Methods of treating focal segmental glomerulosclerosis with atrasentan

Abstract

Provided herein are methods of treating focal segmental glomerular sclerosis (FSGS) comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. Also provided herein are methods of reducing renal inflammation and / or fibrosis, reducing the rate of decrease in eGFR, delaying the onset of ESKD, reducing proteinuria, and reducing fatigue in a subject suffering from FSGS, comprising administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 343,574, filed on May 19, 2022, the disclosure of which is incorporated herein by reference in its entirety. Background Art

[0003] Focal segmental glomerulosclerosis (FSGS) is a glomerular disease characterized by proteinuria, frequent progression to end-stage kidney disease (ESKD), and relapse after kidney transplantation in approximately 25% of patients, which negatively affects long-term allograft survival (Cravedi, 2013). It is a heterogeneous disorder caused by podocyte injury and exhaustion due to a variety of precipitating causes. Primary (idiopathic) FSGS is the most common form of the disease and is thought to be caused by unknown circulating factors. Secondary FSGS includes virus-related or drug-induced FSGS. The maladaptive form of secondary FSGS is caused by an adaptive structural-functional response to the overload of a single nephron (Rosenberg, 2017). FSGS may also be caused by mutations in a variety of genes that encode proteins that are primarily expressed in podocytes and their slit diaphragms. Genetic causes of FSGS may present as a sporadic or familial disease with autosomal dominant, autosomal recessive, X-linked, or mitochondrial inheritance patterns (Rood, 2012; Jefferson, 2014; Dummer, 2015; De Vriese, 2018). Apolipoprotein L1 (APOL1) genetic variants increase the risk of ESKD in patients with FSGS of African ancestry (Dummer, 2015). The annual incidence of FSGS is 0.2 to 1.8 per 100,000 person-years (McGrogan, 2011). Conservative management of FSGS includes blood pressure control, particularly with RAS inhibitors, and dietary sodium restriction. Additional 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 immunosuppressive drugs that may also have direct effects on podocytes, including prednisone, calcineurin inhibitors, cyclophosphamide, and mycophenolate mofetil plus high-dose dexamethasone (Korbet, 2012; Rosenberg, 2017).

[0004] There are no approved therapies for FSGS, and there are no established safe and effective treatment options for patients who fail conservative management with agents that block the renin angiotensin-aldosterone axis. Therefore, the development of therapies for FSGS patients who remain at risk for developing progressive renal failure is a significant unmet medical need. Summary of the invention

[0005] Atrasentan is a selective endothelin A (ETA) receptor antagonist (ETA Ki -34 pM; ETB Ki -63 nM, ETA selectivity -1800x). See, e.g., Wu-Wong et al., Clin. Sci. [Clinical Science] (London), 103(48), pp. 107s-111s (2002). Selective ETA receptor antagonists block ETA function while minimally affecting ETB receptors, providing beneficial renal effects including vasodilation and reduced inflammation while still enabling ET-1 clearance. See, e.g., Jandeleit-Dahm and Watson, Curr. Opin. Nephrol. Hypertens. [Current Opinion in Nephrology and Hypertension], 21(1), pp. 66-71 (2012); see also, Nakamura, et al., Nephron [Kidney], Vol. 72, pp. 454-460 (1996). Although ETA receptor antagonists increase renal sodium and water retention, this is typically manageable clinically. See, e.g., Saleh, et al., J. Pharm. Exp. Ther., 338(1), pp. 263-270 (2011).

[0006] Atrasentan has been extensively studied as a once-daily therapy for the treatment of diabetic kidney disease (DKD) in individuals with type 2 diabetes as an addition to optimized doses of renin-angiotensin system (RAS) inhibitors. ETA activation is associated with the progression of many renal diseases, as measured by proteinuria, renal inflammation or fibrosis. (Dhaun, 2012; Vignon-Zellweger, 2012).

[0007] Atrasentan has been shown to be effective for patients with diabetic nephropathy, significantly reducing the risk of renal events defined as doubling of serum creatinine or end-stage renal disease. See, for example, Heerspink, et al., The Lancet [Lancet], 393, pp. 1937-1947 (2019). DKD is considered to be a secondary glomerular disease, in which kidney disease is secondary to established systemic causes, and in the case of DKD, it is a microvascular complication of long-term diabetes. See, for example, Dattani and McAdoo, Medicine [Medicine], 47 (10), pp. 644-648 (2019). The pathogenesis of DKD is multifactorial and complex. Chronically elevated blood glucose levels due to glucose toxicity to renal cells (especially renal endothelial cells) caused by diabetes, and systemic and renal hemodynamic factors associated with hypertension that cause shear stress to be transmitted to resident glomerular cells are key pathogenic drivers of DKD. See, e.g., Thomas et al., Nat. Rev. Disease Primers 1, pp. 15018-15026 (2015). Various factors that are dysregulated in the diabetic environment, including metabolic components (e.g., hyperglycemia, dyslipidemia, and oxidative stress), and hemodynamic factors (e.g., vasoactive substances associated with hypertension) stimulate renal ET-1 formation. In addition, DKD is typically observed in the elderly population due to the need for long-term diabetes before DKD manifestation, 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). In short, this provides a reasonable scientific basis for the ETA receptor blocker atrasentan to treat DKD. See Dhaun, et al., Hypertension, Vol. 57, pp. 772-779 (2011).

[0008] Some embodiments provide a method of treating focal segmental glomerulosclerosis (FSGS) in a subject having FSGS, the method comprising administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0009] Some embodiments provide a method of reducing renal inflammation and / or fibrosis in a subject having FSGS, the method comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0010] Some embodiments provide a method of reducing the rate of decline of estimated glomerular filtration rate (eGFR) in a subject with FSGS, the method comprising administering to the subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0011] Some embodiments provide a method of delaying the onset of ESKD in a subject with FSGS, the method comprising administering to the subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0012] Some embodiments provide a method of reducing proteinuria in a subject having FSGS, the method comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0013] Some embodiments provide a method of reducing fatigue in a subject having FSGS, the method comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0014] Some embodiments provide a method of stabilizing functional podocyte mass in a subject having FSGS, the method comprising administering to the subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0015] Some embodiments provide a method of stabilizing or reducing renal inflammation and / or fibrosis. In some cases, renal inflammation and / or fibrosis is tubulointerstitial inflammation. Some embodiments provide that renal inflammation and / or fibrosis is tubulointerstitial fibrosis. Some embodiments provide that renal inflammation and / or fibrosis include glomerular inflammation and / or glomerulosclerosis. Some embodiments provide that renal inflammation and / or fibrosis include one or more of tubulointerstitial inflammation, tubulointerstitial fibrosis, glomerular inflammation, or glomerulosclerosis.

[0016] Some embodiments provide that the subject has biopsy-proven FSGS. Some embodiments provide that the subject has been diagnosed with biopsy-proven 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.

[0017] Some embodiments provide that FSGS comprises nephrotic syndrome. Some embodiments provide that nephrotic syndrome is selected from proteinuria, hypoalbuminemia, hypercholesterolemia, peripheral edema, or any combination of the foregoing.

[0018] Some embodiments provide that FSGS is perihilar FSGS. Some embodiments provide that FSGS is tip lesion FSGS. Some embodiments provide that FSGS is cellular FSGS. Some embodiments provide that FSGS is collapsing FSGS. Some embodiments provide that FSGS is primary FSGS. Some embodiments provide that FSGS is FSGS of unknown classification (NOS).

[0019] Some embodiments provide that FSGS is virus-related FSGS. Some embodiments provide that virus-related FSGS is non-HIV-related FSGS. Some embodiments provide that FSGS is toxin-related FSGS. Some embodiments provide that FSGS is adaptive FSGS.

[0020] Some embodiments provide that the subject is also administering one or more additional agents. Some embodiments provide that 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. Some embodiments provide that one or more additional agents include calcineurin inhibitors. Some embodiments provide that the calcineurin inhibitor is cyclosporine. Some embodiments provide that one or more additional agents include immunosuppressants. Some embodiments provide that the immunosuppressant is mycophenolate mofetil (MMF), cyclophosphamide, or chlorambucil. Some embodiments provide that one or more additional agents include steroids. Some embodiments provide that steroids are selected from the group consisting of: prednisone, dexamethasone, hydrocortisone, cyclosporine, adrenocorticotropic hormone (ACTH), and any combination of the foregoing. Some embodiments provide that one or more additional agents include aminoquinolines. Some embodiments provide that one or more additional agents are hydroxychloroquine. Some embodiments provide that the subject is not currently receiving one or more immunosuppressants.

[0021] Some embodiments provide for administering one or more additional agents at a dose that was stable for at least 12 weeks prior to administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. Some embodiments provide for a dose of one or more additional agents to be reduced after about 15 days to about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0022] Some embodiments provide a dose reduction of about 25% to about 100% (to 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%) of one or more additional agents. Some embodiments provide a dose reduction of about 50% to about 100% of one or more additional agents. Some embodiments provide a dose reduction of about 75% to about 100% of one or more additional agents.

[0023] 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.

[0024] Some embodiments provide that the subject is also receiving an ACE inhibitor, an ARB, or a combination thereof. Some embodiments provide that statins are selected from: atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin. Some embodiments provide that diuretics are selected from: hydrochlorothiazide, trichlorothiazide, hydroflumethiazide, quinethazone, metolazone, chlorothiazide, chlorthalidone, indapamide, methylchlorothiazide, bumetanide, torsemide, piretanide, ethacrynic acid, bumetanide, furosemide, triamterene, spironolactone, eplerenone, and amiloride. Some embodiments provide an ACE inhibitor selected from the group consisting of quinapril, fosinopril, perindopril, captopril, enalapril, enalaprilat, ramipril, cilazapril, delapril, fosinopril, zofenopril, indolapril, benazepril, lisinopril, spirapril, trandolapril, perindep, pentoprol, moexipril, rispermine and pivopril. Some embodiments provide an ARB selected from the group consisting of candesartan, candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan, olmesartan medoxomil, telmisartan, valsartan, azilsartan medoxomil and BRA-657.

[0025] Some embodiments provide for atrasentan to be administered as a pharmaceutically acceptable salt. Some embodiments provide for atrasentan to be administered as atrasentan hydrochloride or atrasentan mandelate. Some embodiments provide for atrasentan to be administered as atrasentan hydrochloride. Some embodiments provide for atrasentan to be administered as a free base.

[0026] Some embodiments provide that the subject is at high risk for progression to end-stage renal 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 mutations in podocyte proteins associated with FSGS, or a combination of any of the foregoing. Some embodiments provide that the diagnosis of FSGS comprises examining a kidney biopsy.

[0027] Some embodiments provide that at least about 3 months before the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject excretes an average of about 0.75 g / g or more protein in the urine per day. Some embodiments provide that at least about 3 months before the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject excretes an average of about 1.5 g / g or more protein in the urine per day. Some embodiments provide that at least about 3 months before the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject excretes an average of about 3.5 g / g or more protein in the urine per day. Some embodiments provide that at least about 3 months before the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject excretes an average of about 3.5 g / g to about 10 g / g protein in the urine per day.

[0028] Some embodiments provide that for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject excretes an average of about 0.75 grams to about 1.5 grams of protein per day in the urine.

[0029] Some embodiments provide that for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject excretes an average of about 1 gram or more of protein per day in the urine.

[0030] Some embodiments provide that at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject's average eGFR is about 20 to about 120 mL / min / 1.73 m 2 .

[0031] Some embodiments provide that at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject's average eGFR is about 30 to about 90 mL / min / 1.73 m 2 .

[0032] Some embodiments provide that at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the average eGFR of the subject is about 20 to about 60 mL / min / 1.73 m 2 .

[0033] Some embodiments provide that at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject's urine protein to creatinine ratio (UPCR) is 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).

[0034] Some embodiments provide that at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject's average HbA1c is about 4% to about 6%.

[0035] Some embodiments provide that for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject's average fasting blood glucose level is about 125 mg / dL or less.

[0036] Some embodiments provide that potassium levels in a subject are maintained within a normal physiological range.

[0037] Some embodiments provide that a subject's sodium levels are maintained within a normal physiological range.

[0038] Some embodiments provide that the alanine aminotransferase / aspartate aminotransferase (ALT / AST) level of a subject during administration of atrasentan or a pharmaceutically acceptable salt thereof is about the same as the ALT / AST level before the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0039] Some embodiments provide that the bilirubin level of a subject during administration of atrasentan or a pharmaceutically acceptable salt thereof is about the same as the bilirubin level before the first administration of atrasentan or a pharmaceutically acceptable salt thereof. Thus, in some embodiments, bilirubin levels can be used to assess liver function or the effects of administering one or more agents as described herein.

[0040] Some embodiments provide that fluid retention in a subject can be managed with a diuretic.

[0041] Some embodiments provide that the amount of protein in the subject's urine is reduced by about 20% to about 80% after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically 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 4 weeks to about 10 weeks of treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0043] Some embodiments provide that after about 10 weeks of treatment with atrasentan or a pharmaceutically acceptable salt thereof, the amount of protein in the subject's urine is reduced by about 20% to about 80%. Some embodiments provide that after about 12 weeks of treatment with atrasentan or a pharmaceutically acceptable salt thereof, the amount of protein in the subject's urine is reduced by about 20% to about 80%. Some embodiments provide that after about 12 weeks to about 24 weeks of treatment with atrasentan or a pharmaceutically acceptable salt thereof, the amount of protein in the subject's urine is reduced by about 20% to about 80%.

[0044] 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%).

[0045] Some embodiments provide that the amount of protein in the subject's urine is reduced by about 100 mg / dL to about 900 mg / dL after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0046] Some embodiments provide that protein in the subject's urine is reduced by about 100 mg / dL to about 500 mg / dL after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0047] Some embodiments provide that after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof, the amount of protein in the subject's urine is reduced by about 500 mg / dL to about 900 mg / dL.

[0048] Some embodiments provide that after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof, the subject's UPCR is reduced to less than about 1.5 g / g to about 11 g / g. Some embodiments provide that after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof, 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. Some embodiments provide that after about 12 weeks to about 24 weeks of treatment with atrasentan or a pharmaceutically acceptable salt thereof, the subject's UPCR is reduced to less than about 1.5 g / g to about 11 g / g. Some embodiments provide that after about 12 weeks to about 24 weeks of treatment with atrasentan or a pharmaceutically acceptable salt thereof, 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.

[0049] Some embodiments provide that after between about 6 months and about 24 months of treatment with atrasentan or a pharmaceutically acceptable salt thereof, the risk of a subject developing ESKD is reduced by about 20% to about 99%.

[0050] Some embodiments provide that after between about 12 months and 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 pharmaceutically acceptable salt thereof, the risk of a subject developing ESKD is reduced by about 20% to about 99%.

[0051] Some embodiments provide that for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the average rate of decline in eGFR is about 0.75 mL / min / year to about 75 mL / min / year.

[0052] Some embodiments provide that for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the average rate of decline in eGFR is about 3 mL / min / year to about 6 mL / min / year.

[0053] Some embodiments provide that for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the average rate of decline in eGFR is about 4 mL / min / year to about 5 mL / min / year.

[0054] Some embodiments provide that the mean rate of decline in eGFR is reduced by about 15% to about 70% after between about 6 months and about 24 months of treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0055] Some embodiments provide that the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof is from about 0.20 mg to about 1.5 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0056] Some embodiments provide that the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof is from about 0.25 mg to about 1.25 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0057] Some embodiments provide that the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof is from about 0.40 mg to about 0.85 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0058] Some embodiments provide that the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof is about 0.75 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0059] Some embodiments provide that the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof is from about 0.75 mg to about 1.5 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0060] Some embodiments provide that the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof is from about 0.80 mg to about 1.5 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0061] Some embodiments provide that the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof is from about 1.0 mg to about 1.5 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0062] Some embodiments provide that the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof is from about 1.25 mg to about 1.5 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0063] Some embodiments provide that the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof is about 1.5 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0064] 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 bepagliflozin, canagliflozin, dapagliflozin, empagliflozin, erpagliflozin, ipagliptin, rupagliflozin, repagliflozin, sergliflozin, lipagliflozin, soglipflozin and togliflozin.

[0065] Some embodiments provide that the SGLT-2 inhibitor is canagliflozin, dapagliflozin, empagliflozin, or erpagliflozin.

[0066] Some embodiments provide that the subject has been determined to have at least 1 g / day of proteinuria in at least two of three consecutive readings in the year prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0067] Some embodiments provide that the subject has been administered a maximum tolerated stable dose of a RAS inhibitor at least 12 weeks prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0068] Some embodiments provide for concurrently administering to a subject a maximum tolerated stable dose of a RAS inhibitor and a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0069] Some embodiments provide that prior to administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof, the subject has been determined to have a blood pressure of at least 30 mL / min / 1.73 m 2 eGFR.

[0070] 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 3 months prior to administration of the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0071] Some embodiments provide that FSGS is associated with one or more gene mutations. Some embodiments provide that the one or more gene mutations occur in genes encoding podocyte proteins associated with FSGS. Some embodiments provide that the one or more gene 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 gene mutations are in APOL1.

[0072] Some embodiments provide that the subject has been administered a prior therapy for FSGS and has not responded to the prior therapy.

[0073] Some embodiments provide that the prior therapy is a standard of care therapy for FSGS. Some embodiments provide that the prior therapy is selected from: axar, sparsentan, rituximab combined with plasmapheresis, volcosporin, 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-pyridinyl]-3-(trifluoromethyl)benzenesulfonamide (CCX140-B), abatacept, bardoxolone, or any combination of the foregoing.

[0074] Some embodiments provide that the subject has not been or is not being treated with a sodium-glucose co-transporter 2 (SGLT2) inhibitor.

[0075] Some embodiments provide that the subject has not been or is not being treated with antiretroviral therapy.Examples of antiretroviral therapy include, but are not limited to, protease inhibitors, reverse transcription inhibitors, integrase inhibitors, and combinations thereof, such as HAART (Highly Active Antiretroviral Therapy).

[0076] 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 known as diabetic kidney disease or "DKD"), IgA nephropathy, sickle cell nephropathy, HIV / AIDS, or acute renal failure.

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

[0078] Some embodiments provide that the subject has not been previously diagnosed with HIV.

[0079] Some embodiments provide that the subject is not currently diagnosed with HIV.

[0080] Some embodiments provide that the subject is not currently receiving treatment for HIV.

[0081] Some embodiments provide that the subject has not been previously diagnosed with renovascular hypertension.

[0082] Some embodiments provide that the subject is not currently receiving treatment for renovascular hypertension. BRIEF DESCRIPTION OF THE DRAWINGS

[0083] Figure 1 The overall study plan (all cohorts) for the Phase 2 study disclosed herein is presented.Abbreviations: DKD = diabetic kidney disease; FSGS = focal segmental glomerulosclerosis; IgAN = immunoglobulin A nephropathy; PK = pharmacokinetics; QD = once daily. a: Subjects in Cohort 2 (FSGS) may elect to dose escalate at or after Week 12. These subjects will move to Cohort 2b.

[0084] Figure 2 Dose escalation for Cohort 2 (2b) and Cohort 5 of the Phase 2 study disclosed herein is shown.

[0085] Figure 3 Baseline characteristics of FSGS patients included in the Phase 2 study disclosed herein are presented.

[0086] Figure 4 The urine protein to creatinine ratio (UPCR) measured at Weeks 0, 6, 12, and 24 of the Phase 2 study disclosed herein is shown.

[0087] Description of the table

[0088] Table 1: Objectives and endpoints for each cohort in the Phase 2 studies disclosed herein.

[0089] Table 2: Information on atrasentan used in the Phase 2 studies disclosed in this article.

[0090] Table 3: Protocol-Required Laboratory Assessments in the Phase 2 Studies Disclosed in This Article. DETAILED DESCRIPTION

[0091] I. Definitions

[0092] In order to more easily understand the present disclosure, first define certain terms. As used in this application, unless otherwise expressly provided herein, each of the following terms should have the meaning listed below. Additional definitions are listed throughout the application.

[0093] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present disclosure belongs. For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd edition, 2002, CRC Press; Dictionary of Cell and Molecular Biology, 3rd edition, 1999, Academic Press; and Oxford Dictionary of Biochemistry And Molecular Biology, Revised Edition, 2000, Oxford University Press provide general dictionary annotations of many terms used in the present disclosure for those of skill. For the purposes of the present disclosure, the following terms are defined.

[0094] Units, prefixes and symbols are expressed in the form accepted by their International System of Units (Système International de Unites) (SI). Numerical ranges include numbers that limit the range. The headings provided herein are not limitations of the various aspects of the disclosure, which can be obtained by reference to this specification as a whole. Therefore, the terms defined immediately below are more fully defined by reference to the specification in its entirety.

[0095] The terms "a," "an," or "the" include not only aspects having one member, but also aspects having more than one member. For example, 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, and reference to "an agent" includes reference to one or more agents known to those skilled in the art, and so forth.

[0096] As used herein, the term "or" should generally be interpreted non-exclusively. For example, a requirement for "a composition comprising A or B" will typically present aspects of a composition comprising both A and B. However, "or" should be interpreted to exclude those aspects presented that cannot be combined without contradiction (e.g., a composition pH between 9 and 10 or between 7 and 8).

[0097] The group "A or B" is typically equivalent to a group "selected from the group consisting of A and B".

[0098] The term "and / or" as used herein will be considered as a specific disclosure of each of two specified features or components with or without the other specified feature or component. Thus, the term "and / or" as used in phrases such as "A and / or B" in this article is intended to include "A and B", "A or B", "A" (alone), and "B" (alone). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to cover each of the following aspects: A, B, and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0099] As used herein, the terms "about" and "approximately" generally refer to an acceptable degree of error for a quantity measured given the nature or precision of the measurement. Typically, exemplary degrees of error are within 20%, within 10%, or within 5% of a given value or range of values. Any reference to "about X" specifically indicates 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 required limitation of, for example, "0.98X." The terms "about" and "approximately" specifically refer to a given amount, encompassing and describing the given amount itself.

[0100] When "about" is applied to the front 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 of a group of values, it applies to all values ​​in the group. Thus, "about 0.5, 0.75 or 1.0 mg" is equivalent to "about 0.5, about 0.75 or about 1.0 mg".

[0101] As used herein, when preceding a series of peak positions (e.g., 2θ values) of X-ray powder diffraction, the term "about" means that all peaks in the group thereafter are reported in angular positions with 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°.

[0102] "Treatment" or "therapy" of a subject refers to any type of intervention or procedure performed on a subject or administered to a subject with the goal of reversing, alleviating, ameliorating, inhibiting or slowing the onset, progression, development, severity or recurrence of symptoms, complications, signs or biochemical markers associated with a disease.

[0103] "Administering" or "administration" refers to the physical introduction of a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. Routes of administration can include oral, intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion (e.g., intravenous infusion). Administration can also be performed, for example, once, multiple times and / or over one or more extended periods of time.

[0104] The terms "preventative" or "preventively" refer to any type of intervention or process performed on a subject or administering an active agent to a subject with the goal of preventing or preventing the development or at least not fully developing a disease or condition (e.g., reducing the symptoms or severity of the disease or condition), such as in the development of side effects.

[0105] "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 (e.g., mice, rats, and guinea pigs). In some embodiments, the subject is a human. The terms "subject" and "patient" and "individual" are used interchangeably herein.

[0106] In some cases, subjects with FSGS have one or more gene mutations associated with FSGS. Gene mutations as described herein include deletions, insertions or substitutions of at least one amino acid compared to the wild-type protein (and, for example, resulting in the expression of FSGS); mutations in genes that result in the expression of proteins with one or more point mutations compared to the wild-type protein (and, for example, resulting in the expression of FSGS); mutations in genes that result in the expression of proteins with at least one deletion, insertion or substitution of at least one amino acid compared to the wild-type protein; gene duplications that result in increased protein levels in cells; or mutations in regulatory sequences (e.g., promoters and / or enhancers) that result in increased transcription or translation levels in cells; alternative splicing forms of mRNA molecules that result in proteins with at least one amino acid deletion compared to the wild-type form of the protein; or increased expression (e.g., increased levels) of the wild-type form in mammalian cells (and, for example, resulting in the expression of FSGS) due to, for example, abnormal cell signaling and / or dysregulated signaling (e.g., compared to control cells). As another example, deregulation of a gene, protein, or any expression or activity or level thereof can be a mutation in a gene encoding a protein that is constitutively active or has increased activity compared to the protein encoded by the gene not comprising the mutation.

[0107] The term "wild-type" describes a nucleic acid (eg, a DNA or mRNA sequence) or protein sequence that is typically found in a subject not suffering from a disease or disorder (eg, FSGS) associated with the reference nucleic acid or protein.

[0108] An "effective amount" or "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent is any amount that, when used alone or in combination with another therapeutic agent, slows the onset of a disease or promotes regression of a disease, as evidenced by a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or an improvement in impairment or disability caused by disease afflictions. The ability of a therapeutic agent to promote regression of a disease can be assessed using a variety of methods known to skilled practitioners, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by measuring the activity of the agent in in vitro assays.

[0109] The phrase "pharmaceutically acceptable" indicates a substance or composition that must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal being treated therewith.

[0110] As used herein, "polymorph" refers to different solids with the same molecular formula, but each polymorph may have different solid-state physical properties. A single compound may produce a variety of polymorphic forms, each of which has different solid-state physical properties, such as different solubility curves, melting point temperatures, fluidity, dissolution rates and / or different X-ray diffraction peaks. These actual physical characteristics are affected by the conformation and orientation of the molecules in the unit cell, which defines the specific polymorphic form of the substance. The polymorphic form of a compound can be distinguished in the laboratory by X-ray diffraction spectroscopy (e.g., X-ray powder diffraction ("XRPD")) and by other methods (e.g., infrared spectrometry). In addition, the polymorphic form of the same bulk drug or active pharmaceutical ingredient can be administered alone or formulated into a drug product (drug composition), and is well known in the pharmaceutical field, which affects, for example, the solubility, stability, fluidity, ease of handling and compressibility of the bulk drug and the safety and efficacy of the drug product. For more information, see Hilfiker, Rolf (ed.), Polymorphism in the Pharmaceutical Industry. Weinheim, Germany: Wiley-VCH 2006.

[0111] As used herein, the term "amorphous" means a solid in a non-crystalline state in a solid state. Amorphous solids generally have a crystal-like short-range molecular arrangement, but do not have the long-range order of molecular packing found in crystalline solids. The solid state form of a solid can be determined by polarized optical microscopy, X-ray powder diffraction ("XRPD"), differential scanning calorimetry ("DSC"), or other standard techniques known to those skilled in the art.

[0112] As used herein, the term "crystalline" means a solid having a regular repeating arrangement of molecules or external surface planes. The solid form of a solid can be determined by polarized optical 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" means the percentage of certain crystalline polymorphs of atrasentan or its pharmaceutically acceptable salt in a sample that may contain amorphous atrasentan or a pharmaceutically acceptable salt thereof, one or more additional crystalline polymorphs of atrasentan or its pharmaceutically acceptable salt, or a mixture thereof. When a crystalline polymorph of atrasentan or its pharmaceutically acceptable salt is described as having "substantial crystalline purity", it means that the polymorph is substantially free of (e.g., contains <10%, <5%, <2%, <1%, <0.5%, <0.1% or <0.05%) other polymorphs (amorphous and / or crystalline).

[0113] As used herein, the term "chemical purity" means the percentage of a particular compound (e.g., atrasentan or a pharmaceutically acceptable salt thereof) in a sample. Therefore, atrasentan or a pharmaceutically acceptable salt thereof and a composition comprising or prepared 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)-1-(N-(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid, (2R, 3R, 4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)- 1-((N-(n-butyl)-N-ethyl)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 (2R,3R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid ethyl ester. When a sample of atrasentan or a pharmaceutically acceptable salt thereof is described as having "substantially pure", the sample is substantially free of impurities (e.g., containing <10%, <5%, <2%, <1%, <0.5%, <0.1% or <0.05%).

[0114] As used herein, the term "diastereomeric excess" means the amount of one diastereomer of a compound (e.g., atrasentan or a pharmaceutically acceptable salt thereof) in a mixture (you may have other diastereomers of the same compound in the mixture). As used herein, the term "substantial diastereomeric purity" means a diastereomeric excess of greater than about 90%, 95%, 99%, 99.5%, 99.9%, or 100%.

[0115] As used herein, the term "pharmaceutically acceptable carrier" refers to a material that helps to apply an active agent to a cell, an organism, or a subject. "Pharmaceutically acceptable carrier" refers to a carrier or excipient that can be included in the compositions of the present disclosure and does not cause significant adverse toxicological effects to a subject. Non-limiting examples of pharmaceutically acceptable carriers include water, NaCl, saline solutions, lactated Ringer's solution, physiological sucrose, physiological glucose, adhesives, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents and pigments, liposomes, dispersion media, microcapsules, cationic lipid carriers, isotonic agents and absorption delay agents, etc. Carriers can also be materials (e.g., antimicrobial preservatives, antioxidants, chelating agents, and buffers) for providing stability, sterility, and isotonicity for formulations, materials (e.g., antimicrobial agents and antifungals, such as parabens, chlorobutanol, phenol, sorbic acid, etc.) for preventing microbial action, or materials for providing edible flavoring agents, etc. for formulations. In some cases, the carrier is an agent that facilitates the delivery of a small molecule drug or antibody to a target cell or tissue. One skilled in the art will recognize that other drug carriers may be used in the present disclosure.

[0116] As used herein, the term "expression" refers to the level of protein or mRNA in mammalian cells.

[0117] As used herein, the term "activity" refers to one or more activities of a protein, such as binding activity or enzymatic activity (e.g., one or more of phosphorylation, dephosphorylation, nuclear import, transcriptional activation, transcriptional repression, and / or binding activity with a substrate or binding partner).

[0118] As used herein, the term "IL-6 signaling" means 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.

[0119] 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 the activity of NF-kB (e.g., one or more of TNF-α, IL-1, CAM, COX-2 and iNOS).

[0120] As used herein, the term "PDGF signaling" means the expression and / or activity of one or more of PDGF receptor, PKC, PI3K, Src, Ras, ERK1 / 2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, and cPLA2.

[0121] As used herein, the term "SGLT-2 inhibitor" refers to a compound that inhibits sodium glucose cotransporter-2 (SGLT-2). SGLT-2 inhibitors disrupt the reabsorption of glucose by the kidneys, thereby exerting a hypoglycemic 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. [American Journal of Physiology-Renal Physiology] 280: F10; and Scheen, 2018, Circ. Res. [Circulation Research] 122: 1439. In some embodiments, the term "SGLT-2 inhibitor" refers to a compound whose main effect is to inhibit SGLT-2, but is not limited to compounds that only inhibit SGLT-2, and therefore includes compounds that have other activities (e.g., inhibiting SGLT-1) in addition to inhibiting SGLT-2.

[0122] In some embodiments, SGLT-2 inhibitors include compounds from a class of drugs known as gliflozins. In some embodiments, SGLT-2 inhibitors include compounds approved as SGLT-2 inhibitors by regulatory agencies (e.g., FDA or EMA). Non-limiting examples of SGLT-2 inhibitors include bepagliflozin, canagliflozin, Dapagliflozin Empagliflozin STEGLATRO TM ), Ipagliflozin Rupagliflozin Repagliflozin, serpagliflozin, lipagliflozin, sopagliflozin (ZYNQUISTA TM ) and topagliflozin.

[0123] In some embodiments, SGLT-2 inhibitors include but are not limited to dapagliflozin, canagliflozin, ispagliflozin, empagliflozin, bepagliflozin, lipagliflozin, janagliflozin (XZP-5695), togliflozin, erpagliflozin, hengagliflozin (SHR-3824), enagliflozin (DWP-16001), TA-1887 (3-(4-cyclopropylbenzyl)-4-fluoro-1-(β-D-pyranoglucopyranosyl)-1H-indole), indole-N-glycosides 18 (3-(4-ethylbenzyl)-1-(β-D-glucopyranosyl)-1H-indole), sogliflozin, rugliflozin, sergliflozin etabonate (ethyl carbonate), repagliflozin, repagliflozin 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).

[0124] In some embodiments, SGLT-2 inhibitors include C-glycosides, such as dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, bepagliflozin, lipagliflozin, gagliflozin (XZP-5695), togliflozin, ergliflozin, henggliflozin (SHR-3824), enagliflozin (DWP-16001). In some embodiments, SGLT-2 inhibitors include C-glycosides with bicyclic or spiropyran groups, such as togliflozin, ergliflozin and henggliflozin (SHR-3824). In some embodiments, SGLT-2 inhibitors include C-glycosides without bicyclic or spiropyran groups, such as dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, bepagliflozin, lipagliflozin, gagliflozin (XZP-5695) and enagliflozin (DWP-16001).

[0125] In some embodiments, SGLT-2 inhibitors include N-glycosides, 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).

[0126] In some embodiments, the SGLT-2 inhibitor includes 2-methylthio-C-glycosides, such as sogliflozin.

[0127] In some embodiments, the SGLT-2 inhibitor comprises a thiopyranoside, such as rupagliflozin.

[0128] In some embodiments, SGLT-2 inhibitors include O-glycosides and O-glycoside prodrugs, such as sergliflozin etabonate (ethyl carbonate), repagliflozin, repagliflozin 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).

[0129] In some embodiments, SGLT-2 inhibitors as defined herein include any compound that exhibits SGLT-2 inhibitory activity. In some embodiments, the selectivity of the SGLT-2 inhibitor to SGLT-2 is greater than the selectivity to SGLT-1, for example, its activity to SGLT-2 is about 2 times, about 5 times, about 10 times, about 20 times, about 50 times, about 100 times, about 200 times, about 300 times, about 400 times, about 500 times, about 750 times, about 1,000 times, about 1,250 times, about 1,500 times, about 1,750 times, about 2,000 times, about 2,500 times, or any value therebetween. Exemplary SGLT-2 inhibitors may exhibit an inhibitory activity (IC) against SGLT-2 of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM as measured in an assay as described herein. 50 In some embodiments, the SGLT-2 inhibitor may exhibit an inhibitory activity (IC) against SGLT-2 of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM as measured in an assay as provided 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 were stably transfected with cDNA encoding human SGLT-2 (GenBank No. M95549). The cells were washed and then incubated with 10 μM [ 14 C]α-Methylpyranoglucoside (AMG) was incubated with 10 μM inhibitor. 14 C]AMG uptake was quenched with cold buffer containing phlorizin, and the cells were lysed. 14 C]AMG uptake.

[0130] SGLT-2 inhibitors include pharmaceutically acceptable salts, solvates, complexes and salts of solvates thereof, for example, "dapagliflozin" includes salts (e.g., hydrochloride) and solvates (e.g., propylene glycol hydrate) of dapagliflozin; similarly, "canagliflozin" includes solvates (e.g., canagliflozin hemihydrate) and salts of solvates (e.g., hydrochloride of hydrates). Similarly, hengagliflozin (SHR-3824) and dapagliflozin include complexes (e.g., complexes proline hengagliflozin and proline dapagliflozin, respectively).

[0131] As used herein, when a subject is described as having a "controlled serum glucose level", this means that the subject's serum glucose level is within a normal or healthy range. In some embodiments, the subject's fasting serum glucose level is between about 70 mg / dL and about 130 mg / dL. For example, it has been determined that the subject's fasting serum glucose level is 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.

[0132] As used in the methods described herein, the term "reduction" refers to a decrease in the indicated parameter in a subject relative to one or more baseline measurements of the same parameter taken before the start of administration of atrasentan or a pharmaceutically acceptable salt thereof, or a decrease in the indicated parameter in a healthy subject (e.g., a subject not suffering from FSGS). Similarly, as used herein, the term "increase" refers to an increase in the indicated parameter in a subject relative to one or more baseline measurements of the indicated parameter taken before the start of administration of atrasentan or a pharmaceutically acceptable salt thereof, or an increase in the indicated parameter in a healthy subject (e.g., a subject not suffering from FSGS).

[0133] 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. The glomerular filtration rate (GFR) can be calculated by measuring any chemical substance in the blood that has a stable level and is freely filtered but neither reabsorbed nor secreted by the kidneys. Therefore, the measured rate is the amount of substance in the urine that originates from a calculable volume of blood. GFR is typically recorded in volume units / time (e.g., milliliters / minute), and the following formula can be used: GFR=(urine concentration×urine volume) / plasma concentration. GFR can be determined by injecting inulin into the plasma. Since inulin is neither reabsorbed nor secreted by the kidneys after glomerular filtration, its excretion rate is directly proportional to the filtration rate of water and solutes through the glomerular filter. Normal values ​​are: GFR=90-125mL / min / 1.73m 2 , especially GFR = 100-125mL / min / 1.73m 2 . Other principles for determining GFR include measuring 51Cr-EDTA, [125I]iothalamate or iohexol. "Estimated glomerular filtration rate (eGFR)" is defined as the value derived from serum creatinine at screening, which is based on, for example, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, the Cockcroft-Gault formula or the Modification of Diet in Renal Disease (MDRD) formula, 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 a disease or disease progression measure recognized in the art. For example, after treatment with atrasentan or a pharmaceutically acceptable salt thereof, the rate of decline of eGFR can 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. The reduction can last, 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 after treatment, or any value therebetween. In some embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days. In some embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 6 months and about 1 year.

[0134] "ESKD" is an abbreviation for end-stage renal disease. As used herein, the onset of ESKD is defined as when a subject's eGFR falls below about 15 mL / min / 1.73 m 2 and / or a time point when the subject has already begun chronic dialysis. When a subject is defined as "at high risk of progression to ESKD," the subject has protein in the urine > 1 g / day and / or eGFR < 60 for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. As used herein, and as recognized by those skilled in the art, any historical or inadvertent reference to ESRD (end stage renal disease) is used interchangeably in the art to refer to ESKD (end stage renal disease), which is a more current term for the condition.

[0135] As used herein, when a subject is described as having "potassium levels maintained within the normal physiological range," the subject's blood potassium level is from about 3.5 mEq / L to about 5.2 mEq / L.

[0136] As used herein, when a subject is described as having "sodium levels maintained within the normal physiological range," the subject's blood sodium level is from about 135 to about 145 mEq / L.

[0137] As used herein, the term "proteinuria" refers to the presence of protein in urine exceeding normal levels. "Proteinuria" includes "albuminuria" and "microalbuminuria". Normal human protein levels appear in the range of about 0 to 30 mg / L in urine, although for any given urine sample, the level can reach about 80 mg / L. For 24-hour urine collection, normal human urine protein levels are in the range of about 0 to 150 mg. Proteinuria can be indicated by the ratio of total protein / creatinine in urine (UPCR) or by the ratio of specific proteins (e.g., urine albumin / creatinine ratio (ACR) greater than about 30 mg / g). Typically, the urine UACR value in mg / g is approximately equal to the albumin excretion of the subject in mg / day. Proteinuria (including albuminuria and microalbuminuria) usually causes or indicates a disease, but is not limited to the generation of a disease. Proteinuria is intended to cover all forms of proteinuria, including but not limited to physiological proteinuria; functional proteinuria; and exercise proteinuria, which involves a functional proteinuria after muscle overwork. In addition, proteinuria encompasses benign proteinuria (also called "primary" proteinuria), which refers to a type or proteinuria that is not caused by pathological changes in the kidneys. Proteinuria also encompasses pathological proteinuria, such as protein levels in the urine that are greater than normal physiological levels.

[0138] As used herein, the term "albuminuria" (also referred to as "macroalbuminuria") refers to the presence of albumin in the urine above normal levels. Since the urine protein is primarily albumin, normal human urine UACR levels are in the range of about 0 to 30 mg / mmol. As used herein, the term "microalbuminuria" refers to the presence of albumin excreted at a rate of about 20 to 200 μg / min or at a level of about 30 to 300 mg / L in human urine. When defined by urine ACR, "microalbuminuria" refers to a urine UACR greater than about 30 mg / g, or a urine UACR of about 3.5 mg / mmol or greater for women and about 2.5 mg / mmol or greater for men. Microalbuminuria is often an early warning of kidney disease, but may also be present for other reasons.

[0139] As used herein, "ALT" refers to alanine aminotransferase. As used herein, "AST" refers to aspartate aminotransferase.

[0140] The term "synergistic effect" or "synergy" 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 an amount in which the combination of two or more therapeutic agents produces a synergistic effect ("synergistic" as defined herein). In some embodiments, a synergistically effective amount of a combination can be therapeutically effective even when one or more of the compounds in the combination are administered at a dose that would be subtherapeutic when the compounds are administered alone.

[0141] It will be appreciated that different concentrations of each compound can be used for a variety of art-recognized factors, 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 equal or increased efficacy levels, reduced or delayed development of drug resistance, and simultaneous enhanced or equal therapeutic effects of at least one therapeutic agent (e.g., having the same therapeutic effect as at least one therapeutic agent) and reduced undesirable drug effects (e.g., side effects and adverse events) of at least one therapeutic agent.

[0142] In some embodiments, as used herein, "synergistic effect" refers to the effect of atrasentan or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents (e.g., SGLT-2 inhibitors) in combination, for example, any beneficial or desired result including clinical results as described herein, which is greater than the sum of the effects observed when atrasentan or a pharmaceutically acceptable salt thereof and an SGLT-2 inhibitor are administered alone. Such clinical results include, but are not limited to, treating FSGS, reducing renal inflammation and / or fibrosis, reducing proteinuria (e.g., albuminuria), reducing fatigue, reducing the rate of decline of eGFR, delaying the onset of ESKD, reducing fatigue, and reducing the activation of mesangial cells.

[0143] In some embodiments, as used herein, "synergistic effect" means that the combination of atrasentan or a pharmaceutically acceptable salt thereof and a SGLT-2 inhibitor provides a greater reduction in proteinuria (e.g., albuminuria) than the sum of the effects observed when atrasentan or a pharmaceutically acceptable salt thereof and a SGLT-2 inhibitor are administered alone.

[0144] In certain embodiments, as used herein, "synergistic effect" refers to the combination of atrasentan or its pharmaceutically acceptable salt and SGLT-2 inhibitor produces the desired therapeutic effect and reduces the occurrence and / or severity of undesirable drug effects, side effects or adverse events. In certain embodiments, undesirable drug effects, side effects or adverse events are related to the monotherapy of atrasentan or its pharmaceutically acceptable salt or SGLT-2 inhibitor or are observed in the monotherapy of atrasentan or its pharmaceutically acceptable salt or SGLT-2 inhibitor. In certain embodiments, undesirable drug effects, side effects or adverse events are one or more of the following: fluid retention, anemia, nausea, constipation, thirst, fracture, increased urination, urinary tract infection, yeast infection, vaginal itching, LDL cholesterol level increase, brain natriuretic peptide (BNP) level increase, acute sodium retention and acute increase in creatinine level. In certain embodiments, fluid retention is related to a weight gain greater than about 3kg. In certain embodiments, the increased BNP level is greater than about 300pg / mL.

[0145] An adverse event (AE) is any uncontrolled or unfavorable medical occurrence in a human subject, including any abnormal sign (e.g., abnormal physical examination or laboratory findings), symptom, or disease temporally associated with 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 with an onset date prior to the first dose is a pre-existing condition that must be recorded as part of the medical history and should not be considered an AE unless the condition 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.

[0146] An AE may be any abnormal laboratory test result (hematology, clinical chemistry, or urinalysis) requiring intervention or other safety assessment (e.g., ECG, vital sign measurement), including those that are worse than baseline and are considered clinically significant (i.e., not related to underlying disease progression) based on the medical and scientific judgment of the investigator. AEs may include exacerbation of a chronic or intermittent pre-existing condition, including an increase in the frequency and / or intensity of the condition. Detection or diagnosis of a new condition after administration of the study drug, even if the condition may have existed prior to the start of the study. Signs, symptoms, or clinical sequelae of suspected drug-drug interactions. Signs, symptoms, or clinical sequelae of suspected overdose of the study drug or concomitant medications. Overdose itself is not considered an AE / SAE unless it is an intentional overdose with possible suicidal / self-harm intent. Such overdoses should be reported regardless of sequelae.

[0147] A "serious adverse event" (SAE) is any AE that results in: death; a life-threatening condition (placing the subject at risk of immediate death); hospitalization of a subject or prolongation of an existing hospitalization; persistent or severe disability / incapacity; congenital anomaly / birth defect; or any other AE that, in 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 treatment in the emergency room or at home, blood dyscrasias or seizures that do not result in the subject being hospitalized, or the development of drug dependence or drug abuse).

[0148] Adverse events of special interest (AESI) included fluid retention, dilutional anemia, vasodilation / hypotension / acute kidney injury, or heart failure.

[0149] As described herein, unless otherwise indicated, any concentration range, percentage range, ratio range, or integer range should be understood to include values ​​of any integer within the range, and where appropriate, fractions thereof (e.g., tenths and hundredths of integers).

[0150] Unless otherwise stated, any reference to the amount of atrasentan in this disclosure is based on the free equivalent weight of atrasentan. For example, 0.75 mg of atrasentan refers to 0.75 mg of atrasentan in free form or an equivalent amount of atrasentan in salt form.

[0151] Various aspects of the disclosure are described in more detail in the following subsections.

[0152] II. Treatment Methods

[0153] In normal and healthy human kidneys, the expression of endothelin-1 (ET-1) and endothelin A receptor (ET-RA) is more intense in vascular tissue, and less intense in glomerular structure. In contrast, subjects with FSGS show increased expression of ET-1 and ET-RA in the kidney. In this group, ET-1 expression is positively correlated with proteinuria, and proteinuria is at least partially improved by administering ACE inhibitors. In fact, the current therapy for FSGS is to optimize antihypertensive and antiproteinuric agents (e.g., angiotensin converting enzyme inhibitors and / or angiotensin II receptor blockers) and corticosteroid courses to inhibit disease progression. See, for example, Penfold et al., Int. J. Nephrol. and Renovascular Dis. [International Journal of Kidney Disease and Renal Vascular Disease] 11, pp. 137-148 (2017). However, the combination of these agents may show significant dose-limiting side effects, such as hyperkalemia, and may require further immunosuppression in more severe cases.

[0154] Clinically, FSGS is diagnosed by renal biopsy, indicating the presence of mesangial cell proliferation and / or matrix expansion (or late focal segmental glomerulosclerosis), with immunofluorescence showing predominant mesangial granular deposition of IgA (2+ or more). This pathology is different from other progressive renal diseases, such as diabetic nephropathy, which typically presents with diffuse capillary basement membrane thickening with peripheral clear PAS-positive nodules, with late segmental or global glomerulosclerosis, and thickened arterioles with clear deposits. See, e.g., Zanatta, et al., Renal Failure, 34(3), pp. 308-315 (2012).

[0155] Therefore, in one aspect, a method for treating FSGS is provided herein, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof. On the other hand, a method for reducing renal inflammation and / or fibrosis in a subject with FSGS is provided herein, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof. On the other hand, a method for reducing the rate of decline of eGFR in a subject with FSGS is provided herein, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof. On the other hand, a method for delaying the onset of ESKD in a subject with FSGS is provided herein, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof. On the other hand, a method for reducing proteinuria in a subject with FSGS is provided herein, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof. On the other hand, a method for reducing fatigue in a subject with FSGS is provided herein, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically 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, the method comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. As indicated herein, in some embodiments, according to certain methods disclosed herein, disease progression is stabilized, reduced or slowed, including as measured by parameters accepted in the art, examples of which are provided herein.

[0156] In some cases, FSGS has been diagnosed as having biopsy-proven FSGS. Some embodiments provide a genetic diagnosis of FSGS in a subject due to a known podocyte protein mutation. Additional embodiments include subjects with mutations in APOL1. In some cases, FSGS comprises 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, tip lesion FSGS, cellular FSGS, collapsed FSGS, primary FSGS, virus-associated FSGS, non-HIV-associated FSGS, toxin-associated FSGS, adaptive FSGS, or a combination thereof. In some cases, FSGS is FSGS of unclear classification (NOS).

[0157] 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.

[0158] In some embodiments, the subject is not currently diagnosed with cancer. In some embodiments, the subject is not currently receiving treatment for cancer. In some embodiments, the cancer is lung cancer or prostate cancer.

[0159] 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 suffers from diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject does not suffer from diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject suffers from diabetes and does not suffer from diabetic nephropathy. In some embodiments, the subject suffers from type 2 diabetes. In some embodiments, the subject does not suffer from type 2 diabetes. In some embodiments, the subject suffers from type 2 diabetes and does not suffer from diabetic nephropathy.

[0160] 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 suffers from diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject suffers from diabetes (e.g., type 1 diabetes or type 2 diabetes), but does not suffer from diabetic nephropathy. In some embodiments, the subject does not suffer from type 2 diabetes. In some embodiments, the subject does not suffer from type 2 diabetes. In some embodiments, the subject suffers from type 2 diabetes, but does not suffer from diabetic nephropathy.

[0161] In some embodiments, the subject is not receiving treatment 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 receiving treatment for any of diabetic nephropathy, HIV / AIDS, HIV-associated nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject is not receiving treatment for diabetic nephropathy. In some embodiments, the subject is not receiving treatment for HIV / AIDS. In some embodiments, the subject is not receiving treatment for HIV-associated nephropathy. In some embodiments, the subject is not receiving treatment for prostate cancer. In some embodiments, the subject is not receiving treatment for acute renal failure. In some embodiments, the subject is not receiving treatment 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 receiving treatment for diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject is receiving treatment for diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject is receiving treatment for diabetes (e.g., type 1 diabetes or type 2 diabetes), but is not receiving treatment for diabetic nephropathy. In some embodiments, the subject is not receiving treatment 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.

[0162] In certain embodiments, it has been determined that the subject has a controlled serum glucose level. In some embodiments, the subject with the controlled serum glucose level is not receiving treatment for diabetes. In some embodiments, the subject with the controlled serum glucose level is receiving treatment for diabetes. In some embodiments, the subject with the controlled serum glucose level is not receiving treatment for type 2 diabetes. In some embodiments, the subject with the controlled serum glucose level is receiving treatment for type 2 diabetes. In some embodiments, it has been determined that the subject has a controlled serum glucose level; wherein the subject has not been diagnosed with one or more of HIV-associated nephropathy or acute renal failure. For example, it has been determined that the fasting serum glucose level of the subject is 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, it has been determined that the subject has 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. In certain embodiments, it has been determined that the subject has a controlled serum glucose level; and the subject has not been diagnosed with one or more of HIV-associated nephropathy or acute renal failure.

[0163] On the other hand, provided herein is a method for stabilizing or reducing renal inflammation and / or fibrosis in a subject with FSGS, the method comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some cases, renal inflammation and / or fibrosis is tubulointerstitial inflammation. In some cases, renal inflammation and / or fibrosis is tubulointerstitial fibrosis. In some cases, renal inflammation and / or fibrosis includes glomerular inflammation and / or glomerulosclerosis. In some cases, renal inflammation and / or fibrosis includes tubulointerstitial inflammation, tubulointerstitial fibrosis, glomerular inflammation, and / or glomerulosclerosis.

[0164] In some embodiments, renal inflammation in a subject with FSGS is reduced by at least about 10% after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks of treatment or any value therebetween). In certain embodiments, the subject's renal inflammation 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 pharmaceutically acceptable salt thereof for between about 15 days and about 30 days.

[0165] In some embodiments, after treatment with atrasentan or a pharmaceutically 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), renal fibrosis in a subject with FSGS is reduced by at least about 10%. 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 pharmaceutically acceptable salt thereof for between about 15 days and about 30 days.

[0166] In some embodiments, after treatment with atrasentan or a pharmaceutically 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), the renal fibrosis of a subject with FSGS is reduced to less than about 50% of the cortical area of ​​the affected kidney. In certain embodiments, the renal fibrosis of the 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 pharmaceutically acceptable salt thereof for between about 15 days and about 30 days.

[0167] In some embodiments, after treatment with atrasentan or a pharmaceutically 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), the urine red blood cell count per high power (microscopic) field (rbc / hpf) of a subject with FSGS is reduced by at least about 10%. In certain embodiments, the subject's urine rbc / hpf 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 pharmaceutically acceptable salt thereof for between about 15 days and about 30 days.

[0168] 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 to a subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, provided herein is a method for reducing the rate of decline of eGFR in a subject with FSGS, the method comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after treatment for 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), the rate of decline of the subject's eGFR is reduced by at least about 10%. In some embodiments, the rate of decline of the subject's eGFR is reduced 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 pharmaceutically acceptable salt thereof for between about 15 days and about 30 days. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 6 months and about 1 year.

[0170] In some embodiments, after treatment with atrasentan or a pharmaceutically acceptable salt thereof, the rate of decline in eGFR in a subject with FSGS is reduced to less than about 10 mL / min / 1.73 m 2 For example, after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks of treatment, or any value therebetween. In certain embodiments, after about 6 months to about 1 year of treatment with atrasentan or a pharmaceutically acceptable salt thereof, the rate of decline of the subject's eGFR is reduced to less than about 9 mL / min / 1.73 m 2 , about 8mL / min / 1.73m 2 , about 7mL / min / 1.73m 2 , about 6mL / min / 1.73m 2 , about 5mL / min / 1.73m 2 , about 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 or any value therebetween. For example, in subjects between about 20 and about 30 years of age, the typical decline in eGFR with age is about 1 mL / min / 1.73 m 2 / Year.

[0171] In another aspect, provided herein is a method of delaying the onset of ESKD in a subject with FSGS, the method comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0172] In some embodiments, the method increases the diagnosis of FSGS in a subject and the subject's eGFR decreases to less than 15 mL / min / 1.73 m 2 In certain embodiments, the method diagnoses FSGS in a subject and the subject's eGFR falls below 15 mL / min / 1.73 m 2 For example, in some embodiments, the method diagnoses FSGS in a subject and the subject's eGFR decreases to less than 15 mL / min / 1.73 m 2 The time between the time of treatment and the time of recovery is increased by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, or about 500%, or any value therebetween. Thus, in some embodiments, the method slows the progression of FSGS-related disease as measured by industry accepted benchmarks.

[0173] In certain embodiments, the method diagnoses FSGS in a subject and the subject's eGFR decreases to less than 15 mL / min / 1.73 m 2 For example, the method can reduce the eGFR of the subject to less than 15 mL / min / 1.73 m 2 The time delay of 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 or 20 years.

[0174] In another aspect, provided herein is a method of reducing proteinuria in a subject with FSGS, the method comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. As used throughout, it is understood that proteinuria measures protein in urine. Although albumin is typically the major protein in urine, other and multiple proteins can be tested as part of one or more methods described herein. In some embodiments described herein, reference to "protein" can refer to albumin or one or more other proteins typically detected in urine, as will be understood by those skilled in the art.

[0175] 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 pharmaceutically acceptable salt thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks of treatment 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 pharmaceutically acceptable salt thereof for between about 15 days and about 30 days.

[0176] 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 between about 2 days and about 30 days of treatment with atrasentan or a pharmaceutically 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 between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically 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 urine of the subject is reduced by about 50% to about 80%. In the foregoing embodiments, the reduction in the amount of protein (eg, albumin) in the urine of a subject with FSGS is relative to the amount of protein (eg, albumin) in the urine prior to initiating treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0177] 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 pharmaceutically acceptable salt thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks of treatment or any value therebetween). In certain embodiments, the amount of protein in the urine of a subject is reduced by about 100 mg / dL to about 2,500 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 100 mg / dL to about 2,000 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 100 mg / dL to about 1,500 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 100 mg / dL to about 1,000 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 100 mg / dL to about 500 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 100 mg / dL to about 400 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 100 mg / dL to about 300 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 100 mg / dL to about 200 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 500 mg / dL to about 2,500 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 500 mg / dL to about 2,000 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 500 mg / dL to about 1,500 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 500 mg / dL to about 1,000 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 500 mg / dL to about 900 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 500 mg / dL to about 800 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 600 mg / dL to about 900 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 700 mg / dL to about 900 mg / dL. In certain embodiments, the amount of protein in the urine of a subject 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 pharmaceutically acceptable salt thereof for between about 15 days and about 30 days.In the foregoing embodiments, the reduction in the amount of protein (eg, albumin) in the urine of a subject with FSGS is relative to the amount of protein (eg, albumin) in the urine prior to initiating treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0178] 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 between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 200 mg / dL to about 500 mg / dL after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 300 mg / dL to about 500 mg / dL after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically 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 starting treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0179] 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 between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 600 mg / dL to about 900 mg / dL after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 700 mg / dL to about 900 mg / dL after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically 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 starting treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, 50 weeks, 60 weeks, 70 weeks, 80 weeks, 90 weeks, 100 weeks, 110 weeks, 120 weeks, 130 weeks, 140 weeks, 150 weeks, 160 weeks, 170 weeks, 180 weeks, 190 weeks, or 200 weeks of treatment), the level of protein (e.g., albumin) in the urine of a subject with FSGS is reduced to less than about 1.0 grams per day. In certain embodiments, the level of protein in the urine of the subject is reduced to less than about 0.9 grams per day. In certain embodiments, the level of protein in the urine of the subject is reduced to less than about 0.8 grams per day. In certain embodiments, the level of protein in the urine of the subject is reduced to less than about 0.7 grams per day. In certain embodiments, the level of protein in the subject's urine is reduced to less than about 0.6 grams per day. In certain embodiments, the level of protein in the subject's urine is reduced to less than about 0.5 grams per day. In certain embodiments, the level of protein in the subject's urine is reduced to less than about 0.4 grams per day. In certain embodiments, the level of protein in the subject's urine is reduced to less than about 0.3 grams per day. In certain embodiments, the level of protein in the subject's urine is reduced to less than about 0.2 grams per day. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days. 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 starting treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0181] In another aspect, provided herein is a method of reducing fatigue in a subject with FSGS, the method comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, it has been determined that the subject does not suffer from one or more of diabetic nephropathy, HIV-associated nephropathy, prostate cancer, or acute renal failure. In certain embodiments, it has been determined that the subject does not suffer from diabetic nephropathy. In certain embodiments, it has been determined that the subject does not suffer from HIV-associated nephropathy. In certain embodiments, it has been determined that the subject does not suffer from prostate cancer. In certain embodiments, it has been determined that the subject does not suffer from acute renal failure.

[0182] In some embodiments, fatigue in a subject with FSGS is reduced by about 5% to about 80% after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks of treatment 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 pharmaceutically acceptable salt thereof for about 15 days and about 30 days. In certain embodiments, fatigue reduction includes a decrease in one or more of the following scores: fatigue severity scale, Chalder fatigue scale, FACIT fatigue scale, brief fatigue scale, FACT-F subscale, overall vitality and impact, May and Kline adjective checklist, Pearson-Byars fatigue checklist, Rhoten fatigue scale, fatigue and weakness schedule, visual analog scale or personal fatigue intensity scale. In the foregoing embodiments, the reduction in fatigue experienced by a subject with FSGS is relative to the fatigue experienced by the subject prior to initiating treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the reduction in fatigue comprises a decrease in the score on the Brief Fatigue Inventory.

[0183] III. Subject Selection

[0184] A subject with FSGS as described anywhere herein may be diagnosed using one or more methods known in the art. Non-limiting examples include: kidney biopsy, detection of anti-glycan antibodies, detection of deposited fibrosis in the kidney, or any combination of the foregoing.

[0185] In some embodiments, the presence and / or level of a specific protein in a subject is determined before administering atrasentan or a pharmaceutically acceptable salt thereof. For example, the level of Gd-IgA1 in serum, the level of Gd-IgA1-specific autoantibodies in serum, and / or the level of immune complexes containing IgA1 in serum and / or urine. See, for example, Knoppova, et al., Front.Immunol. [Immunology Frontier], Vol. 17, No. 117 (2016), which is hereby incorporated by reference in its entirety. In some embodiments, before administering atrasentan or a pharmaceutically acceptable salt thereof, the subject's Gd-IgA level is at or above the 90th percentile. In some embodiments, before administering atrasentan or a pharmaceutically acceptable salt thereof, the subject's Gd-IgA level is at or above the 95th percentile. In some embodiments, after about 6 months to 1 year of treatment with atrasentan or a pharmaceutically acceptable salt thereof, the subject's Gd-IgA level drops to below the 90th percentile.

[0186] In certain embodiments, the subject has mesangial cellularity in about ≥50% (e.g., about ≥60%, about ≥70% or about ≥80%) of the glomerulus, wherein mesangial cellularity is defined as more than four mesangial cells in any mesangial region of the glomerulus. In certain embodiments, there is too much cell in the capillary in the subject, wherein too much cell in the capillary is defined as too many cells caused by an increase in the number of cells in the glomerular capillary cavity. In certain embodiments, there is segmental sclerosis in the subject, wherein segmental sclerosis is defined as adhesion or sclerosis (capillary cavity is blocked by matrix) of part but not the entire glomerular cluster. 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, wherein tubular atrophy / interstitial fibrosis is defined as the estimated percentage of the cortical area showing tubular atrophy or interstitial fibrosis. In certain embodiments, there are crescents on the glomeruli of the subject. In some of these embodiments, the subject has crescents on the glomeruli less than about 25% (e.g., less than about 20%, about 15%, about 10% or about 5%). In certain embodiments, according to the Oxford MEST-C classification system, the MEST-C score of the subject is M1; E1; S1; T1 or T2; and / or C0 or C1. The Oxford MEST-C classification system is defined in Kidney International [Kidney International] (2009) 76, 546–556 and Nature Reviews Nephrology [Natural Review: Nephrology] (2017) 13, 385-386, each of which is incorporated herein by reference in its entirety (see also: Kidney Research and Clinical Practice [Kidney Research and Clinical Practice] (2016) 35, 197-203, which is incorporated herein by reference in its entirety).

[0187] In some embodiments, the subject is at high risk of developing ESKD. In some of these embodiments, at least about 3 months before the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject excretes an average of about 1 gram or more of protein in the urine per day. In some of these embodiments, at least about 3 months before the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject excretes an average of about 0.75 grams or more of protein in the urine per day. In some of these embodiments, at least about 3 months before the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject excretes an average of about 0.75 grams to about 1.5 grams of protein in the urine per day. In some of these embodiments, at least about 3 months before the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject excretes an average of about 1 gram or more of protein in the urine per day.

[0188] In certain embodiments, at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject's mean eGFR is about 20 to about 120 mL / min / 1.73 m 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's average eGFR is about 20 to about 90 mL / min / 1.73 m at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. 2 In certain embodiments, at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject's average eGFR is about 20 to about 60 mL / min / 1.73 m 2 .

[0189] In certain embodiments, at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject's average eGFR is ≤ 60 mL / min / 1.73 m 2 (e.g., about ≤55, about ≤50, about ≤45, about ≤40, about ≤35). In certain of these embodiments, prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject's eGFR>30 mL / min / 1.73 m 2 .

[0190] In some 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 (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years) prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, at least three months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject may excrete an average of about 1.1 grams, 1.2 grams, 1.3 grams, 1.4 grams, 1.5 grams, 1.6 grams, 1.7 grams, 1.8 grams, 1.9 grams, 2.0 grams, 2.1 grams, 2.2 grams, 2.3 grams, 2.4 grams, 2.5 grams, 2.6 grams, 2.7 grams, 2.8 grams, 2.9 grams, 3.0 grams, 3.1 grams, 3.2 grams, 3.3 grams, 3.4 grams, 3.5 grams, 5 grams or 7.5 grams or 10 grams of protein per day in the urine, or any value therebetween.

[0191] In some embodiments, the subject excretes an average of about 0.3 grams to about 2 grams of protein in the urine per day for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years) prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the subject may excrete about 0.3 grams to 0.5 grams, 0.5 grams to 1 gram, about 0.5 grams to 1.5 grams, about 1 gram to 1.5 grams, or about 1.5 grams to 2 grams of protein in the urine per day for at least 3 months.

[0192] 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 before the first administration of atrasentan or a pharmaceutically 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 or 7.5 grams or 10 grams of protein per day or any value therebetween in the urine in at least two of three consecutive measurements one year before the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0193] In some embodiments, at least three months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject's UACR value is at least about 300 mg / g, e.g., 300 mg / g to about 5,000 mg / g. In some embodiments, at least three months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject's UACR value is about 800 mg / g, e.g., 800 mg / g to about 5,000 mg / g. In some embodiments, the subject's UACR value is 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, at least three months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0194] In some embodiments, the UACR value of the subject is reduced by at least about 30% relative to the average UACR value of the subject at least three months before the first administration of atrasentan or a pharmaceutically acceptable salt thereof, for example, the average UACR value of the subject at least three months before the first administration of atrasentan or a pharmaceutically acceptable salt thereof is reduced by about 30% to about 100%. In some embodiments, the UACR value of the subject is reduced by 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 average UACR value of the subject at least three months before the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject with a reduced UACR value also does not experience significant sodium retention and / or significant fluid retention. In some embodiments, significant fluid retention can be about 1 kg to about 4 kg within six weeks, 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 or any value therebetween within six weeks. In some embodiments, a subject with significant fluid retention exhibits clinical symptoms of edema.

[0195] In certain embodiments, the subject's mean eGFR is about 20 to about 90 mL / min / 1.73 m 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 pharmaceutically acceptable salt thereof. 2 For example, at least about 20 to about 50 mL / min / 1.73 m at least about 3 months before the first administration of atrasentan or a pharmaceutically acceptable salt thereof 2 ; about 30 to about 60 mL / min / 1.73 m 2 ; about 40 to about 70mL / min / 1.73m 2 ; about 50 to about 80 mL / min / 1.73 m 2 ; or about 60 to about 90 mL / min / 1.73 m 2 In some embodiments, at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject's average eGFR is ≤ 60 mL / min / 1.73 m 2 In certain embodiments, the subject's average eGFR is ≤ 55 mL / min / 1.73 m 2 , for at least about 3 months. In certain embodiments, the subject's average eGFR is ≤ 50 mL / min / 1.73 m 2 , for at least about 3 months. In certain embodiments, the subject's average eGFR is ≤ 45 mL / min / 1.73 m 2, for at least about 3 months. In certain embodiments, the subject's average eGFR is ≤ 40 mL / min / 1.73 m 2 , for at least about 3 months. In certain embodiments, the subject's average eGFR is ≤ 35 mL / min / 1.73 m 2 , for at least about 3 months. In certain embodiments, the subject's average eGFR is ≤ 25 mL / min / 1.73 m 2 , for at least about 3 months. In certain embodiments, the subject's average eGFR is ≤ 20 mL / min / 1.73 m 2 , for at least about 3 months. In certain of the foregoing embodiments, the average eGFR of the subject is about 30 mL / min / 1.73 m at least 3 months prior to the administration of atrasentan or a pharmaceutically acceptable salt thereof. 2 About 60mL / min / 1.73m 2 For example, the average eGFR of a subject may be about 30 mL / min / 1.73 m 2 About 55mL / min / 1.73m 2 Between, about 30mL / min / 1.73m 2 About 50mL / min / 1.73m 2 Between, about 30mL / min / 1.73m 2 About 45mL / min / 1.73m 2 Between, or about 30mL / min / 1.73m 2 About 40mL / min / 1.73m 2 between.

[0196] In certain embodiments, the subject's mean eGFR is about 30 mL / min / 1.73 m at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years) prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. 2 to about 45mL / min / 1.73m 2 , for example, about ≤45, about ≤40, about ≤35, or about ≤30. In some embodiments, at least about 3 months before the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject's average eGFR is about 25 mL / min / 1.73 m 2 to about 75mL / min / 1.73m 2 For example, at least about 3 months before the first administration of atrasentan or a pharmaceutically acceptable salt thereof, about 25 mL / min / 1.73 m 2, about 30mL / min / 1.73m 2 , about 35mL / min / 1.73m 2 , about 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.

[0197] In some embodiments, the average HbA1c of the subject is about 4% to about 6% at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years) prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the average HbA1c of the subject can be 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.

[0198] In some embodiments, the average fasting blood glucose level of the subject is 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 pharmaceutically acceptable salt thereof. For example, the average fasting blood glucose level of the subject can be 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.

[0199] In some embodiments, the potassium level of the subject is maintained within the normal physiological range. In certain embodiments, the potassium level of the subject is maintained 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 pharmaceutically acceptable salt thereof. In certain embodiments, the potassium level of the subject is maintained within 3.5 to 5.2 mEq / L. For example, the subject's average potassium level is maintained at about 3.5 mEq / L, about 3.6 mEq / L, about 3.7 mEq / L, about 3.8 mEq / L, about 3.9 mEq / L, about 4.0 mEq / L, about 4.1 mEq / L, about 4.2 mEq / L, about 4.3 mEq / L, about 4.4 mEq / L, about 4.5 mEq / L, about 4.6 mEq / L, about 4.7 mEq / L, about 4.8 mEq / L, about 4.9 mEq / L, about 5.0 mEq / L, about 5.1 mEq / L, or about 5.2 mEq / L, or any value therebetween.

[0200] In some embodiments, the subject's sodium level is maintained within the normal physiological range. In certain embodiments, the subject's potassium level is maintained 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 pharmaceutically acceptable salt thereof. In certain embodiments, the subject's sodium level is maintained within 135 to 145 mEq / L. For example, the subject's average sodium level is maintained at about 135 mEq / L, about 136 mEq / L, about 137 mEq / L, about 138 mEq / L, about 139 mEq / L, about 140 mEq / L, about 141 mEq / L, about 142 mEq / L, about 143 mEq / L, about 144 mEq / L, or about 145 mEq / L, or any value therebetween.

[0201] In some embodiments, the subject's ALT / AST level during administration of atrasentan or a pharmaceutically acceptable salt thereof is about the same as the ALT / AST level prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the subject's ALT / AST level during administration of atrasentan or a pharmaceutically acceptable salt thereof is within about 25%, about 20%, about 15%, about 10%, about 5%, or about 2.5% of the level prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, or any value therebetween.

[0202] In some embodiments, the subject's bilirubin level during administration of atrasentan or a pharmaceutically acceptable salt thereof is about the same as the bilirubin level before the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the subject's bilirubin level during administration of atrasentan or a pharmaceutically acceptable salt thereof is within about 25%, about 20%, about 15%, about 10%, about 5%, or about 2.5% of the level before the first administration of atrasentan or a pharmaceutically acceptable salt thereof, or any value therebetween.

[0203] In some embodiments, the subject's fluid retention can be managed with a diuretic (e.g., during treatment with atrasentan or a pharmaceutically acceptable salt thereof and / or prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof). For example, fluid retention can be less than about 3 kilograms (kg) of weight gain over 6 weeks. In some embodiments, fluid retention is less than about 4 kg, about 3.5 kg, about 3 kg, about 2.5 kg, about 2 kg, about 1.5 kg, or about 1 kg, or any value therebetween, over 6 weeks.

[0204] 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, other chemical and / or biological therapeutic agents are administered to the subject prior to, substantially simultaneously with, or after administration of atrasentan or a pharmaceutically acceptable salt thereof as disclosed herein.

[0205] In some embodiments, the subject has one or more gene mutations associated with FSGS. In some embodiments, it has been previously determined that the subject has one or more gene mutations associated with FSGS. In some embodiments, the methods described herein further include determining that the subject has one or more gene mutations associated with FSGS. Gene mutations may include, for example, point mutations, substitutions, or deletions. In some cases, gene mutations result in mutations in the protein coding sequence of a gene. In some cases, gene mutations result in mutations in the 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.

[0206] In some cases, the subject has, has previously been determined to have, or is determined to have a mutation in APOL1. In some cases, the mutation comprises expression of a G1 or G2 risk allele. See, e.g., Genovese G, et al. Science. 2010 Aug 13;329(5993):841-5.; see also, 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 foregoing references in this paragraph is hereby incorporated 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.

[0207] In some cases, the subject has, has previously been determined to have, or is determined to have a mutation in NPHS1. See, e.g., 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 foregoing references in this paragraph is hereby incorporated by reference in its entirety. In some cases, a subject with FSGS has one or more mutations selected from the group consisting of 121delCT (frameshift and truncation), R1109X (wherein X is any amino acid except R), 1306_1308insAC (frameshift and truncation), 3250insG (frameshift and truncation), and / or R1160X (wherein X is any amino acid except R).

[0208] In some cases, the subject has, has previously been determined to have, or is 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 foregoing references in this paragraph is hereby incorporated 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.

[0209] In some cases, the subject has, has previously been determined to have, or is determined to have a mutation in CD2AP. See, e.g., Kim JM, et al. Science. 2003 May 23; 300(5623): 1298-300; and MM, et al. Kidney Int. 2007 Nov;72(10):1198-203. Each of the foregoing references in this paragraph is hereby incorporated by reference in its entirety. In some cases, the subject with FSGS has one or more mutations selected from mutations in splice site receptors and / or R612X.

[0210] In some cases, the subject has, has previously been determined to have, or is determined to have a mutation in TRPC6. See, e.g., 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 foregoing references in this paragraph is hereby incorporated 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.

[0211] In some cases, the subject has, has previously been determined to have, or is determined to have a mutation in ACTN4. See, e.g., 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 foregoing references in this paragraph is hereby incorporated 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.

[0212] In some cases, the subject has, has previously been determined to have, or is 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 foregoing references in this paragraph is hereby incorporated 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.

[0213] In some cases, the subject has, has previously been determined to have, or is determined to have a mutation in MYO1E. See, e.g., Mele C, et al. N Engl J Med. 2011 Jul 28;365(4):295-306, which is hereby incorporated by reference in its entirety. In some cases, the subject with FSGS has one or more mutations selected from A159P and / or Y695X.

[0214] In some cases, the subject has, has previously been determined to have, or is determined to have a mutation in ARHGAP24. See, e.g., Akilesh S, et al. J Clin Invest. 2011 Oct; 121(10):4127-37, which is hereby incorporated by reference in its entirety. In some cases, the subject with FSGS has one or more mutations including Q158R.

[0215] In some cases, the subject has, has previously been determined to have, or is 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 foregoing references in this paragraph is hereby incorporated 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).

[0216] In some cases, the subject has, has previously been determined to have, or is determined to have a mutation in WT1. See, e.g., Hall G, et al. J Am Soc Nephrol. 2015 Apr; 26(4):831-43, which is hereby incorporated by reference in its entirety. In some cases, the subject with FSGS has one or more mutations including R458Q.

[0217] In some cases, the subject has, has previously been determined to have, or is determined to have a mutation in LMX1B. See, e.g., 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 foregoing references in this paragraph is hereby incorporated by reference in its entirety. In some cases, the subject with FSGS has one or more mutations selected from R246P and / or R246Q.

[0218] In some cases, the subject has, has previously been determined to have, or is determined to have a mutation in COQ6. See, e.g., Heeringa SF, et al. J Clin Invest. 2011 May; 121(5):2013-24; see also, Park E, et al. Am J Kidney Dis. 2017 July; 70(1):139-144. Each of the foregoing references in this paragraph is hereby incorporated by reference in its entirety. In some cases, the subject with FSGS has one or more mutations selected from the group consisting of G255R, A353D, Q447X (wherein X is any amino acid except Q), R162X (wherein X is any amino acid except R), W188X (wherein X is any amino acid except W), P261L, and / or Q229P.

[0219] In some cases, the subject has, has previously been determined to have, or is determined to have a mutation in LAMB2. See, e.g., Hasselbacher K, et al. Kidney Int. 2006 Sep;70(6):1008-12, which is hereby incorporated 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.

[0220] In some cases, the subject has, has previously been determined to have, or is determined to have a mutation in PAX2. See, e.g., Barua M, et al. J Am Soc Nephrol. 2014 Sep; 25(9): 1942-53, which is hereby incorporated by reference in its entirety. In some cases, the subject with FSGS has one or more mutations selected from R56Q and / or G189R.

[0221] In some cases, the subject has, has previously been determined to have, or is determined to have a mutation in ANLN. See, e.g., Gbadegesin RA, et al. J Am Soc Nephrol. 2014 Sep;25(9):1991-2002, which is hereby incorporated by reference in its entirety. In some cases, the subject with FSGS has one or more mutations selected from R431C and / or G618C.

[0222] In some cases, the subject has, has previously been determined to have, or is determined to have a mutation in CRB2. See, e.g., Ebarasi L, et al. Am J Hum Genet. 2015 Jan 8; 96(1): 153-61, which is hereby incorporated 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.

[0223] It is to be understood that a subject may have one or more mutations described herein (ie, in any combination).

[0224] In some embodiments, the subject has received one or more renin-angiotensin system inhibitors for at least about 60 weeks prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the subject has received one or more renin-angiotensin system inhibitors 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 pharmaceutically acceptable salt thereof.

[0225] In some embodiments, the subject has been receiving one or more renin-angiotensin system inhibitors at a maximum tolerated stable dose. For example, before the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject may 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. In some embodiments, one or more renin-angiotensin system inhibitors are selected from the group consisting of: angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), renin inhibitors and aldosterone antagonists. For example, one or more renin-angiotensin system inhibitors may be ACE inhibitors, ARBs or a combination thereof, wherein the ACE inhibitor or ARB may be described anywhere herein. For example, ACE inhibitors can be selected from the group consisting of quinapril, fosinopril, perindopril, captopril, enalapril, enalaprilat, ramipril, cilazapril, delapril, fosinopril, zofenopril, indolapril, benazepril, lisinopril, spirapril, trandolapril, poredip, penttopril, moexipril, rispermine and pivopril. For example, ARBs can be selected from the group consisting of candesartan, candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan, olmesartan medoxomil, telmisartan, valsartan, azisartan medoxomil and BRA-657.

[0226] In some embodiments, the subject is also administering 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 co-transporter-2 inhibitors (SGLT2i) and steroids. In some embodiments, after treatment with atrasentan or a pharmaceutically acceptable salt thereof for about 15 to about 30 days, the dosage of the one or more additional agents is reduced. In some embodiments, the one or more additional agents are immunosuppressants.

[0227] In some embodiments, the subject is not currently receiving one or more additional pharmaceutical agents. In certain embodiments, the subject has not used one or more additional pharmaceutical agents for two or more weeks within 6 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0228] 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.

[0229] In certain embodiments, the one or more additional agents are steroids. For example, the one or more additional agents can be selected from the group consisting of: prednisone, dexamethasone, hydrocortisone, cyclosporine, and any combination of the foregoing.

[0230] In certain embodiments, the one or more additional agents are aminoquinolines. For example, the one or more additional agents can be hydroxychloroquine.

[0231] In some embodiments, the subject is receiving one or more additional agents while being treated with atrasentan. In certain embodiments, after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, 50 weeks, 60 weeks, 70 weeks, 80 weeks, 90 weeks, 100 weeks, 110 weeks, 120 weeks, 130 weeks, 140 weeks, 150 weeks, 160 weeks, 170 weeks, 180 weeks, 190 weeks, or 200 weeks of treatment), the dosage of the one or more additional agents is reduced. In some of these embodiments, after treatment with atrasentan or a pharmaceutically acceptable salt thereof for about 15 days to about 30 days, the dosage of the one or more additional agents is reduced. In some of the foregoing embodiments, the dosage of the additional agent is reduced by about 10% to about 100%. In certain embodiments, the additional dose of the agent is reduced by about 15% to about 100%. In certain embodiments, the additional dose of the agent is reduced by about 20% to about 100%. In certain embodiments, the additional dose of the agent is reduced by about 25% to about 100%. In certain embodiments, the additional dose of the agent is reduced by about 30% to about 100%. In certain embodiments, the additional dose of the agent is reduced by about 35% to about 100%. In certain embodiments, the additional dose of the agent is reduced by about 40% to about 100%. In certain embodiments, the additional dose of the agent is reduced by about 45% to about 100%. In certain embodiments, the additional dose of the agent is reduced by about 50% to about 100%. In certain embodiments, the additional dose of the agent is reduced by about 55% to about 100%. In certain embodiments, the additional dose of the agent is reduced by about 60% to about 100%. In certain embodiments, the additional dose of the agent is reduced by about 65% to about 100%. In certain embodiments, the additional dose of the agent is reduced by about 70% to about 100%. In certain embodiments, the additional agent dosage is reduced by about 75% to about 100%. In certain embodiments, the additional agent dosage is reduced by about 80% to about 100%. In certain embodiments, the additional agent dosage is reduced by about 85% to about 100%. In certain embodiments, the additional agent dosage is reduced by about 90% to about 100%. In some of the foregoing embodiments, after treatment with atrasentan or a pharmaceutically acceptable salt thereof for about 15 days to about 30 days (e.g., about 15 days, about 20 days, about 25 days, or about 30 days), the dosage of one or more additional agents is reduced. When the dosage of the additional agent as described herein is reduced by 100%, the subject no longer needs the additional agent.

[0232] In certain embodiments, the dosage of one or more steroids is reduced after treatment with atrasentan or a pharmaceutically acceptable salt thereof, for example, after about 15 days to about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the steroid dosage 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% after treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0233] In certain embodiments, the dosage of one or more aminoquinolines is reduced after treatment with atrasentan or a pharmaceutically acceptable salt thereof, for example, after about 15 days to about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the aminoquinoline dosage 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% after treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0234] In certain embodiments, the subject is receiving one or more other therapeutic agents at the same time. The one or more other therapeutic agents are described herein. For example, the subject is receiving an inhibitor of one or more elements of the renin-angiotensin-aldosterone system at the same time. In certain embodiments, the subject is receiving SGLT-2 inhibitors, ACE inhibitors, ARBs, statins, diuretics, calcium channel blockers, beta blockers, aldosterone antagonists, fish oils, hydroxychloroquine or any of the aforementioned combinations at the same time. In some of these embodiments, the subject is receiving SGLT-2 inhibitors at the same time. In some of these embodiments, the subject is receiving ACE inhibitors, ARBs or their combinations at the same time. In certain embodiments, the subject is receiving one or more statins at the same time, such as atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin and pitavastatin. In certain embodiments, the subject is simultaneously receiving one or more diuretics, such as hydrochlorothiazide, trichlorothiazide, hydroflumethiazide, quinethazone, metolazone, chlorothiazide, chlorthalidone, indapamide, methylclothiazide, bumetanide, torasemide, piretanide, ethacrynic acid, bumetanide, furosemide, triamterene, spironolactone, eplerenone and amiloride. In certain embodiments, the subject is simultaneously receiving SGLT-2 inhibitors, such as canagliflozin, dapagliflozin, empagliflozin or ergliflozin. In certain embodiments, the subject is receiving one or more ACE inhibitors at the same time, such as quinapril, fosinopril, perindopril, captopril, enalapril, enalaprila, ramipril, cilazapril, delapril, fosinopril, zofenopril, indolapril, benazepril, lisinopril, spirapril, trandolapril, poredip, penttopril, moexipril, rispermine and pivopril. In certain embodiments, the subject is receiving ARB at the same time, 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 diuretics and ACE inhibitors or ARBs at the same time. In certain embodiments, the subject is receiving diuretics, ACE inhibitors and ARBs at the same time. In certain embodiments, the subject is receiving a diuretic and 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 other therapeutic agents simultaneously did not previously receive one or more therapeutic agents. For example, the subject receiving an SGLT-2 inhibitor simultaneously did not previously receive an SGLT-2 inhibitor.

[0235] In certain embodiments, the subject has previously received but not simultaneously received one or more other therapeutic agents, such as those described herein. For example, the subject has previously received but not simultaneously received SGLT-2 inhibitors, ACE inhibitors, ARBs, statins, diuretics, calcium channel blockers, beta blockers, aldosterone antagonists, fish oils, hydroxychloroquine or any of the aforementioned combinations, as described herein. In certain of these embodiments, the subject has previously received but not simultaneously received SGLT-2 inhibitors.

[0236] In some embodiments, within 6 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject has cellular glomerular crescents in about ≤ 25% of the glomeruli. For example, the subject may have cellular glomerular crescents in about 25%, about 20%, about 15%, about 10%, about 5%, or about 1%, or any value therebetween. In some embodiments, the subject does not have cellular glomerular crescents in the glomeruli. In certain embodiments, the subject is not clinically suspected of having rapidly progressive glomerulonephritis (RPGN).

[0237] In some embodiments, the subject has not undergone an organ transplant prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0238] In some embodiments, prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject's systolic blood pressure is less than about 160 mmHg. For example, the subject's systolic blood pressure may be less than about 155 mmHg, less than about 150 mmHg, less than about 145 mmHg, or less than about 140 mmHg. In some embodiments, prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject's diastolic blood pressure is less than about 100 mmHg. For example, the subject's diastolic blood pressure may be less than about 100 mmHg, less than about 95 mmHg, or less than about 90 mmHg. In some embodiments, the subject's systolic blood pressure is between about 100 mm Hg and about 130 mm Hg, and the diastolic blood pressure is about 70 mm Hg to about 90 mm Hg.

[0239] In some embodiments, before the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject has not been diagnosed with heart failure. In some embodiments, before the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject has not been previously hospitalized for a condition associated with fluid overload. Non-limiting examples of conditions include uncontrolled peripheral edema, pleural effusion, or ascites. In some embodiments, before the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject has not been diagnosed with clinically significant liver disease. In some embodiments, before the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject's transaminase or bilirubin value is no more than twice the upper limit of normal. For example, the subject's ALT level is less than about 110U / L (e.g., less than about 100U / L, less than 90U / L, less than about 80U / L, less than about 70U / L, less than about 60U / L, less than about 50U / L, or less than about 40U / L or any value therebetween). As another example, the subject's AST level is less than 100 U / L (e.g., less than 90 U / L, less than about 80 U / L, less than about 70 U / L, less than about 60 U / L, less than about 50 U / L, or less than about 40 U / L, or any value therebetween). As yet another example, the subject's bilirubin level is less than about 2.5 mg / dL (e.g., less than about 2 mg / dL, less than about 1.5 mg / dL, less than about 1.4 mg / dL, less than about 1.3 mg / dL, less than about 1.2 mg / dL, less than about 1.1 mg / dL, less than about 1.0 mg / dL, or less than about 0.9 mg / dL, or any value therebetween).

[0240] In some embodiments, prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject's hemoglobin level is above about 9 g / dL (e.g., above about 10 g / dL, about 11 g / dL, about 12 g / dL, or about 13 g / dL, or any value therebetween). 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 one year) prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not been diagnosed with cancer for at least 5 years prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not been diagnosed with cancer (e.g., lung cancer or prostate cancer) for at least 5 years prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not been diagnosed with cancer for at least 5 years prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, unless the cancer is a non-melanoma skin cancer that does not require ongoing treatment. In some embodiments, the subject did not have cancer prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, unless the cancer was a non-melanoma skin cancer that did not require ongoing treatment. In some embodiments, the subject did not have cancer prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, unless the cancer was a non-melanoma skin cancer that did not require ongoing treatment. In some embodiments, the subject was not receiving treatment for cancer for at least 5 years prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, unless the cancer was a non-melanoma skin cancer that did not require ongoing treatment.

[0241] In some embodiments of the method, use or product used 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 method, use or product used 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 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 of diabetic nephropathy, HIV / AIDS, and acute renal failure. In certain embodiments, the subject has not been previously diagnosed with any of diabetic nephropathy, HIV / AIDS, prostate cancer, and acute renal failure. In certain embodiments, the subject has not been previously diagnosed with any of diabetic nephropathy, HIV-associated nephropathy, prostate cancer, and acute renal failure. In certain embodiments, the subject has not been previously diagnosed with any of diabetic nephropathy, HIV-associated nephropathy, and acute renal failure. In certain embodiments, the subject has not been previously diagnosed with any of diabetic nephropathy, HIV-associated nephropathy, and acute renal failure. In some embodiments of the methods, uses, or products used herein, the subject has not been previously diagnosed with diabetes. In some embodiments of the methods, uses, or products used herein, the subject has not been previously diagnosed with type 2 diabetes. In some of the foregoing embodiments, it has been determined that the subject has a controlled serum glucose level as described anywhere herein.

[0242] 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-related nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject does not have one or more of diabetic nephropathy, HIV-related 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-related nephropathy. In certain embodiments, the subject does not have prostate cancer. In certain embodiments, the subject does not have any of diabetic nephropathy, HIV / AIDS, and acute renal failure. In certain embodiments, the subject does not have any of diabetic nephropathy, HIV / AIDS, prostate cancer, and acute renal failure. In certain embodiments, the subject does not have any of diabetic nephropathy, HIV-related nephropathy, prostate cancer, and acute renal failure. In certain embodiments, the subject does not have any of diabetic nephropathy, HIV-related nephropathy, prostate cancer, and acute renal failure. In certain embodiments, the subject does not have any of diabetic nephropathy, HIV-related 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, it has been determined that the subject has a controlled serum glucose level as described anywhere herein.

[0243] 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-related nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject does not have one or more of diabetic nephropathy, HIV-related 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-related nephropathy. In certain embodiments, the subject does not have prostate cancer. In certain embodiments, the subject does not have any of diabetic nephropathy, HIV / AIDS, and acute renal failure. In certain embodiments, the subject does not have any of diabetic nephropathy, HIV / AIDS, prostate cancer, and acute renal failure. In certain embodiments, the subject does not have any of diabetic nephropathy, HIV-related nephropathy, prostate cancer, and acute renal failure. In certain embodiments, the subject does not have any of diabetic nephropathy, HIV-related nephropathy, prostate cancer, and acute renal failure. In certain embodiments, the subject does not have any of diabetic nephropathy, HIV-related 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, it has been determined that the subject has a controlled serum glucose level as described anywhere herein.

[0244] In some embodiments, the subject is not receiving treatment for one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure. In some embodiments, the subject is not receiving treatment for one or more of diabetic nephropathy, HIV / AIDS, prostate cancer, or acute renal failure. In some embodiments, the subject is not receiving treatment for one or more of diabetic nephropathy, HIV-related nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject is not receiving treatment for one or more of diabetic nephropathy, HIV-related nephropathy, or acute renal failure. In certain embodiments, the subject is not receiving treatment for diabetic nephropathy. In certain embodiments, the subject is not receiving treatment for HIV / AIDS. In certain embodiments, the subject is not receiving treatment for acute renal failure. In certain embodiments, the subject is not receiving treatment for HIV-related nephropathy. In certain embodiments, the subject is not receiving treatment for prostate cancer. In certain embodiments, the subject is not receiving treatment for any of diabetic nephropathy, HIV / AIDS, and acute renal failure. In certain embodiments, the subject is not receiving treatment for any of diabetic nephropathy, HIV / AIDS, prostate cancer, and acute renal failure. In certain embodiments, the subject is not receiving treatment for any of diabetic nephropathy, HIV-associated nephropathy, prostate cancer, and acute renal failure. In certain embodiments, the subject is not receiving treatment for any of diabetic nephropathy, HIV-associated nephropathy, and acute renal failure. In certain embodiments, the subject is not receiving treatment for diabetes. In certain embodiments, the subject is not receiving treatment for type 2 diabetes. In some of the foregoing embodiments, it has been determined that the subject has a controlled serum glucose level as described anywhere herein.

[0245] In some embodiments, it has been determined that the subject has 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, it has been determined that the subject has a controlled serum glucose level. For example, it has been determined that the fasting serum glucose level of the subject is less than about 130mg / dL, about 125mg / dL, about 120mg / dL, about 115mg / dL, about 110mg / dL, about 105mg / dL, about 100mg / dL, about 95mg / dL, about 90mg / dL, about 85mg / dL, about 80mg / dL or about 75mg / 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, it has been determined that the subject has 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.

[0246] In some embodiments, the subject has not been previously diagnosed with a chronic kidney disease other than FSGS. Non-limiting examples include diabetic nephropathy, hypertensive nephropathy, IgA nephropathy, or a primary glomerulopathy determined to be unrelated to FSGS. In certain embodiments, the subject has not been previously diagnosed with diabetic nephropathy. In certain embodiments, the subject has not been previously diagnosed with hypertensive nephropathy. In certain embodiments, the subject has not been diagnosed with a primary glomerulopathy determined to be unrelated to FSGS.

[0247] In some embodiments, the subject does not have chronic kidney disease other than FSGS. Non-limiting examples include diabetic nephropathy, hypertensive nephropathy, or a primary glomerulopathy determined to be unrelated to FSGS. In certain embodiments, the subject does not have diabetic nephropathy. In certain embodiments, the subject does not have hypertensive nephropathy. In certain embodiments, the subject does not have a primary glomerulopathy determined to be unrelated to FSGS.

[0248] In some embodiments, the subject does not have chronic kidney disease other than FSGS. Non-limiting examples include diabetic nephropathy, hypertensive nephropathy, or a primary glomerulopathy determined to be unrelated to FSGS. In certain embodiments, the subject does not have diabetic nephropathy. In certain embodiments, the subject does not have hypertensive nephropathy. In certain embodiments, the subject does not have a primary glomerulopathy determined to be unrelated to FSGS.

[0249] In some embodiments, the subject is not receiving treatment for a chronic kidney disease other than FSGS. Non-limiting examples include diabetic nephropathy, hypertensive nephropathy, or a primary glomerulopathy determined to be unrelated to FSGS. In certain embodiments, the subject is not receiving treatment for diabetic nephropathy. In certain embodiments, the subject is not receiving treatment for hypertensive nephropathy. In certain embodiments, the subject is not receiving treatment for a primary glomerulopathy determined to be unrelated to FSGS.

[0250] IV. Treatment Outcomes

[0251] In some embodiments of the methods, uses, or products used herein, renal inflammation is reduced after treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, renal inflammation in a subject is reduced by at least about 10% after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks of treatment or any value therebetween). In some embodiments, the subject's renal inflammation 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 pharmaceutically acceptable salt thereof for between about 15 days and about 30 days.

[0252] In some embodiments, after treatment with atrasentan or a pharmaceutically acceptable salt thereof, renal fibrosis is reduced. In some embodiments, after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after 1 week of treatment, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween), the subject's renal fibrosis is reduced by at least about 10%. 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 pharmaceutically acceptable salt thereof for between about 15 days and about 30 days.

[0253] In some embodiments, after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks of treatment or any value therebetween), the subject's renal fibrosis is reduced to less than about 50% of the cortical area. 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 pharmaceutically acceptable salt thereof for between about 15 days and about 30 days.

[0254] In some embodiments, after treatment with atrasentan or a pharmaceutically 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 of treatment or any value therebetween), the rate of decline of the subject's eGFR is reduced by at least about 10%. In certain embodiments, the rate of decline of the subject's eGFR is reduced by at least about 20%. For example, in some embodiments, the rate of decline of 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 some of the foregoing embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 6 months and about 1 year.

[0255] In some embodiments, after treatment with atrasentan or a pharmaceutically 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), the rate of decline of the subject's eGFR is reduced to less than about 10 mL / min / year. In some embodiments, the rate of decline of the subject's eGFR is reduced to less than about 9 mL / min / year. For example, in some embodiments, the rate of decline of the subject's eGFR is reduced to 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 pharmaceutically acceptable salt thereof for between about 15 days and about 30 days. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 6 months and about 1 year.

[0256] In some embodiments, after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks of treatment or any value therebetween), the subject's risk of developing ESKD is reduced by about 20% to about 99%. For example, the risk of a subject developing ESKD can be reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 99%, or any value therebetween. In some of the foregoing embodiments, the subject has been treated for about 90 to about 180 days. In certain embodiments, after between about 90 and about 180 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof, the risk of a subject developing ESKD is reduced by about 20% to about 99%. In some of the foregoing embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 6 months and about 1 year.

[0257] In some embodiments, the method increases the diagnosis of FSGS in a subject and the subject's eGFR decreases to less than about 15 mL / min / 1.73 m 2 In certain embodiments, the method diagnoses FSGS in a subject and the subject's eGFR falls below 15 mL / min / 1.73 m 2 For example, in some embodiments, the method diagnoses FSGS in a subject and the subject's eGFR decreases to less than about 15 mL / min / 1.73 m 2 The time between the times of administration of the therapeutic agent and the therapeutic agent 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.

[0258] In some embodiments, the method diagnoses FSGS in a subject and the subject's eGFR decreases to less than 15 mL / min / 1.73 m 2 For example, the method can reduce the eGFR of the subject to less than 15 mL / min / 1.73 m 2 The time delay of 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 in between.

[0259] 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 at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years) prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the method reduces the average rate of decline in eGFR by about 0.75 mL / min / year, about 1 mL / min / year, about 1.5 mL / min / year, about 2 mL / min / year, about 2.5 mL / min / year, about 3 mL / min / year, about 3.5 mL / min / year, about 4 mL / min / year, about 4.5 mL / min / year, about 5 mL / min / year, about 5.5 mL / min / year, or about 6 mL / min / year. In some embodiments, at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the method reduces the average rate of decline in eGFR by about 4 mL / min / year to about 5 mL / min / year. In some embodiments, at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the method reduces the average rate of decline in eGFR by about 3 mL / min / year to about 6 mL / min / year. In some embodiments, at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the method reduces the average rate of decline in eGFR by about 4 mL / min / year to about 5 mL / min / year. In some embodiments, a decline in eGFR in mL / min / year refers to a decrease in eGFR per 1.73 m 2 Unit of.

[0260] In some embodiments, the method reduces the average rate of decline of 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 between about 6 months and about 24 months of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the average rate of decline of eGFR may be reduced by about 15% after about 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the average rate of decline of eGFR may be reduced by about 20% after about 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the average rate of decline in eGFR can be reduced by about 25% after about 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the average rate of decline in eGFR can be reduced by about 30% after about 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months of treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0261] In another aspect, provided herein is a method of reducing proteinuria, the method comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0262] In some embodiments, after treatment with atrasentan or a pharmaceutically 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), the amount of protein (e.g., albumin) in the subject's urine is reduced by at least about 10%. 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 pharmaceutically acceptable salt thereof for about 10 weeks to about 24 weeks. In some cases, after about 10 weeks of treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after 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), the amount of protein in the subject's urine is reduced by about 20% to about 80%. In some cases, after about 12 weeks of treatment with atrasentan or a pharmaceutically acceptable salt thereof, the amount of protein in the subject's urine is reduced by about 20% to about 80%. In some cases, after about 12 weeks to about 24 weeks (and including all ranges) of treatment with atrasentan or a pharmaceutically acceptable salt thereof, the amount of protein in the subject's urine is reduced by about 20% to about 80%. In some cases, after about 12 weeks to about 24 weeks of treatment with atrasentan or a pharmaceutically acceptable salt thereof, the amount of protein in the subject's urine is reduced by about 20% to about 80%.

[0263] In certain embodiments, after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof, the amount of protein (e.g., albumin) in the urine of the subject is reduced by about 20% to about 80%. 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 urine of the subject is reduced by about 50% to about 80%.

[0264] In some embodiments, after treatment with atrasentan or a pharmaceutically 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), 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. 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 urine of a subject is reduced by about 100 mg / dL to about 2,000 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 100 mg / dL to about 1,500 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 100 mg / dL to about 1,000 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 100 mg / dL to about 500 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 100 mg / dL to about 400 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 100 mg / dL to about 300 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 100 mg / dL to about 200 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 500 mg / dL to about 2,500 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 500 mg / dL to about 2,000 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 500 mg / dL to about 1,500 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 500 mg / dL to about 1,000 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 500 mg / dL to about 900 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 500 mg / dL to about 800 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 600 mg / dL to about 900 mg / dL. In certain embodiments, the amount of protein in the urine of a subject is reduced by about 700 mg / dL to about 900 mg / dL. In certain embodiments, the amount of protein in the urine of a subject 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 pharmaceutically acceptable salt thereof for between about 15 days and about 30 days.

[0265] In certain embodiments, the amount of protein (e.g., albumin) in the subject's urine is reduced by about 100 mg / dL to about 500 mg / dL after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In certain embodiments, the amount of protein in the subject's urine is reduced by about 200 mg / dL to about 500 mg / dL after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In certain embodiments, the amount of protein in the subject's urine is reduced by about 300 mg / dL to about 500 mg / dL after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0266] In certain embodiments, the amount of protein (e.g., albumin) in the subject's urine is reduced by about 500 mg / dL to about 900 mg / dL after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In certain embodiments, the amount of protein in the subject's urine is reduced by about 600 mg / dL to about 900 mg / dL after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In certain embodiments, the amount of protein in the subject's urine is reduced by about 700 mg / dL to about 900 mg / dL after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0267] In some embodiments, after treatment with atrasentan or a pharmaceutically 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), the subject's urine protein (e.g., albumin) level is reduced to less than about 1.0 g / day. In some embodiments, the subject's urine protein level is reduced to less than about 0.9 g / day. For example, in some embodiments, the level of protein in the subject's urine is reduced to less than about 0.8 g / day, about 0.7 g / day, about 0.6 g / day, 0.5 g / day, about 0.4 g / day, about 0.3 g / day, or about 0.2 g / day, or any value therebetween. In certain of the foregoing embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days.

[0268] In another aspect, provided herein is a method of reducing fatigue, the method comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof. Fatigue can be measured using methods known in the art. See, e.g., Machado.M., Int J Dermatol [International Journal of Dermatology], September 2021; 60(9): 1053-1069, which is incorporated by reference in its entirety.

[0269] In some embodiments, the subject is between about 15 and about 40 years old. In some embodiments, the subject is between 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 between 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.

[0270] In some embodiments, after treatment with atrasentan or a pharmaceutically acceptable salt thereof, the patient's fatigue level is reduced. In some embodiments, after treatment with atrasentan or a pharmaceutically 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), fatigue is reduced by about 5% to about 80%. In certain embodiments, fatigue is reduced by about 10% to about 75%. In certain embodiments, fatigue is reduced by about 10% to about 70%. 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 pharmaceutically acceptable salt thereof for between about 15 days and about 30 days. In some embodiments, the reduction in fatigue comprises a decrease in a score on one or more of the following: the Fatigue Severity Scale, the Chalder Fatigue Inventory, the FACIT Fatigue Scale, the Brief Fatigue Inventory, the FACT-F subscales, Global Vitality and Affect, the May and Kline Adjective Checklist, the Pearson-Byars Fatigue Perception Checklist, the Rhoten Fatigue Scale, the Fatigue and Asthenia Schedule, or the Personal Fatigue Intensity Scale.

[0271] Some embodiments provide a method of inhibiting mesangial cell activation in a subject having FSGS, the method comprising administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof; wherein the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure.

[0272] Some embodiments provide a method of inhibiting PDGF signaling activity in mesangial cells of a subject having FSGS (e.g., reducing the expression and / or activity of one or more of PIK3R1, PDGFRA, NFKBIA, PIK3CG, PLA2G4A, TIAM1, PDGFB, NFKB1, and MAP3K1), the method comprising administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof; wherein the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure.

[0273] Some embodiments provide a method of inhibiting mesangial cell activation, the method comprising contacting the mesangial cells with an effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0274] In some embodiments, mesangial cell activation is induced by IgA immune complexes. In some embodiments, mesangial cell activation is associated with the presence of IgA immune complexes. The presence and / or amount of IgA immune complexes can be detected by a variety of methods. For example, the complex can be detected in serum or urine, and can also be detected in a renal biopsy sample.

[0275] In some embodiments, inhibition of mesangial cell activation comprises reducing the expression and / or activity of one or more biomarkers indicative of mesangial cell proliferation. In some embodiments, inhibition of mesangial cell activation comprises reducing mesangial cell inflammation. In 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. In some embodiments, reducing mesangial cell inflammation comprises reducing the 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% after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks of treatment or any value therebetween). In some embodiments, the expression and / or activity of one or more biomarkers indicative of mesangial cell inflammation is reduced by about 25% to about 50%, about 40% to about 60%, about 50% to about 75%, about 60% to about 80%, about 75% to about 90%, about 85% to about 99%, or any value therebetween. For example, in some such embodiments, the one or more biomarkers may be IL-6.

[0276] In some embodiments, the inhibition of mesangial cell activation includes reducing mesangial cell inflammation. In some embodiments, reducing mesangial cell inflammation includes reducing IL-6 signaling (e.g., reducing the expression and / or activity of one or more proteins involved in the IL-6 signaling pathway, e.g., reducing the expression and / or activity of one or more of Cntfr, Il1b, Csf1, Il2ra, Map3k8, and Il1r1). In some embodiments, reducing mesangial cell inflammation includes reducing the expression and / or activity of one or more (e.g., 1, 2, 3, 4, or 5) of the following: Cntfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1.

[0277] In some embodiments, inhibition of mesangial cell activation comprises reducing profibrotic responses in mesangial cells. In some embodiments, reducing profibrotic responses in mesangial cells comprises reducing the expression and / or activity of one or more of NF-κB, TGF, PDGF, CTGF, MMP, TIMPS or other biomarkers indicative of mesangial cell fibrosis. In some embodiments, after treatment with atrasentan or a pharmaceutically 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), 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% relative to the expression and / or activity prior to administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the expression and / or activity of one or more of NF-κB, TGF, PDGF, CTGF, MMP and TIMPS is reduced by about 25% to about 50%, about 40% to about 60%, about 50% to about 75%, about 60% to about 80%, about 75% to about 90%, about 85% to about 99%, or any value therebetween.

[0278] In some embodiments, inhibition of mesangial cell activation comprises reducing profibrotic responses in mesangial cells. In some embodiments, reducing profibrotic responses comprises reducing NF-κB signaling. In some embodiments, reducing profibrotic responses comprises reducing the expression and / or activity of one or more (e.g., 1, 2, 3, 4, or 5) of the following: 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, and / or increasing the expression and / or activity of one or more (e.g., 1, 2, 3, 4, or 5) of the following: Ehd1, Snn, Tnfaip8, Ackr3, Id2, Ccn1, Efna1, Ccnd1, Cdkn1a, Pnrc1 (in the case where the component inhibits NF-κB signaling).

[0279] In some embodiments, reducing the profibrotic response comprises reducing PDGF signaling. In some embodiments, reducing the profibrotic response comprises reducing the 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 the expression and / or activity of one or more (e.g., 1, 2, 3, 4, or 5) of the following: Hras (in the case where the component inhibits PDGF signaling).

[0280] In some embodiments, after treatment with atrasentan or a pharmaceutically 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), the expression and / or activity of NF-κB and / or PDGF expression and / or activity is reduced by about 25% to about 99% relative to the expression and / or activity prior to administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the expression and / or activity of NF-κB and / or PDGF is reduced by about 25% to about 50%, about 40% to about 60%, about 50% to about 75%, about 60% to about 80%, about 75% to about 90%, about 85% to about 99%, or any value therebetween.

[0281] In some embodiments, reducing a profibrotic response in mesangial cells comprises reducing matrix secretion by mesangial cells. In some embodiments, reducing matrix secretion by mesangial cells comprises decreasing the expression and / or activity of one or more excess matrix secretions by mesangial cells.

[0282] Some embodiments provide a method of reducing activation of mesangial cells contacted with IgA immune complexes, the method comprising contacting the mesangial cells with an effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, reducing mesangial cell activation comprises reducing the expression and / or activity of one or more biomarkers indicative of mesangial cell proliferation.

[0283] In some embodiments, reducing mesangial cell activation comprises reducing mesangial cell inflammation. In 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.

[0284] In some embodiments, reducing mesangial cell activation comprises reducing profibrotic responses in mesangial cells. In some embodiments, reducing profibrotic responses in mesangial cells comprises reducing the expression and / or activity of one or more of TGF, PDGF, CTGF, MMP, TIMPS or other biomarkers indicative of mesangial cell fibrosis.

[0285] In some embodiments, reducing the profibrotic response in mesangial cells comprises reducing matrix secretion by mesangial cells. In some embodiments, reducing matrix secretion by mesangial cells comprises decreasing the expression and / or activity of one or more biomarkers indicative of excess matrix secretion by mesangial cells.

[0286] In some embodiments, reducing mesangial cell activation comprises reducing unwanted mesangial cell migration. In some embodiments, the reduction in unwanted mesangial cell migration occurs after about 15 days to about 30 days following treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the reduction in unwanted mesangial cell migration occurs after about 3 months to about 6 months following treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0287] In some embodiments, reducing mesangial cell activation comprises reducing undesirable mesangial cell proliferation. In some embodiments, the reduction in undesirable mesangial cell proliferation occurs after about 15 days to about 30 days following treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the reduction in undesirable mesangial cell proliferation occurs after about 3 months to about 6 months following treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0288] In some embodiments, undesirable mesangial cell proliferation is reduced by about 25% to about 99% after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks of treatment or any value therebetween). In some embodiments, undesirable 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.

[0289] In some embodiments, mesangial cell activation can be assessed by one or more of serum analysis, urine analysis, and microscopy (eg, light microscopy and / or immunofluorescence microscopy) of a kidney biopsy sample.

[0290] In some embodiments, the contacting is performed in vitro. In some embodiments, the contacting is performed in vivo.

[0291] 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 to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV / AIDS, or acute renal failure. In some embodiments, the subject has not been previously diagnosed with HIV-associated nephropathy. In some embodiments, the subject has not been previously diagnosed with cancer. In some embodiments, the cancer is lung cancer or prostate cancer.

[0292] Some embodiments provide a method of treating FSGS in a subject in need thereof, the method comprising: a) determining that the subject has elevated levels of mesangial cell activation; and b) administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0293] In some embodiments, determining an elevated level of mesangial cell activation comprises obtaining a sample from the subject and assessing the level of mesangial cell 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.

[0294] In some embodiments, the sample exhibits elevated levels of one or more of: matrix secretion by mesangial cells, IgA immune complex deposition, mesangial cell proliferation, and endocapillary cell proliferation. In some embodiments, the sample exhibits elevated levels of IgA immune complex deposition.

[0295] 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 elevated serum Gd-IgA1 levels; and c) administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0296] 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 elevated serum Gd-IgA1 levels; and c) administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0297] 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 elevated levels of mesangial cell activation; and c) administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0298] 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 elevated levels of mesangial cell activation; and c) administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0299] In some embodiments, the subject has been determined to have at least about 1 g / day of proteinuria in at least two of three consecutive readings in the year prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has been determined to have about 1 g / day to about 15 g / day of proteinuria in at least two of three consecutive readings in the year prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically 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.

[0300] In some embodiments, at least 12 weeks before administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof, a RAS inhibitor at a maximum tolerated stable dose has been administered to the subject. In some embodiments, a RAS inhibitor at a maximum tolerated stable dose and a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof are administered to the subject 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).

[0301] In some embodiments, prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof, the subject has been determined to have a blood pressure of at least 30 mL / min / 1.73 m 2 In some embodiments, prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof, the subject has been determined to have an eGFR of about 30 mL / min / 1.73 m2 to about 60mL / min / 1.73m 2 eGFR.

[0302] 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.

[0303] Some embodiments provide a method of treating FSGS in a subject in need thereof, the method comprising: a) determining elevated levels of IgA immune complexes in the kidney of the subject; and b) administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0304] In some embodiments, determining the elevated level 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 renal biopsy sample. In some embodiments, the sample is selected from a blood sample, a urine sample, a renal biopsy sample, or a combination of two or three of the foregoing. In some embodiments, the IgA immune complexes are deposited in the glomerular mesangium.

[0305] In some embodiments, the level of IgA immune complexes can be assessed by one or more of serum analysis, urine analysis, and microscopy (eg, light microscopy and / or immunofluorescence microscopy) of a kidney biopsy sample.

[0306] In some embodiments, the sample exhibits elevated levels of one or more of: matrix secretion by mesangial cells, IgA immune complex deposition in the glomerular mesangium, mesangial cell activation, mesangial cell proliferation, and endocapillary cell proliferation.

[0307] In some embodiments, the subject has been determined to have at least about 1 g / day of proteinuria in at least two of three consecutive readings in the year prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has been determined to have about 1 g / day to about 15 g / day of proteinuria in at least two of three consecutive readings in the year prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically 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.

[0308] In some embodiments, at least 12 weeks before administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof, a RAS inhibitor at a maximum tolerated stable dose has been administered to the subject. In some embodiments, a RAS inhibitor at a maximum tolerated stable dose and a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof are administered to the subject 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).

[0309] In some embodiments, prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof, the subject has been determined to have a blood pressure of at least 30 mL / min / 1.73 m 2 In some embodiments, prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof, the subject has been determined to have an eGFR of about 30 mL / min / 1.73 m 2 to about 60mL / min / 1.73m 2 eGFR.

[0310] 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.

[0311] In some embodiments, the method comprises determining 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 a subject. In some embodiments, the expression and / or activity is determined prior to administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the expression and / or activity is determined after administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0312] In some embodiments, expression and / or activity is determined prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, expression and / or activity is determined after administration of a therapeutically effective amount of atrasentan or a pharmaceutically 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).

[0313] In some embodiments, the subject has been determined to have elevated expression and / or activity of 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, cPLA2, TNF-α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt / PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK, MCP1, Cn tfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, 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, NF-kB, PKC, PI3K, Src, Ras, ERK1 / 2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA2, TNF-α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt / PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK, and MCP1.In some embodiments, the subject has been determined to have elevated expression and / or activity of one or more of: Cntfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1, and Pdgfb. In some embodiments, the subject has been determined to have increased expression and / or activity of one or more of the following: 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 increased expression and / or activity of one or more of the following: ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, and SLC6A19.

[0314] Some embodiments provide a method of treating FSGS in a subject, the method comprising: (a) determining that the subject has elevated expression and / or activity of 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, cPLA2, TNF-α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt / PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK, MCP1, Cntfr, I 2a1, 11a, 11b, 12b, 13b, 15b, 20b, 25b, 30b, 40b, 50b, 70b, 80b, 100, 150, 200, 300, 400, 500, 700, 800, 900, 1000, 1500, 2000, 3000, 4000, 5000, 7000, 8000, 9000, 10000, 15000, 20000, 30000, 40000, 50000, 70000, 80000, 90000, 100000, 300000, 400000

[0315] Some embodiments provide a method of treating FSGS in a subject 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, NF-kB, PKC, PI3K, Src, Ras, ERK1 / 2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA2, 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, The method comprises administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0316] V. Atrasentan

[0317] Atrasentan, also known as (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid, ABT-627, A-147627, or A-127722, is a small molecule with the following chemical structure:

[0318]

[0319] Atrasentan and methods for its preparation are described in US Pat. No. 7,208,517 and International Patent Application Publication No. WO 1997 / 030045 (see, e.g., Example 501), each of which is incorporated herein by reference in its entirety.

[0320] In some embodiments, atrasentan is administered as the free base. In some other embodiments, atrasentan is administered as a pharmaceutically acceptable salt as described anywhere herein.

[0321] Atrasentan is an ET A Inhibitors of ET A The selectivity is for ET B As used herein, “ET A ” is the abbreviation for endothelin receptor A; and “ET B ” is an abbreviation for endothelin receptor B. See, e.g., Ann Rheum Dis., 66(11), 1467–1472 (2007); Eur. Resp. J., 37, 475–476 (2011); Plos One, 9, e87548 (2014); J. Clin. Oncol., 10, 31(14), 1740–7 (2013); Pharmacol. Rev., 68(2), 357–418 (2016); and Nephrol. Dial. Transplant., 29, i69–i73 (2014).

[0322] Salt

[0323] 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 reaction between atrasentan and 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), gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate and p-toluenesulfonate, pamoate (i.e., 4,4'-methylene-bis-(2-hydroxy-3-naphthoate)). Exemplary salts also include base addition salts formed by reaction between atrasentan and a base. Non-limiting examples include: alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule, such as an acetate ion, a succinate ion, or other counterions. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. In addition, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Cases where multiple charged atoms are part of a pharmaceutically acceptable salt may have multiple counterions. Therefore, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions. When referring to atrasentan, the term "one or more salts" should be understood as salts of atrasentan, which may exist alone or mixed with free atrasentan.

[0324] In some embodiments, atrasentan is in the form of a hydrochloride salt. Atrasentan hydrochloride, also known as atrasentan hydrochloride (CAS No. 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; Abbott-147627.1, has the following structure:

[0325]

[0326] wherein the molar ratio of atrasentan to chloride is 1: 1. Atrasentan hydrochloride and methods for its preparation are further described in U.S. Patent No. 7,208,517 and International Patent Application Publication No. WO 1997 / 030045 (see, e.g., Example 501), each of which is incorporated herein by reference in its entirety.

[0327] In some embodiments, atrasentan is in the form of a mandelate. In certain embodiments, atrasentan is in the form of a (S)-mandelate. In certain embodiments, atrasentan is in the form of a (R)-mandelate. In certain embodiments, in atrasentan mandelate, the molar ratio of atrasentan to mandelate is 1: 1. In certain embodiments, in atrasentan mandelate, the molar ratio of atrasentan to mandelate is 2: 1. Atrasentan mandelate and methods for preparing the same 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.

[0328] 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. Pat. Nos. 8,962,675 and 9,637,476, each of which is incorporated herein by reference in its entirety.

[0329] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof is in the form of an anhydrate. In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is in the form of a hydrate. In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is in the form of a solvate.

[0330] Stereochemistry

[0331] Atrasentan has three asymmetric centers and can be prepared as individual stereoisomers (e.g., enantiomers or diastereomers) or as mixtures thereof, as described in U.S. Pat. No. 7,208,517 and International Patent Application Publication No. WO 1997 / 030045. In some embodiments, atrasentan as described herein comprises the (2R, 3R, 4S)-stereoisomer, i.e., (2R, 3R, 4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid. In certain embodiments, atrasentan is the (2R,3R,4S)-stereoisomer substantially free of other stereoisomers (e.g., containing <10%, <5%, <2%, <1%, <0.5%, <0.1%, or <0.05% of other stereoisomers).

[0332] Polymorph

[0333] Atrasentan or a pharmaceutically acceptable salt thereof as described herein may be in one or more polymorphic forms. In some embodiments, atrasentan or a pharmaceutically 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 pharmaceutically acceptable salt thereof is substantially crystalline (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% crystalline).

[0334] In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof comprises atrasentan hydrochloride crystalline Form 1. In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is substantially atrasentan hydrochloride crystalline Form 1 (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% Form 1). Atrasentan hydrochloride crystalline Form 1 and methods for its preparation are described in International Patent Application Publication No. WO 2006 / 034094, which is incorporated herein by reference in its entirety.

[0335] In some embodiments, the atrasentan hydrochloride crystalline Form 1 is characterized by an X-ray powder diffraction pattern having at least three (e.g., 3, 4, 5, 6, or 7) peaks, each of which has a 2θ value of about 8.3°, 9.7°, 10.0°, 13.0°, 15.6°, 17.2°, or 19.5°, when measured at about 25°C using Cu-Kα radiation. In certain embodiments, the atrasentan hydrochloride crystalline Form 1 is characterized by an X-ray powder diffraction pattern having at least three peaks, each of which has a 2θ value of about 8.3°, 9.7°, 10.0°, 13.0°, 15.6°, 17.2°, or 19.5°, when measured at about 25°C using Cu-Kα radiation, and substantially no peaks having a 2θ value below about 6.2° and / or between about 6.6° and 8.0°.

[0336] In some embodiments, atrasentan hydrochloride crystalline form 1 is characterized by having an orthorhombic crystal system and a P2 l 2 l 2 l In the space group, when measured with Cu-Kα radiation at about 25 °C, the lattice parameters a, b, and c are and

[0337] 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.

[0338] Representative characteristic peak positions in the X-ray powder diffraction pattern of atrasentan hydrochloride crystalline form I, expressed in degrees relative to 2θ, when measured at about 25°C using Cu-Ka radiation, are about 8.3° ((020), 77.35%); 9.7° ((120), 76.37%); 10.0° ((200), 14.53%); 13.2° ((220), 28.03%); 13.6° ((130), 16.71%); 14.9° ((121), 38.93%); 15.8° ((310), 33.73%); 16.9° ((411), 34.77%); 17.0° ((431), 36.97%); 18.1° ((412), 37.70%); 19. ), 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 the peak heights may vary and will depend on variables such as temperature, crystal size or morphology, sample preparation, or sample height in the analysis well of the Scintag×2 diffractogram system. It should also be understood that the peak positions may vary when measured with different radiation sources. For example, the wavelengths are and The Cu-Kα1, Mo-Kα, Co-Kα and Fe-Kα radiations may provide peak positions different from those measured with Cu-Kα radiation.

[0339] In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof comprises atrasentan hydrochloride crystalline Form 2. In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is substantially atrasentan hydrochloride crystalline Form 2 (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% Form 2). Atrasentan hydrochloride crystalline Form 2 and methods for its preparation are described in International Patent Application Publication No. WO 2006 / 034084, which is incorporated herein by reference in its entirety.

[0340] In certain embodiments, the atrasentan hydrochloride crystalline Form 2 is characterized by an X-ray powder diffraction pattern having peaks with respective 2θ values ​​of about 6.7° and 22.05° and at least one peak with respective 2θ values ​​of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6° when measured at about 25°C with Cu-Kα radiation.

[0341] In certain embodiments, the atrasentan hydrochloride crystalline Form 2 has substantial crystalline purity and is characterized by an X-ray powder diffraction pattern having peaks with respective 2θ values ​​of about 6.7° and 22.05° and at least one peak with respective 2θ values ​​of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6° when measured at about 25°C with Cu-Kα radiation.

[0342] In certain embodiments, the atrasentan hydrochloride crystalline Form 2 has substantial crystalline purity and substantial chemical purity; and the atrasentan hydrochloride crystalline Form 2 is characterized by an X-ray powder diffraction pattern having peaks with respective 2θ values ​​of about 6.7° and 22.05° and at least one peak with respective 2θ values ​​of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6° when measured at about 25°C using Cu-Kα radiation.

[0343] In certain embodiments, the atrasentan hydrochloride crystalline Form 2 has substantial crystalline purity, substantial chemical purity, and substantial diastereomeric purity; and the atrasentan hydrochloride crystalline Form 2 is characterized by an X-ray powder diffraction pattern having peaks with respective 2θ values ​​of about 6.7° and 22.05° and at least one peak with respective 2θ values ​​of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6° when measured at about 25°C using Cu-Kα radiation.

[0344] In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof comprises atrasentan hydrochloride crystalline Form 3. In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is substantially atrasentan hydrochloride crystalline Form 3 (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% Form 3). Atrasentan hydrochloride crystalline Form 3 and methods for its preparation are described in International Patent Application Publication No. WO 2006 / 034234 and U.S. Patent No. 9,051,301, each of which is incorporated herein by reference in its entirety.

[0345] In certain embodiments, the atrasentan hydrochloride crystalline Form 3 is characterized by an X-ray powder diffraction pattern having peaks with respective 2θ values ​​of about 6.7° and 21.95° and at least one peak with respective 2θ values ​​of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6° when measured at about 25°C with Cu-Kα radiation.

[0346] In certain embodiments, the atrasentan hydrochloride crystalline Form 3 has substantial crystalline purity and is characterized by an X-ray powder diffraction pattern having peaks with respective 2θ values ​​of about 6.7° and 21.95° and at least one peak with respective 2θ values ​​of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6° when measured at about 25°C with Cu-Kα radiation.

[0347] In certain embodiments, the atrasentan hydrochloride crystalline Form 3 has substantial crystalline purity and substantial chemical purity; and the atrasentan hydrochloride crystalline Form 3 is characterized by an X-ray powder diffraction pattern having peaks with respective 2θ values ​​of about 6.7° and 21.95° and at least one peak with respective 2θ values ​​of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6° when measured at about 25°C using Cu-Kα radiation.

[0348] In certain embodiments, the atrasentan hydrochloride crystalline Form 3 has substantial crystalline purity, substantial chemical purity, and substantial diastereomeric purity; and the atrasentan hydrochloride crystalline Form 3 is characterized by an X-ray powder diffraction pattern having peaks with respective 2θ values ​​of about 6.7° and 21.95° and at least one peak with respective 2θ values ​​of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8°, or 20.6° when measured at about 25°C using Cu-Kα radiation.

[0349] In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof comprises amorphous atrasentan hydrochloride. In certain embodiments, atrasentan hydrochloride is substantially amorphous (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% amorphous). Amorphous atrasentan hydrochloride and methods for its preparation are described in International Patent Application Publication No. WO 2006 / 034085, which is incorporated herein by reference in its entirety.

[0350] In certain embodiments, the amorphous atrasentan hydrochloride has substantial chemical purity. In certain embodiments, the amorphous atrasentan hydrochloride has substantial diastereomeric purity.

[0351] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof comprises crystalline atrasentan mandelate. In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is substantially crystalline atrasentan mandelate (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% crystalline atrasentan mandelate).

[0352] In certain embodiments, crystalline atrasentan mandelate is crystalline atrasentan (S)-mandelate. In certain embodiments, atrasentan (S)-mandelate is an anhydrous salt. In certain embodiments, atrasentan (S)-mandelate is a solvated salt. In certain embodiments, atrasentan (S)-mandelate is a solvated salt selected from the group consisting of acetonitrile solvate, ethanol solvate, and pyridine solvate. In certain embodiments, atrasentan (S)-mandelate is a hydrated salt.

[0353] (a) (S)-Mandelate (1:1 stoichiometry)

[0354] In certain embodiments, crystalline atrasentan (S)-mandelate is crystalline atrasentan (S)-mandelate, wherein the molar ratio of atrasentan to (S)-mandelate is about 1:1. In certain embodiments, atrasentan (S)-mandelate is an anhydrous salt. In certain embodiments, atrasentan (S)-mandelate is a solvated salt. In certain embodiments, atrasentan (S)-mandelate is a solvated salt selected from the group consisting of acetonitrile solvate, ethanol solvate, and pyridine solvate. In certain embodiments, atrasentan (S)-mandelate is a hydrated salt. In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is substantially (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5%) crystalline atrasentan (S)-mandelate, wherein the molar ratio of atrasentan to (S)-mandelate is about 1:1.

[0355] 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 with 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 with 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 with monochromatic Kα1 radiation at about 25°C. In certain embodiments, the experimental error associated with the X-ray powder diffraction peaks 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.

[0356] In certain embodiments, the crystalline (S)-mandelate salt has an orthorhombic lattice type. In certain embodiments, the crystalline (S)-mandelate salt has a P212121 space group. In certain embodiments, the unit cell a, b, and c values ​​of the crystalline (S)-mandelate salt are about about Peace 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 properties: (a) an orthorhombic lattice type, (b) a P212121 space group, (c) unit cell a, b, and c values ​​of about about Peace and / or (d) unit cell α, β, and γ values ​​are about 90°, about 90°, and about 90°, respectively. In certain embodiments, the crystalline (S)-mandelate salt has: (a) an orthorhombic lattice type, (b) a P212121 space group, (c) unit cell a, b, and c values ​​are about about Peace and (d) unit cell α, β, and γ values ​​are 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.

[0357] (b) (S)-Mandelate (2:1 stoichiometry)

[0358] In certain embodiments, the crystalline (S)-mandelate is crystalline atrasentan (S)-mandelate, wherein the molar ratio of atrasentan to (S)-mandelate is about 2: 1. In certain embodiments, the crystalline atrasentan (S)-mandelate is an anhydrous salt. In certain embodiments, the crystalline atrasentan (S)-mandelate is a solvated salt. In certain embodiments, the crystalline atrasentan (S)-mandelate is a hydrated salt. In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is substantially (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99% or >99.5%) crystalline atrasentan (S)-mandelate, wherein the molar ratio of atrasentan to (S)-mandelate is about 2: 1.

[0359] 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 with 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 with 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 with monochromatic Kα1 radiation at about 25°C. In certain embodiments, the experimental error associated with the X-ray powder diffraction peaks 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.

[0360] In certain embodiments, crystalline atrasentan mandelate is crystalline atrasentan (R)-mandelate. In certain embodiments, crystalline atrasentan (R)-mandelate is an anhydrous salt. In certain embodiments, crystalline atrasentan (R)-mandelate is a solvated salt. In certain embodiments, crystalline atrasentan (R)-mandelate is a hydrated salt.

[0361] (c)(R)-Mandelate (1:1 stoichiometry)

[0362] In certain embodiments, crystalline atrasentan (R)-mandelate is crystalline atrasentan (R)-mandelate, wherein the molar ratio of atrasentan to (R)-mandelate is about 1: 1. In certain embodiments, crystalline atrasentan (R)-mandelate is an anhydrous salt. In certain embodiments, crystalline atrasentan (R)-mandelate is a solvated salt. In certain embodiments, crystalline atrasentan (R)-mandelate is a hydrated salt. In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is substantially (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99% or >99.5%) crystalline atrasentan (R)-mandelate, wherein the molar ratio of atrasentan to (R)-mandelate is about 1: 1.

[0363] 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 with monochromatic Kα1 radiation at about 25°C. 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 with monochromatic Kα1 radiation at about 25°C. 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 with monochromatic Kα1 radiation at about 25°C. In certain embodiments, the experimental error associated with the X-ray powder diffraction peaks listed in the various Examples above is ±0.1 degrees 2Θ. In certain embodiments, the crystalline atrasentan (R)-mandelate salt is an anhydrous salt.

[0364] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof comprises amorphous atrasentan mandelate. In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is substantially amorphous atrasentan mandelate (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% amorphous atrasentan mandelate).

[0365] In certain embodiments, amorphous atrasentan mandelate is amorphous atrasentan (S)-mandelate. In certain embodiments, amorphous atrasentan (S)-mandelate is an anhydrous salt. In certain embodiments, amorphous atrasentan (S)-mandelate is a solvated salt. In certain embodiments, amorphous atrasentan (S)-mandelate is a solvated salt selected from the group consisting of: acetonitrile solvate, ethanol solvate and pyridine solvate. In certain embodiments, amorphous atrasentan (S)-mandelate is a hydrated salt. In certain embodiments, in amorphous atrasentan (S)-mandelate, the molar ratio of atrasentan to (S)-mandelate is about 1: 1. In certain embodiments, in amorphous atrasentan (S)-mandelate, the molar ratio of atrasentan to (S)-mandelate is about 2: 1.

[0366] In certain embodiments, amorphous atrasentan mandelate is amorphous atrasentan (R)-mandelate. In certain embodiments, amorphous atrasentan (R)-mandelate is an anhydrous salt. In certain embodiments, amorphous atrasentan (R)-mandelate is a solvated salt. In certain embodiments, amorphous atrasentan (R)-mandelate is a solvated salt selected from the group consisting of: acetonitrile solvate, ethanol solvate and pyridine solvate. In certain embodiments, amorphous atrasentan (R)-mandelate is a hydrated salt. In certain embodiments, in amorphous atrasentan (R)-mandelate, the molar ratio of atrasentan to (R)-mandelate is about 1: 1. In certain embodiments, in amorphous atrasentan (R)-mandelate, the molar ratio of atrasentan to (R)-mandelate is about 2: 1.

[0367] Crystalline and amorphous atrasentan mandelate are further described in US Pat. Nos. 8,962,675 and 9,637,476, each of which is incorporated herein by reference in its entirety.

[0368] VI. Preparations

[0369] As used herein, the term "pharmaceutical composition" is intended to encompass products comprising active ingredients and inert ingredients constituting a carrier, as well as any product produced directly or indirectly by the combination, complex or aggregation of any two or more of these ingredients, or by the dissociation of one or more of these ingredients, or by other types of reactions or interactions of one or more of these ingredients. Thus, the pharmaceutical composition of the present disclosure encompasses any composition made by mixing a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, or a solvate of a salt, with a pharmaceutically acceptable carrier.

[0370] The dosage depends on the compound formulation, route of administration, etc., and is usually determined empirically, and will inevitably vary according to the target, host, route of administration, etc. Typically, the amount of active compound in a unit dose formulation 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, depending on the specific application. For convenience, the total daily dose can be divided and administered in portions throughout the day.

[0371] The pharmaceutical composition of the disclosure for injection comprises pharmaceutically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, and the sterile powder that is reconstituted into sterile injectable solution or dispersion before use.The example of suitable aqueous and non-aqueous carrier, diluent, solvent or vehicle comprises water, ethanol, polyol (such as glycerol, propylene glycol, polyethylene glycol etc.) and its suitable mixture, vegetable oil (such as olive oil) and injectable organic ester (such as ethyl oleate).Suitable fluidity can be maintained, for example, in the following manner: by using coating material (such as lecithin), by maintaining required particle size in the case of dispersion, and by using surfactant.

[0372] These pharmaceutical compositions can also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. It is possible to ensure that microorganisms are prevented from working by including various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, etc.). It is also possible to wish to include isotonic agents, such as sugar, sodium chloride, etc. The extended absorption of injectable drug forms can be achieved by including agents (e.g., aluminum monostearate and gelatin) that delay absorption. Compounds can be incorporated into sustained release or targeted delivery systems (e.g., polymer matrices, liposomes, and microspheres). Such preparations can provide more effective compound distribution.

[0373] Pharmaceutical compositions for injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0374] Solid dosage forms of the pharmaceutical composition of the present invention for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrants 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 glyceryl monostearate, h) adsorbents such as kaolin and bentonite clays, 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 form may also comprise buffering agents.

[0375] 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.

[0376] The solid dosage forms of the pharmaceutical composition of the present invention are tablets, dragees, capsules, pills and granules, which can be prepared with coatings and shells, such as enteric coatings and other pharmaceutical coatings. They may optionally contain opacifiers and may also be such formulations: they release the active ingredient only or preferably in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedded pharmaceutical compositions that can be used include polymeric substances and waxes.

[0377] The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0378] Liquid dosage forms of the pharmaceutical composition of the present invention for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.

[0379] Besides inert diluents, oral pharmaceutical compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0380] Suspensions of the compounds of this invention, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0381] The compounds and compositions described herein can be administered, for example, orally or parenterally, in a dosage range of about 0.01 milligrams per kilogram (mg / kg) to about 0.05 mg / kg every 4 to 120 hours, or as required by a particular drug, dosage form, and / or route of administration. Freireich et al., Cancer Chemother. Rep. [Cancer Chemotherapy Report] 50, 219-244 (1966) describe the dosage relationship for animals and humans (based on mg / square meter of body surface). The body surface area can be roughly determined by the height and weight of the patient. See, for example, Scientific Tables [Scientific Tables], Geigy Pharmaceuticals [Jiaji Pharmaceuticals], Ardsley, New York, 537 (1970). In certain embodiments, the composition is administered orally or by injection. The methods herein contemplate administering an effective amount of a compound or compound composition to achieve a desired or prescribed effect. Typically, the pharmaceutical composition of the present disclosure will be administered about 1 to about 6 times a day, or alternatively as a continuous infusion. Such administration can be used as a chronic or acute therapy.

[0382] 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 specific compound employed, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, severity and course of the disease, disorder or symptom, the patient's predisposition to disease, and the judgment of the treating physician.

[0383] The dosage form includes about 0.01 mg to about 10 mg (including about 0.1 mg to about 5 mg, about 0.2 mg to about 4 mg, about 0.3 mg to about 3 mg, about 0.4 mg to about 2 mg, about 0.5 mg to about 1.5 mg, about 0.6 mg to about 1 mg, or about 1.25 mg to about 1.75 mg) of atrasentan compound or a pharmaceutically 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 pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises about 0.75 mg of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises about 1.5 mg of atrasentan or a pharmaceutically acceptable salt thereof.

[0384] The dosage form may further include a pharmaceutically acceptable carrier and / or an additional therapeutic agent.

[0385] Appropriate dosage level can be determined by any suitable method. Preferably, for topical application, the active substance is applied at a frequency of 1 to 4 times per day, or less frequently if a drug delivery system is used. However, the actual dosage level and application schedule of the active ingredient in the pharmaceutical composition of the present disclosure can be changed to obtain a certain amount of active ingredient, the amount of which effectively achieves the desired therapeutic response for a specific patient, composition and mode of administration, without producing unbearable toxicity to the patient. In some cases, the dosage may deviate from the prescribed amount, and in particular, the prescribed amount may vary according to the patient's age, sex, weight, diet and general health, route of administration, individual response to the active ingredient, the nature of the preparation, and the time or interval at which it is applied. Therefore, in some cases, it may be satisfactory to manage with an amount less than the aforementioned minimum amount, and in other cases, it may exceed the prescribed upper limit. If a larger amount is applied, it is recommended to divide these amounts into multiple separate doses, scattered throughout the day.

[0386] Exemplary Dosage Forms of Atrasentan

[0387] 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 pharmaceutically acceptable salt thereof; wherein the weight percentage of atrasentan or a pharmaceutically acceptable salt thereof in the dosage form is about 0.05 weight percent to about 2.0 weight percent based on the equivalent weight of atrasentan free base; and (b) a pharmaceutically acceptable diluent.

[0388] 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 pharmaceutically acceptable salt thereof; wherein the weight percentage of atrasentan or a pharmaceutically acceptable salt thereof in the dosage form is about 0.05 weight percent to about 2.0 weight percent based on the equivalent weight of atrasentan free base; (b) a pharmaceutically acceptable antioxidant; wherein the molar ratio of the antioxidant to atrasentan or a pharmaceutically acceptable salt thereof is about 10:1 to about 1:10; and (c) a pharmaceutically acceptable diluent.

[0389] 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 pharmaceutically acceptable salt thereof; wherein the weight percentage of atrasentan or a pharmaceutically acceptable salt thereof in the dosage form is about 0.05 weight percent to about 2.0 weight percent based on the equivalent weight of atrasentan free base; and (b) a pharmaceutically acceptable diluent.

[0390] 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 pharmaceutically acceptable salt thereof; wherein the weight percentage of atrasentan or a pharmaceutically acceptable salt thereof in the dosage form is about 0.05 weight percent to about 2.0 weight percent based on the equivalent weight of atrasentan free base; (b) a pharmaceutically acceptable antioxidant; wherein the molar ratio of the antioxidant to atrasentan or a pharmaceutically acceptable salt thereof is about 10:1 to about 1:10; and (c) a pharmaceutically acceptable diluent.

[0391] In certain of these embodiments, when the dosage form is stored at about 40° C. and about 75% relative humidity for a shelf life of six months, degradation of atrasentan in the dosage form is less than degradation of atrasentan in an otherwise identical dosage form lacking the antioxidant.

[0392] In some embodiments, the dosage form is stored in a semipermeable container or a substantially impermeable container during the storage period. In some embodiments, the dosage form is stored in a sealed HDPE bottle or blister pack 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 pack during the storage period.

[0393] (i) Atrasentan

[0394] The dosage form may comprise a free base of atrasentan, a pharmaceutically acceptable salt of atrasentan, or a combination thereof. In some embodiments, the dosage form comprises a free base of atrasentan. In some embodiments, the dosage form comprises a pharmaceutically 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 (when 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.

[0395] In certain embodiments, the dosage form comprises amorphous atrasentan hydrochloride; and it is substantially free (e.g., contains <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) of other forms (e.g., other salts and / or other polymorphs) of atrasentan. In certain embodiments, the dosage form comprises atrasentan hydrochloride crystalline Form 1; and it is substantially free (e.g., contains <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) of other forms (e.g., other salts and / or other polymorphs) of atrasentan. In certain embodiments, the dosage form comprises atrasentan hydrochloride crystalline Form 2; and it is substantially free of other forms (e.g., other salts and / or other polymorphs) of atrasentan. In certain embodiments, the dosage form comprises crystalline Form 3 of atrasentan hydrochloride; and it is substantially free (e.g., contains <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) of other forms (e.g., other salts and / or other polymorphs) of atrasentan. In certain embodiments, the dosage form comprises crystalline atrasentan (S)-mandelate; and it is substantially free (e.g., contains <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) of other forms (e.g., other salts and / or other polymorphs) of atrasentan. In certain embodiments, the dosage form comprises crystalline atrasentan (R)-mandelate; and it is substantially free (e.g., contains <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) of other forms (e.g., other salts and / or other polymorphs) of atrasentan. In certain embodiments, the dosage form comprises amorphous atrasentan (S)-mandelate; and it is substantially free (e.g., contains <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) of other forms (e.g., other salts and / or other polymorphs) of atrasentan. In certain embodiments, the dosage form comprises amorphous atrasentan (R)-mandelate; and it is substantially free (e.g., contains <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) of other forms (e.g., other salts and / or other polymorphs) of atrasentan.

[0396] In some embodiments, the weight percentage of atrasentan or a pharmaceutically acceptable salt thereof in the dosage form is about 0.1 weight percent to about 2.0 weight percent based on the equivalent weight of atrasentan free base. In some embodiments, the weight percentage of atrasentan or a pharmaceutically acceptable salt thereof in the dosage form is about 0.2 weight percent to about 1.0 weight percent based on the equivalent weight of atrasentan free base. In some embodiments, the weight percentage of atrasentan or a pharmaceutically acceptable salt thereof in the dosage form is about 0.3 weight percent to about 0.8 weight percent based on the equivalent weight of atrasentan free base. In some embodiments, the weight percentage of atrasentan or a pharmaceutically acceptable salt thereof in the dosage form is about 0.40 weight percent to about 0.45 weight percent based on the equivalent weight of atrasentan free base. In some embodiments, the weight percentage of atrasentan or a pharmaceutically acceptable salt thereof in the dosage form is about 0.60 weight percent to about 0.65 weight percent based on the equivalent weight of atrasentan free base.

[0397] In some embodiments, the dosage form comprises about 0.40 mg to about 1.00 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises about 0.40 mg to about 0.85 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises about 0.50 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises about 0.75 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises about 1.25 mg to about 1.75 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises about 1.5 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0398] (ii) Diluent

[0399] Suitable diluents for use in the disclosed dosage forms include, but are not limited to, lactose (e.g., lactose monohydrate, anhydrous lactose, and DCL21), sucrose, glucose, mannitol, sorbitol, isomalt, microcrystalline cellulose (e.g. PH101 and PH102), silicified microcrystalline cellulose (e.g. 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.

[0400] In certain embodiments, the weight percentage of the diluent in the dosage form is about 70 weight percentages to about 99 weight percentages. In certain embodiments, the weight percentage of the diluent in the dosage form is about 80 weight percentages to about 99 weight percentages. In certain embodiments, the weight percentage of the diluent in the dosage form is about 85 weight percentages to about 99 weight percentages. 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.

[0401] (iii) Adhesives

[0402] In certain embodiments, the dosage form further comprises a pharmaceutically acceptable binder (e.g., a polymer binder). Suitable binders for use in the disclosed dosage form include, but are not limited to, cellulose, such as hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose E5 (Premium LV)), hydroxypropyl ethylcellulose and hydroxypropyl cellulose, and other pharmaceutically acceptable substances with bonding properties. In certain embodiments, the binder is selected from the group consisting of: hydroxymethyl propyl cellulose, hydroxyethyl propyl cellulose and hydroxypropyl cellulose. In certain embodiments, the binder is hydroxypropyl methylcellulose. In certain embodiments, the binder is hydroxypropyl methylcellulose. In certain embodiments, the binder is hydroxypropyl cellulose. In certain embodiments, the binder is hydroxyethyl propyl cellulose.

[0403] In some embodiments, the dosage form further comprises a pharmaceutically acceptable binder; and the weight percentage of the binder in the dosage form is about 1.0 weight percent to about 10.0 weight percent. In some embodiments, the weight percentage of the binder in the dosage form is about 1.0 weight percent to about 8.0 weight percent. In some embodiments, the weight percentage of the binder in the dosage form is about 1.0 weight percent to about 5.0 weight percent. In some of the foregoing embodiments, the binder is a polymer binder selected from the group consisting of: hydroxymethylpropyl cellulose, hydroxyethylpropyl cellulose, and hydroxypropyl cellulose.

[0404] In some embodiments, the dosage form further comprises a pharmaceutically acceptable binder; and the weight ratio of the binder to atrasentan or a pharmaceutically acceptable salt thereof is about 2:1 to about 25:1 by weight of atrasentan free base equivalent. In some embodiments, the weight ratio of the binder to atrasentan or a pharmaceutically acceptable salt thereof is about 1:1 to about 20:1 by weight of atrasentan free base equivalent. In some embodiments, the weight ratio of the binder to atrasentan or a pharmaceutically acceptable salt thereof is about 1:1 to about 15:1 by weight of atrasentan free base equivalent. In certain embodiments, the binder is a polymer binder selected from the group consisting of hydroxymethylpropyl cellulose, hydroxyethylpropyl cellulose, and hydroxypropyl cellulose;

[0405] (iv) Disintegrant

[0406] In some embodiments, the dosage form optionally comprises a pharmaceutically acceptable disintegrant. Suitable disintegrants for use in the disclosed dosage forms include, but are not limited to, cross-linked polyvinyl pyrrolidone (e.g., POLYPLASDONE TM In some embodiments, the disintegrant is selected from the group consisting of: crospovidone, sodium starch glycolate, and crospovidone. In some embodiments, the disintegrant is cross-linked polyvinyl pyrrolidone. In some embodiments, the disintegrant is crospovidone.

[0407] In some embodiments, the dosage form further comprises a pharmaceutically acceptable disintegrant. In certain embodiments, the weight percentage of the disintegrant in the dosage form is about 1.0 weight percentage to about 10.0 weight percentage. In some embodiments, the weight percentage of the disintegrant in the dosage form is about 1.0 weight percentage to about 6.0 weight percentage. In some embodiments, the weight percentage of the disintegrant in the dosage form is about 1.0 weight percentage to about 4.0 weight percentage. In some of the foregoing embodiments, the disintegrant is crospovidone.

[0408] In some embodiments, the dosage form further comprises a pharmaceutically acceptable disintegrant, and the weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine) or a pharmaceutically acceptable salt or ester thereof is about 60: 1 to about 3: 1. In some embodiments, the weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine) or a pharmaceutically acceptable salt or ester thereof is about 50: 1 to about 4: 1. In some embodiments, the weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine) or a pharmaceutically acceptable salt or ester thereof is about 35: 1 to about 5: 1.

[0409] (v) Additional excipients

[0410] In further embodiments, the dosage form optionally comprises a pharmaceutically acceptable lubricant and / or glidant. Suitable lubricants and glidants for use in the disclosed dosage forms include, but are not limited to, silicon dioxide (e.g. 244FP and 200), Glyceryl Behenate (e.g. ), talc, stearic acid, solid polyethylene glycol, silica gel and mixtures thereof, and other substances having lubricating or flow-aiding properties. In certain embodiments, the lubricant is glyceryl behenate (e.g. In certain embodiments, the glidant is silicon dioxide (eg 244FP). In certain embodiments, the lubricant is glyceryl behenate and the glidant is silicon dioxide.

[0411] In some embodiments, the dosage form further comprises a pharmaceutically acceptable glidant. On the other hand, the weight percentage of the glidant in the dosage form is about 0.1 weight percentage to about 1.5 weight percentage. In some embodiments, the weight percentage of the glidant in the dosage form is about 0.1 weight percentage to about 1.0 weight percentage. In some embodiments, the weight percentage of the glidant in the dosage form is about 0.1 weight percentage to about 0.8 weight percentage. In some embodiments, the glidant is silicon dioxide.

[0412] In some embodiments, the dosage form further comprises a pharmaceutically acceptable lubricant. In some embodiments, the dosage form further comprises a pharmaceutically acceptable hydrophobic lubricant. In some embodiments, the weight percent of the lubricant in the dosage form is about 0.05 weight percent to about 5.0 weight percent. In some embodiments, the weight percent of the lubricant in the dosage form is about 0.2 weight percent to about 3.0 weight percent. In some embodiments, the weight percent of the lubricant in the dosage form is about 0.5 weight percent to about 2.0 weight percent. In certain embodiments, the lubricant is glyceryl behenate.

[0413] In some embodiments, the dosage form further comprises a disintegrant, a glidant, and a lubricant.

[0414] (vi) Antioxidants

[0415] Suitable antioxidants for use in the disclosed dosage forms include antioxidants that are used as reducing agents and are oxidized to pharmaceutically acceptable reduction products in the dosage form. In some embodiments, the redox potential of the antioxidant is less than the redox potential of atrasentan (i.e., the redox potential is less than about 900mV) and greater than about 550mV. In some embodiments, the redox potential of the antioxidant is less than about 550mV. In some embodiments, the redox potential of the antioxidant is about 1mV to about 550mV. In some embodiments, the solubility of the antioxidant in water at about 25°C is greater than about 24mg / mL. In some embodiments, the antioxidant is an amino acid or a pharmaceutically acceptable salt or ester thereof. In some embodiments, the antioxidant is cysteine. In some embodiments, the antioxidant is L-cysteine ​​or a pharmaceutically acceptable salt or ester thereof. In some embodiments, the antioxidant is selected from the group consisting of: L-cysteine ​​hydrochloride monohydrate, L-cysteine ​​hydrochloride anhydrate and L-cysteine ​​ethyl ester. In some embodiments, the dosage form comprises L-cysteine ​​hydrochloride monohydrate.

[0416] In some embodiments, the weight percent of the antioxidant in the dosage form is about 0.05 weight percent to about 1.0 weight percent. In some embodiments, the weight percent of the antioxidant in the dosage form is about 0.07 weight percent to about 0.7 weight percent. In some embodiments, the weight percent of the antioxidant in the dosage form is about 0.09 weight percent to about 0.5 weight percent.

[0417] In some embodiments, the molar ratio of the antioxidant to atrasentan or a pharmaceutically acceptable salt thereof is about 10:1 to about 1:10. In some embodiments, the molar ratio of the antioxidant to atrasentan or a pharmaceutically acceptable salt thereof in the dosage form is about 5:1 to about 1:5. In some embodiments, the molar ratio of the antioxidant to atrasentan or a pharmaceutically acceptable salt thereof is about 2:1 to about 1:2. In some embodiments, the molar ratio of the antioxidant to atrasentan or a pharmaceutically acceptable salt thereof is about 1:1.

[0418] In some embodiments, the antioxidant is L-cysteine ​​or a pharmaceutically acceptable salt thereof. In certain embodiments, the weight percentage of L-cysteine ​​or a pharmaceutically acceptable salt or ester thereof in the dosage form is about 0.05 weight percentage to about 1.0 weight percentage. In certain embodiments, the weight percentage of L-cysteine ​​or a pharmaceutically acceptable salt or ester thereof in the dosage form is about 0.07 weight percentage to about 0.7 weight percentage. In certain embodiments, the weight percentage of L-cysteine ​​or a pharmaceutically acceptable salt or ester thereof in the dosage form is about 0.09 weight percentage to about 0.5 weight percentage.

[0419] In certain embodiments, the molar ratio of L-cysteine ​​or a pharmaceutically acceptable salt or ester thereof to atrasentan or a pharmaceutically 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 pharmaceutically acceptable salt or ester thereof to atrasentan or a pharmaceutically 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 pharmaceutically acceptable salt or ester thereof to atrasentan or a pharmaceutically acceptable salt thereof is about 2:1 to about 1:2. In certain embodiments, the molar ratio of L-cysteine ​​or a pharmaceutically acceptable salt or ester thereof to atrasentan or a pharmaceutically acceptable salt thereof is about 1:1.

[0420] In certain embodiments, the antioxidant is selected from the group consisting of L-cysteine ​​hydrochloride monohydrate, L-cysteine ​​hydrochloride anhydrate, and L-cysteine ​​ethyl ester. In some embodiments, the dosage form comprises L-cysteine ​​hydrochloride monohydrate.

[0421] (vii) Other Embodiments

[0422] In some embodiments, the dosage form comprises atrasentan or a pharmaceutically acceptable salt thereof and an antioxidant. In some of these embodiments, the antioxidant is L-cysteine ​​or a pharmaceutically acceptable salt or ester thereof. In some embodiments, the molar ratio of the antioxidant (e.g., L-cysteine ​​or a pharmaceutically acceptable salt or ester thereof) is about 5:1 to about 1:5. In some of the foregoing embodiments, the dosage form further comprises a pharmaceutically 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 pharmaceutically acceptable salt or ester thereof) to atrasentan or a pharmaceutically acceptable salt thereof is about 5:1 to about 1:5; and the weight ratio of the binder to atrasentan or a pharmaceutically acceptable salt thereof is about 1:1 to about 20:1 by weight of the atrasentan free base equivalent. In some embodiments, the dosage form further comprises a disintegrant, and the weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine ​​or a pharmaceutically acceptable salt or ester thereof) is about 60: 1 to about 3: 1. In some embodiments, the weight percentage of atrasentan or a pharmaceutically acceptable salt thereof in the dosage form is about 0.2 weight percent to about 1.0 weight percent based on the equivalent weight of atrasentan free base. In some embodiments, the dosage form comprises about 0.40 mg to about 0.85 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0423] In some embodiments, the dosage form comprises a pharmaceutically 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 pharmaceutically acceptable salt or ester thereof) to atrasentan or a pharmaceutically acceptable salt thereof is about 2:1 to about 1:2; and the weight ratio of the binder to atrasentan or a pharmaceutically acceptable salt thereof is about 1:1 to about 15:1 based on the equivalent weight of atrasentan free base. In some embodiments, the dosage form further comprises a disintegrant, and the weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine ​​or a pharmaceutically acceptable salt or ester thereof) is about 50:1 to about 4:1. In some embodiments, the weight percentage of atrasentan or a pharmaceutically acceptable salt thereof in the dosage form is about 0.2 weight percent to about 1.0 weight percent based on the equivalent weight of atrasentan free base. In some embodiments, the dosage form comprises about 0.40 mg to about 0.85 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0424] In some embodiments, the dosage form comprises a pharmaceutically 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 pharmaceutically acceptable salt or ester thereof) to atrasentan or a pharmaceutically acceptable salt thereof is about 1:1; and the weight ratio of the binder to atrasentan or a pharmaceutically acceptable salt thereof is about 1:1 to about 15:1 based on the equivalent weight of atrasentan free base. In some embodiments, the dosage form further comprises a disintegrant, and the weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine ​​or a pharmaceutically acceptable salt or ester thereof) is about 35:1 to about 5:1. In some embodiments, the weight percentage of atrasentan or a pharmaceutically acceptable salt thereof in the dosage form is about 0.3 weight percent to about 0.8 weight percent based on the equivalent weight of atrasentan free base. In some embodiments, the dosage form comprises about 0.40 mg to about 0.85 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises about 1.25 mg to about 1.75 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0425] In some embodiments, the dosage form comprises a pharmaceutically acceptable polymer binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, and hydroxypropylcellulose; the dosage form comprises about 0.05 weight percent to about 1.0 weight percent of an antioxidant (e.g., L-cysteine ​​or a pharmaceutically acceptable salt or ester thereof); and the dosage form comprises about 1.0 weight percent to about 10.0 weight percent of a binder. In some embodiments, the dosage form further comprises a disintegrant, and the weight percent of the disintegrant in the dosage form is about 1.0 weight percent to about 10.0 weight percent. In some embodiments, the weight percent of atrasentan or a pharmaceutically acceptable salt thereof in the dosage form is about 0.1 weight percent to about 2.0 weight percent based on the equivalent weight of atrasentan free base. In some embodiments, the dosage form comprises about 0.40 mg to about 0.85 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises about 1.25 mg to about 1.75 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0426] In some embodiments, the dosage form comprises a pharmaceutically acceptable polymer binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, and hydroxypropylcellulose; the dosage form comprises about 0.07 weight percent to about 0.70 weight percent of an antioxidant (e.g., L-cysteine ​​or a pharmaceutically acceptable salt or ester thereof); and the dosage form comprises about 1.0 weight percent to about 8.0 weight percent of a binder. In some embodiments, the dosage form further comprises a disintegrant, and the weight percent of the disintegrant in the dosage form is about 1.0 weight percent to about 6.0 weight percent. In some embodiments, the weight percent of atrasentan or a pharmaceutically acceptable salt thereof in the dosage form is about 0.2 weight percent to about 1.0 weight percent based on the equivalent weight of atrasentan free base. In some embodiments, the dosage form comprises about 0.40 mg to about 0.85 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises about 1.25 mg to about 1.75 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0427] In some embodiments, the dosage form comprises a pharmaceutically acceptable polymer binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, and hydroxypropylcellulose; the dosage form comprises about 0.09 weight percent to about 0.80 weight percent of an antioxidant (e.g., L-cysteine ​​or a pharmaceutically acceptable salt or ester thereof), and the dosage form comprises about 1.0 weight percent to about 5.0 weight percent of a binder. In some embodiments, the dosage form further comprises a disintegrant, and the weight percent of the disintegrant in the dosage form is about 1.0 weight percent to about 4.0 weight percent. In some embodiments, the weight percent of atrasentan or a pharmaceutically acceptable salt thereof in the dosage form is about 0.3 weight percent to about 0.8 weight percent based on the equivalent weight of atrasentan free base. In some embodiments, the dosage form comprises about 0.40 mg to about 0.85 mg of atrasentan or an equivalent amount of its pharmaceutically acceptable salt. In some embodiments, the dosage form comprises about 1.25 mg to about 1.75 mg of atrasentan or an equivalent amount of its pharmaceutically acceptable salt.

[0428] In some embodiments, the dosage form comprises:

[0429] (a) from about 0.1 weight percent to about 2.0 weight percent of atrasentan or a pharmaceutically acceptable salt thereof, based on the equivalent weight of atrasentan free base;

[0430] (b) about 0.05 weight percent to about 1.0 weight percent of an antioxidant (e.g., L-cysteine ​​or a pharmaceutically acceptable salt or ester thereof);

[0431] (c) from about 75 weight percent to about 99 weight percent of a diluent;

[0432] (d) from about 1.0 weight percent to about 10.0 weight percent of a pharmaceutically acceptable binder;

[0433] (e) optionally, from about 1.0 weight percent to about 10.0 weight percent of a pharmaceutically acceptable disintegrant;

[0434] (f) optionally, from about 0 weight percent to about 1.5 weight percent of a pharmaceutically acceptable glidant; and

[0435] (g) optionally, from about 0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable lubricant;

[0436] The cumulative weight percentages of all components of the dosage form are equal to 100%.

[0437] In some embodiments, the dosage form comprises:

[0438] (a) from about 0.1 weight percent to about 2.0 weight percent of atrasentan or a pharmaceutically acceptable salt thereof, based on the equivalent weight of atrasentan free base;

[0439] (b) about 0.05 weight percent to about 1.0 weight percent of an antioxidant (L-cysteine ​​or a pharmaceutically acceptable salt or ester thereof);

[0440] (c) from about 75 weight percent to about 99 weight percent of a diluent;

[0441] (d) from about 1.0 weight percent to about 10.0 weight percent of a pharmaceutically acceptable binder;

[0442] (e) from about 1.0 weight percent to about 10.0 weight percent of a pharmaceutically acceptable disintegrant;

[0443] (f) optionally, from about 0 weight percent to about 1.5 weight percent of a pharmaceutically acceptable glidant; and

[0444] (g) optionally, from about 0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable lubricant;

[0445] The cumulative weight percentages of all components of the dosage form are equal to 100%.

[0446] In some embodiments, the dosage form comprises:

[0447] (a) from about 0.2 weight percent to about 1.0 weight percent of atrasentan or a pharmaceutically acceptable salt thereof, based on the equivalent weight of atrasentan free base;

[0448] (b) about 0.07 weight percent to about 0.7 weight percent of an antioxidant (L-cysteine ​​or a pharmaceutically acceptable salt or ester thereof);

[0449] (c) from about 82 weight percent to about 99 weight percent of a diluent;

[0450] (d) from about 1.0 weight percent to about 8.0 weight percent of a pharmaceutically acceptable binder;

[0451] (e) optionally, from about 1.0 weight percent to about 6.0 weight percent of a pharmaceutically acceptable disintegrant;

[0452] (f) optionally, from about 0 weight percent to about 1.0 weight percent of a pharmaceutically acceptable glidant; and

[0453] (g) optionally, from about 0 weight percent to about 3.0 weight percent of a pharmaceutically acceptable lubricant;

[0454] The cumulative weight percentages of all components of the dosage form are equal to 100%.

[0455] In some embodiments, the dosage form comprises:

[0456] (a) from about 0.2 weight percent to about 1.0 weight percent of atrasentan or a pharmaceutically acceptable salt thereof, based on the equivalent weight of atrasentan free base;

[0457] (b) about 0.07 weight percent to about 0.70 weight percent of L-cysteine ​​or a pharmaceutically acceptable salt or ester thereof;

[0458] (c) from about 82 weight percent to about 99 weight percent of a diluent;

[0459] (d) from about 1.0 weight percent to about 8.0 weight percent of a pharmaceutically acceptable binder;

[0460] (e) from about 1.0 weight percent to about 6.0 weight percent of a pharmaceutically acceptable disintegrant;

[0461] (f) optionally, from about 0 weight percent to about 1.0 weight percent of a pharmaceutically acceptable glidant; and

[0462] (g) optionally, from about 0 weight percent to about 3.0 weight percent of a pharmaceutically acceptable lubricant;

[0463] The cumulative weight percentages of all components of the dosage form are equal to 100%.

[0464] In some embodiments, the dosage form comprises:

[0465] (a) about 0.3 weight percent to about 0.8 weight percent of atrasentan or a pharmaceutically acceptable salt thereof, based on the equivalent weight of atrasentan free base;

[0466] (b) about 0.09 weight percent to about 0.50 weight percent of L-cysteine ​​or a pharmaceutically acceptable salt or ester thereof;

[0467] (c) from about 87 weight percent to about 99 weight percent of a pharmaceutically acceptable diluent;

[0468] (d) from about 1.0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable binder;

[0469] (e) optionally, from about 1.0 weight percent to about 4.0 weight percent of a pharmaceutically acceptable disintegrant;

[0470] (f) optionally, from about 0 weight percent to about 0.75 weight percent of a pharmaceutically acceptable glidant; and

[0471] (g) optionally, from about 0 weight percent to about 2.0 weight percent of a pharmaceutically acceptable lubricant;

[0472] The cumulative weight percentages of all components of the dosage form are equal to 100%.

[0473] In some embodiments, the dosage form comprises:

[0474] (a) about 0.3 weight percent to about 0.8 weight percent of atrasentan or a pharmaceutically acceptable salt thereof, based on the equivalent weight of atrasentan free base;

[0475] (b) about 0.09 weight percent to about 0.50 weight percent of L-cysteine ​​or a pharmaceutically acceptable salt or ester thereof;

[0476] (c) from about 87 weight percent to about 99 weight percent of a pharmaceutically acceptable diluent;

[0477] (d) from about 1.0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable binder;

[0478] (e) from about 1.0 weight percent to about 4.0 weight percent of a pharmaceutically acceptable disintegrant;

[0479] (f) optionally, from about 0 weight percent to about 0.75 weight percent of a pharmaceutically acceptable glidant; and

[0480] (g) optionally, from about 0 weight percent to about 2.0 weight percent of a pharmaceutically acceptable lubricant;

[0481] The cumulative weight percentages of all components of the dosage form are equal to 100%.

[0482] In some embodiments, the dosage form comprises:

[0483] (a) from about 0.1 weight percent to about 2.0 weight percent of atrasentan or a pharmaceutically acceptable salt thereof, based on the equivalent weight of atrasentan free base;

[0484] (b) from about 75 weight percent to about 99 weight percent of a diluent;

[0485] (c) from about 1.0 weight percent to about 10.0 weight percent of a pharmaceutically acceptable binder;

[0486] (d) optionally, from about 1.0 weight percent to about 10.0 weight percent of a pharmaceutically acceptable disintegrant;

[0487] (e) optionally, from about 0 weight percent to about 1.5 weight percent of a pharmaceutically acceptable glidant; and

[0488] (f) optionally, from about 0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable lubricant;

[0489] The cumulative weight percentages of all components of the dosage form are equal to 100%.

[0490] In some embodiments, the dosage form comprises:

[0491] (a) from about 0.1 weight percent to about 2.0 weight percent of atrasentan or a pharmaceutically acceptable salt thereof, based on the equivalent weight of atrasentan free base;

[0492] (b) from about 75 weight percent to about 99 weight percent of a diluent;

[0493] (c) from about 1.0 weight percent to about 10.0 weight percent of a pharmaceutically acceptable binder;

[0494] (d) from about 1.0 weight percent to about 10.0 weight percent of a pharmaceutically acceptable disintegrant;

[0495] (e) optionally, from about 0 weight percent to about 1.5 weight percent of a pharmaceutically acceptable glidant; and

[0496] (f) optionally, from about 0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable lubricant;

[0497] The cumulative weight percentages of all components of the dosage form are equal to 100%.

[0498] In some embodiments, the dosage form comprises:

[0499] (a) from about 0.2 weight percent to about 1.0 weight percent of atrasentan or a pharmaceutically acceptable salt thereof, based on the equivalent weight of atrasentan free base;

[0500] (b) from about 82 weight percent to about 99 weight percent of a diluent;

[0501] (c) from about 1.0 weight percent to about 8.0 weight percent of a pharmaceutically acceptable binder;

[0502] (d) optionally, from about 1.0 weight percent to about 6.0 weight percent of a pharmaceutically acceptable disintegrant;

[0503] (e) optionally, from about 0 weight percent to about 1.0 weight percent of a pharmaceutically acceptable glidant; and

[0504] (f) optionally, from about 0 weight percent to about 3.0 weight percent of a pharmaceutically acceptable lubricant;

[0505] The cumulative weight percentages of all components of the dosage form are equal to 100%.

[0506] In some embodiments, the dosage form comprises:

[0507] (a) from about 0.2 weight percent to about 1.0 weight percent of atrasentan or a pharmaceutically acceptable salt thereof, based on the equivalent weight of atrasentan free base;

[0508] (b) from about 82 weight percent to about 99 weight percent of a diluent;

[0509] (c) from about 1.0 weight percent to about 8.0 weight percent of a pharmaceutically acceptable binder;

[0510] (d) from about 1.0 weight percent to about 6.0 weight percent of a pharmaceutically acceptable disintegrant;

[0511] (e) optionally, from about 0 weight percent to about 1.0 weight percent of a pharmaceutically acceptable glidant; and

[0512] (f) optionally, from about 0 weight percent to about 3.0 weight percent of a pharmaceutically acceptable lubricant;

[0513] The cumulative weight percentages of all components of the dosage form are equal to 100%.

[0514] In some embodiments, the dosage form comprises:

[0515] (a) about 0.3 weight percent to about 0.8 weight percent of atrasentan or a pharmaceutically acceptable salt thereof, based on the equivalent weight of atrasentan free base;

[0516] (b) from about 87 weight percent to about 99 weight percent of a pharmaceutically acceptable diluent;

[0517] (c) from about 1.0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable binder;

[0518] (d) optionally, from about 1.0 weight percent to about 4.0 weight percent of a pharmaceutically acceptable disintegrant;

[0519] (e) optionally, from about 0 weight percent to about 0.75 weight percent of a pharmaceutically acceptable glidant; and

[0520] (f) optionally, from about 0 weight percent to about 2.0 weight percent of a pharmaceutically acceptable lubricant;

[0521] The cumulative weight percentages of all components of the dosage form are equal to 100%.

[0522] In some embodiments, the dosage form comprises:

[0523] (a) about 0.3 weight percent to about 0.8 weight percent of atrasentan or a pharmaceutically acceptable salt thereof, based on the equivalent weight of atrasentan free base;

[0524] (b) from about 87 weight percent to about 99 weight percent of a pharmaceutically acceptable diluent;

[0525] (c) from about 1.0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable binder;

[0526] (d) from about 1.0 weight percent to about 4.0 weight percent of a pharmaceutically acceptable disintegrant;

[0527] (e) optionally, from about 0 weight percent to about 0.75 weight percent of a pharmaceutically acceptable glidant; and

[0528] (f) optionally, from about 0 weight percent to about 2.0 weight percent of a pharmaceutically acceptable lubricant;

[0529] The cumulative weight percentages of all components of the dosage form are equal to 100%.

[0530] In some embodiments, the dosage form satisfies one or more of the following conditions:

[0531] (a) the diluent is lactose;

[0532] (b) the dosage form comprises a pharmaceutically acceptable binder, and the binder is hydroxypropyl methylcellulose;

[0533] (c) the dosage form comprises a pharmaceutically acceptable disintegrant, and the disintegrant is crospovidone;

[0534] (d) the dosage form comprises a pharmaceutically acceptable glidant, and the glidant is silicon dioxide;

[0535] (e) The dosage form comprises a pharmaceutically acceptable lubricant, and the lubricant is glyceryl behenate.

[0536] 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 pharmaceutically acceptable salt thereof (e.g., atrasentan hydrochloride) by weight equivalent to the atrasentan parent. In some embodiments, the pharmaceutical composition comprises about 0.40 mg to about 1.00 mg of atrasentan or a pharmaceutically acceptable salt thereof (e.g., atrasentan hydrochloride) by weight equivalent to the atrasentan parent. In some embodiments, the pharmaceutical composition comprises about 0.40 mg to about 0.85 mg of atrasentan or a pharmaceutically acceptable salt thereof (e.g., atrasentan hydrochloride) by weight equivalent to the atrasentan parent. In some embodiments, the pharmaceutical composition comprises about 0.50 mg of atrasentan or a pharmaceutically acceptable salt thereof (e.g., atrasentan hydrochloride) by weight equivalent to the atrasentan parent. In some embodiments, the pharmaceutical composition comprises about 0.75 mg of atrasentan or a pharmaceutically acceptable salt thereof (e.g., atrasentan hydrochloride) by weight equivalent to the atrasentan parent. 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 pharmaceutically acceptable salt thereof (e.g., atrasentan hydrochloride) by atrasentan parent equivalent weight. In some embodiments, the pharmaceutical composition comprises about 1.5 mg of atrasentan or a pharmaceutically acceptable salt thereof (e.g., atrasentan hydrochloride) by atrasentan parent equivalent weight. In certain of the foregoing embodiments, the dosage form is a tablet.

[0537] In some embodiments, the dosage form is a tablet. In some embodiments, the weight of the tablet is about 37.5 mg to about 1500 mg. In some embodiments, the weight of the tablet is about 50 mg to about 750 mg. In some embodiments, the weight of the tablet is about 50 mg to about 250 mg. In some embodiments, the weight of the tablet is about 75 mg to about 500 mg. In some embodiments, the weight of the tablet is about 75 mg to about 150 mg. In some embodiments, the weight of the tablet is about 100 mg to about 250 mg. In some embodiments, the weight of the tablet is about 100 mg to about 230 mg. In some embodiments, the water content of the tablet is less than about 10%. In certain embodiments, the water content of the tablet is about 4%-6% (e.g., about 4%-5%).

[0538] In general, the tablet may optionally be surrounded or coated with at least one non-rate controlling layer. The non-rate controlling layer may be formed as a monolayer, coating or film or multiple monolayers, coatings or films. The functions of the non-rate controlling layer may include, for example, providing further stability to atrasentan, serving as a processing aid and / or cosmetic enhancer for the formulation, and / or serving as a masking agent to reduce any undesirable odor associated with the formulation (e.g., odors typically associated with L-cysteine).

[0539] When the dosage form includes a non-rate controlling layer, the non-rate controlling layer can be made of one or more polymers and other ingredients known in the art (such as but not limited to plasticizers, pigments / sunscreens, waxes, etc.). The example of operable polymer includes but is not limited to hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinyl alcohol and polyethylene glycol. The example of operable plasticizer includes but is not limited to polyethylene glycol, glycerol, triacetin, triethyl citrate, diethyl phthalate, L-cysteine ​​and mineral oil. The example of operable pigments / sunscreens includes but is not limited to water-soluble dyes (such as sunset yellow, quinoline yellow, erythrosine and lemon yellow), pigments (such as aluminum lakes, titanium oxide, iron oxide and talc) and natural products (such as riboflavin, carotenoids, chlorophyll, anthocyanin and carmine). The example of operable wax includes but is not limited to paraffin.

[0540] In some embodiments, the dosage form is a tablet coated with a pharmaceutically acceptable polymer.

[0541] In some embodiments, the dosage form is a capsule.

[0542] In some embodiments, the dosage form is packaged in a semipermeable container. In some embodiments, the semipermeable container is a blister pack.

[0543] In some embodiments, the dosage form is packaged in a substantially impermeable container.

[0544] 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 ...

Claims

1. A method of treating focal segmental glomerulosclerosis (FSGS) in a subject, the method comprising administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

2. A method of reducing renal inflammation and / or fibrosis in a subject with FSGS, the method comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

3. A method of reducing the rate of decline of estimated glomerular filtration rate (eGFR) in a subject with FSGS, the method comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

4. A method of delaying the onset of end-stage renal disease (ESKD) in a subject with FSGS, the method comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

5. A method of reducing proteinuria in a subject suffering from FSGS, the method comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

6. A method of reducing fatigue in a subject suffering from FSGS, the method comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

7. A method of stabilizing functional podocyte mass in a subject suffering from FSGS, the method comprising administering to a subject in need thereof a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

8. The method of claim 2, wherein the renal inflammation and / or fibrosis comprises tubulointerstitial inflammation.

9. The method of claim 2 or claim 8, wherein the renal inflammation and / or fibrosis comprises tubulointerstitial fibrosis.

10. The method of any one of claims 2, 8 or 9, wherein the renal inflammation and / or fibrosis comprises glomerular inflammation.

11. The method of any one of claims 2 or 8-10, wherein the renal inflammation and / or fibrosis comprises glomerulosclerosis.

12. The method of any one of claims 1-10, wherein the subject has biopsy-proven FSGS.

13. The method of any one of claims 1-10, wherein the subject has been diagnosed with biopsy-proven FSGS.

14. The method of any one of claims 1-10, wherein the subject has a mutated podocyte protein.

15. The method of any one of claims 1-10, wherein the subject has a mutation in apolipoprotein L1 (APOL1).

16. The method of any one of claims 1-10, wherein the subject has a mutation in one or more of: APOL1, NPHS1, NPHS2, CD2AP, TRPC6, ACTN4, INF2, MYO1E, ARHGAP24, PLCE1, WT1, LMX1B, COQ6, LAMB2, PAX2, ANLN, and / or CRB2.

17. The method of any one of claims 1-16, wherein the FSGS comprises nephrotic syndrome.

18. The method of claim 17, wherein the nephrotic syndrome is selected from proteinuria, hypoalbuminemia, hypercholesterolemia, peripheral edema, or any combination of the foregoing.

19. The method of any one of claims 1-18, wherein the FSGS is peri-gate FSGS.

20. The method of any one of claims 1-18, wherein the FSGS is tip lesion FSGS.

21. The method of any one of claims 1-18, wherein the FSGS is cellular FSGS.

22. The method of any one of claims 1-18, wherein the FSGS is collapsed FSGS.

23. The method of any one of claims 1-18, wherein the FSGS is primary FSGS.

24. The method of any one of claims 1-18, wherein the FSGS is FSGS of poorly classified type (NOS).

25. The method of any one of claims 1-18, wherein the FSGS is virus-associated FSGS.

26. The method of claim 25, wherein the virus-related FSGS is non-HIV-related FSGS.

27. The method of any one of claims 1-18, wherein the FSGS is toxin-associated FSGS.

28. The method of any one of claims 1-18, wherein the FSGS is adaptive FSGS.

29. The method of any one of claims 1-28, further comprising administering to the subject one or more additional pharmaceutical agents.

30. The method of claim 29, wherein the one or more additional agents are selected from the group consisting of calcineurin inhibitors, proteasome inhibitors, aminoquinolines, complement inhibitors, B-cell inhibitors, cytotoxic agents, mTOR inhibitors, and steroids, and combinations thereof.

31. The method of claim 29, wherein the one or more additional agents comprises a calcineurin inhibitor.

32. The method of claim 31, wherein the calcineurin inhibitor is cyclosporine.

33. The method of any one of claims 29-32, wherein the one or more additional agents comprises an immunosuppressant.

34. The method of claim 33, wherein the immunosuppressant is mycophenolate mofetil (MMF), cyclophosphamide, or chlorambucil.

35. The method of any one of claims 29-34, wherein the one or more additional agents comprises a steroid.

36. The method of claim 35, wherein the steroid is selected from the group consisting of prednisone, dexamethasone, hydrocortisone, cyclosporine, adrenocorticotropic hormone (ACTH), and any combination of the foregoing.

37. The method of any one of claims 29-35, wherein the one or more additional agents comprises an aminoquinoline.

38. The method of claim 37, wherein the one or more additional agents is hydroxychloroquine.

39. The method of any one of claims 1-32, wherein the subject is not currently receiving one or more immunosuppressants.

40. The method of any one of claims 29-39, wherein the one or more additional agents are administered at a dose that was stable for at least 12 weeks prior to administration of the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

41. The method of claims 29-40, wherein the dosage of the one or more additional agents is reduced after about 15 days to about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof.

42. The method of any one of claims 29-41, wherein the dose of the one or more additional agents is reduced by about 25% to about 100%.

43. The method of any one of claims 29-42, wherein the dose of the one or more additional agents is reduced by about 50% to about 100%.

44. The method of any one of claims 29-43, wherein the dose of the one or more additional pharmaceutical agents is reduced by about 75% to about 100%.

45. The method of any one of claims 1-38, wherein 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, or any combination of the foregoing.

46. ​​The method of any one of claims 1-39, wherein the subject is concurrently receiving an ACE inhibitor, an ARB, or a combination thereof.

47. The method of claim 45 or claim 46, wherein the statin is selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin.

48. The method of claim 45 or claim 46, wherein the diuretic is selected from the group consisting of hydrochlorothiazide, trichlorothiazide, hydroflumethiazide, quinethazone, metolazone, chlorothiazide, chlorthalidone, indapamide, methylclothiazide, bumetanide, torsemide, piretanide, ethacrynic acid, bumetanide, furosemide, triamterene, spironolactone, eplerenone, and amiloride.

49. The method of any one of claims 46-48, wherein the ACE inhibitor is selected from the group consisting of quinapril, fosinopril, perindopril, captopril, enalapril, enalaprilat, ramipril, cilazapril, delapril, fosinopril, zofenopril, indopril, benazepril, lisinopril, spirapril, trandolapril, boredipril, pentapril, moexipril, lecithinamine, and pivopril.

50. The method of any one of claims 46-49, wherein the ARB is selected from the group consisting of candesartan, candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan, olmesartan medoxomil, telmisartan, valsartan, azilsartan medoxomil, and BRA-657.

51. The method of any one of claims 1-50, wherein the atrasentan is administered as a pharmaceutically acceptable salt.

52. The method of any one of claims 1-51, wherein the atrasentan is administered as atrasentan hydrochloride or atrasentan mandelate.

53. The method of any one of claims 1-52, wherein the atrasentan is administered as atrasentan hydrochloride.

54. The method of any one of claims 1-50, wherein the atrasentan is administered as the free base.

55. The method of any one of claims 1-54, wherein the subject is at high risk for progression to ESKD.

56. The method of any one of claims 1-55, wherein the subject has been diagnosed with FSGS.

57. The method of claim 56, wherein diagnosis of FSGS comprises renal biopsy, genetic testing for mutations in podocyte proteins associated with FSGS, or any combination of the foregoing.

58. The method of claim 55 or 56, wherein diagnosis of FSGS comprises examining a renal biopsy.

59. The method of any one of claims 1-58, wherein the subject excretes an average of about 1.0 g / g to about 3.5 g / g or more protein per day in the urine for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

60. The method of any one of claims 1-59, wherein the subject excretes an average of greater than about 3.5 g / g to about 10 g / g of protein per day in the urine for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

61. The method of any one of claims 1-60, wherein at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject's mean eGFR is about 20 to about 120 mL / min / 1.73 m 2 .

62. The method of any one of claims 1-61, wherein at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject's mean eGFR is about 20 to about 90 mL / min / 1.73 m 2 .

63. The method of any one of claims 1-62, wherein at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject's mean eGFR is about 20 to about 60 mL / min / 1.73 m 2 .

64. The method of any one of claims 1-63, wherein the subject has a urine protein to creatinine ratio (UPCR) of greater than about 1.5 g / g to about 11 g / g at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

65. The method of any one of claims 1-64, wherein the subject's mean HbA1c is from about 4% to about 6% at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

66. The method of any one of claims 1-65, wherein the subject's mean fasting blood glucose level is about 125 mg / dL or less for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

67. The method of any one of claims 1-66, wherein the subject's potassium levels are maintained within a normal physiological range.

68. The method of any one of claims 1-67, wherein the subject's sodium levels are maintained within a normal physiological range.

69. The method of any one of claims 1-68, wherein the subject's alanine aminotransferase / aspartate aminotransferase (ALT / AST) level during administration of atrasentan or a pharmaceutically acceptable salt thereof is about the same as the ALT / AST level before the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

70. The method of any one of claims 1-69, wherein the subject's bilirubin level during administration of atrasentan or a pharmaceutically acceptable salt thereof is about the same as the bilirubin level prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

71. The method of any one of claims 1-70, wherein the subject's fluid retention can be managed with a diuretic.

72. The method of any one of claims 1-71, wherein 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 pharmaceutically acceptable salt thereof.

73. The method of any one of claims 1-72, wherein 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 pharmaceutically acceptable salt thereof.

74. The method of any one of claims 1-73, wherein 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 pharmaceutically acceptable salt thereof.

75. The method of claim 74, wherein the amount of protein in the subject's urine is reduced by about 35% to about 80%.

76. The method of any one of claims 1-75, wherein the subject's UPCR decreases to less than about 1.5 g / g after about 10 weeks of treatment with atrasentan or a pharmaceutically acceptable salt thereof.

77. The method of any one of claims 1-76, wherein the subject's UPCR decreases to less than about 1.5 g / g after about 12 weeks of treatment with atrasentan or a pharmaceutically acceptable salt thereof.

78. The method of any one of claims 1-77, wherein the subject's UPCR decreases to less than about 1.5 g / g after about 12 weeks to about 24 weeks of treatment with atrasentan or a pharmaceutically acceptable salt thereof.

79. The method of any one of claims 1-78, wherein the subject's risk of developing ESKD is reduced by about 20% to about 99% after between about 6 months and about 24 months of treatment with atrasentan or a pharmaceutically acceptable salt thereof.

80. The method of any one of claims 1-79, wherein the subject's risk of developing ESKD is reduced by about 20% to about 99% after between about 12 months and about 60 months of treatment with atrasentan or a pharmaceutically acceptable salt thereof.

81. The method of any one of claims 1-80, wherein 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 pharmaceutically acceptable salt thereof.

82. The method of any one of claims 1-81, wherein the mean 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 pharmaceutically acceptable salt thereof.

83. The method of any one of claims 1-82, wherein the mean rate of decline in eGFR is from 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.

84. The method of any one of claims 1-83, wherein the mean rate of decline in eGFR is reduced by about 15% to about 70% after between about 6 months and about 24 months of treatment with atrasentan or a pharmaceutically acceptable salt thereof.

85. The method of any one of claims 1-84, wherein the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof is from about 0.75 mg to about 1.5 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

86. The method of any one of claims 1-85, wherein the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof is from about 1.0 mg to about 1.5 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

87. The method of any one of claims 1-86, wherein the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof is from about 1.25 mg to about 1.5 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

88. The method of any one of claims 1-87, wherein the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof is about 1.5 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

89. The method of any one of claims 1-88, further comprising administering a therapeutically effective amount of a SGLT-2 inhibitor.

90. The method of claim 89, wherein the SGLT-2 inhibitor is selected from the group consisting of bepagliflozin, canagliflozin, dapagliflozin, empagliflozin, erpagliflozin, ipagliptin, rupagliflozin, repagliflozin, sergliflozin, lipagliflozin, soglipflozin, and topagliflozin.

91. The method of claim 89 or 90, wherein the SGLT-2 inhibitor is canagliflozin, dapagliflozin, empagliflozin, or erpagliflozin.

92. The method of any one of claims 1-91, wherein the subject has been determined to have at least 1 g / day of proteinuria in at least two of three consecutive readings in the year prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

93. The method of any one of claims 1-92, wherein the subject has been administered a maximum tolerated stable dose of a RAS inhibitor at least 12 weeks prior to administering the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

94. The method of any one of claims 1-93, wherein the subject is administered a maximum tolerated stable dose of a RAS inhibitor and a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof simultaneously.

95. The method of any one of claims 1-94, wherein prior to administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof, the subject has been determined to have a blood pressure of at least 30 mL / min / 1.73 m 2 eGFR.

96. The method of any one of claims 1-95, wherein the FSGS comprises non-nephrotic range proteinuria of less than 3.5 grams of protein in the urine per day for at least about 3 months prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

97. The method of any one of claims 1-96, wherein the FSGS is associated with one or more genetic mutations.

98. The method of any one of claims 1-97, wherein the one or more genetic mutations occur in a gene encoding a podocyte protein associated with FSGS.

99. The method of claim 98, wherein 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, tRNA leu , COQ2, COQ6, ITGB4, PDSS2, CD151, CUBN, LAMB2, APOL1, and any combination of the foregoing.

100. The method of claim 98 or 99, wherein the one or more genetic mutations are in APOL1.

101. The method of any one of claims 1-100, wherein the subject has been administered a prior therapy for FSGS and has not responded to the prior therapy.

102. The method of claim 101, wherein the prior therapy was a standard of care therapy for FSGS.

103. The method of claim 101 or 102, wherein the prior therapy is selected from: axar, sparsentan, rituximab combined with plasmapheresis, cyclosporine, 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-pyridinyl]-3-(trifluoromethyl)benzenesulfonamide (CCX140-B), abatacept, bardoxolone, or any combination of the foregoing.

104. The method of any one of claims 1-103, wherein the subject has not been or is not being treated with a sodium-glucose co-transporter 2 (SGLT2) inhibitor.

105. The method of any one of claims 1-104, wherein the subject has not been or is not being treated with antiretroviral therapy.

106. The method of any one of claims 1-105, wherein the subject has not been previously diagnosed with one or more of diabetic nephropathy, IgA nephropathy, sickle cell nephropathy, HIV / AIDS, or acute renal failure.

107. The method of any one of claims 1-106, wherein the subject has not been previously diagnosed with HIV-associated nephropathy.

108. The method of any one of claims 1-107, wherein the subject has not been previously diagnosed with HIV.

109. The method of any one of claims 1-108, wherein the subject is not currently diagnosed with HIV.

110. The method of any one of claims 1-109, wherein the subject is not currently receiving treatment for HIV.

111. The method of any one of claims 1-110, wherein the subject has not been previously diagnosed with renovascular hypertension.

112. The method of any one of claims 1-111, wherein the subject is not currently receiving treatment for renovascular hypertension.

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