodiments, the subject has a mean eGFR ≦45 mL / min / 1.73 m for at least about 3 months. 2 In certain embodiments, the subject has a mean eGFR ≦40 mL / min / 1.73 m for at least about 3 months. 2 In certain embodiments, the subject has a mean eGFR≦35 mL / min / 1.73 m for at least about 3 months. 2 In certain embodiments, the subject has a mean eGFR ≦25 mL / min / 1.73 m for at least about 3 months. 2 In certain embodiments, the subject has a mean eGFR≦20 mL / min / 1.73 m for at least about 3 months. 2 In certain of the foregoing embodiments, the subject has an arterial flow rate of about 30 mL / min / 1.73 m for at least 3 months prior to administration of atrasentan or a pharma- ceutical acceptable salt thereof.2 ~Approx. 60mL / min / 1.73m 2 For example, subjects have an average eGFR of about 30 mL / min / 1.73 m 2 ~Approx. 55mL / min / 1.73m 2 , about 30mL / min / 1.73m 2 ~About 50mL / min / 1.73m 2 , about 30mL / min / 1.73m 2 ~About 45mL / min / 1.73m 2 , or about 30 mL / min / 1.73 m 2 ~ approx. 40mL / min / 1.73m 2 The patient may have a mean eGFR of

[0186] In certain embodiments, the subject is administered at least about 30 mL / min / 1.73 m for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years) prior to the first administration of atrasentan, or a pharma- ceutical acceptable salt thereof. 2 ~About 45mL / min / 1.73m 2 , e.g., about ≦45, about ≦40, about ≦35, or about ≦30. In some embodiments, the subject has a mean eGFR of about 25 mL / min / 1.73 m for at least about 3 months prior to the first administration of atrasentan, or a pharma- ceutical acceptable salt thereof. 2 ~Approx. 75mL / min / 1.73m 2 For example, for at least about 3 months prior to the first administration of atrasentan, or a pharma- ceutical acceptable salt thereof, the patient has a mean eGFR of about 25 mL / min / 1.73 m 2 , about 30mL / min / 1.73m 2 , about 35mL / min / 1.73m 2 , approx. 40mL / min / 1.73m 2 , about 45mL / min / 1.73m 2 , about 50mL / min / 1.73m 2 , about 55mL / min / 1.73m 2 , about 60mL / min / 1.73m 2 , about 65mL / min / 1.73m 2, about 70mL / min / 1.73m 2 , about 75mL / min / 1.73m 2 , or any value in between.

[0187] In some embodiments, the subject has an average HbA1c of about 4% to about 6% for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years) prior to the first administration of atrasentan, or a pharma- ceutically acceptable salt thereof. For example, the subject may have an average HbA1c of about 4.2%, about 4.4%, about 4.6%, about 4.8%, about 5.0%, about 5.2%, about 5.4%, about 5.6%, about 5.8%, or about 6%, or any value therebetween.

[0188] In some embodiments, the subject has an average fasting blood glucose level of about 125 mg / dL or less for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years) prior to the first administration of atrasentan, or a pharma- ceutically acceptable salt thereof. For example, the subject may have an average fasting blood glucose level of about 120 mg / dL, about 115 mg / dL, about 110 mg / dL, about 105 mg / dL, about 100 mg / dL, about 95 mg / dL, about 90 mg / dL, about 85 mg / dL, about 80 mg / dL, or about 75 mg / dL, or any value therebetween.

[0189] In some embodiments, the subject maintains potassium levels within the normal physiological range. In certain embodiments, the subject maintains potassium levels within the normal physiological range for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years) prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. In certain embodiments, the subject maintains potassium levels within 3.5-5.2 mEq / L. For example, the subject maintains an average potassium level of about 3.5mEq / L, about 3.6mEq / L, about 3.7mEq / L, about 3.8mEq / L, about 3.9, about mEq / L, about 4.0mEq / L, about 4.1mEq / L, about 4.2mEq / L, about 4.3mEq / L, about 4.4mEq / L, about 4.5mEq / L, about 4.6mEq / L, about 4.7mEq / L, about 4.8mEq / L, about 4.9mEq / L, about 5.0mEq / L, about 5.1mEq / L, or about 5.2mEq / L, or any value therebetween.

[0190] In some embodiments, the subject maintains sodium levels within the normal physiological range. In certain embodiments, the subject maintains potassium levels within the normal physiological range for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years) prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. In certain embodiments, the subject maintains sodium levels between 135 and 145 mEq / L. For example, the subject maintains an average sodium level of about 135mEq / L, about 136mEq / L, about 137mEq / L, about 138mEq / L, about 139mEq / L, about 140mEq / L, about 141mEq / L, about 142mEq / L, about 143mEq / L, about 144mEq / L, about or 145mEq / L, or any value therebetween.

[0191] In some embodiments, the subject has ALT / AST levels during administration of atrasentan, or a pharma- ceutically acceptable salt thereof, that are about the same as the ALT / AST levels prior to the first administration of atrasentan, or a pharma- ceutically acceptable salt thereof. For example, the subject has ALT / AST levels during administration of atrasentan, or a pharma- ceutically acceptable salt thereof, that are within about 25%, about 20%, about 15%, about 10%, about 5%, about or 2.5%, or any value therebetween, of the levels prior to the first administration of atrasentan, or a pharma- ceutically acceptable salt thereof.

[0192] In some embodiments, the subject has a bilirubin level during administration of atrasentan, or a pharma- ceutically acceptable salt thereof, that is about the same as the bilirubin level prior to the first administration of atrasentan, or a pharma- ceutically acceptable salt thereof. For example, the subject has a bilirubin level during administration of atrasentan, or a pharma- ceutically acceptable salt thereof, that is within about 25%, about 20%, about 15%, about 10%, about 5%, or about 2.5%, or any value therebetween, of the level prior to the first administration of atrasentan, or a pharma- ceutically acceptable salt thereof.

[0193] In some embodiments, the subject's fluid retention is manageable with a diuretic (e.g., during treatment with atrasentan or a pharma- ceutically acceptable salt thereof and / or prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof). For example, the fluid retention can be a weight gain of less than about 3 kilograms (kg) over 6 weeks. In some embodiments, the fluid retention is less than about 4 kg, about 3.5 kg, about 3 kg, about 2.5 kg, about 2 kg, about 1.5 kg, or about 1 kg, or any value therebetween, over 6 weeks.

[0194] In some embodiments, the subject undergoes surgery and / or other regimens prior to, substantially simultaneously with, or after administration of atrasentan, or a pharmaceutically acceptable salt thereof, as disclosed herein. In some embodiments, the subject is administered a chemical and / or biological therapeutic agent prior to, substantially simultaneously with, or after administration of atrasentan, or a pharmaceutically acceptable salt thereof, as disclosed herein.

[0195] In some embodiments, the subject has one or more genetic mutations associated with FSGS. In some embodiments, the subject has previously been determined to have one or more genetic mutations associated with FSGS. In some embodiments, the methods described herein further include determining that the subject has one or more genetic mutations associated with FSGS. The genetic mutation may include, for example, a point mutation, a substitution, or a deletion. In some cases, the genetic mutation results in a mutation in a protein coding sequence of a gene. In some cases, the genetic mutation results in a mutation in a non-coding sequence of a gene. In some embodiments, the subject has a mutation in one or more of the following genes: APOL11, NPHS1, NPHS2, CD2AP, TRPC6, ACTN4, INF2, MYO1E, ARHGAP24, PLCE1, WT1, LMX1B, COQ6, LAMB2, PAX2, ANLN, and / or CRB2.

[0196] In some cases, the subject has, has previously been determined to have, or has been determined to have a mutation in APOL1. In some cases, the mutation comprises the expression of a G1 or G2 risk allele. See, for example, Genovese G, et al. Science. 2010 Aug 13; 329(5993): 841-5; also see Parsa A, et al., N Engl J Med. 2013 Dec 5; 369(23): 2183-96; and Daneshpajouhnejad P, et al. Nat Rev Nephrol. 2022 Feb 25: 1-14. Each of the above references in this paragraph is incorporated herein by reference in its entirety. In some cases, the subject with FSGS has one or more mutations selected from S342G, I384M, and / or 6bp del N388 / Y389.

[0197] In some cases, the subject has, has previously been determined to have, or has been determined to have a mutation in NPHS1.See, for example, Kestilae M, et al.Mol Cell.1998 Mar;1(4):575-82; and Koziell A, et al.Hum Mol Genet.2002 Feb 15;11(4):379-88.Each of the above references in this paragraph is incorporated herein by reference in its entirety.In some cases, the subject with FSGS has one or more mutations selected from 121delCT (frameshift and truncation), R1109X (wherein X is any amino acid other than R), 1306_1308insAC (frameshift and truncation), 3250insG (frameshift and truncation), and / or R1160X (wherein X is any amino acid other than R).

[0198] In some cases, the subject has, has previously been determined to have, or has been determined to have a mutation in NPHS2.See, e.g., Boute N, et al. Nat Genet. 2000 Apr; 24(4): 349-54; Caridi G, et al. J Am Soc Nephrol. 2001 Dec; 12(12): 2742-2746; and Tsukaguchi H, et al. J Clin Invest. 2002 Dec; 110(11): 1659-66. Each of the above references in this paragraph is incorporated herein by reference in its entirety. In some cases, a subject with FSGS has one or more mutations selected from R138Q; R138X; 104insG (frameshift and truncation); 419delG; P20L; G92C; D160G; V180M; R291W; R138Q; 419delG; P20L; and / or R229Q.

[0199] In some cases, the subject has, has previously been determined to have, or has been determined to have a mutation in CD2AP.See, for example, Kim JM, et al. Science. 2003 May 23; 300(5623): 1298-300; and Loewik MM, et al. Kidney Int. 2007 Nov; 72(10): 1198-203. Each of the above references in this paragraph is incorporated herein by reference in its entirety.In some cases, the subject with FSGS has one or more mutations selected from a mutation in a splice site acceptor and / or R612X.

[0200] In some cases, the subject has, has previously been determined to have, or has been determined to have a mutation in TRPC6.See, for example, Winn MP, et al.Science.2005 Jun 17;308(5729):1801-4; and Reiser J, et al.Nat Genet.2005 Jul;37(7):739-44.Each of the above references in this paragraph is incorporated herein by reference in its entirety.In some cases, the subject with FSGS has one or more mutations selected from P112Q;N143S;S270T;K874X;R895C;and / or E897K.

[0201] In some cases, the subject has, has previously been determined to have, or has been determined to have a mutation in ACTN4.See, for example, Kaplan JM, et al.Nat Genet.2000 Mar;24(3):251-6;Bartram MP, et al.Hum Mol Genet.2016 Mar 15;25(6):1152-64;Shao H, et al.Sci Rep.2019 Oct 29;9(1):15517;and Weins A, et al.J Am Soc Nephrol.2005 Dec;16(12):3694-701.Each of the above references in this paragraph is incorporated herein by reference in its entirety. In some cases, a subject with FSGS has one or more mutations selected from K228G; T232I; S235P; K255E; T259I; S262P; G195D; W59R; I149del; K255E; T259I; and / or S262P.

[0202] In some cases, the subject has, has previously been determined to have, or has been determined to have a mutation in INF2.See, e.g., Brown EJ, et al. Nat Genet. 2010 Jan; 42(1): 72-6. doi: 10.1038 / ng.505. Epub 2009 Dec 20. Erratum in: Nat Genet. 2010 Apr; 42(4): 361; and Boyer O, et al. J Am Soc Nephrol. 2011 Feb; 22(2): 239-45. Each of the preceding references in this paragraph is incorporated herein by reference in its entirety. In some cases, a subject with FSGS has one or more mutations selected from S186P; L198R; R218Q; R218W; R214H; L42P; A13T; E184K; E220K; L76P; R177H; Y193H; and / or R214C.

[0203] In some cases, the subject has, has previously been determined to have, or has been determined to have a mutation in MYO1E.See, for example, Mele C, et al.N Engl J Med.2011 Jul 28;365(4):295-306 (incorporated herein by reference in its entirety).In some cases, the subject with FSGS has one or more mutations selected from A159P and / or Y695X.

[0204] In some cases, the subject has, has previously been determined to have, or has been determined to have a mutation in ARHGAP24.See, for example, Akilesh S, et al.J Clin Invest.2011 Oct;121(10):4127-37 (incorporated herein by reference in its entirety).In some cases, the subject with FSGS has one or more mutations, including Q158R.

[0205] In some cases, the subject has, has previously been determined to have, or has been determined to have a mutation in PLCE1.See, e.g., Hinkes B, et al. Nat Genet. 2006 Dec; 38(12): 1397-405; and Boyer O, et al. J Med Genet. 2010 Jul; 47(7): 445-52. Each of the above references in this paragraph is incorporated herein by reference in its entirety. In some cases, a subject with FSGS has one or more mutations selected from R493X (wherein X is an amino acid other than R); R1116X (wherein X is an amino acid other than R); Q1616X (wherein X is an amino acid other than Q); Q1854X (wherein X is an amino acid other than Q); S1484L; R2150X (wherein X is an amino acid other than R); R321X (wherein X is an amino acid other than R); and / or R1246X (wherein X is an amino acid other than R).

[0206] In some cases, the subject has, has previously been determined to have, or has been determined to have a mutation in WT1.See, for example, Hall G, et al.J Am Soc Nephrol.2015 Apr;26(4):831-43 (incorporated herein by reference in its entirety).In some cases, the subject with FSGS has one or more mutations, including R458Q.

[0207] In some cases, the subject has, has previously been determined to have, or has been determined to have a mutation in LMX1B.See, for example, Boyer O, et al.J Am Soc Nephrol.2013 Jul;24(8):1216-22;Isojima T, et al.Nephrol Dial Transplant.2014 Jan;29(1):81-8;Hall G, et al.Sci Rep.2017 Jan 6;7:39933;and Pinto E et al.BMC Nephrol.2020 Aug 13;21(1):341.Each of the above references in this paragraph is incorporated herein by reference in its entirety.In some cases, the subject with FSGS has one or more mutations selected from R246P and / or R246Q.

[0208] In some cases, the subject has, has previously been determined to have, or has been determined to have a mutation in COQ6.See, for example, Heeringa SF,et al.J Clin Invest.2011 May;121(5):2013-24;see also Park E,et al.Am J Kidney Dis.2017 Jul;70(1):139-144.Each of the above references in this paragraph is incorporated herein by reference in its entirety.In some cases, the subject with FSGS has one or more mutations selected from G255R;A353D;Q447X (wherein X is any amino acid other than Q);R162X (wherein X is any amino acid other than R);W188X (wherein X is any amino acid of W);P261L;and / or Q229P.

[0209] In some cases, the subject has, has previously been determined to have, or has been determined to have a mutation in LAMB2.See, for example, Hasselbacher K, et al.Kidney Int.2006 Sep;70(6):1008-12 (incorporated herein by reference in its entirety).In some cases, the subject with FSGS has one or more mutations selected from R264Q;N1380K;L1393F;and / or C321R.

[0210] In some cases, the subject has, has previously been determined to have, or has been determined to have a mutation in PAX2.See, e.g., Barua M, et al.J Am Soc Nephrol.2014 Sep;25(9):1942-53 (incorporated herein by reference in its entirety).In some cases, the subject with FSGS has one or more mutations selected from R56Q and / or G189R.

[0211] In some cases, the subject has, has previously been determined to have, or has been determined to have a mutation in ANLN.See, for example, Gbadegesin RA, et al.J Am Soc Nephrol.2014 Sep;25(9):1991-2002 (incorporated herein by reference in its entirety).In some cases, the subject with FSGS has one or more mutations selected from R431C and / or G618C.

[0212] In some cases, the subject has, has previously been determined to have, or has been determined to have a mutation in CRB2.See, for example, Ebarasi L, et al.Am J Hum Genet.2015 Jan 8;96(1):153-61 (incorporated herein by reference in its entirety).In some cases, the subject with FSGS has one or more mutations selected from C620S;R628C;c.3089_3104dup (16-bp duplication);C629S;and / or R1249Q.

[0213] It is understood that a subject may present with one or more of the mutations described herein (i.e., any combination).

[0214] In some embodiments, the subject has been receiving one or more inhibitors of the renin-angiotensin system for at least about 60 weeks prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof, For example, in some embodiments, the subject has been receiving one or more inhibitors of the renin-angiotensin system for at least about 12 weeks, about 24 weeks, about 48 weeks, or about 60 weeks, or any value therebetween, prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof.

[0215] In some embodiments, the subject is receiving a maximum tolerated stable dose of one or more renin-angiotensin system inhibitors. For example, the subject can receive a maximum tolerated stable dose of one or more renin-angiotensin system inhibitors for at least about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 25 weeks, about 30 weeks, about 35 weeks, about 40 weeks, about 45 weeks, or about 50 weeks, or any value therebetween, prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the one or more inhibitors of the renin-angiotensin system are selected from the group consisting of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), renin inhibitors, and aldosterone antagonists. For example, the one or more inhibitors of the renin-angiotensin system can be an ACE inhibitor, an ARB, or a combination thereof, and the ACE inhibitor or ARB can be described anywhere herein. For example, the ACE inhibitor may be selected from quinapril, fosinopril perindopril, captopril, enalapril, enalaprilat, ramipril, cilazapril, delapril, fosinopril, zofenopril, indolapril, benazepril, lisinopril, spirapril, trandolapril, perindep, pentopril, moexipril, rescinnamine, and pivopril.For example, the ARB may be selected from candesartan, candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan, olmesartan medoxomil, telmisartan, valsartan, azilsartan medoxomil, and BRA-657.

[0216] In some embodiments, the subject is also administered one or more additional agents. In some embodiments, the one or more additional agents are selected from calcineurin inhibitors, proteasome inhibitors, aminoquinolines, complement inhibitors, B cell inhibitors, cytotoxic agents, mTOR inhibitors, sodium / glucose cotransporter-2 inhibitors (SGLT2i), and steroids. In some embodiments, the dosage of the one or more additional agents is decreased after about 15 to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In some embodiments, the one or more additional agents are immunosuppressants.

[0217] In some embodiments, the subject is not currently receiving one or more additional medications. In certain embodiments, the subject has not used one or more additional medications for 2 weeks or more within 6 months prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof.

[0218] In some embodiments, the one or more additional agents are selected from calcineurin inhibitors, proteasome inhibitors, aminoquinolines, complement inhibitors, B cell inhibitors, cytotoxic agents, mTOR inhibitors, steroids, and combinations thereof.

[0219] In certain embodiments, the one or more additional agents is a steroid, for example, the one or more additional agents is selected from the group consisting of prednisone, dexamethasone, hydrocortisone, cyclosporine, and any combination of the foregoing.

[0220] In certain embodiments, the one or more additional agents is an aminoquinoline. For example, the one or more additional agents can be hydroxychloroquine.

[0221] In some embodiments, the subject is receiving one or more additional agents during treatment with atrasentan. In certain embodiments, the dosage of the one or more additional agents is decreased after treatment with atrasentan, or a pharma- ceutically acceptable salt thereof (e.g., after 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, 50 weeks, 60 weeks, 70 weeks, 80 weeks, 90 weeks, 100 weeks, 110 weeks, 120 weeks, 130 weeks, 140 weeks, 150 weeks, 160 weeks, 170 weeks, 180 weeks, 190 weeks, or 200 weeks of treatment). In certain of these embodiments, the dosage of the one or more additional agents is decreased after about 15 days to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In certain of the foregoing embodiments, the dosage of the additional agent is decreased by about 10% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 15% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 20% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 25% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 30% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 35% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 40% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 45% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 50% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 55% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 60% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 65% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 70% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 75% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 80% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 85% to about 100%. In certain embodiments, the dosage of the additional agent is reduced by about 90% to about 100%.In certain of the foregoing embodiments, the dosage of the one or more additional agents is reduced after about 15 days to about 30 days (e.g., about 15 days, about 20 days, about 25 days, or about 30 days) of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. When the dosage of the additional agent is reduced 100% as described herein, the subject no longer requires the additional agent.

[0222] In certain embodiments, the dosage of one or more steroids is reduced following treatment with atrasentan, or a pharma- ceutically acceptable salt thereof, for example, after about 15 days to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage of steroids is reduced by about 10% to about 100%, as described herein. In some embodiments, the dosage of prednisone, dexamethasone, hydrocortisone, cyclosporine, or a combination of any of the foregoing is reduced by about 10% to about 100% following treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0223] In certain embodiments, the dosage of one or more aminoquinolines is reduced following treatment with atrasentan, or a pharma- ceutically acceptable salt thereof, for example, after about 15 days to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage of the aminoquinoline is reduced by about 10% to about 100%, as described herein. In some embodiments, the dosage of hydroxychloroquine is reduced by about 10% to about 100% following treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0224] In some embodiments, the subject is concurrently receiving one or more additional therapeutic agents. The one or more additional therapeutic agents are described herein. For example, the subject is concurrently receiving an inhibitor of one or more elements of the renin-angiotensin-aldosterone system. In certain embodiments, the subject is concurrently receiving an SGLT-2 inhibitor, an ACE inhibitor, an ARB, a statin, a diuretic, a calcium channel blocker, a beta blocker, an aldosterone antagonist, fish oil, hydroxychloroquine, or a combination of any of the foregoing. In certain of these embodiments, the subject is concurrently receiving an SGLT-2 inhibitor. In certain of these embodiments, the subject is concurrently receiving an ACE inhibitor, an ARB, or a combination thereof. In certain embodiments, the subject is concurrently receiving one or more statins, such as atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin. In certain embodiments, the subject is concurrently receiving one or more diuretics, such as hydrochlorothiazide, trichlormethiazide, hydroflumethiazide, quinethazone, metolazone, chlorothiazide, chlorthalidone, indapamide, methyclothiazide bumetanide, torsemide, piretanide, ethacrynic acid, bumetanide, furosemide, triamterene, spironolactone, eplerenone, and amiloride. In certain embodiments, the subject is concurrently receiving an SGLT-2 inhibitor, such as canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin. In certain embodiments, the subject is concurrently receiving one or more ACE inhibitors, such as quinapril, fosinopril, perindopril, captopril, enalapril, enalaprilat, ramipril, cilazapril, delapril, fosinopril, zofenopril, indolapril, benazepril, lisinopril, spirapril, trandolapril, perindep, pentopril, moexipril, rescinnamine, and pivopril. In certain embodiments, the subject is concurrently receiving an ARB, such as candesartan, candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan, olmesartan medoxomil, telmisartan, valsartan, azilsartan medoxomil, and BRA-657.In certain embodiments, the subject is receiving a diuretic and an ACE inhibitor or an ARB simultaneously. In certain embodiments, the subject is receiving a diuretic, an ACE inhibitor, and an ARB simultaneously. In certain embodiments, the subject is receiving a diuretic, an SGLT-2 inhibitor, and an ACE inhibitor or an ARB simultaneously. In certain embodiments, the subject is receiving a diuretic, an SGLT-2 inhibitor, an ACE inhibitor, and an ARB simultaneously. In certain embodiments, the subject receiving one or more additional therapeutic agents simultaneously has not previously received the one or more therapeutic agents. For example, the subject receiving an SGLT-2 inhibitor simultaneously has not previously received an SGLT-2 inhibitor.

[0225] In some embodiments, the subject has previously received one or more additional therapeutic agents, such as those described herein, but not simultaneously. For example, the subject has previously received, but not simultaneously, an SGLT-2 inhibitor, an ACE inhibitor, an ARB, a statin, a diuretic, a calcium channel blocker, a beta blocker, an aldosterone antagonist, fish oil, hydroxychloroquine, or any combination of the foregoing, as described herein. In certain of these embodiments, the subject has previously received, but not simultaneously, an SGLT-2 inhibitor.

[0226] In some embodiments, the subject has cellular crescents present in about ≦25% of the glomeruli within 6 months prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. For example, the subject has cellular crescents present in about 25%, about 20%, about 15%, about 10%, about 5%, or about 1% of the glomeruli, or any value therebetween. In some embodiments, the subject has no cellular crescents present in the glomeruli. In certain embodiments, the subject is under clinical suspicion of rapidly progressive glomerulonephritis (RPGN).

[0227] In some embodiments, the subject has not undergone an organ transplant prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof.

[0228] In some embodiments, the subject has a systolic blood pressure of less than about 160 mmHg before the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. For example, the subject may have a systolic blood pressure of less than about 155 mmHg, less than about 150 mmHg, less than about 145 mmHg, or less than about 140 mmHg. In some embodiments, the subject has a diastolic blood pressure of less than about 100 mmHg before the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. For example, the subject may have a diastolic blood pressure of less than about 100 mmHg, less than about 95 mmHg, or less than about 90 mmHg. In some embodiments, the subject has a systolic blood pressure of about 100 mmHg to about 130 mmHg, and a diastolic blood pressure of about 70 mmHg to about 90 mmHg.

[0229] In some embodiments, the subject has not been diagnosed with heart failure prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject has been previously hospitalized for a condition associated with fluid overload prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. Non-limiting examples of conditions include uncontrolled peripheral edema, pleural effusion, or ascites. In some embodiments, the subject has not been diagnosed with clinically significant liver disease prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject's transaminase or bilirubin values ​​are less than or equal to two times the upper limit of normal prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. For example, the subject's ALT level is less than about 110 U / L (e.g., less than about 100 U / L, less than about 90 U / L, less than about 80 U / L, less than about 70 U / L, less than about 60 U / L, less than about 50 U / L, or less than about 40 U / L, or any value therebetween). As another example, the subject's ALT level is less than 100 U / L (e.g., less than 90 U / L, less than about 80 U / L, less than about 70 U / L, less than about 60 U / L, less than about 50 U / L, or less than about 40 U / L, or any value therebetween). As yet another example, the subject's bilirubin level is less than about 2.5 mg / dL (e.g., less than about 2 mg / dL, less than about 1.5 mg / dL, less than about 1.4 mg / dL, less than about 1.3 mg / dL, less than about 1.2 mg / dL, less than about 1.1 mg / dL, less than about 1.0 mg / dL, or less than about 0.9 mg / dL, or any value therebetween).

[0230] In some embodiments, the subject has a hemoglobin level greater than about 9 g / dL (e.g., greater than about 10 g / dL, about 11 g / dL, about 12 g / dL, or about 13 g / dL, or any value therebetween) prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject has not received a blood transfusion for anemia for at least about 3 months (e.g., at least about 4 months, about 5 months, about 6 months, or about 1 year) prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject has not been diagnosed with cancer for at least 5 years prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject has not been diagnosed with cancer (e.g., lung cancer or prostate cancer) for at least 5 years prior to the first administration of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject has not been diagnosed with cancer for at least 5 years prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, except when the cancer is a non-melanoma skin cancer that does not require ongoing treatment. In some embodiments, the subject does not have cancer prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, except when the cancer is a non-melanoma skin cancer that does not require ongoing treatment. In some embodiments, the subject does not have cancer prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, except when the cancer is a non-melanoma skin cancer that does not require ongoing treatment. In some embodiments, the subject has not been treated for cancer for at least 5 years prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, except when the cancer is a non-melanoma skin cancer that does not require ongoing treatment.

[0231] In some embodiments of the methods, uses, or products for use herein, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure. In some embodiments of the methods, uses, or products for use herein, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, cancer (e.g., prostate cancer or lung cancer), or acute renal failure. In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, prostate cancer, or acute renal failure. In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV-associated nephropathy, cancer (e.g., lung cancer or prostate cancer), or acute renal failure. In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV-associated nephropathy, or acute renal failure. In certain embodiments, the subject has not been previously diagnosed with diabetic nephropathy. In certain embodiments, the subject has not been previously diagnosed with HIV / AIDS. In certain embodiments, the subject has not been previously diagnosed with acute renal failure. In certain embodiments, the subject has not been previously diagnosed with HIV-associated nephropathy. In certain embodiments, the subject has not been diagnosed with cancer. In certain embodiments, the subject has not been diagnosed with prostate cancer. In certain embodiments, the subject has not been diagnosed with lung cancer. In certain embodiments, the subject has not been previously diagnosed with any one of diabetic nephropathy, HIV / AIDS, and acute renal failure. In certain embodiments, the subject has not been previously diagnosed with any one of diabetic nephropathy, HIV / AIDS, prostate cancer, and acute renal failure. In certain embodiments, the subject has not been previously diagnosed with any one of diabetic nephropathy, HIV-associated nephropathy, prostate cancer, and acute renal failure. In certain embodiments, the subject has not been previously diagnosed with any one of diabetic nephropathy, HIV-associated nephropathy, and acute renal failure. In some embodiments of the methods, uses, or products for use herein, the subject has not been previously diagnosed with diabetes. In some embodiments of the methods, uses, or products for use herein, the subject has not been previously diagnosed with type 2 diabetes.In certain of the foregoing embodiments, the subject has been determined to have controlled serum glucose levels, as described elsewhere herein.

[0232] In some embodiments, the subject does not have one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure. In some embodiments, the subject does not have one or more of diabetic nephropathy, HIV / AIDS, prostate cancer, or acute renal failure. In some embodiments, the subject does not have one or more of diabetic nephropathy, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject does not have one or more of diabetic nephropathy, HIV-associated nephropathy, or acute renal failure. In certain embodiments, the subject does not have diabetic nephropathy. In certain embodiments, the subject does not have HIV / AIDS. In certain embodiments, the subject does not have acute renal failure. In certain embodiments, the subject does not have HIV-associated nephropathy. In certain embodiments, the subject does not have prostate cancer. In certain embodiments, the subject does not have any one of diabetic nephropathy, HIV / AIDS, and acute renal failure. In certain embodiments, the subject does not have any one of diabetic nephropathy, HIV / AIDS, prostate cancer, and acute renal failure. In certain embodiments, the subject does not have any one of diabetic nephropathy, HIV-associated nephropathy, prostate cancer, and acute renal failure. In certain embodiments, the subject does not have any one of diabetic nephropathy, HIV-associated nephropathy, and acute renal failure. In some embodiments, the subject does not have diabetes. In some embodiments, the subject does not have type 2 diabetes. In certain of the foregoing embodiments, the subject has been determined to have a controlled serum glucose level as described elsewhere herein.

[0233] In some embodiments, the subject does not suffer from one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure. In some embodiments, the subject does not suffer from one or more of diabetic nephropathy, HIV / AIDS, prostate cancer, or acute renal failure. In some embodiments, the subject does not suffer from one or more of diabetic nephropathy, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject does not suffer from one or more of diabetic nephropathy, HIV-associated nephropathy, or acute renal failure. In certain embodiments, the subject does not suffer from diabetic nephropathy. In certain embodiments, the subject does not suffer from HIV / AIDS. In certain embodiments, the subject does not suffer from acute renal failure. In certain embodiments, the subject does not suffer from HIV-associated nephropathy. In certain embodiments, the subject does not suffer from prostate cancer. In certain embodiments, the subject does not suffer from any one of diabetic nephropathy, HIV / AIDS, and acute renal failure. In certain embodiments, the subject does not suffer from any one of diabetic nephropathy, HIV / AIDS, prostate cancer, and acute renal failure. In certain embodiments, the subject does not suffer from any one of diabetic nephropathy, HIV-associated nephropathy, prostate cancer, and acute renal failure. In certain embodiments, the subject does not suffer from any one of diabetic nephropathy, HIV-associated nephropathy, and acute renal failure. In some embodiments, the subject does not suffer from diabetes. In some embodiments, the subject does not suffer from type 2 diabetes. In certain of the foregoing embodiments, the subject has been determined to have a controlled serum glucose level as described elsewhere herein.

[0234] In some embodiments, the subject is not being treated for one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure. In some embodiments, the subject is not being treated for one or more of diabetic nephropathy, HIV / AIDS, prostate cancer, or acute renal failure. In some embodiments, the subject is not being treated for one or more of diabetic nephropathy, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject is not being treated for one or more of diabetic nephropathy, HIV-associated nephropathy, or acute renal failure. In certain embodiments, the subject is not being treated for diabetic nephropathy. In certain embodiments, the subject is not being treated for HIV / AIDS. In certain embodiments, the subject is not being treated for acute renal failure. In certain embodiments, the subject is not being treated for HIV-associated nephropathy. In certain embodiments, the subject is not being treated for prostate cancer. In certain embodiments, the subject is not being treated for any one of diabetic nephropathy, HIV / AIDS, and acute renal failure. In certain embodiments, the subject is not being treated for any one of diabetic nephropathy, HIV / AIDS, prostate cancer, and acute renal failure. In certain embodiments, the subject is not being treated for any one of diabetic nephropathy, HIV-associated nephropathy, prostate cancer, and acute renal failure. In certain embodiments, the subject is not being treated for any one of diabetic nephropathy, HIV-associated nephropathy, and acute renal failure. In some embodiments, the subject is not being treated for diabetes. In some embodiments, the subject is not being treated for type 2 diabetes. In certain of the foregoing embodiments, the subject has been determined to have a controlled serum glucose level as described elsewhere herein.

[0235] In some embodiments, the subject is determined to have a controlled serum glucose level; or the subject has not been diagnosed with one or more of HIV-associated nephropathy or acute renal failure. In certain embodiments, the subject is determined to have a controlled serum glucose level. For example, the subject is determined to have a fasting serum glucose level of less than about 130 mg / dL, about 125 mg / dL, about 120 mg / dL, about 115 mg / dL, about 110 mg / dL, about 105 mg / dL, about 100 mg / dL, about 95 mg / dL, about 90 mg / dL, about 85 mg / dL, about 80 mg / dL, or about 75 mg / dL, or any value therebetween. In certain embodiments, the subject has not been diagnosed with one or more of HIV-associated nephropathy or acute renal failure. In certain embodiments, the subject has been determined to have a controlled serum glucose level as described anywhere herein; and the subject has not been diagnosed with one or more of HIV-associated nephropathy or acute renal failure.

[0236] In some embodiments, the subject has not been previously diagnosed with a chronic kidney disease other than FSGS. Non-limiting examples include diabetic kidney disease, hypertensive kidney disease, IgA nephropathy, or primary glomerulopathy that is determined to be not associated with FSGS. In certain embodiments, the subject has not been previously diagnosed with diabetic kidney disease. In certain embodiments, the subject has not been previously diagnosed with hypertensive kidney disease. In certain embodiments, the subject has not been previously diagnosed with primary glomerulopathy that is determined to be not associated with FSGS.

[0237] In some embodiments, the subject does not have a chronic kidney disease other than FSGS. Non-limiting examples include diabetic kidney disease, hypertensive kidney disease, or a primary glomerulopathy that is determined not to be associated with FSGS. In certain embodiments, the subject does not have diabetic kidney disease. In certain embodiments, the subject does not have hypertensive kidney disease. In certain embodiments, the subject does not have a primary glomerulopathy that is determined not to be associated with FSGS.

[0238] In some embodiments, the subject does not suffer from chronic kidney disease other than FSGS. Non-limiting examples include diabetic kidney disease, hypertensive kidney disease, or primary glomerulopathy that is determined not to be associated with FSGS. In certain embodiments, the subject does not suffer from diabetic kidney disease. In certain embodiments, the subject does not suffer from hypertensive kidney disease. In certain embodiments, the subject does not suffer from primary glomerulopathy that is determined not to be associated with FSGS.

[0239] In some embodiments, the subject is not being treated for a chronic kidney disease other than FSGS. Non-limiting examples include diabetic kidney disease, hypertensive kidney disease, or a primary glomerulopathy that is determined not to be associated with FSGS. In certain embodiments, the subject is not being treated for a diabetic kidney disease. In certain embodiments, the subject is not being treated for a hypertensive kidney disease. In certain embodiments, the subject is not being treated for a primary glomerulopathy that is determined not to be associated with FSGS.

[0240] IV. Treatment results In some embodiments of the methods, uses, or products for use herein, nephritis is reduced after treatment with atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject's nephritis is reduced by at least about 10% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In some embodiments, the subject's nephritis is reduced by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%, or any value therebetween. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days.

[0241] In some embodiments, renal fibrosis is reduced following treatment with atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, renal fibrosis in a subject is reduced by at least about 10% following treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In certain embodiments, the subject's renal fibrosis is reduced by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%, or any value therebetween. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days.

[0242] In some embodiments, the subject's renal fibrosis is reduced to less than about 50% of the cortical area after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween).In certain embodiments, the subject's renal fibrosis is reduced to less than about 40% of the cortical area. For example, in some embodiments, the subject's renal fibrosis is reduced to less than about 35%, about 30%, about 25%, about 20%, about 15%, or about 10% of the cortical area, or any value therebetween. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days.

[0243] In some embodiments, the subject's rate of decline in eGFR is reduced by at least about 10% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after 1 week, 2 weeks, 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween).In certain embodiments, the subject's rate of decline in eGFR is reduced by at least about 20%. For example, in some embodiments, the subject's eGFR is reduced by at least about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%, or any value therebetween. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 6 months to about 1 year.

[0244] In some embodiments, the subject's rate of decline in eGFR is less than about 10 mL / min / year after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In some embodiments, the subject's rate of decline in eGFR is less than about 9 mL / min / year. For example, in some embodiments, the subject's rate of decline in eGFR is less than about 8 mL / min / year, about 7 mL / min / year, about 6 mL / min / year, about 5 mL / min / year, about 4 mL / min / year, about 3 mL / min / year, about 2 mL / min / year, or about 1 mL / min / year, or any value therebetween. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 6 months to about 1 year.

[0245] In some embodiments, a subject's risk of developing ESKD is reduced by about 20% to about 99% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). For example, the subject's risk of developing ESKD may be reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 99%, or any value therebetween. In certain of the foregoing embodiments, the subject has been treated for about 90 days to about 180 days. In certain embodiments, the subject's risk of developing ESKD is reduced by about 20% to about 99% after about 90 to about 180 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In certain of the foregoing embodiments, the subject has been treated with atrasentan, or a pharma- ceutically acceptable salt thereof, for about 6 months to about 1 year.

[0246] In some embodiments, the method includes diagnosing FSGS in a subject and determining whether the subject's eGFR is about 15 mL / min / 1.73 m 2 In certain embodiments, the method increases the time between a diagnosis of FSGS in a subject and the time the subject's eGFR drops below 15 mL / min / 1.73 m. 2 For example, in some embodiments, the method increases the time between a diagnosis of FSGS in a subject and the time the subject's eGFR drops to less than about 15 mL / min / 1.73 m by at least about 10%. 2The time between when the concentration drops below 100%, is increased by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 100%, about 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, or about 500%, or any value therebetween.

[0247] In some embodiments, the method includes a diagnosis of FSGS in a subject and a determination of whether the subject's eGFR is 15 mL / min / 1.73 m 2 For example, the method may increase the time between when the subject's eGFR drops below 15 mL / min / 1.73 m by at least about 1 year. 2 The time for the antibody to decrease to less than 1.5 years may be delayed by at least about 1.5 years, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about 5 years, about 5.5 years, about 6 years, about 6.5 years, about 7 years, about 7.5 years, about 8 years, about 8.5 years, about 9 years, about 9.5 years, about 10 years, about 11 years, about 12 years, about 13 years, about 15 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years, or about 20 years, or any value therebetween.

[0248] In some embodiments, the method reduces the average rate of decline in eGFR by about 0.75 mL / min / year to about 75 mL / min / year for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years) prior to the first administration of atrasentan, or a pharma- ceutically acceptable salt thereof. For example, the method reduces the average rate of decline in eGFR by about 0.75 mL / min / year, about 1 mL / min / year, about 1.5 mL / min / year, about 2 mL / min / year, about 2.5 mL / min / year, about 3 mL / min / year, about 3.5 mL / min / year, about 4 mL / min / year, about 4.5 mL / min / year, about 5 mL / min / year, about 5.5 mL / min / year, or about 6 mL / min / year. In some embodiments, the method reduces the average rate of decline in eGFR by about 4 mL / min / year to about 5 mL / min / year for at least about 3 months prior to the first administration of atrasentan, or a pharma- ceutically acceptable salt thereof. In some embodiments, the method reduces the average rate of decline in eGFR by about 3 mL / min / year to about 6 mL / min / year for at least about 3 months prior to the first administration of atrasentan, or a pharma-ceutically acceptable salt thereof. In some embodiments, the method reduces the average rate of decline in eGFR by about 4 mL / min / year to about 5 mL / min / year for at least about 3 months prior to the first administration of atrasentan, or a pharma-ceutically acceptable salt thereof. In some embodiments, the decline in eGFR in mL / min / year is 1.73 msec. 2 Refers to the unit of measure.

[0249] In some embodiments, the method reduces the average percent decline in eGFR by about 15% to about 70% (about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%) after about 6 months to about 24 months of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In some embodiments, the average percent decline in eGFR may be reduced by about 15% after about 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In some embodiments, the average percent decline in eGFR may be reduced by about 20% after about 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In some embodiments, the mean percent decline in eGFR may be about 25% after about 6, 9, 12, 15, 18, 21, or 24 months of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In some embodiments, the mean percent decline in eGFR may be about 30% after about 6, 9, 12, 15, 18, 21, or 24 months of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0250] In another aspect, provided herein is a method of reducing proteinuria, comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof.

[0251] In some embodiments, the amount of protein (e.g., albumin) in the subject's urine is reduced by at least about 10% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In some embodiments, the amount of protein in the subject's urine is reduced by at least about 15%. For example, in some embodiments, the amount of protein in the subject's urine is reduced by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%, or any value therebetween. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 10 weeks to about 24 weeks. In some cases, the amount of protein in the subject's urine is reduced by about 20% to about 80% after about 10 weeks (e.g., about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 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) of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In some cases, the amount of protein in the subject's urine is reduced by about 20% to about 80% after about 12 weeks of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In some cases, the amount of protein in the subject's urine is reduced by about 20% to about 80% after about 12 to about 24 weeks (and all ranges included) of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In some cases, the amount of protein in the subject's urine is reduced by about 20% to about 80% after about 12 to about 24 weeks of treatment with atrasentan, or a pharma-ceutically acceptable salt thereof.

[0252] In certain embodiments, the amount of protein (e.g., albumin) in the subject's urine is reduced by about 20% to about 80% after about 15 to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In certain of these embodiments, the amount of protein in the subject's urine is reduced by about 25% to about 80%. In certain of these embodiments, the amount of protein in the subject's urine is reduced by about 30% to about 80%. In certain of these embodiments, the amount of protein in the subject's urine is reduced by about 35% to about 80%. In certain of these embodiments, the amount of protein in the subject's urine is reduced by about 40% to about 80%. In certain of these embodiments, the amount of protein in the subject's urine is reduced by about 45% to about 80%. In certain of these embodiments, the amount of protein in the subject's urine is reduced by about 50% to about 80%.

[0253] In some embodiments, the amount of protein (e.g., albumin) in the subject's urine is reduced by about 100 mg / dL to about 3,000 mg / dL after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 2,500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 2,000 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 1,500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 1,000 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 400 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 300 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 200 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 2,500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 2,000 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 1,500 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 1,000 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 900 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 800 mg / dL.In certain embodiments, the amount of protein in the subject's urine is reduced by about 600 mg / dL to about 900 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 700 mg / dL to about 900 mg / dL. In certain embodiments, the amount of protein in the subject's urine is reduced by about 1,000 mg / dL to about 2,000 mg / dL. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days.

[0254] In certain embodiments, the amount of protein (e.g., albumin) in the urine of a subject is reduced by about 100 mg / dL to about 500 mg / dL after about 15 to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In certain embodiments, the amount of protein in the urine of a subject with FSGS is reduced by about 200 mg / dL to about 500 mg / dL after about 15 to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In certain embodiments, the amount of protein in the urine of a subject with FSGS is reduced by about 300 mg / dL to about 500 mg / dL after about 15 to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0255] In certain embodiments, the amount of protein (e.g., albumin) in the urine of a subject is reduced by about 500 mg / dL to about 900 mg / dL after about 15 to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In certain embodiments, the amount of protein in the urine of a subject with FSGS is reduced by about 600 mg / dL to about 900 mg / dL after about 15 to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In certain embodiments, the amount of protein in the urine of a subject with FSGS is reduced by about 700 mg / dL to about 900 mg / dL after about 15 to about 30 days of treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0256] In some embodiments, the subject has a reduction in urinary protein (e.g., albumin) levels of less than about 1.0 gram / day after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks of treatment). In some embodiments, the subject has a reduction in urinary protein levels of less than about 0.9 gram / day. For example, in some embodiments, the subject has a reduction in urinary protein levels of less than about 0.8 grams / day, about 0.7 grams / day, about 0.6 grams / day, 0.5 grams / day, about 0.4 grams / day, about 0.3 grams / day, or about 0.2 grams / day, or any value therebetween. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days.

[0257] In another aspect, provided herein is a method for reducing fatigue, comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Fatigue can be measured using methods known in the art. See, for example, Machado.M., Int J Dermatol, 2021 Sep;60(9):1053-1069, which is incorporated herein by reference in its entirety.

[0258] In some embodiments, the subject is about 15 to about 40 years old. In some embodiments, the subject is about 15 to about 25 years old, about 20 to about 30 years old, about 25 to about 35 years old, about 30 to about 40 years old, or any age therebetween. In some embodiments, the subject is about 20 to about 30 years old, or any age therebetween. In some embodiments, the subject is about 20 years old, about 21 years old, about 22 years old, about 23 years old, about 24 years old, about 25 years old, about 26 years old, about 27 years old, about 28 years old, about 29 years old, or about 30 years old.

[0259] In some embodiments, the patient's level of fatigue is reduced after treatment with atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, fatigue is reduced by about 5% to about 80% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In certain embodiments, fatigue is reduced by about 10% to about 75%. In certain embodiments, fatigue is reduced by about 10% to about 70%. In certain embodiments, fatigue is reduced by about 10% to about 65%. In certain embodiments, fatigue is reduced by about 10% to about 60%. In certain embodiments, fatigue is reduced by about 10% to about 55%. In certain embodiments, fatigue is reduced by about 10% to about 50%. In certain embodiments, fatigue is reduced by about 10% to about 45%. In certain embodiments, fatigue is reduced by about 10% to about 40%. In certain embodiments, fatigue is reduced by about 10% to about 35%. In certain embodiments, fatigue is reduced by about 10% to about 30%. In certain embodiments, fatigue is reduced by about 10% to about 25%. In certain embodiments, fatigue is reduced by about 10% to about 20%. In certain embodiments, fatigue is reduced by about 10% to about 15%. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharma- ceutically acceptable salt thereof for about 15 days to about 30 days.In certain embodiments, the reduction in fatigue comprises a decrease in score on one or more of the Fatigue Severity Scale, the Chalder Fatigue Scale, the FACIT Fatigue Scale, the Brief Fatigue Inventory, the FACT-F subscale, the Global Vigor and Affect, the May and Kline Adjunctive Checklist, the Pearson-Byars Fatigue Checklist, the Rhoten Fatigue Scale, the Schedule for Fatigue and Anergy, or the Personal Physical Fitness Checklist.

[0260] Some embodiments provide a method of inhibiting mesangial cell activation in a subject having FSGS, the method comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to the subject; the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure.

[0261] Some embodiments provide a method of inhibiting PDGF signaling activity (e.g., decreasing the expression and / or activity of one or more of PIK3R1, PDGFRA, NFKBIA, PIK3CG, PLA2G4A, TIAM1, PDGFB, NFKB1, and MAP3K1) in a subject with mesangial cell-type FSGS, the method comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to the subject; the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure.

[0262] Some embodiments provide a method of inhibiting mesangial cell activation, the method comprising contacting mesangial cells with an effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof.

[0263] In some embodiments, mesangial activation is induced by IgA immune complexes. In some embodiments, mesangial activation is associated with the presence of IgA immune complexes. The presence and / or amount of IgA immune complexes can be determined by a variety of methods. For example, the complexes can be detected in serum or urine, and can also be detected in kidney biopsy samples.

[0264] In some embodiments, inhibiting mesangial cell activation comprises decreasing expression and / or activity of one or more biomarkers indicative of mesangial cell proliferation. In some embodiments, inhibiting mesangial cell activation comprises decreasing mesangial cell inflammation. In some embodiments, decreasing mesangial cell inflammation comprises decreasing expression and / or activity of one or more of IL6, MCP1, or other biomarkers indicative of mesangial cell inflammation. In some embodiments, decreasing mesangial cell inflammation comprises decreasing expression and / or activity of IL-6. In some embodiments, the expression and / or activity of one or more biomarkers indicative of mesangial cell inflammation is reduced by about 25% to about 99% following treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In some embodiments, the expression and / or activity of one or more biomarkers indicative of mesangial cell inflammation is decreased by about 25% to about 50%, about 40% to about 60%, about 50% to about 75%, about 60% to about 80%, about 75% to about 90%, about 85% to about 99%, or any value therebetween. For example, in some such embodiments, the one or more biomarkers can be IL-6.

[0265] In some embodiments, inhibiting mesangial cell activation comprises decreasing mesangial cell inflammation. In some embodiments, decreasing mesangial cell inflammation comprises decreasing IL-6 signaling (e.g., decreasing expression and / or activity of one or more proteins involved in the IL-6 signaling pathway, e.g., decreasing expression and / or activity of one or more of Cntfr, Il1b, Csf1, Il2ra, Map3k8, and Il1r1). In some embodiments, decreasing mesangial cell inflammation comprises decreasing expression and / or activity of one or more of the following (e.g., 1, 2, 3, 4, or 5): Cntfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1.

[0266] In some embodiments, inhibiting mesangial cell activation comprises reducing a profibrotic response in a mesangial cell, hi some embodiments, reducing a profibrotic response in a mesangial cell comprises reducing the expression and / or activity of one or more of NF-κB, TGF, PDGF, CTGF, MMPs, TIMPS, or other biomarkers indicative of mesangial cell fibrosis. In some embodiments, the expression and / or activity of one or more of NF-κB, TGF, PDGF, CTGF, MMPs, and TIMPS is reduced by about 25% to about 99% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks of treatment, or any value therebetween), relative to the expression and / or activity prior to administration of atrasentan, or a pharma- ceutically acceptable salt thereof. In some embodiments, expression and / or activity of one or more of NF-κB, TGF, PDGF, CTGF, MMPs, and TIMPS is decreased by about 25% to about 50%, about 40% to about 60%, about 50% to about 75%, about 60% to about 80%, about 75% to about 90%, about 85% to about 99%, or any value therebetween.

[0267] In some embodiments, inhibiting mesangial cell activation comprises decreasing a profibrotic response in mesangial cells. In some embodiments, decreasing the profibrotic response comprises decreasing NF-κB signaling. In some embodiments, decreasing the profibrotic response comprises decreasing the expression and / or activity of one or more of the following (e.g., 1, 2, 3, 4, or 5): Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn 1, Rel, Nr4a3, Nfkb1, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, and / or increasing the expression and / or activity of one or more of the following (e.g., 1, 2, 3, 4, or 5): Ehd1, Snn, Tnfaip8, Ackr3, Id2, Ccn1, Efna1, Ccnd1, Cdkn1a, Pnrc1 (where the component inhibits NF-κB signaling).

[0268] In some embodiments, reducing a profibrotic response comprises reducing PDGF signaling, hi some embodiments, reducing a profibrotic response comprises reducing expression and / or activity of one or more (e.g., 1, 2, 3, 4, or 5) of the following: Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1, Pdgfb, Nfkb1, and / or increasing expression and / or activity of one or more (e.g., 1, 2, 3, 4, or 5) of the following: Hras (where the component inhibits PDGF signaling).

[0269] In some embodiments, NF-κB expression and / or activity, and / or PDGF expression and / or activity is reduced by about 25% to about 99% after treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks of treatment, or any value therebetween), relative to the expression and / or activity prior to administration of atrasentan or a pharma- ceutically acceptable salt thereof. In some embodiments, expression and / or activity of NF-κB and / or PDGF is reduced by about 25% to about 50%, about 40% to about 60%, about 50% to about 75%, about 60% to about 80%, about 75% to about 90%, about 85% to about 99%, or any value therebetween.

[0270] In some embodiments, reducing a pro-fibrotic response in a mesangial cell comprises reducing matrix secretion by a mesangial cell, hi some embodiments, reducing matrix secretion by a mesangial cell comprises reducing the expression and / or activity of one or more of the excessive matrix secretion by a mesangial cell.

[0271] Some embodiments provide a method of reducing activation of mesangial cells contacted with IgA immune complexes, the method comprising contacting mesangial cells with an effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, hi some embodiments, reducing activation of mesangial cells comprises reducing expression and / or activity of one or more biomarkers indicative of mesangial cell proliferation.

[0272] In some embodiments, reducing mesangial cell activation comprises reducing mesangial cell inflammation, hi some embodiments, reducing mesangial cell inflammation comprises reducing the expression and / or activity of one or more of IL6, MCP1, or other biomarkers indicative of mesangial cell inflammation.

[0273] In some embodiments, decreasing mesangial cell activation comprises decreasing a profibrotic response in mesangial cells, hi some embodiments, decreasing a profibrotic response in mesangial cells comprises decreasing the expression and / or activity of one or more of TGF, PDGF, CTGF, MMPs, TIMPS, or other biomarkers indicative of mesangial cell fibrosis.

[0274] In some embodiments, reducing a pro-fibrotic response in a mesangial cell comprises reducing matrix secretion by a mesangial cell, hi some embodiments, reducing matrix secretion by a mesangial cell comprises reducing the expression and / or activity of one or more biomarkers indicative of excessive matrix secretion by a mesangial cell.

[0275] In some embodiments, the reduction in mesangial cell activation comprises reducing unwanted mesangial cell migration. In some embodiments, the reduction in unwanted mesangial cell migration occurs about 15 days to about 30 days after treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In some embodiments, the reduction in unwanted mesangial cell migration occurs about 3 months to about 6 months after treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0276] In some embodiments, the reduction in mesangial cell activation comprises reducing unwanted mesangial cell proliferation. In some embodiments, the reduction in unwanted mesangial cell proliferation occurs about 15 days to about 30 days after treatment with atrasentan, or a pharma- ceutically acceptable salt thereof. In some embodiments, the reduction in unwanted mesangial cell proliferation occurs about 3 months to about 6 months after treatment with atrasentan, or a pharma- ceutically acceptable salt thereof.

[0277] In some embodiments, unwanted mesangial cell proliferation is reduced by about 25% to about 99% following treatment with atrasentan or a pharma- ceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In some embodiments, unwanted mesangial cell proliferation is reduced by about 25% to about 50%, about 40% to about 60%, about 50% to about 75%, about 60% to about 80%, about 75% to about 90%, about 85% to about 99%, or any value therebetween.

[0278] In some embodiments, mesangial cell activation can be assessed by one or more of serum analysis, urinalysis, and microscopic examination (eg, light microscopy and / or immunofluorescence microscopy) of a kidney biopsy sample.

[0279] In some embodiments, the contacting occurs in vitro. In some embodiments, the contacting occurs in vivo.

[0280] Some embodiments provide a method of treating FSGS in a subject in need thereof, the method comprising: a) determining that the subject has an elevated serum Gd-IgA1 level; and b) administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to the subject. In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure. In some embodiments, the subject has not been previously diagnosed with HIV-associated nephropathy. In some embodiments, the subject has not been previously diagnosed with cancer. In some embodiments, the cancer is lung cancer or prostate cancer.

[0281] Some embodiments provide a method of treating FSGS in a subject in need thereof, the method comprising: a) determining that the subject has a high level of mesangial activation; and b) administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to the subject.

[0282] In some embodiments, determining an elevated level of mesangial activation comprises obtaining a sample from the subject and assessing the level of mesangial activation in the sample. In some embodiments, the sample is a kidney biopsy sample. In some embodiments, the sample is selected from a blood sample, a urine sample, a kidney biopsy sample, or a combination of two or three of the foregoing.

[0283] In some embodiments, the sample exhibits elevated levels of one or more of the following: matrix secretion by mesangial cells, IgA-immune complex deposition, mesangial cell proliferation, and intraductal cell proliferation, hi some embodiments, the sample exhibits elevated levels of IgA-immune complex deposition.

[0284] Some embodiments provide a method of treating FSGS in a subject in need thereof, the method comprising: a) determining that the subject does not have one or more of acute kidney injury, diabetic nephropathy, IgA nephropathy, sickle cell nephropathy, HIV / AIDS, or acute renal failure; b) determining that the subject has an elevated serum Gd-IgA1 level; and c) administering a therapeutically effective amount of atrasentan, or a pharmaceutically acceptable salt thereof, to the subject.

[0285] Some embodiments provide a method of treating FSGS in a subject in need thereof, the method comprising: a) determining that the subject does not have one or more of diabetic nephropathy, IgA nephropathy, sickle cell nephropathy, HIV / AIDS, or acute renal failure; b) determining that the subject has an elevated serum Gd-IgA1 level; and c) administering a therapeutically effective amount of atrasentan, or a pharmaceutically acceptable salt thereof, to the subject.

[0286] Some embodiments provide a method of treating FSGS in a subject in need thereof, the method comprising: a) determining that the subject does not have one or more of acute kidney injury, diabetic nephropathy, IgA nephropathy, sickle cell nephropathy, HIV / AIDS, or acute renal failure; b) determining that the subject has an elevated level of mesangial activation; and c) administering a therapeutically effective amount of atrasentan, or a pharmaceutically acceptable salt thereof, to the subject.

[0287] Some embodiments provide a method of treating FSGS in a subject in need thereof, the method comprising: a) determining that the subject does not have one or more of diabetic nephropathy, IgA nephropathy, sickle cell nephropathy, HIV / AIDS, or acute renal failure; b) determining that the subject has an elevated level of mesangial activation; and c) administering a therapeutically effective amount of atrasentan, or a pharmaceutically acceptable salt thereof, to the subject.

[0288] In some embodiments, the subject is determined to have proteinuria of at least about 1 g / day in at least two of three consecutive readings over a one-year period prior to administration of a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject is determined to have proteinuria of about 1 g / day to about 15 g / day in at least two of three consecutive readings over a one-year period prior to administration of a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof. For example, about 1 g / day, about 1.2 g / day, about 1.4 g / day, about 1.6 g / day, about 1.8 g / day, or 2 g / day, about 2.5 g / day, about 3 g / day, about 3.5 g / day, about 4 g / day, about 4.5 g / day, about 5 g / day, about 6 g / day, about 7 g / day, about 8 g / day, about 9 g / day, about 10 g / day, about 11 g / day, about 12 g / day, about 13 g / day, about 14 g / day, or about 15 g / day.

[0289] In some embodiments, the subject has been administered a maximum tolerated stable dose of a RAS inhibitor for at least 12 weeks prior to administration of a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject is administered a maximum tolerated stable dose of a RAS inhibitor and a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, simultaneously. In some embodiments, the RAS inhibitor is an angiotensin-converting enzyme inhibitor. In some embodiments, the RAS inhibitor is an angiotensin receptor blocker (ARB).

[0290] In some embodiments, the subject has an airway volume of at least 30 mL / min / 1.73 m prior to administration of a therapeutically effective amount of atrasentan, or a pharma- ceutical acceptable salt thereof. 2 In some embodiments, the subject has been determined to have an eGFR of about 30 mL / min / 1.73 m prior to administration of a therapeutically effective amount of atrasentan, or a pharmacologic acceptable salt thereof. 2 ~Approx. 60mL / min / 1.73m 2 It has been determined that the patient has an eGFR of .

[0291] In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure. In some embodiments, the subject has not been previously diagnosed with HIV-associated nephropathy. In some embodiments, the subject has not been previously diagnosed with cancer. In some embodiments, the cancer is lung cancer or prostate cancer.

[0292] Some embodiments provide a method of treating FSGS in a subject in need thereof, the method comprising: a) determining that the subject has high levels of IgA-immune complexes in the kidney; and b) administering a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, to the subject.

[0293] In some embodiments, determining elevated levels of IgA-immune complexes in the kidney comprises obtaining a sample from the subject and assessing the level of IgA-immune complexes in the sample. In some embodiments, the sample is a kidney biopsy sample. In some embodiments, the sample is selected from a blood sample, a urine sample, a kidney biopsy sample, or a combination of two or three of the foregoing. In some embodiments, the IgA-immune complexes are deposited in the mesangium.

[0294] In some embodiments, the level of IgA-immune complexes can be assessed by one or more of serum analysis, urinalysis, and microscopic examination (eg, light microscopy and / or immunofluorescence microscopy) of a kidney biopsy sample.

[0295] In some embodiments, samples exhibit elevated levels of one or more of the following: matrix secretion by mesangial cells, deposition of IgA-immune complexes in the mesangium, mesangial cell activation, mesangial cell proliferation, and intraductal cell proliferation.

[0296] In some embodiments, the subject is determined to have proteinuria of at least about 1 g / day in at least two of three consecutive readings over a one-year period prior to administration of a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject is determined to have proteinuria of about 1 g / day to about 15 g / day in at least two of three consecutive readings over a one-year period prior to administration of a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof. For example, about 1 g / day, about 1.2 g / day, about 1.4 g / day, about 1.6 g / day, about 1.8 g / day, about 2 g / day, about 2.5 g / day, about 3 g / day, about 3.5 g / day, about 4 g / day, about 4.5 g / day, about 5 g / day, about 6 g / day, about 7 g / day, about 8 g / day, about 9 g / day, about 10 g / day, about 11 g / day, about 12 g / day, about 13 g / day, about 14 g / day, or about 15 g / day.

[0297] In some embodiments, the subject has been administered a maximum tolerated stable dose of a RAS inhibitor for at least 12 weeks prior to administration of a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject is administered a maximum tolerated stable dose of a RAS inhibitor and a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, simultaneously. In some embodiments, the RAS inhibitor is an angiotensin-converting enzyme inhibitor. In some embodiments, the RAS inhibitor is an angiotensin receptor blocker (ARB).

[0298] In some embodiments, the subject has an airway volume of at least 30 mL / min / 1.73 m prior to administration of a therapeutically effective amount of atrasentan, or a pharma- ceutical acceptable salt thereof. 2 In some embodiments, the subject has been determined to have an eGFR of about 30 mL / min / 1.73 m prior to administration of a therapeutically effective amount of atrasentan, or a pharmacologic acceptable salt thereof. 2 ~Approx. 60mL / min / 1.73m 2 It has been determined that the patient has an eGFR of .

[0299] In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure. In some embodiments, the subject has not been previously diagnosed with HIV-associated nephropathy. In some embodiments, the subject has not been previously diagnosed with cancer. In some embodiments, the cancer is lung cancer or prostate cancer.

[0300] In some embodiments, the method includes determining in the subject the expression and / or activity of one or more of ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, and NF-kB. In some embodiments, the expression and / or activity is determined prior to administration of a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof. In some embodiments, the expression and / or activity is determined after administration of a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof.

[0301] In some embodiments, the determination of expression and / or activity is performed prior to administration of a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof. In some embodiments, the determination of expression and / or activity is performed after administration of a therapeutically effective amount of atrasentan, or a pharma- ceutically acceptable salt thereof, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks of treatment, or any value therebetween.

[0302] In some embodiments, the subject is diagnosed with ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, NF-kB, PKC, PI3K, Src, Ras, ERK1 / 2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA 2, TNF-α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt / PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK, MCP1, Cntfr , Il1b, Csf1, Il2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, They have been determined to have high expression and / or activity of one or more of Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1, and Pdgfb. In some embodiments, the subject is diagnosed with ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, NF-kB, PKC, PI3K, Src, Ras, ERK1 / 2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA 2, TNF-α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt / PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK, and MCP1. In some embodiments, the subject has been determined to have high expression and / or activity of one or more of Cntfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1, and Pdgfb. In some embodiments, the subject has been determined to have elevated expression and / or activity of one or more of ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, and NF-kB. In some embodiments, the subject has been determined to have elevated expression and / or activity of one or more of ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, and SLC6A19.

[0303] Some embodiments provide a method of treating FSGS in a subject, the method including: (a) the subject receiving one or more of the following: ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, NF-kB, PKC, PI3K, Src, Ras, ERK1 / 2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA 2, TNF-α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt / PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK, MCP1, Cntfr, Il1b, Csf1, I l2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1 , Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1, and Pdgfb; and (b) administering a therapeutically effective amount of atrasentan, or a pharmaceutical acceptable salt thereof, to the subject.

[0304] Some embodiments include ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, NF-kB, PKC, PI3K, Src, Ras, ERK1 / 2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA 2, TNF-α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt / PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK, MCP1, Cntfr, Il1b, Csf1, Il2ra , Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Provided is a method for treating FSGS in a subject determined to have high expression and / or activity of one or more of Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1, and Pdgfb, the method comprising administering a therapeutically effective amount of atrasentan, or a pharma- ceutical acceptable salt thereof, to the subject.

[0305] V. Atrasentan Atrasentan, also known as (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxyethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid, ABT-627, A-147627, or A-127722, is a small molecule of the following chemical structure: [ka]

[0306] Atrasentan and methods for its preparation are described in U.S. Pat. No. 7,208,517 and WO 1997 / 030045 (see, e.g., Example 501), each of which is incorporated by reference in its entirety.

[0307] In some embodiments, atrasentan is administered as the free base. In some other embodiments, atrasentan is administered as a pharma- ceutically acceptable salt, as described elsewhere herein.

[0308] Atrasentan is an ET B Than ET A Approximately 1,860 times more selective for ET A As used herein, "ET A " is an abbreviation for endothelin receptor A; "ET B " is an abbreviation for endothelin receptor B. See, e.g., Ann Rheum Dis., 66(11), pp. 1467-1472 (2007); Eur. Resp. J., 37, pp. 475-476 (2011); Plos One, 9, e87548 (2014); J. Clin. Oncol., 10, 31(14), pp. 1740-7 (2013); Pharmacol. Rev., 68(2) pp. 357-418 (2016); and Nephrol. Dial. Transplant., 29, pp. i69-i73 (2014).

[0309] salt In some embodiments, atrasentan is in the form of a pharmaceutically acceptable salt. As used herein, the phrase "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the present disclosure (e.g., atrasentan). Exemplary salts include acid addition salts formed by reacting atrasentan with an acid (e.g., an organic acid or an inorganic acid). Non-limiting examples include: sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, mandelate (e.g., (S)-mandelate or (R)-mandelate), gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate, and p-toluenesulfonate, pamoate (i.e., 4,4'-methylene-bis-(2-hydroxy-3-naphthoate)) salt. Exemplary salts also include base addition salts formed by the reaction of atrasentan with a base. Non-limiting examples include: alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. A pharmaceutically acceptable salt may include the inclusion of another molecule, such as an acetate ion, a succinate ion, or other counterion. A counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. When multiple charged atoms are part of a pharmaceutically acceptable salt, it may have multiple counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions. When referring to atrasentan, the term "salt" is understood to be a salt of atrasentan that may be present alone or in a mixture with free atrasentan.

[0310] In some embodiments, atrasentan is in the form of a hydrochloride salt. Atrasentan hydrochloride (CAS number: 195733-43-8); Atrasentan hydrochloride; Atrasentan hydrochloride; Atrasentan chloride salt; Atrasentan HCl; Atrasentan monohydrochloride; (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid, monohydrochloride; 3-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-pyrrolidinecarboxylic acid, monohydrochloride;3-pyrrolidinecarboxylic acid, 4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)-, monohydrochloride, [2R-(2α,3β,4α)];ABT-627;A-147627.1;The hydrochloride salt of atrasentan, also known as Abbott-147627.1, has the following structure: [ka] wherein the molar ratio of atrasentan to chloride is 1:1. Atrasentan hydrochloride and methods for its preparation are further described in U.S. Pat. No. 7,208,517 and WO 1997 / 030045 (see, e.g., Example 501), each of which is incorporated by reference in its entirety.

[0311] In some embodiments, atrasentan is in the form of a mandelate salt. In certain embodiments, atrasentan is in the form of an (S)-mandelate salt. In certain embodiments, atrasentan is in the form of an (R)-mandelate salt. In certain embodiments, in the atrasentan mandelate salt, atrasentan and the mandelate salt have a molar ratio of 1:1. In certain embodiments, in the atrasentan mandelate salt, atrasentan and the mandelate salt have a molar ratio of 2:1. Atrasentan mandelate salt and methods for its preparation are further described in U.S. Pat. Nos. 8,962,675 and 9,637,476, each of which is incorporated herein by reference in its entirety.

[0312] In some embodiments, atrasentan is in the form of a hemisulfate salt. Hemisulfate salts and methods for their preparation are further described in U.S. Patent Nos. 8,962,675 and 9,637,476, each of which is incorporated herein by reference in its entirety.

[0313] In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is in the form of an anhydrate. In certain embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is in the form of a hydrate. In certain embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is in the form of a solvate.

[0314] stereochemistry Atrasentan has three asymmetric centers and can be produced as individual stereoisomers (e.g., enantiomers or diastereomers) or mixtures thereof, as described in U.S. Patent No. 7,208,517 and WO 1997 / 030045. In some embodiments, atrasentan described herein comprises the (2R,3R,4S)-stereoisomer, i.e., (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxyethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid. In certain embodiments, atrasentan is the (2R,3R,4S)-stereoisomer that is substantially free of other stereoisomers (e.g., contains <10%, <5%, <2%, <1%, <0.5%, <0.1%, or <0.05% of other stereoisomers).

[0315] polymorphism Atrasentan or a pharma- ceutically acceptable salt thereof described herein may be in one or more polymorphic forms. In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is substantially amorphous (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% amorphous). In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is substantially crystalline (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% crystalline).

[0316] In certain embodiments, atrasentan or a pharma- ceutically acceptable salt thereof comprises atrasentan hydrochloride crystalline form 1. In certain embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is substantially atrasentan hydrochloride crystalline form 1 (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% crystalline form 1). Atrasentan hydrochloride crystalline form 1 and methods for making it are described in WO 2006 / 034094, which is incorporated herein by reference in its entirety.

[0317] In some embodiments, Atrasentan hydrochloride Crystalline Form 1 is characterized by an X-ray powder diffraction pattern having at least three peaks (e.g., 3, 4, 5, 6, or 7) having 2θ values ​​of about 8.3°, 9.7°, 10.0°, 13.0°, 15.6°, 17.2°, or 19.5°, respectively, when measured using Cu-Kα radiation at about 25° C. In certain embodiments, Atrasentan hydrochloride Crystalline Form 1 is characterized by an X-ray powder diffraction pattern having at least three peaks having 2θ values ​​of about 8.3°, 9.7°, 10.0°, 13.0°, 15.6°, 17.2°, or 19.5°, respectively, and essentially no peaks having a 2θ value of less than about 6.2° and / or between about 6.6° and 8.0°, when measured using Cu-Kα radiation at about 25° C.

[0318] In some embodiments, the atrasentan hydrochloride crystalline form 1 has an orthorhombic crystal system and a P2 l 2 l 2 l It is characterized by its space group.

[0319] In some embodiments, Atrasentan hydrochloride Crystalline Form 1 has substantial crystalline purity. In some embodiments, Atrasentan hydrochloride Crystalline Form 1 has substantial chemical purity. In some embodiments, Atrasentan hydrochloride Crystalline Form 1 has substantial diastereomeric purity.

[0320] Representative characteristic peak positions in the X-ray powder diffraction pattern of atrasentan hydrochloride crystalline Form I, expressed as angles relative to 2θ, measured at about 25°C using Cu-Kα radiation, are approximately: 8.3° ((020), 77.35%); 9.7° ((120), 76.37%); 10.0° ((200), 14.53%); 13.2° ((220), 28.03%); 13.6° ((130), 16.71%); 14.9° ((121), 38.93%); 5.8° ((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 shown with its associated Miller index (hkl) value and its integrated intensity (peak height). It should be understood that peak heights may vary and are dependent on variables such as temperature, crystal size or morphology, sample preparation, or sample height in the analysis well of the Scintag x2 diffraction pattern system. It should also be understood that peak positions may vary when measured with different radiation sources. For example, Cu-Kα1, Mo-Kα, Co-Kα, and Fe-Kα radiation, which have wavelengths of 1.54060 Å, 0.7107 Å, 1.7902 Å, and 1.9373 Å, respectively, may provide peak positions that differ from those measured with Cu-Kα radiation.

[0321] In certain embodiments, atrasentan or a pharma- ceutically acceptable salt thereof comprises atrasentan hydrochloride crystalline form 2. In certain embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is substantially atrasentan hydrochloride crystalline form 2 (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% crystalline form 2). Atrasentan hydrochloride crystalline form 2 and methods for making it are described in WO 2006 / 034084, which is incorporated herein by reference in its entirety.

[0322] In certain embodiments, atrasentan hydrochloride crystalline form 2 is characterized by an X-ray powder diffraction pattern having peaks having 2θ values ​​of about 6.7° and 22.05°, respectively, and at least one peak having a 2θ value of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6°, respectively, when measured at about 25° C. using Cu-Kα radiation.

[0323] In certain embodiments, atrasentan hydrochloride crystalline Form 2 has substantial crystalline purity and is characterized by an X-ray powder diffraction pattern having peaks having 2θ values ​​of about 6.7° and 22.05°, respectively, and at least one peak having a 2θ value of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6°, respectively, when measured at about 25° C. using Cu-Kα radiation.

[0324] In certain embodiments, Atrasentan hydrochloride Crystalline Form 2 has substantial crystalline purity and substantial chemical purity; said Atrasentan hydrochloride Crystalline Form 2 is characterized by an X-ray powder diffraction pattern having peaks having 2θ values ​​of about 6.7° and 22.05°, respectively, and at least one peak having a 2θ value of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6°, respectively, when measured at about 25° C. using Cu-Kα radiation.

[0325] In certain embodiments, Atrasentan hydrochloride Crystalline Form 2 has substantial crystalline purity, substantial chemical purity, and substantial diastereomeric purity; said Atrasentan hydrochloride Crystalline Form 2 is characterized by an X-ray powder diffraction pattern having peaks having 2θ values ​​of about 6.7° and 22.05°, respectively, and at least one peak having a 2θ value of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6°, respectively, when measured at about 25° C. using Cu-Kα radiation.

[0326] In certain embodiments, atrasentan or a pharma- ceutically acceptable salt thereof comprises atrasentan hydrochloride crystalline form 3. In certain embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is substantially atrasentan hydrochloride crystalline form 3 (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% crystalline form 3). Atrasentan hydrochloride crystalline form 3 and methods for making it are described in WO 2006 / 034234 and U.S. Patent No. 9,051,301, each of which is incorporated herein by reference in its entirety.

[0327] In certain embodiments, atrasentan hydrochloride crystalline Form 3 is characterized by an X-ray powder diffraction pattern having peaks having 2θ values ​​of about 6.7° and 21.95°, respectively, and at least one peak having a 2θ value of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6°, respectively, when measured at about 25° C. using Cu-Kα radiation.

[0328] In certain embodiments, atrasentan hydrochloride crystalline Form 3 has substantial crystalline purity and is characterized by an X-ray powder diffraction pattern having peaks having 2θ values ​​of about 6.7° and 21.95°, respectively, and at least one peak having a 2θ value of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6°, respectively, when measured at about 25° C. using Cu-Kα radiation.

[0329] In certain embodiments, Atrasentan hydrochloride Crystalline Form 3 has substantial crystalline purity and substantial chemical purity; said Atrasentan hydrochloride Crystalline Form 3 is characterized by an X-ray powder diffraction pattern having peaks having 2θ values ​​of about 6.7° and 21.95°, respectively, and at least one peak having a 2θ value of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6°, respectively, when measured at about 25° C. using Cu-Kα radiation.

[0330] In certain embodiments, Atrasentan hydrochloride Crystalline Form 3 has qualitative crystalline purity, substantial chemical purity, and substantial diastereomeric purity; said Atrasentan hydrochloride Crystalline Form 3 is characterized by an X-ray powder diffraction pattern having peaks having 2θ values ​​of about 6.7° and 21.95°, respectively, and at least one peak having a 2θ value of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6°, respectively, when measured at about 25° C. using Cu-Kα radiation.

[0331] In certain embodiments, atrasentan or a pharma- ceutically acceptable salt thereof comprises amorphous atrasentan hydrochloride. In certain embodiments, the atrasentan hydrochloride is substantially amorphous (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% amorphous). Amorphous atrasentan hydrochloride and methods for making it are described in WO 2006 / 034085, which is incorporated herein by reference in its entirety.

[0332] In certain embodiments, the amorphous atrasentan hydrochloride has substantial chemical purity. In certain embodiments, the amorphous atrasentan hydrochloride has substantial diastereomeric purity.

[0333] In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof comprises crystalline atrasentan mandelate. In certain embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is substantially crystalline atrasentan mandelate (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% crystalline atrasentan mandelate).

[0334] In certain embodiments, the crystalline atrasentan mandelate is a crystalline atrasentan (S)-mandelate. In certain embodiments, the atrasentan (S)-mandelate is an anhydrous salt. In certain embodiments, the atrasentan (S)-mandelate is a solvated salt. In certain embodiments, the atrasentan (S)-mandelate is a solvated salt selected from the group consisting of an acetonitrile solvate, an ethanol solvate, and a pyridine solvate. In certain embodiments, the atrasentan (S)-mandelate is a hydrated salt.

[0335] (a) (S)-Mandelate salt (1:1 stoichiometry) In certain embodiments, the crystalline atrasentan (S)-mandelate is a crystalline atrasentan (S)-mandelate, and the molar ratio of atrasentan to (S)-mandelate is about 1:1. In certain embodiments, the atrasentan (S)-mandelate is an anhydrous salt. In certain embodiments, the atrasentan (S)-mandelate is a solvated salt. In certain embodiments, the atrasentan (S)-mandelate is a solvated salt selected from the group consisting of an acetonitrile solvate, an ethanol solvate, and a pyridine solvate. In certain embodiments, the atrasentan (S)-mandelate is a hydrated salt. In certain embodiments, the atrasentan or pharma- ceutically acceptable salt thereof is substantially (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5%) crystalline atrasentan (S)-mandelate salt, and the molar ratio of atrasentan to (S)-mandelate salt is about 1:1.

[0336] In certain embodiments, the crystalline (S)-mandelate salt has an X-ray powder diffraction pattern comprising peaks at 5.5±0.2, 9.7±0.2, and 19.4±0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25° C. In certain embodiments, the crystalline (S)-mandelate salt has an X-ray powder diffraction pattern comprising peaks at 5.5±0.2, 9.7±0.2, 12.1±0.2, and 19.4±0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25° C. In certain embodiments, the crystalline (S)-mandelate salt has an X-ray powder diffraction pattern comprising peaks at 5.5±0.2, 9.7±0.2, 12.1±0.2, 18.0±0.2, 18.4±0.2, and 19.4±0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25° C. In certain embodiments, the experimental error associated with the X-ray powder diffraction peak values ​​listed in the various embodiments above is ±0.1 degrees 2θ. In certain embodiments, the crystalline (S)-mandelate salt is an anhydrous salt. In certain embodiments, the molar ratio of atrasentan to (S)-mandelate salt is about 1:1.

[0337] In certain embodiments, the crystalline (S)-mandelate salt has an orthorhombic lattice type. In certain embodiments, the crystalline (S)-mandelate salt has a P2 1 2 1 2 1 The space group is 0.01 to 0.15. In certain embodiments, the crystalline (S)-mandelate salt has unit cell a, b, and c values ​​of about 9.954 Å, about 11.049 Å, and about 30.861 Å, respectively. In certain embodiments, the crystalline (S)-mandelate salt has unit cell α, β, and γ values ​​of about 90°, about 90°, and about 90°, respectively. In certain embodiments, the crystalline (S)-mandelate salt has at least three or more of the following characteristics: (a) an orthorhombic lattice type; (b) a P2 1 2 1 2 1 (c) unit cell a, b, and c values ​​of about 9.954 Å, about 11.049 Å, and about 30.861 Å, respectively, and / or (d) unit cell α, β, and γ values ​​of about 90°, about 90°, and about 90°, respectively. In certain embodiments, the crystalline (S)-mandelate salt has: (a) an orthorhombic lattice type; (b) a P21 2 1 2 1 space group, (c) unit cell a, b and c values ​​of about 9.954 Å, about 11.049 Å, and about 30.861 Å, respectively, and (d) unit cell α, β and γ values ​​of about 90°, about 90°, and about 90°, respectively. In certain embodiments, the crystalline (S)-mandelate salt is an anhydrous salt. In certain embodiments, the molar ratio of atrasentan to (S)-mandelate salt is about 1:1.

[0338] (b) (S)-Mandelate salt (2:1 stoichiometry) In certain embodiments, the crystalline (S)-mandelate salt is crystalline atrasentan (S)-mandelate salt, and the molar ratio of atrasentan to (S)-mandelate salt is about 2:1. In certain embodiments, the crystalline atrasentan (S)-mandelate salt is an anhydrous salt. In certain embodiments, the crystalline atrasentan (S)-mandelate salt is a solvated salt. In certain embodiments, the crystalline atrasentan (S)-mandelate salt is a hydrated salt. In certain embodiments, the atrasentan or a pharma- ceutically acceptable salt thereof is substantially (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5%) crystalline atrasentan (S)-mandelate salt, and the molar ratio of atrasentan to (S)-mandelate salt is 2:1.

[0339] In certain embodiments, the crystalline (S)-mandelate salt has an X-ray powder diffraction pattern comprising peaks at 4.5±0.2, 8.6±0.2, and 18.1±0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25° C. In certain embodiments, the crystalline (S)-mandelate salt has an X-ray powder diffraction pattern comprising peaks at 4.5±0.2, 8.6±0.2, 18.1±0.2, and 18.7±0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25° C. In certain embodiments, the crystalline (S)-mandelate salt has an X-ray powder diffraction pattern comprising peaks at 4.5±0.2, 8.6±0.2, 9.1±0.2, 18.1±0.2, and 18.7±0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25° C. In certain embodiments, the experimental error associated with the X-ray powder diffraction peak values ​​listed in the various embodiments above is ±0.1 degrees 2θ. In certain embodiments, the crystalline (S)-mandelate salt is an anhydrous salt. In certain embodiments, the crystalline (S)-mandelate salt is a hydrated salt.

[0340] In certain embodiments, the crystalline atrasentan mandelate is crystalline atrasentan (R)-mandelate. In certain embodiments, the crystalline atrasentan (R)-mandelate is an anhydrous salt. In certain embodiments, the crystalline atrasentan (R)-mandelate is a solvated salt. In certain embodiments, the crystalline atrasentan (R)-mandelate is a hydrated salt.

[0341] (c) (R)-Mandelate salt (1:1 stoichiometry) In certain embodiments, the crystalline atrasentan (R)-mandelate is crystalline atrasentan (R)-mandelate, and the molar ratio of atrasentan to the (R)-mandelate is about 1:1. In certain embodiments, the crystalline atrasentan (R)-mandelate is an anhydrous salt. In certain embodiments, the crystalline atrasentan (R)-mandelate is a solvated salt. In certain embodiments, the crystalline atrasentan (R)-mandelate is a hydrated salt. In certain embodiments, the atrasentan or a pharma- ceutically acceptable salt thereof is substantially (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5%) crystalline atrasentan (R)-mandelate, and the molar ratio of atrasentan to the (R)-mandelate is about 1:1.

[0342] In certain embodiments, crystalline atrasentan (R)-mandelate has an X-ray powder diffraction pattern comprising peaks at 5.7±0.2, 11.8±0.2, and 20.9±0.2 degrees 2θ when measured at about 25° C. using monochromatic Kα1 radiation. In certain embodiments, crystalline atrasentan (R)-mandelate has an X-ray powder diffraction pattern comprising peaks at 5.7±0.2, 8.2±0.2, 11.8±0.2, and 20.9±0.2 degrees 2θ when measured at about 25° C. using monochromatic Kα1 radiation. In certain embodiments, crystalline atrasentan (R)-mandelate has an X-ray powder diffraction pattern comprising peaks at 5.7±0.2, 8.2±0.2, 8.6±0.2, 11.8±0.2, and 20.9±0.2 degrees 2θ when measured at about 25° C. using monochromatic Kα1 radiation. In certain embodiments, the experimental error associated with the X-ray powder diffraction peak values ​​listed in the various embodiments above is ±0.1 degrees 2θ. In certain embodiments, the crystalline atrasentan (R)-mandelate salt is an anhydrous salt.

[0343] In some embodiments, atrasentan or a pharma- ceutically acceptable salt thereof comprises amorphous atrasentan mandelate. In certain embodiments, atrasentan or a pharma- ceutically acceptable salt thereof is substantially amorphous atrasentan mandelate (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% amorphous atrasentan mandelate).

[0344] In certain embodiments, the amorphous atrasentan mandelate is amorphous atrasentan (S)-mandelate. In certain embodiments, the amorphous atrasentan (S)-mandelate is an anhydrous salt. In certain embodiments, the amorphous atrasentan (S)-mandelate is a solvated salt. In certain embodiments, the amorphous atrasentan (S)-mandelate is a solvated salt selected from the group consisting of an acetonitrile solvate, an ethanol solvate, and a pyridine solvate. In certain embodiments, the amorphous atrasentan (S)-mandelate is a hydrated salt. In certain embodiments, the amorphous atrasentan (S)-mandelate has a molar ratio of atrasentan to (S)-mandelate of about 1:1. In certain embodiments, the amorphous atrasentan (S)-mandelate has a molar ratio of atrasentan to (S)-mandelate of about 2:1.

[0345] In certain embodiments, the amorphous atrasentan mandelate is amorphous atrasentan (R)-mandelate. In certain embodiments, the amorphous atrasentan (R)-mandelate is an anhydrous salt. In certain embodiments, the amorphous atrasentan (R)-mandelate is a solvated salt. In certain embodiments, the amorphous atrasentan (R)-mandelate is a solvated salt selected from the group consisting of an acetonitrile solvate, an ethanol solvate, and a pyridine solvate. In certain embodiments, the amorphous atrasentan (R)-mandelate is a hydrated salt. In certain embodiments, the molar ratio of atrasentan to (R)-mandelate in the amorphous atrasentan (R)-mandelate is about 1:1. In certain embodiments, the molar ratio of atrasentan to (R)-mandelate in the amorphous atrasentan (R)-mandelate is about 2:1.

[0346] Crystalline and amorphous atrasentan mandelate salts are further described in US Pat. Nos. 8,962,675 and 9,637,476, each of which is incorporated by reference in its entirety.

[0347] VI. Formulations The term "pharmaceutical composition" as used herein is intended to include a product containing an active ingredient and an inactive ingredient that constitutes a carrier, as well as any product that results directly or indirectly from the combination, complex formation or aggregation of any two or more of the ingredients, or the dissociation of one or more of the ingredients, or any other type of reaction or interaction of one or more of the ingredients.Thus, the pharmaceutical composition of the present disclosure includes any composition made by mixing the compound of the present disclosure, or its pharmaceutically acceptable salt, or solvate or solvate of the salt, with a pharmaceutically acceptable carrier.

[0348] The amount to be administered depends on the compound formulation, route of administration, etc., and is generally empirically determined, with variations necessarily occurring depending on the target, host, and route of administration, etc. In general, the amount of active compound in a unit dose of the preparation can vary or be adjusted from about 0.1 milligrams (mg) to about 10 mg, or from about 0.5 mg to about 2 mg, according to the specific application. For convenience, the total daily dose can be divided and administered several times throughout the day.

[0349] The pharmaceutical compositions of the present disclosure for injection include pharma- ceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution immediately before use into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0350] These pharmaceutical compositions may also contain auxiliary agents, such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, etc. It may be desirable to include isotonic agents, such as sugars, sodium chloride, etc. Prolonged absorption of injectable pharmaceutical forms can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin. The compound can be incorporated into sustained release or targeted delivery systems, such as polymer matrices, liposomes, and microspheres. Such formulations can provide more effective distribution of the compound.

[0351] Pharmaceutical compositions that are injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0352] Solid dosage forms of the pharmaceutical composition for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharma- ceutically acceptable excipients such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0353] Solid pharmaceutical compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0354] The solid dosage forms of the pharmaceutical composition of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other pharmaceutical coatings. They can also optionally contain opacifying agents and can be formulations that release the active ingredient only, or preferentially, in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedded pharmaceutical compositions that can be used include polymeric substances and waxes.

[0355] The active compounds can also be in microencapsulated form, if appropriate, with one or more of the excipients described above.

[0356] The liquid dosage form of the pharmaceutical composition for oral administration includes pharma- ceutical acceptable emulsion, solution, suspension, syrup and elixir.In addition to active compounds, liquid dosage form can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (especially cottonseed, peanut, corn, germ, olive, castor and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, and mixtures thereof.

[0357] Besides inert diluents, the oral pharmaceutical compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0358] Suspensions of the present compounds may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0359] The compounds and compositions described herein can be administered orally or parenterally, for example, at dosages ranging from about 0.01 milligrams per kilogram (mg / kg) to about 0.05 mg / kgg, every 4 to 120 hours, or according to the requirements of the particular drug, dosage form, and / or route of administration. The interrelationship of dosages for animals and humans (based on milligrams per square meter of body surface) is described in Freireich et al., Cancer Chemother. Rep. Rep. 50, 219-244 (1966). Body surface area can be determined to a large extent from the height and weight of the patient. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, NY, 537 (1970). In certain embodiments, the compositions are administered orally or by injection. The methods herein contemplate administration of an effective amount of the compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of the present disclosure will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.

[0360] Lower or higher doses than those recited above may be required. The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, severity and course of the disease, condition or symptom, predisposition of the patient to the disease, and the judgment of the treating physician.

[0361] The dosage form contains from about 0.01 mg to about 10 mg (including from about 0.1 mg to about 5 mg, from about 0.2 mg to about 4 mg, from about 0.3 mg to about 3 mg, from about 0.4 mg to about 2 mg, from about 0.5 mg to about 1.5 mg, from about 0.6 mg to about 1 mg, or from about 1.25 mg to about 1.75 mg) of the compound atrasentan, or a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage form comprises about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.65, about 0.7 mg, about 0.75, about 0.8 mg, about 0.85, about 0.9 mg, about 0.95 mg, about 1 mg, about 1.05 mg, about 1.1 mg, about 1.15 mg, about 1.2 mg, about 1.25 mg, about 1.3 mg, about 1.35 mg, about 1.4 mg, about 1.45 mg, about 1.5 mg, about 1.55 mg, about 1.6 mg, about 1.65 mg, about 1.7 mg, about 1.75 mg, about 1.8 mg, about 1.85 mg, about 1.9 mg, about 1.95 mg, about 2 mg, or any value therebetween of atrasentan, or a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage form comprises 0.75 mg of atrasentan, or a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage form comprises 1.5 mg of atrasentan, or a pharma- ceutically acceptable salt thereof.

[0362] The dosage form may further comprise a pharma- ceutically acceptable carrier and / or an additional therapeutic agent.

[0363] The appropriate dosage level may be determined by any suitable method. Preferably, the active substance is administered at a frequency of 1 to 4 times per day for topical administration, or less frequently if a drug delivery system is used. Nevertheless, the actual dosage level and time course of administration of the active ingredient in the pharmaceutical composition of the present disclosure may be varied to obtain an amount of the active ingredient effective to achieve the therapeutic response desired for a particular patient, composition, and mode of administration without intolerable toxicity to the patient. In certain cases, the dosage may deviate from the amounts described as a function of, among other things, the age, sex, weight, diet, and general health of the patient, the route of administration, the individual response to the active ingredient, the nature of the preparation, and the time or interval at which administration is performed. Thus, in some cases, less than the minimum amount mentioned above may be adequately manageable, while in other cases the upper limit described may be exceeded. When larger amounts are administered, it may be appropriate to divide these into multiple individual doses throughout the day.

[0364] Exemplary Dosage Forms of Atrasentan In some embodiments, provided herein is a stable solid pharmaceutical dosage form comprising: (a) about 0.25 mg to about 1.25 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof; wherein the weight percent of atrasentan, or a pharma- ceutically acceptable salt thereof, in the dosage form is about 0.05% to about 2.0% by weight, based on an atrasentan free base equivalent amount; and (b) a pharma- ceutically acceptable diluent.

[0365] In some embodiments, provided herein is a stable solid pharmaceutical dosage form comprising: (a) about 0.25 mg to about 1.25 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof; wherein the weight percent of atrasentan, or a pharma- ceutically acceptable salt thereof, in the dosage form is about 0.05% to about 2.0% by weight, based on an atrasentan free base equivalent; (b) a pharma- ceutically acceptable antioxidant; wherein the molar ratio of the antioxidant to atrasentan, or a pharma- ceutically acceptable salt thereof, is about 10:1 to about 1:10; and (c) a pharma- ceutically acceptable diluent.

[0366] In some embodiments, provided herein is a stable solid pharmaceutical dosage form comprising: (a) about 0.25 mg to about 1.75 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof; wherein the weight percent of atrasentan, or a pharma- ceutically acceptable salt thereof, in the dosage form is about 0.05% to about 2.0% by weight, based on an atrasentan free base equivalent amount; and (b) a pharma- ceutically acceptable diluent.

[0367] In some embodiments, provided herein is a stable solid pharmaceutical dosage form comprising: (a) about 1.25 mg to about 1.75 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof; wherein the weight percent of atrasentan, or a pharma- ceutically acceptable salt thereof, in the dosage form is about 0.05% to about 2.0% by weight, based on an atrasentan free base equivalent basis; (b) a pharma- ceutically acceptable antioxidant; wherein the molar ratio of the antioxidant to atrasentan, or a pharma- ceutically acceptable salt thereof, is about 10:1 to about 1:10; and (c) a pharma- ceutically acceptable diluent.

[0368] In certain of these embodiments, degradation of atrasentan in the dosage form is less than the degradation of atrasentan in an otherwise identical dosage form lacking the antioxidant when the dosage form is stored for a storage period of six months at about 40° C. and a relative humidity of about 75%. In some embodiments, the dosage form is stored in a semi-permeable or substantially impermeable container during the storage period. In some embodiments, the dosage form is stored in a sealed HDPE bottle or blister package during the storage period. 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 a blister package during the storage period.

[0369] (i) Atrasentan The dosage form may comprise atrasentan free base, a pharma- ceutically acceptable salt of atrasentan, or a combination thereof. In some embodiments, the dosage form comprises atrasentan free base. In some embodiments, the dosage form comprises a pharma- ceutically acceptable salt of atrasentan. In some embodiments, the dosage form comprises atrasentan hydrochloride. In some embodiments, the dosage form comprises atrasentan hydrochloride having a polymorphic form selected from the group consisting of amorphous atrasentan hydrochloride, atrasentan hydrochloride crystalline form 1, atrasentan hydrochloride crystalline form 2, and atrasentan hydrochloride crystalline form 3. In some embodiments, the dosage form comprises amorphous atrasentan hydrochloride. In some embodiments, the dosage form comprises atrasentan hydrochloride crystalline form 1. In some embodiments, the dosage form comprises atrasentan hydrochloride crystalline form 2. In some embodiments, the dosage form comprises atrasentan hydrochloride crystalline form 3. In some embodiments, the dosage form comprises atrasentan mandelate. In certain embodiments, the dosage form comprises crystalline atrasentan mandelate (e.g., crystalline atrasentan (S)-mandelate and / or crystalline atrasentan (R)-mandelate). In certain embodiments, the dosage form comprises amorphous atrasentan mandelate (e.g., amorphous atrasentan (S)-mandelate and / or amorphous atrasentan (R)-mandelate). In certain of the foregoing embodiments (where the dosage form comprises crystalline and / or amorphous atrasentan (S)- and / or (R)-mandelate), the molar ratio of atrasentan to mandelate is 1:1. In certain other embodiments, the molar ratio of atrasentan to mandelate is 2:1.

[0370] In certain embodiments, the dosage form comprises amorphous atrasentan hydrochloride; substantially free (including, for example, <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) of other forms of atrasentan (e.g., other salts and / or other polymorphs). In certain embodiments, the dosage form comprises atrasentan hydrochloride crystalline Form 1; substantially free (including, for example, <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) of other forms of atrasentan (e.g., other salts and / or other polymorphs). In certain embodiments, the dosage form comprises atrasentan hydrochloride crystalline Form 2; substantially free (including, for example, <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) of other forms of atrasentan (e.g., other salts and / or other polymorphs). In certain embodiments, the dosage form comprises atrasentan hydrochloride crystalline Form 3; and is substantially free (including, for example, <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) of other forms of atrasentan (e.g., other salts and / or other polymorphs). In certain embodiments, the dosage form comprises crystalline atrasentan (S)-mandelate salt; and is substantially free (including, for example, <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) of other forms of atrasentan (e.g., other salts and / or other polymorphs). In certain embodiments, the dosage form comprises crystalline atrasentan (R)-mandelate salt; and is substantially free (including, for example, <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) of other forms of atrasentan (e.g., other salts and / or other polymorphs). In certain embodiments, the dosage form comprises non-crystalline atrasentan (S)-mandelate salt; substantially free (including, for example, <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) of other forms of atrasentan (e.g., other salts and / or other polymorphs). In certain embodiments, the dosage form comprises non-crystalline atrasentan (R)-mandelate salt; substantially free (including, for example, <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) of other forms of atrasentan (e.g., other salts and / or other polymorphs).

[0371] In some embodiments, the weight percent of atrasentan, or a pharma- ceutically acceptable salt thereof, in the dosage form is about 0.1 wt% to about 2.0 wt% based on the atrasentan free base equivalent. In some embodiments, the weight percent of atrasentan, or a pharma- ceutically acceptable salt thereof, in the dosage form is about 0.2 wt% to about 1.0 wt% based on the atrasentan free base equivalent. In some embodiments, the weight percent of atrasentan, or a pharma- ceutically acceptable salt thereof, in the dosage form is about 0.3 wt% to about 0.8 wt% based on the atrasentan free base equivalent. In some embodiments, the weight percent of atrasentan, or a pharma- ceutically acceptable salt thereof, in the dosage form is about 0.40 wt% to about 0.45 wt% based on the atrasentan free base equivalent. In some embodiments, the weight percent of atrasentan, or a pharma- ceutically acceptable salt thereof, in the dosage form is about 0.60% to about 0.65% by weight on an atrasentan free base equivalent basis.

[0372] In some embodiments, the dosage form contains about 0.40 mg to about 1.00 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage form contains about 0.40 mg to about 0.85 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage form contains about 0.50 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage form contains about 0.75 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage form contains about 1.25 mg to about 1.75 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage form contains about 1.5 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0373] (ii) Diluent Diluents suitable for use in the disclosed dosage forms include, but are not limited to, lactose (such as lactose monohydrate, lactose anhydrous, and PHARMATOSE® DCL21), sucrose, glucose, mannitol, sorbitol, isomalt, microcrystalline cellulose (such as AVICEL® PH101 and AVICEL® PH102), silicified microcrystalline cellulose (such as PROSOLV® SMCC 50 and SMCC 90), dicalcium phosphate, starch, and combinations thereof. In some embodiments, the diluent is selected from the group consisting of lactose, mannitol, isomalt, microcrystalline cellulose, dicalcium phosphate, and combinations thereof. In some embodiments, the diluent is lactose.

[0374] In some embodiments, the weight percent of the diluent in the dosage form is about 70% to about 99% by weight. In some embodiments, the weight percent of the diluent in the dosage form is about 80% to about 99% by weight. In some embodiments, the weight percent of the diluent in the dosage form is about 85% to about 99% by weight. In certain of the foregoing embodiments, the diluent is selected from the group consisting of lactose, mannitol, isomalt, and combinations thereof. As a non-limiting example, the diluent can be lactose.

[0375] (iii) Binder In some embodiments, the dosage form further comprises a pharma- ceutically acceptable binder (e.g., a polymeric binder). Suitable binders for use in the disclosed dosage forms include, but are not limited to, celluloses, such as hydroxypropyl methylcellulose (e.g., hypromellose E5 (premium LV)), hydroxypropyl ethylcellulose, and hydroxypropylcellulose, and other pharma- ceutically acceptable substances having cohesive properties. In some embodiments, the binder is selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, and hydroxypropylcellulose. In some embodiments, the binder is hydroxypropylmethylcellulose. In some embodiments, the binder is hydroxypropylcellulose. In some embodiments, the binder is hydroxyethylpropylcellulose.

[0376] In some embodiments, the dosage form further comprises a pharma- ceutically acceptable binder; the weight percent of the binder in the dosage form is about 1.0% to about 10.0% by weight. In some embodiments, the weight percent of the binder in the dosage form is about 1.0% to about 8.0% by weight. In some embodiments, the weight percent of the binder in the dosage form is about 1.0% to about 5.0% by weight. In certain of the foregoing embodiments, the binder is a polymeric binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, and hydroxypropylcellulose.

[0377] In some embodiments, the dosage form further comprises a pharma- ceutically acceptable binder; the weight-to-weight ratio of the binder to atrasentan, or a pharma- ceutically acceptable salt thereof, is about 2:1 to about 25:1, based on an atrasentan free base equivalent weight basis. In some embodiments, the weight-to-weight ratio of the binder to atrasentan, or a pharma- ceutically acceptable salt thereof, is about 1:1 to about 20:1, based on an atrasentan free base equivalent weight basis. In some embodiments, the weight-to-weight ratio of the binder to atrasentan, or a pharma- ceutically acceptable salt thereof, is about 1:1 to about 15:1, based on an atrasentan free base equivalent weight basis. In certain embodiments, the binder is a polymeric binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, and hydroxypropylcellulose;

[0378] (iv) Disintegrant In some embodiments, the dosage form optionally comprises a pharma- ceutically acceptable disintegrant. Disintegrants suitable for use in the disclosed dosage form include, but are not limited to, cross-linked polyvinylpyrrolidone (such as POLYPLASDONE™ XL), corn starch, potato starch, maize starch and modified starches (including sodium starch glycolate), agar, alginic acid, microcrystalline cellulose, croscarmellose sodium, and combinations thereof. In some embodiments, the disintegrant is selected from the group consisting of crospovidone, sodium starch glycolate, and croscarmellose sodium. In some embodiments, the disintegrant is cross-linked polyvinylpyrrolidone. In some embodiments, the disintegrant is crospovidone.

[0379] In some embodiments, the dosage form further comprises a pharma- ceutically acceptable disintegrant. In certain embodiments, the weight percent of the disintegrant in the dosage form is about 1.0% to about 10.0% by weight. In some embodiments, the weight percent of the disintegrant in the dosage form is about 1.0% to about 6.0% by weight. In some embodiments, the weight percent of the disintegrant in the dosage form is about 1.0% to about 4.0% by weight. In certain of the foregoing embodiments, the disintegrant is crospovidone.

[0380] In some embodiments, the dosage form further comprises a pharma- ceutically acceptable disintegrant, and the weight to weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine), or a pharma- ceutically acceptable salt or ester thereof, is about 60:1 to about 3:1. In some embodiments, the weight to weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine), or a pharma- ceutically acceptable salt or ester thereof, is about 50:1 to about 4:1. In some embodiments, the weight to weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine), or a pharma- ceutically acceptable salt or ester thereof, is about 35:1 to about 5:1.

[0381] (v) Additional excipients In further embodiments, the dosage form optionally comprises a pharma- ceutically acceptable lubricant and / or glidant. Lubricants and glidants suitable for use in the disclosed dosage form include, but are not limited to, silicon dioxide (such as SYLOID® 244FP and AEROSIL® 200), glyceryl behenate (such as COMPRITOL®), talc, stearic acid, solid polyethylene glycol, silica gel and mixtures thereof, and other substances with lubricating and glidant properties. In certain embodiments, the lubricant is glyceryl behenate (such as COMPRITOL®). In certain embodiments, the glidant is silicon dioxide (such as SYLOID® 244FP). In certain embodiments, the lubricant is glyceryl behenate and the glidant is silicon dioxide.

[0382] In some embodiments, the dosage form further comprises a pharma- ceutically acceptable glidant. In another aspect, the weight percent of the glidant in the dosage form is about 0.1% to about 1.5% by weight. In some embodiments, the weight percent of the glidant in the dosage form is about 0.1% to about 1.0% by weight. In some embodiments, the weight percent of the glidant in the dosage form is about 0.1% to about 0.8% by weight. In some embodiments, the glidant is silicon dioxide.

[0383] In some embodiments, the dosage form further comprises a pharma- ceutically acceptable lubricant. In some embodiments, the dosage form further comprises a pharma- ceutically acceptable, hydrophobic lubricant. In some embodiments, the weight percent of the lubricant in the dosage form is about 0.05% to about 5.0% by weight. In some embodiments, the weight percent of the lubricant in the dosage form is about 0.2% to about 3.0% by weight. In some embodiments, the weight percent of the lubricant in the dosage form is about 0.5% to about 2.0% by weight. In certain embodiments, the lubricant is glyceryl behenate.

[0384] In some embodiments, the dosage form further comprises a disintegrant, a glidant, and a lubricant.

[0385] (vi) Antioxidants Antioxidants suitable for use in the disclosed dosage forms include antioxidants that function as reducing agents and are oxidized to pharma- ceutically acceptable reduction products in the dosage form. In some embodiments, the antioxidant has an oxidation-reduction potential less than that of atrasentan (i.e., an oxidation-reduction potential less than about 900 mV) and greater than about 550 mV. In some embodiments, the antioxidant has an oxidation-reduction potential less than about 550 mV. In some embodiments, the antioxidant has an oxidation-reduction potential between about 1 mV and about 550 mV. In some embodiments, the antioxidant has a solubility in water at about 25° C. greater than about 24 mg / mL. In some embodiments, the antioxidant is an amino acid, or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, the antioxidant is cysteine. In some embodiments, the antioxidant is L-cysteine, or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, the antioxidant is selected from the group consisting of L-cysteine ​​hydrochloride monohydrate, L-cysteine ​​hydrochloride anhydrate, and L-cysteine ​​ethyl ester, hi some embodiments, the dosage form comprises L-cysteine ​​hydrochloride monohydrate.

[0386] In some embodiments, the weight percent of the antioxidant in the dosage form is about 0.05% to about 1.0% by weight. In some embodiments, the weight percent of the antioxidant in the dosage form is about 0.07% to about 0.7% by weight. In some embodiments, the weight percent of the antioxidant in the dosage form is about 0.09% to about 0.5% by weight.

[0387] In some embodiments, the molar ratio of antioxidant to atrasentan, or a pharma- ceutically acceptable salt thereof, is about 10:1 to about 1:10. In some embodiments, the molar ratio of antioxidant to atrasentan, or a pharma- ceutically acceptable salt thereof, in the dosage form is about 5:1 to about 1:5. In some embodiments, the molar ratio of antioxidant to atrasentan, or a pharma- ceutically acceptable salt thereof, is about 2:1 to about 1:2. In some embodiments, the molar ratio of antioxidant to atrasentan, or a pharma- ceutically acceptable salt thereof, is about 1:1.

[0388] In some embodiments, the antioxidant is L-cysteine ​​or a pharma- ceutically acceptable salt thereof. In certain embodiments, the weight percent of L-cysteine ​​or a pharma- ceutically acceptable salt or ester thereof in the dosage form is about 0.05% to about 1.0% by weight. In certain embodiments, the weight percent of L-cysteine ​​or a pharma- ceutically acceptable salt or ester thereof in the dosage form is about 0.07% to about 0.7% by weight. In certain embodiments, the weight percent of L-cysteine ​​or a pharma- ceutically acceptable salt or ester thereof in the dosage form is about 0.09% to about 0.5% by weight.

[0389] In certain embodiments, the molar ratio of L-cysteine, or a pharma- ceutically acceptable salt or ester thereof, to atrasentan, or a pharma- ceutically acceptable salt thereof, in the dosage form is about 10:1 to about 1:10. In certain embodiments, the molar ratio of L-cysteine, or a pharma- ceutically acceptable salt or ester thereof, to atrasentan, or a pharma- ceutically acceptable salt thereof, in the dosage form is about 5:1 to about 1:5. In certain embodiments, the molar ratio of L-cysteine, or a pharma- ceutically acceptable salt or ester thereof, to atrasentan, or a pharma- ceutically acceptable salt thereof, is about 2:1 to about 1:2. In certain embodiments, the molar ratio of L-cysteine, or a pharma- ceutically acceptable salt or ester thereof, to atrasentan, or a pharma- ceutically acceptable salt thereof, is about 1:1.

[0390] In certain embodiments, the antioxidant is selected from the group consisting of L-cysteine ​​hydrochloride monohydrate, L-cysteine ​​hydrochloride anhydrate, and L-cysteine ​​ethyl ester, hi some embodiments, the dosage form comprises L-cysteine ​​hydrochloride monohydrate.

[0391] (vii) Additional Embodiments In some embodiments, the dosage form comprises atrasentan or a pharma- ceutically acceptable salt thereof and an antioxidant. In certain of these embodiments, the antioxidant is L-cysteine ​​or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, the molar ratio of the antioxidant (e.g., L-cysteine ​​or a pharma- ceutically acceptable salt or ester thereof) is about 5:1 to about 1:5. In certain of the foregoing embodiments, the dosage form further comprises a pharma- ceutically acceptable polymer binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, and hydroxypropylcellulose; the molar ratio of the antioxidant (e.g., L-cysteine ​​or a pharma- ceutically acceptable salt or ester thereof) to atrasentan or a pharma- ceutically acceptable salt thereof is about 5:1 to about 1:5; and the weight-to-weight ratio of the binder to atrasentan or a pharma- ceutically acceptable salt thereof is about 1:1 to about 20:1 based on atrasentan free base equivalents. In some embodiments, the dosage form further comprises a disintegrant, and the weight to weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine, or a pharma- ceutically acceptable salt or ester thereof) is about 60:1 to about 3:1. In some embodiments, the weight percent of atrasentan, or a pharma- ceutically acceptable salt thereof, in the dosage form is about 0.2% to about 1.0% by weight on an atrasentan free base equivalent basis. In some embodiments, the dosage form comprises about 0.40 mg to about 0.85 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0392] In some embodiments, the dosage form comprises a pharma- ceutically acceptable polymeric binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, and hydroxypropylcellulose; the molar ratio of the antioxidant (e.g., L-cysteine, or a pharma- ceutically acceptable salt or ester thereof) to atrasentan, or a pharma- ceutically acceptable salt thereof is about 2:1 to about 1:2; and the weight-to-weight ratio of the binder to atrasentan, or a pharma- ceutically acceptable salt thereof is about 1:1 to about 15:1 based on atrasentan free base equivalents. In some embodiments, the dosage form further comprises a disintegrant, and the weight-to-weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine, or a pharma- ceutically acceptable salt or ester thereof) is about 50:1 to about 4:1. In some embodiments, the weight percent of atrasentan, or a pharma- ceutically acceptable salt thereof in the dosage form is about 0.2% to about 1.0% by weight based on atrasentan free base equivalents. In some embodiments, the dosage form contains from about 0.40 mg to about 0.85 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0393] In some embodiments, the dosage form comprises a pharma- ceutically acceptable polymeric binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, and hydroxypropylcellulose; the molar ratio of the antioxidant (e.g., L-cysteine, or a pharma- ceutically acceptable salt or ester thereof) to atrasentan, or a pharma- ceutically acceptable salt thereof, is about 1:1; and the weight-to-weight ratio of the binder to atrasentan, or a pharma- ceutically acceptable salt thereof, is about 1:1 to about 15:1, based on atrasentan free base equivalents. In some embodiments, the dosage form further comprises a disintegrant, and the weight-to-weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine, or a pharma- ceutically acceptable salt or ester thereof) is about 35:1 to about 5:1. In some embodiments, the weight percent of atrasentan, or a pharma- ceutically acceptable salt thereof, in the dosage form is about 0.3% to about 0.8% by weight, based on atrasentan free base equivalents. In some embodiments, the dosage form contains from about 0.40 mg to about 0.85 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage form contains from about 1.25 mg to about 1.75 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0394] In some embodiments, the dosage form comprises a pharma- ceutically acceptable polymeric binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, and hydroxypropylcellulose; the dosage form comprises about 0.05% to about 1.0% by weight of an antioxidant (e.g., L-cysteine, or a pharma- ceutically acceptable salt or ester thereof); the dosage form comprises about 1.0% to about 10.0% by weight of the binder. In some embodiments, the dosage form further comprises a disintegrant, and the weight % of the disintegrant in the dosage form is about 1.0% to about 10.0% by weight. In some embodiments, the weight % of atrasentan, or a pharma- ceutically acceptable salt thereof, in the dosage form is about 0.1% to about 2.0% by weight based on the atrasentan free base equivalent. In some embodiments, the dosage form comprises about 0.40 mg to about 0.85 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage form contains from about 1.25 mg to about 1.75 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0395] In some embodiments, the dosage form comprises a pharma- ceutically acceptable polymeric binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, and hydroxypropylcellulose; the dosage form comprises about 0.07% to about 0.70% by weight of an antioxidant (e.g., L-cysteine, or a pharma- ceutically acceptable salt or ester thereof); the dosage form comprises about 1.0% to about 8.0% by weight of the binder. In some embodiments, the dosage form further comprises a disintegrant, and the weight % of the disintegrant in the dosage form is about 1.0% to about 6.0% by weight. In some embodiments, the weight % of atrasentan, or a pharma- ceutically acceptable salt thereof, in the dosage form is about 0.2% to about 1.0% by weight based on the atrasentan free base equivalent. In some embodiments, the dosage form comprises about 0.40 mg to about 0.85 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage form contains from about 1.25 mg to about 1.75 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0396] In some embodiments, the dosage form comprises a pharma- ceutically acceptable polymeric binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, and hydroxypropylcellulose; the dosage form comprises about 0.09% to about 0.80% by weight of an antioxidant (e.g., L-cysteine, or a pharma- ceutically acceptable salt or ester thereof), and the dosage form comprises about 1.0% to about 5.0% by weight of the binder. In some embodiments, the dosage form further comprises a disintegrant, and the weight % of the disintegrant in the dosage form is about 1.0% to about 4.0% by weight. In some embodiments, the weight % of atrasentan, or a pharma- ceutically acceptable salt thereof, in the dosage form is about 0.3% to about 0.8% by weight based on the atrasentan free base equivalent. In some embodiments, the dosage form comprises about 0.40 mg to about 0.85 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage form contains from about 1.25 mg to about 1.75 mg of atrasentan, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0397] In some embodiments, the dosage form is: (a) about 0.1% to about 2.0% by weight of atrasentan, or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) about 0.05% to about 1.0% by weight of an antioxidant (e.g., L-cysteine, or a pharma- ceutically acceptable salt or ester thereof); (c) about 75% to about 99% by weight of a diluent; (d) about 1.0% to about 10.0% by weight of a pharma- ceutically acceptable binder; (e) optionally, about 1.0% to about 10.0% by weight of a pharma- ceutically acceptable disintegrant; (f) optionally, from about 0% to about 1.5% by weight of a pharma- ceutically acceptable glidant; and (g) optionally, from about 0% to about 5.0% by weight of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100%.

[0398] In some embodiments, the dosage form is: (a) about 0.1% to about 2.0% by weight of atrasentan, or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) about 0.05% to about 1.0% by weight of an antioxidant (L-cysteine, or a pharma- ceutically acceptable salt or ester thereof); (c) about 75% to about 99% by weight of a diluent; (d) about 1.0% to about 10.0% by weight of a pharma- ceutically acceptable binder; (e) about 1.0% to about 10.0% by weight of a pharma- ceutically acceptable disintegrant; (f) optionally, from about 0% to about 1.5% by weight of a pharma- ceutically acceptable glidant; and (g) optionally, from about 0% to about 5.0% by weight of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100%.

[0399] In some embodiments, the dosage form is: (a) about 0.2% to about 1.0% by weight of atrasentan, or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) about 0.07% to about 0.7% by weight of an antioxidant (L-cysteine, or a pharma- ceutically acceptable salt or ester thereof); (c) about 82% to about 99% by weight of a diluent; (d) about 1.0% to about 8.0% by weight of a pharma- ceutically acceptable binder; (e) optionally, about 1.0% to about 6.0% by weight of a pharma- ceutically acceptable disintegrant; (f) optionally, from about 0% to about 1.0% by weight of a pharma- ceutically acceptable glidant; and (g) optionally, from about 0% to about 3.0% by weight of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100%.

[0400] In some embodiments, the dosage form further comprises: (a) about 0.2% to about 1.0% by weight of atrasentan, or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) about 0.07% to about 0.70% by weight of L-cysteine, or a pharma- ceutically acceptable salt or ester thereof; (c) about 82% to about 99% by weight of a diluent; (d) about 1.0% to about 8.0% by weight of a pharma- ceutically acceptable binder; (e) about 1.0% to about 6.0% by weight of a pharma- ceutically acceptable disintegrant; (f) optionally, from about 0% to about 1.0% by weight of a pharma- ceutically acceptable glidant; and (g) optionally, from about 0% to about 3.0% by weight of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100%.

[0401] In some embodiments, the dosage form further comprises: (a) about 0.3% to about 0.8% by weight of atrasentan, or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) about 0.09% to about 0.50% by weight of L-cysteine, or a pharma- ceutically acceptable salt or ester thereof; (c) about 87% to about 99% by weight of a pharma- ceutically acceptable diluent; (d) about 1.0% to about 5.0% by weight of a pharma- ceutically acceptable binder; (e) optionally, about 1.0% to about 4.0% by weight of a pharma- ceutically acceptable disintegrant; (f) optionally, from about 0% to about 0.75% by weight of a pharma- ceutically acceptable glidant; and (g) optionally, from about 0% to about 2.0% by weight of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100%.

[0402] In some embodiments, the dosage form is: (a) about 0.3% to about 0.8% by weight of atrasentan, or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) about 0.09% to about 0.50% by weight of L-cysteine, or a pharma- ceutically acceptable salt or ester thereof; (c) about 87% to about 99% by weight of a pharma- ceutically acceptable diluent; (d) about 1.0% to about 5.0% by weight of a pharma- ceutically acceptable binder; (e) about 1.0% to about 4.0% by weight of a pharma- ceutically acceptable disintegrant; (f) optionally, from about 0% to about 0.75% by weight of a pharma- ceutically acceptable glidant; and (g) optionally, from about 0% to about 2.0% by weight of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100%.

[0403] In some embodiments, the dosage form is: (a) about 0.1% to about 2.0% by weight of atrasentan, or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) about 75% to about 99% by weight of a diluent; (c) about 1.0% to about 10.0% by weight of a pharma- ceutically acceptable binder; (d) optionally, about 1.0% to about 10.0% by weight of a pharma- ceutically acceptable disintegrant; (e) optionally, from about 0% to about 1.5% by weight of a pharma- ceutically acceptable glidant; and (f) optionally, from about 0% to about 5.0% by weight of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100%.

[0404] In some embodiments, the dosage form is: (a) about 0.1% to about 2.0% by weight of atrasentan, or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) about 75% to about 99% by weight of a diluent; (c) about 1.0% to about 10.0% by weight of a pharma- ceutically acceptable binder; (d) about 1.0% to about 10.0% by weight of a pharma- ceutically acceptable disintegrant; (e) optionally, from about 0% to about 1.5% by weight of a pharma- ceutically acceptable glidant; and (f) optionally, from about 0% to about 5.0% by weight of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100%.

[0405] In some embodiments, the dosage form is: (a) about 0.2% to about 1.0% by weight of atrasentan, or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) about 82% to about 99% by weight of a diluent; (c) about 1.0% to about 8.0% by weight of a pharma- ceutically acceptable binder; (d) optionally, about 1.0% to about 6.0% by weight of a pharma- ceutically acceptable disintegrant; (e) optionally, from about 0% to about 1.0% by weight of a pharma- ceutically acceptable glidant; and (f) optionally, from about 0% to about 3.0% by weight of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100%.

[0406] In some embodiments, the dosage form is: (a) about 0.2% to about 1.0% by weight of atrasentan, or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) about 82% to about 99% by weight of a diluent; (c) about 1.0% to about 8.0% by weight of a pharma- ceutically acceptable binder; (d) about 1.0% to about 6.0% by weight of a pharma- ceutically acceptable disintegrant; (e) optionally, from about 0% to about 1.0% by weight of a pharma- ceutically acceptable glidant; and (f) optionally, from about 0% to about 3.0% by weight of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100%.

[0407] In some embodiments, the dosage form further comprises: (a) about 0.3% to about 0.8% by weight of atrasentan, or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) about 87% to about 99% by weight of a pharma- ceutically acceptable diluent; (c) about 1.0% to about 5.0% by weight of a pharma- ceutically acceptable binder; (d) optionally, about 1.0% to about 4.0% by weight of a pharma- ceutically acceptable disintegrant; (e) optionally, from about 0% to about 0.75% by weight of a pharma- ceutically acceptable glidant; and (f) optionally, from about 0% to about 2.0% by weight of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100%.

[0408] In some embodiments, the dosage form is: (a) about 0.3% to about 0.8% by weight of atrasentan, or a pharma- ceutically acceptable salt thereof, on an atrasentan free base equivalent basis; (b) about 87% to about 99% by weight of a pharma- ceutically acceptable diluent; (c) about 1.0% to about 5.0% by weight of a pharma- ceutically acceptable binder; (d) about 1.0% to about 4.0% by weight of a pharma- ceutically acceptable disintegrant; (e) optionally, from about 0% to about 0.75% by weight of a pharma- ceutically acceptable glidant; and (f) optionally, from about 0% to about 2.0% by weight of a pharma- ceutically acceptable lubricant; The cumulative weight percentages of all components of a dosage form equal 100%.

[0409] In some embodiments, the dosage form meets one or more of the following conditions: (a) the diluent is lactose; (b) the dosage form comprises a pharma- ceutically acceptable binder, the binder being hydroxypropyl methylcellulose; (c) the dosage form comprises a pharma- ceutically acceptable disintegrant, wherein the disintegrant is crospovidone; (d) the dosage form comprises a pharma- ceutically acceptable glidant, wherein the glidant is silicon dioxide; (e) the dosage form comprises a pharma- ceutically acceptable lubricant, the lubricant being glyceryl behenate.

[0410] In some embodiments, the dosage form is a solid pharmaceutical dosage form comprising about 0.25 mg to about 1.25 mg of atrasentan or a pharma- ceutically acceptable salt thereof (e.g., atrasentan hydrochloride) based on the atrasentan parent equivalent. In some embodiments, the pharmaceutical composition comprises about 0.40 mg to about 1.00 mg of atrasentan or a pharma- ceutically acceptable salt thereof (e.g., atrasentan hydrochloride) based on the atrasentan parent equivalent. In some embodiments, the pharmaceutical composition comprises about 0.40 mg to about 0.85 mg of atrasentan or a pharma- ceutically acceptable salt thereof (e.g., atrasentan hydrochloride) based on the atrasentan parent equivalent. In some embodiments, the pharmaceutical composition comprises about 0.50 mg of atrasentan or a pharma- ceutically acceptable salt thereof (e.g., atrasentan hydrochloride) based on the atrasentan parent equivalent. In some embodiments, the pharmaceutical composition comprises about 0.75 mg of atrasentan or a pharma- ceutically acceptable salt thereof (e.g., atrasentan hydrochloride) based on the atrasentan parent equivalent. In some embodiments, the dosage form is a solid pharmaceutical dosage form comprising about 1.25 mg to about 1.75 mg of atrasentan or a pharma- ceutically acceptable salt thereof (e.g., atrasentan hydrochloride) based on the atrasentan parent equivalent. In some embodiments, the pharmaceutical composition comprises about 1.5 mg of atrasentan or a pharma- ceutically acceptable salt thereof (e.g., atrasentan hydrochloride) based on the atrasentan parent equivalent. In certain of the foregoing embodiments, the dosage form is a tablet.

[0411] In some embodiments, the dosage form is a tablet. In some embodiments, the tablet has a weight of about 37.5 mg to about 1500 mg. In some embodiments, the tablet has a weight of about 50 mg to about 750 mg. In some embodiments, the tablet has a weight of about 50 mg to about 250 mg. In some embodiments, the tablet has a weight of about 75 mg to about 500 mg. In some embodiments, the tablet has a weight of about 75 mg to about 150 mg. In some embodiments, the tablet has a weight of about 100 mg to about 250 mg. In some embodiments, the tablet has a weight of about 100 mg to about 230 mg. In some embodiments, the tablet has a moisture content of less than about 10%. In certain embodiments, the tablet has a moisture content of about 4% to 6% (e.g., about 4% to 5%).

[0412] Generally, the tablet may be optionally surrounded or coated with at least one non-rate controlling layer. The non-rate controlling layer may be formed as a single layer, coating or film, or multiple single layers, coatings or films. The function of the non-rate controlling layer may include, for example, providing additional stability of atrasentan, acting as a processing aid and / or cosmetic enhancer for the formulation, and / or acting as a masking agent to reduce any undesirable odor associated with the formulation (such as the odor commonly associated with L-cysteine).

[0413] If the dosage form includes a non-rate controlling layer, the non-rate controlling layer can be made of one or more polymers and other components known in the art, such as, but not limited to, plasticizers, pigments / opacifiers, waxes, etc. Examples of polymers that can be used include, but are not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, and polyethylene glycol. Examples of plasticizers that can be used include, but are not limited to, polyethylene glycol, glycerin, triacetin, triethyl citrate, diethyl phthalate, L-cysteine, and mineral oil. Examples of pigments / opacifiers that can be used include, but are not limited to, water-soluble dyes (e.g., sunset yellow, quinoline yellow, erythrosine, and tartrazine), pigments (e.g., aluminum lake, titanium oxide, iron oxide, and talc), and natural products (e.g., riboflavin, carotenoids, chlorophyll, anthocyanins, and carmine). Examples of waxes that can be used include, but are not limited to, paraffin wax.

[0414] In some embodiments, the dosage form is a tablet coated with a pharma- ceutically acceptable polymer.

[0415] In some embodiments, the dosage form is a capsule.

[0416] In some embodiments, the formulation is packaged in a semi-permeable container. In some embodiments, the semi-permeable container is a blister.

[0417] In some embodiments, the formulation is packaged in a substantially impermeable container.

[0418] In some embodiments, the dosage form is an immediate release dosage form. In some embodiments, the dosage form is an immediate release tablet and releases at least about 85% of the atrasentan or pharma- ceutically acceptable salt thereof within about 45 minutes as determined in an in vitro dissolution test performed using a USP Paddle Apparatus 2, 0.01 N hydrochloric acid dissolution medium, and a paddle rotation of 50 RPM. In some embodiments, the dosage form is an immediate release tablet and releases at least about 75% of the atrasentan or pharma- ceutically acceptable salt thereof within about 30 minutes.

[0419] In some embodiments, the dosage form contains less than about 1.0 weight percent total impurities resulting from decomposition of atrasentan or a pharma- ceutically acceptable salt thereof after a storage period of six months at about 40° C. and about 75% relative humidity. In some embodiments, the decomposition of atrasentan, or a pharma- ceutically acceptable salt thereof, is analyzed using high performance liquid chromatography.

[0420] In some embodiments, the dosage form contains less than about 0.6 percent by weight of any single impurity resulting from decomposition of atrasentan or a pharma- ceutically acceptable salt thereof after a storage period of six months at about 40° C. and about 75% relative humidity. In some embodiments, the decomposition of atrasentan, or a pharma- ceutically acceptable salt thereof, is analyzed using high performance liquid chromatography.

[0421] In some embodiments, the dosage form contains less than about 1.0 percent by weight total impurities and less than about 0.6 percent by weight of any single impurity resulting from degradation of atrasentan or a pharma- ceutically acceptable salt thereof after a storage period of six months at about 40° C. and about 75% relative humidity. In some embodiments, the degradation of atrasentan, or a pharma- ceutically acceptable salt thereof, is analyzed using high performance liquid chromatography.

[0422] In certain embodiments, the dosage form is selected from the group consisting of:

[0423] [Table 1]

[0424] [Table 2]

[0425] [Table 3]

[0426] In certain embodiments, the dosage form is selected from th...

Claims

1. (i) For treating focal segmental glomerulosclerosis (FSGS) in a subject having FSGS, (ii) To reduce nephritis and / or fibrosis in subjects with FSGS, (iii) To reduce the rate of decline in estimated glomerular filtration rate (eGFR) in subjects with FSGS, (iv) To delay the onset of end-stage renal disease (ESKD) in subjects with FSGS, (v) To reduce proteinuria in subjects with FSGS, (vi) for reducing fatigue in subjects having FSGS, and / or (vii) To stabilize the functional podocyte mass in subjects with FSGS, A composition comprising a therapeutically effective amount of atrasentan, or a pharmaceutically acceptable salt thereof.

2. The composition for use according to claim 1, wherein the nephritis and / or fibrosis comprises tubulointerstitial inflammation, tubulointerstitial fibrosis, glomerular inflammation, and / or glomerulosclerosis.

3. The composition for use according to claim 1, wherein the FSGS comprises nephrotic syndrome selected from proteinuria, hypoalbuminemia, hypercholesterolemia, peripheral edema, or any combination thereof.

4. The composition for use according to claim 1, wherein the FSGS is a perihilosopharyngeal FSGS, a glomerular apex FSGS, a cell-type FSGS, a collapsed FSGS, a primary FSGS, a non-specific FSGS (NOS), a virus-related FSGS, not an HIV-related FSGS, a toxin-related FSGS, or an adaptive FSGS.

5. The composition for use according to claim 1, further comprising administering to the subject one or more additional agents selected from calcineurin inhibitors, immunosuppressants, proteasome inhibitors, aminoquinolines, complement inhibitors, B cell inhibitors, cytotoxic agents, mTOR inhibitors, steroids, hydroxychloroquine, and combinations thereof.

6. The calcineurin inhibitor is cyclosporine. The immunosuppressant is mycophenolate mofetil (MMF), cyclophosphamide, or chlorambucil, and The composition for use according to claim 5, wherein the steroid is selected from the group consisting of prednisone, dexamethasone, hydrocortisone, cyclosporine, and adrenocorticotropic hormone (ACTH).

7. The composition for use according to claim 1, wherein the one or more additional agents are administered in a stable dose for at least 12 weeks prior to the administration of a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof.

8. The composition for use according to claim 5, wherein the dose of the one or more additional agents decreases after about 15 to about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof, typically by about 25% to about 100%, about 50% to about 100%, or about 75% to about 100%.

9. The composition for use according to claim 1, wherein the subject is simultaneously receiving an ACE inhibitor, an ARB, a statin, a diuretic, a calcium channel blocker, a beta-blocker, an aldosterone antagonist, fish oil, hydroxychloroquine, or any combination thereof.

10. The composition for use according to claim 1, wherein the subject is simultaneously receiving an ACE inhibitor, an ARB, or a combination thereof.

11. The statin is selected from atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin. The diuretic is selected from hydrochlorothiazide, trichlormethiazide, hydroflumethiazide, quinetazone, metrazone, chlorothiazide, chlorthalidone, indapamide, meticlothiazide bumetanide, torsemide, pyretanide, ethacrine, bumetanide, furosemide, triamterene, spironolactone, eplerenone, and amiloride. The ACE inhibitor is selected from quinapril, hosinopril, perindopril, captopril, enalapril, enalaprilat, ramipril, cilazapril, delapril, hosinopril, zofenopril, indolapril, benazepril, lisinopril, spirapril, trandolapril, perindep, pentopril, moexipril, resinamin, and pivopril, and The ARB is selected from candesartan, candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan, olmesartan medoxomil, telmisartan, valsartan, azilsartan medoxomil, and BRA-657. A composition for use according to claim 9.

12. The composition for use according to claim 1, wherein atrasentan is administered as a pharmaceutically acceptable salt, for example, atrasentan hydrochloride.

13. The composition for use according to claim 1, wherein the subject has a high risk of progressing to ESKD.

14. The composition for use according to claim 1, wherein the subject is diagnosed with FSGS, typically confirmed by biopsy.

15. The composition for use according to claim 14, wherein the diagnosis of FSGS comprises a kidney biopsy, a genetic test for mutations in podocyte proteins associated with FSGS, or any combination thereof.

16. (i) The subject excretes an average of about 1.0 g / g to about 3.5 g / g or more, or about 3.5 g / g to about 10 g / g of protein per day in the urine for at least about three months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. (ii) The subject was given approximately 20 to approximately 120 mL / min / 1.73 m³ for at least approximately 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. ２ Having an average eGFR of approximately 20 to approximately 90 mL / min / 1.73 m², or approximately 20 to approximately 60 mL / min / 1.73 m², (iii) The subject has a urinary protein-to-creatinine ratio (UPCR) of more than 1.5 g / g to about 11 g / g for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. (iv) The subject has an average HbA1c of about 4% to about 6% for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, and / or (v) The subject has an average fasting blood glucose level of approximately 125 mg / dL or less for at least approximately three months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. A composition for use according to claim 1.

17. (i) The subject maintains potassium levels within a normal physiological range. (ii) The subject maintains sodium levels within a normal physiological range. (iii) The subject has an alanine transaminase / aspartate transaminase (ALT / AST) level that is approximately the same as the ALT / AST level prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, and / or (iv) The subject has a bilirubin level during administration of atrasentan or a pharmaceutically acceptable salt thereof that is approximately the same as the bilirubin level before the first administration of atrasentan or a pharmaceutically acceptable salt thereof. A composition for use according to claim 1.

18. The composition for use according to claim 1, wherein the fluid retention in the subject can be controlled with a diuretic.

19. The amount of protein in the urine of the subject is (i) After approximately 10 weeks of treatment with atrasentan or a pharmaceutically acceptable salt thereof, the levels decrease by approximately 20% to approximately 80%. (ii) After approximately 12 weeks of treatment with atrasentan or a pharmaceutically acceptable salt thereof, the levels decrease by approximately 20% to approximately 80%, or (iii) After treatment with atrasentan or a pharmaceutically acceptable salt thereof for approximately 12 to 24 weeks, the levels decrease by approximately 20% to 80%, or approximately 35% to 80%. A composition for use according to claim 1.

20. The aforementioned UPCR (i) After approximately 10 weeks of treatment with atrasentan or a pharmaceutically acceptable salt thereof, the level decreases to less than approximately 1.5 g / g. (ii) After approximately 12 weeks of treatment with atrasentan or a pharmaceutically acceptable salt thereof, the level decreases to less than approximately 1.5 g / g, or (iii) After approximately 12 to 24 weeks of treatment with atrasentan or a pharmaceutically acceptable salt thereof, the level decreases to less than approximately 1.5 g / g. A composition for use according to claim 1.

21. The risk of developing ESKD in the aforementioned subject is (i) After treatment with atrasentan or a pharmaceutically acceptable salt thereof for approximately 6 to 24 months, the level decreases by approximately 20% to 99%, or (ii) After treatment with atrasentan or a pharmaceutically acceptable salt thereof for approximately 12 to 60 months, the levels decrease by approximately 20% to 99%. A composition for use according to claim 1.

22. The composition for use according to claim 1, wherein the average rate of decrease of eGFR is about 0.75 mL / min / year to about 75 mL / min / year, about 3 mL / min / year to about 6 mL / min / year, or about 4 mL / min / year to about 5 mL / min / year for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

23. The composition for use according to claim 1, wherein the average rate of reduction of the eGFR is reduced by about 15% to about 70% after treatment with atrasentan or a pharmaceutically acceptable salt thereof for about 6 to about 24 months.

24. The composition for use according to claim 1, wherein the therapeutically effective amount of atrasentan, or a pharmaceutically acceptable salt thereof, is about 0.75 mg to about 1.5 mg, about 1.0 mg to about 1.5 mg, about 1.25 mg to about 1.5 mg, about 0.75 mg, or about 1.5 mg of atrasentan, or an equivalent amount of a pharmaceutically acceptable salt thereof.

25. The composition for use according to claim 1, further comprising administering a therapeutically effective amount of a sodium glucose cotransporter 2 (SGLT-2) inhibitor.

26. The composition for use according to claim 25, wherein the SGLT-2 inhibitor is selected from bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, erzgliflozin, ipragliflozin, luseogliflozin, remogliflozin, cergliflozin, licogliflozin, sotagliflozin, and tofogliflozin.

27. ​​(i) The subject has been determined to have at least 1 g / day of proteinuria in at least two of three consecutive readings over a year prior to administration of a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof, and / or (ii) The subject has been given at least 30 mL / min / 1.73 m³ of atrasentan or a pharmaceutically acceptable salt thereof prior to administration of a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof. ２ It has been determined that it has eGFR. A composition for use according to claim 1.

28. (i) The subject has been administered a maximum tolerable stable dose of a RAS inhibitor for at least 12 weeks prior to the administration of a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof, and / or (ii) The subject is administered simultaneously with the maximum tolerable stable dose of a RAS inhibitor and a therapeutically effective dose of atrasentan or a pharmaceutically acceptable salt thereof. A composition for use according to claim 1.

29. The composition for use according to claim 1, wherein the FSGS comprises non-nephrotic range proteinuria of less than 3.5 grams of the urinary protein per day for at least about three months prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

30. The composition for use according to claim 1, wherein the FSGS is located in a gene that typically encodes a podocyte protein associated with an FSGS, which is associated with one or more gene mutations.

31. The aforementioned gene mutations affect NPHS1, NPHS2, CD2AP, TRPC6, ACTN4, INF2, MYO1E, ARHGAP24, ARHGDIA, PLCE1, PTPRO, WT1, LXMB1, and tRNA. ｌｅｕ The composition for use according to claim 30, which is selected from one or more mutations in genes selected from the group consisting of COQ2, COQ6, ITGB4, PDSS2, CD151, CUBN, LAMB2, APOL1, LMX1B, PAX2, ANLN, CRB2, and any combination thereof.

32. The composition for use according to claim 1, wherein the subject has been administered a prior treatment for FSGS and has not responded to the prior treatment, and the prior treatment is a standard treatment for FSGS selected from Actor, Spalsentan, Rituximab with plasma exchange therapy, Volcosporine, 10-nitro-9(E)-octadeca-9-enoic acid (CXA-10), PF-06730512, 4-chloro-N-[5-methyl-2-[7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl]-3-pyridyl]-3-(trifluoromethyl)benzenesulfonamide (CCX140-B), Abatacept, Bardoxolone, or any combination thereof.

33. (i) The subject has not been treated with a sodium glucose cotransporter 2 (SGLT2) inhibitor, (ii) The subject has not been treated with antiretroviral therapy, or has not been treated with antiretroviral therapy. (iii) The subject has not been previously diagnosed with one or more of the following conditions: diabetic nephropathy, IgA nephropathy, sickle cell nephropathy, HIV / AIDS, or acute renal failure. (iv) The subject has not been previously diagnosed with HIV-related nephropathy, (v) The subject has not been previously diagnosed with HIV, (vi) The subject has not been diagnosed with HIV at present. (vii) The subject is currently not being treated for HIV, (viiii) The subject has not been previously diagnosed with renovascular hypertension, and / or (ix) The subject is currently not being treated for renovascular hypertension. A composition for use according to claim 1.

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