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USOO8623819B2

(12) United States Patent (10) Patent No.: US 8,623,819 B2 ROden et al. (45) Date of Patent: Jan. 7, 2014

(54) THERAPY FOR COMPLICATIONS OF 8,257,725 B2 9/2012 Cromack et al. DABETES 2002/0055457 A1 5/2002 Janus et al. 2003/0022811 A1 1/2003 Singh et al. 2003/0092757 A1 5/2003 Singh et al. (71) Applicant: AbbVie Deutschland GmbH & Co. 2004/O186083 A1 9, 2004 McMahon KG, Wiesbaden (DE) 2005/0107354 A1 5/2005 Koizumi et al. 2005.0113306 A1 5/2005 Janus et al. (72) Inventors: Robert L. Roden, Foster City, CA (US); 2005/O113307 A1 5/2005 Janus et al. 2005/0214294 A1* 9/2005 Flyvbjerg et al...... 424,145.1 Richard J. Gorczynski, Westminister, 2006.0035867 A1 2/2006 Janus et al. CO (US); Michael J. Gerber, Denver, 2006, OO63825 A1 3/2006 Dziki et al. CO (US) 2006, OO74058 A1 4/2006 Holmes et al. 2006/O135596 A1 6/2006 Zhang (73) Assignee: AbbVie Deutschland GmbH & Co. 2006/O1896.75 A1 8/2006 King 2007/O123582 A1 5/2007 Zhang KG, Wiesbaden (DE) 2008. O132710 A1 6/2008 Henry et al. (*) Notice: Subject to any disclaimer, the term of this 2008. O161321 A1 7/2008 Feldman et al. patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. FOREIGN PATENT DOCUMENTS DE 19743140 4f1999 (21) Appl. No.: 13/766,266 DE 19743.142 4f1999 DE 19744799 4f1999 (22) Filed: Feb. 13, 2013 EP O647449 4f1995 EP O885215 4/2006 (65) Prior Publication Data WO 9606095 A1 2, 1996 US 2013/O178424 A1 Jul. 11, 2013 (Continued) OTHER PUBLICATIONS Related U.S. Application Data Banes-Berceli AKL. Ketsawatsomkron P. Ogbi S. Patel B, Pollock DM, Marrero MB, " II and endotelin-1 augment the (63) Continuation of application No. 12/196,635, filed on vascular complications of diabetes via JAK2 activation.” Am J Aug. 22, 2008. Physiol Heart Circ Physiol, May 25, 2007, 293: H1291-H1299.* (60) Provisional application No. 60/957,300, filed on Aug. Marre M. Chatellier G. Leblanc H. Guyene TT. Menard J. Passa P. 22, 2007. “Prevention of diabetic nephropathy with in normotensive diabetes with microalbuminuria.” BMJ, 1988, 297: 1092-1095.* Kowala et al., “Selective Blockade of the Subtype A (51) Int. Cl. Receptor Decreases Early Atherosclerosis in Hamsters Fed Choles A6 IK 45/06 (2006.01) terol.” American Journal of Pathology, vol. 146, No. 4. pp. 819-826 A6 IK3I/549 (2006.01) (1995). A6 IK3I/4025 (2006.01) Opgenorth et al., “Pharmacological Characterization of A-127722: An Orally Active and Highly Potent ETA-Selective Receptor Antago (52) U.S. Cl. nist' The Journal of Pharmacology and Experimental Therapeutics, USPC ...... 514/6.8; 514/16.2 JPET 276: 473–481 (1996). (58) Field of Classification Search CPC ...... A61K 38/556; A61K 38/085; A61 K (Continued) 31/4025; A61K 3.1/549 USPC ...... 514/6.8, 16.2 Primary Examiner — Julie Ha See application file for complete search history. (74) Attorney, Agent, or Firm — Michael B. Harlin; Neal, Gerber & Eisenberg LLP (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS A method for enhancing glycemic control and/or sen 5,567,713 A 10, 1996 Cullinan et al. sitivity in a human Subject having diabetic nephropathy and/ 5,622,971 A 4/1997 Winn et al. or metabolic syndrome comprises administering to the Sub 5,731,434 A 3, 1998 Winnet al. ject a selective endothelin A (ET) in a 5,767,144 A 6, 1998 Winnet al. glycemic control and/or insulin sensitivity enhancing effec 6,121.416 A 9, 2000 Clark et al. tive amount. A method for treating a complex of comorbidi 6,162.927 A 12/2000 Winn et al. ties in an elderly diabetic human Subject comprises adminis 6, 197,780 B1 3, 2001 Munter tering to the Subject a selective ET receptor antagonist in 6,238,708 B1 5/2001 Hayek et al. 6,329,384 B1 12/2001 Munter combination or as adjunctive therapy with at least one addi 6,352.992 B1 3/2002 Kirchengast et al. tional agent that is (i) other than a selective ET receptor 6,380,241 B1 4/2002 Winn et al. antagonist and (ii) effective in treatment of diabetes and/or at 6,462,194 B1 10/2002 Winn et al. least one of said comorbidities other than . A 6,559,188 B1 5, 2003 Gatlin et al. therapeutic combination useful in Such a method comprises a 6,946,481 B1 9, 2005 Winnet al. selective ET receptor antagonist and at least one antidia 7,208,517 B1 4/2007 Winn et al. 7,365,093 B2 4/2008 Winn et al. betic, anti-obesity or antidyslipidemic agent other than a 7,445,792 B2 11/2008 Toner et al. selective ET receptor antagonist. 8,057,813 B2 11/2011 Toner et al. 8,257,724 B2 9/2012 Cromack et al. 15 Claims, 1 Drawing Sheet US 8,623,819 B2 Page 2

(56) References Cited Chade et al., “Endothelin—A Receptor Blockade Improves Renal Microvascular Architecture and Function in Experimental Hypercholesterolemia', American Society of Nephrology, pp. 3394 FOREIGN PATENT DOCUMENTS 3403 (2006). WO 96.06.095 A1 2, 1996 Brouwer KR et al., “, , , and WO 973OO45 A1 8, 1997 Sitaxsentan Differences in Inhibition of Hepatobiliary Transporters WO 9906397 A2 2, 1999 in Two Species'. Drug Metab. Rev. p. 296(2007) (abstract). WO OO15599 A1 3, 2000 Sasser et al., “ Blockade Reduces Diabetic WO O211713 A2 2, 2002 Renal Injury via an Anti-Inflammatory Mechanism”. J. Am Soc. WO O2 17912 A1 3, 2002 Nephrol. 18(1): 143-154, pp. 1-19 (2007). WO 02085351 A1 10, 2002 Lakhdar et al., “Safety and Tolerability of Angiotensin-Converting WO 2004/082637 9, 2004 Enzyme Inhibitor Versus the Combination of Angiotensin-Convert WO 2006.034084 A1 3, 2006 ing Enzyme Inhibitor and Angiotensin Receptor Blocker in Patients WO 2006.034085 A1 3, 2006 With Left Ventricular Dysfunction: A Systematic Review and Meta WO 2006.034094 A1 3, 2006 Analysis of Randomized Controlled Trials”,Journal of Cardiac Fail WO 2006.034234 A1 3, 2006 ure. vol. 14, No. 3, pp. 181-188 (2008). OTHER PUBLICATIONS Raichlin et al., “Efficacy and Safety of in Patients With Benigni et al., “Renoprotective effect of contemporary blocking of Cardiovascular Risk and Early Atherosclerosis'. Hypertension, 52(3): 522-528, pp. 1-15 (2008). angiotensin II and endothelin-1 in rats with membranous Kohan et al., “Biology of endothelin receptors in the collecting duct”. nephropathy Kidney International. vol. 54. pp. 353-359 (1998). Div. of Nephrology, Univ. of Utah Health Sciences Center, Kohan, "Angiotensin II and endothelin in chronic MiniReview pp. 481-486, (2009). glomerulonephritis.” (1998) (comment to Benigni et al Weber et al., “A selective endothelin-receptor antagonist to reduce “Renoprotective effect of contemporary blocking of angiotensin II blood pressure in patients with treatment-resistant hypertension: a and endothelin-1 in rats with membranous nephropathy” Kidney randomised, double-blind, placebo-controlled trial”, thelancet.com, International. vol. 54 pp. 646-647(1998).). Articles, vol. 374, pp. 1423-1431 (2009). Barton et al., “Endothelin ETA receptor blockade restores NO-me Wenzel et al., “Avosentan Reduces Albumin Excretion in Diabetics diated endothelial function and inhibits atherosclerosis in with Macroalbuminuria'. J. Am. Soc. Nephrol 20: pp. 65-(2009). apolipoprotein E-deficient mice.” Proc. Natl. Acad. Sci. USA. vol. Mannet al., “Avosentan for Overt Diabetic Nephropathy'. J. am. 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Nephrol. 22: pp. 763-772 (2011). progressionof diabetic nephropathy', (2001) (abstract), Nephron. 87 Mohanan et al., “TRC 120038, a Novel Dual AT1/ETA Receptor (2):161-9 (Feb. 2001). Blocker for Control of Hypertension, Diabetic Nephropathy, and Taner et al., “Treatment with endothelin-receptor antagonists Cardiomyopathy in ob-ZSF1 Rats'. International Journal of Hyper increases NOS activity in hypercholesterolemia', J. Appl. Physiol. tension, vol. 2011, Article ID 75.1513, pp. 3-12 (2011). 90: 816-820 (2001). Saleh et al., “Endothelin receptor A-specific stimulation of d'Uscio et al., “Chronic ET receptor blockade prevents endothelial glomerular inflammation and injury in a streptozotocin-induced rat dysfunction of Small arteries in apolipoprotein E-deficient mice'. model of diabetes', Diabetologia 54:979-988 (2011). Cardiovascular Research, 53, pp. 487-495 (2002). 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Blood Press, 14(2): pp. 114-119 (2005) (abstract). American Diabetes Association (2004) Diabetes Care 27 &Supp. Battistini et al., “Profile of Past and Current Clinical Trials Involving 1):S79-83. Endothelin Receptor Antagonists: The Novel '. Sentan Class of Balsiger et al. (2002) Clin. Sci. 103(Suppl. 48): 430S-433S. Drug, MiniReview, pp. 653-695 (2006). Battistini et al. (2006) Exp. Biol. Med. 231:653-695. US 8,623,819 B2 Page 3

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(56) References Cited Lakhar R. et al., “Safety and Tolerability of Angiotensin-Converting Enzyme Inhibitor Versus the Combination of Angiotensin-Convert OTHER PUBLICATIONS ing Enzyme Inhibitor and Angiotensin Receptor Blocker in Patients with Left Ventricular Dysfunction: A Systematic Review and Meta TeradaY., et al., “Cyclin D1, p16, and Retinoblastoma Gene Regulate Analysis of Randomized Controlled Trials.” JCardiac Failure. 14(3): Mitogenic Signaling of Endothelin in Rat Mesangial Cells.” Kidney 181-88 (2008). International, 1998, vol. 53 (1), pp. 76-83. Novartis Pharmaceuticals Corporation, Label for Aliskiren, dated Mar. 2012, pp. 1-16. Torre-Amione G. et al., “Hemodynamic and Clinical Effects of Valeant Pharmaceuticals North America LLC, Label for Enalapril, TeZosentan, an Intravenous Dual Endothelin Receptor Antagonist, in dated Jan. 30, 2012, pp. 1-20. Patients Hospitalized for Acute Decompensated Heart Failure.” Jour Schepkens, H., et al., “Life-threatening Hyperkalemia during Com nal of the American College of Cardiology, 2003, vol. 42 (1), pp. bined Therapy with Angiotensin-converting Enzyme Inhibitors and 140-147. Spironolactone: An Analysis of 25 Cases.” The American Journal of Torre-Amione G. et al., “Hemodynamic Effects of Tezosentan, an Medicine, vol. 110, Apr. 15, 2001, pp. 438-441. Intravenous Dual Endothelin Receptor Antagonist, in Patients with Pitt, B., et al., “Aldosterone receptor antagonists for heart failure: Class III to IV Congestive Heart Failure.” Circulation, 2001, vol. 103 Current status, future indications.” Cleveland Clinic Journal of Medi (7), pp. 973-980. cine, vol. 73, No. 3, Mar. 2006, pp. 257-268. Webb M.L., et al., “Endothelin Receptors as a Potential Therapeutic Atkins R.C., et al., “Proteinuria Reduction and Progression to Renal Target in the Treatment of Cardiovascular Disease: Rationale for Failure in Patients with Type 2 Diabetes Mellitus and Overt Selective Antagonism of the ETa Subtype.” DN&P 1996, vol. 9 (6), Nephropathy.” American Journal of Kidney Diseases, 2005., vol. 45 pp. 348-350. (2), pp. 281-287. Wessale J.L., et al., “Pharmacology of Endothelin Receptor Antago MacKinnon M., et al., “Combination Therapy with an Angiotensin nists ABT-627, ABT-546, A-182086 and A-192621: Ex Vivo and in Receptor Blocker and an ACE Inhibitor in Proteinuric Renal Disease: Vivo Studies.” Clinical Science, 2002, vol. 103 (Suppl. 48), pp. A Systematic Review of the Efficacy and Safety Data.” American 112S-117S. Journal of Kidney Diseases, 2006, vol. 48 (1), pp. 8-20. Misra S, et al., ACE inhibitors and ARBs: “One or the other—not both for high-risk patients.” JFamily Practice. 58(1): 24-26 (2009). * cited by examiner U.S. Patent Jan. 7, 2014 US 8,623,819 B2

Placebo Treatment Screening Run-in Period (Co-Co-CD 300 mg (n=77) Optional 100 mg (n=77) Long-Term Extension 50 50 mg (n=77) D

Placebo (n=121) Week -4 -2 i 2 4 6 8 10 12 14

Randomization US 8,623,819 B2 1. 2 THERAPY FOR COMPLICATIONS OF cholesterol and triglycerides and reduced HDL (high density DABETES lipoprotein) cholesterol), obesity and susceptibility to cardio vascular disease; these effects are thought to involve a com CROSS-REFERENCE TO RELATED mon mechanism in which insulin resistance plays an impor APPLICATIONS tant part. The earliest clinical evidence of diabetic nephropathy is This is a continuation from U.S. patent application Ser. No. microalbuminuria, the appearance of low but abnormal levels 12/196,635, filed on Aug. 22, 2008, which claims priority to (>30 mg/day) of albumin in the urine. This early stage in U.S. Provisional Patent Application No. 60/957,300, filed on development of the disease is known as incipient diabetic Aug. 22, 2007, the contents of each of which are herein fully 10 nephropathy. Without intervention, about 80% of subjects incorporated by reference. with type 1 diabetes who develop sustained microalbumin This application claims the benefit of U.S. provisional uria exhibit a progressive increase in urinary albumin, even application Ser. No. 60/957,300 filed on Aug. 22, 2007, the tually (typically after 10-15 years) reaching clinical albumin disclosure of which is incorporated herein by reference in its entirety. Further, this application contains subject matter 15 uria (>300 mg/day), a stage known as overt diabetic related to copending U.S. application Ser. No. 1 1/509,897, nephropathy. Accompanying the increase in albumin excre the disclosure of which is incorporated herein by reference in tion is development of arterial hypertension. In subjects with its entirety without admission that Such disclosure constitutes overt diabetic nephropathy, without intervention, glomerular prior art to the present invention. filtration rate (GFR) gradually falls over a period of 10-20 years, culminating in end-stage renal disease. See American FIELD OF THE INVENTION Diabetes Association (2004) Diabetes Care 27 (suppl. 1):S79-S83. Structural changes in diabetic nephropathy The present invention relates to methods and therapeutic include, in the incipient stage, mesangial expansion and a combinations useful for improving clinical outcomes in dia thickening of the glomerular basement membrane (GBM). betic patients having complications of diabetes Such as dia 25 An increase in glomerular and kidney size is generally betic nephropathy and/or metabolic syndrome. observed. Later, during the overt stage, mesangial nodules and tubular interstitial fibrosis develop. BACKGROUND OF THE INVENTION Hocher et al. (2001) Nephron 87:161-169 reported that in rats with Streptozotocin-induced diabetes, administration of Hyperglycemia in diabetes mellitus, if not controlled, over 30 either the selective ET receptor antagonist LU 135252 time causes certain irreversible morphologic changes includ (darusentan) or the nonselective ET/ET receptorantagonist ing glomerular fibrosis in kidneys of affected subjects, a LU 224332, in both cases at a dose of 100 mg/kg/day, nor condition known as diabetic nephropathy that is associated malized glomerular matrix protein deposition, indicating an with decline in renal function, eventually leading to end-stage antifibrotic effect. However, neither compound was found to renal disease. In type 1 (insulin-dependent) diabetes, glyce 35 influence serum glucose concentrations in the course of the mic control is usually achievable with chronic insulin study. therapy; however, in type 2 (non-insulin-dependent) diabetes, Dhien et al. (2000).J. Pharmacol. Exp. Therap. 293:351 insulin alone may be ineffective in preventing hyperglycemia. 359 reported that LU 135252 at 100 mg/kg/day partially or Even in patients with type 1 diabetes, insulin sensitivity can fully reversed various renal effects of streptozotocin-induced be partially or completely lost. Insulin resistance, or loss of 40 diabetes in rats, including increased glomerular diameter and insulin sensitivity, is one of an array of physiological changes deposition of eosinophilic material within the glomeruli, but that occur in some individuals who are both obese and dia that plasma glucose levels were unaffected by LU 135252. betic; Such physiological changes are collectively known as Sorokin & Kohan (2003) Am. J. Physiol. Renal Physiol. metabolic syndrome. Diabetic nephropathy and metabolic 285:F579-F589 remarked that the stage was set for clinical syndrome are serious complications of diabetes that can dra 45 trials of ET inhibitors in patients with glomerular disease matically reduce quality of life and survival time. A feature of characterized by increased ET-1 production and actions. both these complications is arterial hypertension, which Avosentan, which may be classified as a selective ET or Superimposes risk of serious cardiac adverse events on the dual ET/ET receptor antagonist, has been reported to be in already high risk of chronic kidney failure arising from these Phase III clinical development for diabetic nephropathy. See complications. 50 Battistini et al. (2006) Exp. Biol. Med. 231:653-695. Endothelins (ETs), particularly ET-1, are believed to playa U.S. Pat. No. 6,197,780 to Minter & Kirchengast reported role in mediating the damaging effects of hyperglycemia in that treatment of obese mice with “substance 23 (darusen the kidney and elsewhere. Expression of ET-1 in endothelial tan) at 50 mg/kg/day completely prevented increase in body cells of the renal vasculature is upregulated by hyperglyce weight. A method is claimed therein for treating a patient mia; the potent profibrotic action of ET-1 thus generated in 55 having hyperlipidemia, comprising administeringatherapeu the kidney is believed to be involved in the morphologic tically effective amount of an ETantagonist (e.g., darusentan) changes seen in diabetic nephropathy. ET-1 acts via endothe to the patient. lin A (ET) and endothelin B (ET) receptors. Elevated Balsigeretal. (2002) Clin. Sci. 103 (Suppl. 48):4305-4335 plasma ET levels have been reported in patients with diabetes reported that in a rat model of type 2 diabetes, BSF208075 mellitus. See, for example, Takahashi et al. (1990) Diabeto 60 (said to be a selective ET receptor antagonist) reduced logia 33:306–310. plasma glucose levels and improved plasma glucose clear Elevated plasma ET levels have also been reported in ance rates in hyperglycemic rats. patients with metabolic syndrome. See Ferrietal. (1997) Exp. On the other hand, Shaw et al. (2006) Exp. Biol. Med. Clin. Endocrinol. Diabetes 105:38-40. Metabolic syndrome 231: 1101-1105 reported that in a mouse model of non-obese (sometimes referred to as “syndrome X) is characterized by 65 type 1 diabetes, the selective ET receptor antagonist LU coexistence of glucose intolerance, hypertension, dyslipi 208075 (ambrisentan) did not reduce the elevated plasma demia (specifically elevated LDL (low density lipoprotein) glucose levels seen in untreated animals. US 8,623,819 B2 3 4 According to Berthiaume et al. (2005) Metab. Clin. Exp. ticularly acute for segments of the population which exhibit 54:735-740, some studies have shown desensitization by complications of diabetes Such as diabetic nephropathy or ET-1 of insulin signaling, leading to a decrease in glucose metabolic syndrome. uptake, while other studies have shown opposite results. A It should be noted that the British Hypertensive Society study is reported therein of effects of the selective ET recep (BHD-IV: J. Human Hypertens. (2004) 18:139-185), the tor antagonist atrasentan in a rat model of insulin resistance. European Society of Hypertension/European Society of Car At a dose of 5 mg/kg/day, atrasentan was reported to signifi diology (ESH/ESC; J. Hypertens. (2003) 21:1011-1053), and cantly reduce 3-hour fasting insulin level but not 3-hour fast the World Health Organization/International Society of ing glucose level, and to significantly reduce A, a measure Hypertension (WHO/ISH: J. Hypertens. (2003) 21:1983 10 1992) guidelines propose similar but not identical blood pres of incremental area under the curve induced by a meal toler Sure goals for diabetic patients. ance test, for glucose, insulin and glucose-insulin index. In a news release dated Aug. 18, 2005 (http://stockjunc These results were said to demonstrate an improvement in tion.com/modules.php?name=News&file print&sid=7332), glucose tolerance and insulin sensitivity and to suggest that Myogen Inc. reported positive results in a clinical trial (DAR chronic endothelin antagonism may have benefits in treat 15 201) evaluating darusentan in resistant hypertension. Among ment of insulin resistance and/or diabetes. It was further inclusion criteria for DAR-201 were subjects with diabetes reported that ET receptor blockade by atrasentan led to an and/or chronic kidney disease with mean systolic blood pres increase rather than a decrease in plasma ET-1 levels. sure >130 mmHg (http://clinicaltrials.gov/ct/show/ Shaw & Boden (2005) Current Vascular Pharmacology NCT00364026). 3:359-363 reviewed evidence on effects of ET-1 and pro Weber et al. (2006) presented a poster, available at http:// posed that chronically elevated ET-1 levels may be a cause of www.secinfo.com/dvdin.vbZ.d.htm, posted May 16, 2006, insulin resistance and impaired glucose tolerance in early reporting, inter alfa, Subject demographics in the DAR-201 stages of type 2 diabetes, obesity and metabolic syndrome. study. Of 115 subjects enrolled, 70 had diabetes and/or Recent data were said therein to indicate that combined ET/ chronic kidney disease, 55 had diabetes and 29 had chronic ET, receptorantagonists may function as effectively as selec 25 kidney disease. tive ET blockers. A need was proposed for prospective trials Nakov et al. (2002) Am. J. Hypertens. 15:583-589 to assess whether ET-1 antagonists, either alone or in combi described a 392-patient study in which moderate hyperten nation, are Superior to other more conventional treatments sion was treated with darusentan at 10 to 100 mg/day. Exclu Such as insulin sensitizers and to evaluate effects of combined sion criteria included concomitant with other therapies on development of insulin resistance and progres 30 antihypertensive drugs. Darusentan was reported to signifi sion of diabetes. cantly reduce SBP and DBP by comparison with placebo. Subjects having diabetic nephropathy and/or metabolic German Patent No. DE 19744799 of Knollmentions, in the syndrome represent a particularly challenging Subpopulation abstract thereof, combinations of an endothelin antagonist, of diabetic patients, for whom therapies giving improved Such as darusentan, and a said to show Synergistic outcomes with respect to quality of life and Survival time, 35 activity in treatment of hypertension, coronary artery disease, through enhanced glycemic control and/or insulin sensitivity, cardiac or renal insufficiency, renal or myocardial ischemia, would represent an important advance in the art. Subarachnoid hemorrhage, Raynaud's disease and peripheral Recognizing that elevated blood pressure occurs in both arterial occlusion. diabetic nephropathy and metabolic syndrome, and brings its U.S. Pat. No. 6,352.992 to Kirchengast et al. proposes own attendant risks to quality of life and Survival time, an 40 pharmaceutical combination preparations comprising a beta even more challenging patient population comprises Subjects receptor blocker and an endothelin antagonist for treatment of having at least one of these complications of diabetes and vasoconstrictive disorders. Among endothelin antagonists exhibiting inadequate blood pressure control by standard mentioned is darusentan. antihypertensive therapies. Subjects exhibiting resistance to a German Patent No. DE 19743142 of Knoll proposes com baseline antihypertensive therapy with one or more drugs 45 binations of an endothelin antagonist, Such as darusentan, and include patients having clinically diagnosed resistant hyper a calcium antagonist for treatment of cardiovascular disorders tension. Resistant hypertension is defined by the Seventh Such as and renal and myocardial Report of the Joint National Committee on Prevention, ischemia. Detection, Evaluation, and Treatment of High Blood Pressure U.S. Pat. No. 6,329,384 to Munter et al. proposes combi (JNC 7: Chobanian et al. (2003) Hypertension 42:1206-1252) 50 nations of endothelin antagonists, such as darusentan, and as a failure to achieve goal blood pressure in patients who are renin-angiotensin system inhibitors, in particular angiotensin adhering to full doses of an appropriate three-drug regimen II antagonists and angiotensin converting enzyme (ACE) that includes a diuretic. Further, resistant hypertension is inhibitors for treatment of vasoconstrictive disorders such as diagnosed by many physicians on the basis of a patients hypertension, heart failure, ischemia or vasospasms. resistance to adequate, but less than full, doses of an appro 55 German Patent No. DE 19743140 of Knoll proposes com priate three-drug regimen because of the risk or occurrence of binations of an endothelin antagonist, Such as darusentan, and adverse events associated with full doses. The terms a vasodilator for treatment of cardiovascular disorders such as "adequate” and “full” in the present context are defined here pulmonary hypertension, renal or myocardial ischemia, Sub inbelow. arachnoid hemorrhage, Raynaud's disease, and peripheral For patients with serious or compelling conditions such as 60 arterial occlusion. diabetes and chronic kidney disease, JNC 7 recommends a International Patent Publication No. WO 2004/082637 of goal of systolic blood pressure (SBP)<130 mmHg and dias Pharmacia proposes combinations of an aldosterone receptor tolic blood pressure (DBP)<80 mmHg. Despite intensive, antagonist with an endothelin receptor antagonist and/or an multi-drug therapy, only about 50% of patients with diabetes endothelin converting enzyme inhibitor, compositions or chronic kidney disease reach traditional blood pressure 65 thereof, and therapeutic methods for use in treatment of goals, with even fewer reaching the more stringent goals now pathological conditions such as hypertension, cardiovascular recommended by JNC 7. Thus, resistant hypertension is par disease and renal dysfunction. US 8,623,819 B2 5 6 Improved drug therapies for treatment of patients having Insulin sensitivity may be measured by standard insulin mod complications of diabetes Such as diabetic nephropathy and/ els, such as HOMA-IR (homeostasis model assessment of or metabolic syndrome, especially such patients exhibiting insulin resistance). resistance to a baseline antihypertensive therapy with one or In yet another embodiment, practice of the method leads to more drugs, for example patients having clinically diagnosed 5 enhancement in both glycemic control and insulin sensitivity, resistant hypertension, would be highly desirable. particularly in a Subject having diabetic nephropathy and/or metabolic syndrome. SUMMARY OF THE INVENTION Enhancement of glycemic control is typically manifested by a reduction intendency for hyperglycemia. A fasting (e.g., There is now provided a method for enhancing glycemic 10 preprandial) blood glucose level greater than about 140 control and/or insulin sensitivity in a human Subject having mg/dl., or a bedtime blood glucose level greater than about diabetic nephropathy and/or metabolic syndrome, compris 160 mg/dl., can be evidence of hyperglycemia. Any reduction ing administering to the Subject a selective endothelin A in blood glucose level can be beneficial to a Subject having (ET) receptorantagonist in a glycemic control and/or insulin hyperglycemia, for example a reduction by at least about 5, at 15 least about 10, at least about 15 or at least about 20 mg/dl. sensitivity enhancing effective amount. Ideally, glucose level is brought into a goal range for healthy There is further provided a method for treating a complex subjects of about 80 to about 120 mg/dl (preprandial) or about of comorbidities in an elderly diabetic human subject, com 100 to about 140 mg/dl (bedtime). Reduction of glucose level prising administering to the Subject a selective ET receptor in urine can also provide evidence of enhanced glycemic antagonist in combination or adjunctive therapy with at least control, but is less reliable than blood measurements because one additional agent that is (i) other than a selective ET excretion of glucose in urine typically does not occur unless receptor antagonist and (ii) effective in treatment of diabetes blood glucose level exceeds about 180 mg/dl. and/or at least one of said comorbidities other than hyperten For some purposes, a Superior measure of glycemic control Sion. Optionally the combination or adjunctive therapy fur is the glycosylated hemoglobin (HbA) test. This test reflects ther comprises administration of at least one antihypertensive 25 blood glucose concentration over a period of time related to other than a selective ET receptor antagonist. the life-span of red blood cells (about 120 days), and conse There is still further provided a therapeutic combination quently is not affected by daily or hourly fluctuations in blood comprising a selective ET receptor antagonist and at least glucose level. A patient having an HbA test result greater one antidiabetic, anti-obesity or antidyslipidemic agent other than about 8% is normally considered hyperglycemic. Any than a selective ET receptor antagonist. 30 reduction in HbA level can be beneficial to such a patient, Other embodiments, including particular aspects of the for example a reduction by at least about 0.5, at least about 1, at least about 1.5 or at least about 2 percentage points. Ideally, embodiments summarized above, will be evident from the HbA level is brought into a goal range for healthy subjects detailed description that follows. of about 4% to about 6%. BRIEF DESCRIPTION OF THE DRAWINGS 35 Subjects having diabetic nephropathy and/or metabolic syndrome can be of any age, but incidence of these compli cations of diabetes increases markedly with age. Older sub FIG. 1 is a schematic diagram of the clinical study jects can respond differently from younger Subjects to treat described in Example 2 herein. ment, and can have a different spectrum of adverse effects. It 40 is contemplated herein that elderly Subjects (i.e., Subjects at DETAILED DESCRIPTION least about 50, for example at least about 55, at least about 60 or at least about 65 years old) can benefit especially greatly The term "diabetic nephropathy’ as used herein will be from treatment according to the present method, in part understood to include both incipient and overt stages of dia because of the severity with which their quality of life and betic nephropathy, whether diagnosed or not, but most typi 45 Survival time are impacted by these complications of diabe cally as diagnosed by a clinician or physician. The term tes, and in part because the particular adverse side effects that “metabolic syndrome' as used herein refers to a complex of have been noted for ET antagonists, including reproductive obesity, hypertension, dyslipidemia and diabetes marked by a effects, are of lesser significance later in life. degree of insulin resistance. The existence of metabolic Syn In one embodiment the Subject has incipient diabetic neph drome as a true clinical syndrome is not universally accepted; 50 ropathy. it will be understood that in the present context a patient In another embodiment the subject has overt diabetic neph having metabolic syndrome is one exhibiting a complex of ropathy. conditions as itemized above, whether or not “metabolic syn In a further embodiment the subject has incipient or overt drome' is formally diagnosed in the patient. diabetic nephropathy and practice of the method provides a In one embodiment, the method of the invention is “for 55 further beneficial effect in one or more morphologic markers enhancing glycemic control and/or insulin sensitivity” in a of diabetic nephropathy. A “morphologic marker” in the human Subject. Where glycemic control is enhanced. Such present context is any structural or histological feature of the enhancement can, but does not necessarily, arise from kidney or a tissue thereof, whether observable macroscopi increased insulin sensitivity. Likewise, where insulin sensi cally, by light microscopy or by electron microscopy. Such tivity is enhanced, Such enhancement can, but does not nec 60 markers can be observable directly, for example by biopsy, or essarily, lead to improved glycemic control. indirectly, through a secondary effect specific to the marker. In one embodiment, practice of the method leads to Examples of morphologic markers of diabetic nephropathy enhancement of glycemic control, particularly in a subject include, without limitation, kidney size, kidney weight, GBM having diabetic nephropathy and/or metabolic syndrome. thickening, mesangial expansion, deposition of , In another embodiment, practice of the method leads to 65 fibronectin and , nephron density, nodular glomeru enhancement of insulin sensitivity, particularly in a subject losclerosis, atherosclerosis of renal vasculature or a combi having diabetic nephropathy and/or metabolic syndrome. nation thereof. US 8,623,819 B2 7 8 In a still further embodiment the subject has incipient or oxy-3.3-diphenylpropionic acid in racemic form has K. (ET) overt diabetic nephropathy and practice of the method pro of 6 nM and K. (ET) of 371 nM, thus selectivity K. (ET)/K, vides a further beneficial effect in one or more indicators of (ET) for the racemate based on these data can be calculated renal function, for example GFR, creatinine clearance, albu as about 62. It was further reported therein that the pure minuria or a combination thereof. 5 enantiomers have an affinity for ET of 3 nM and 150 nM. A “beneficial effect of the present method can take the The more potent enantiomer was concluded to be the (S)- form of an improvement over baseline, i.e., an improvement enantiomer. over a measurement or observation made prior to initiation of More recently, Lip (2001) IDrugs 4(11):1284-1292 therapy according to the method. For example, a reduction in reported the (S)-enantiomer (darusentan) as having K. (ET) amount of collagen deposited, an increase in GFR (in a Sub 10 1.4 nM and selectivity K. (ET)/K,(ET) about 160. ject having overt diabetic nephropathy) or a reduction in It has now been found that K. (ET)/K,(ET) for darusen albuminuria by comparison with a baseline level would rep tan, when measured in a system that achieves steady-state resent Such an improvement. binding, is much greater than previously reported. A “beneficial effect can also take the form of an arresting, To measure affinities of darusentan for ET and ET recep slowing, retarding or stabilizing of a deleterious progression 15 tors in the same humantissuepreparation, 'III-endothelin-1 in any of the above markers or functional effects of diabetic receptor binding cold ligand competition curves were per nephropathy. For example, even if GFR is not increased or formed in human myocardial membranes prepared from fail albuminuria is not reduced by comparison with baseline mea ing and non-failing left ventricles, and cold ligand dissocia surements, a reduction in the rate of decrease of GFR or the tion constants (K) for ET and ET receptors were rate of increase of albuminuria would represent a beneficial determined by computer modeling. Assay conditions effect of the present method. included 10 uMGpp (NH)p (guanylyl-5'-imidodiphosphate) Thus in one embodiment, practice of the invention leads to to eliminate high-affinity agonist binding, 18-point competi an arresting, slowing, retarding or stabilizing of the progres tion curves from 1 pM to 100 uM, and a 4-hour incubation sion of diabetic nephropathy in the Subject. Such arresting, 25 time to achieve steady-state binding. Darusentan was found slowing, retarding or stabilizing of progression of the disease to have the following properties under these conditions (mean can result in extension of the time to end-stage renal disease of 8 assays): or chronic kidney failure, which in turn can extend survival K(ET): 0.178+0.055 nM time of the subject. K. (ET): 216+85 nM A selective ET receptor antagonist useful herein exhibits 30 K(ET)/K(ET): 1181+148 an affinity (as expressed by dissociation constant K.) for ET According to the present method, the selective ET recep not greater than about 10 nM and a selectivity for ET over tor antagonist is administered “in a glycemic control and/or ET (as expressed by the ratio K. (ET)/K,(ET)) of at least insulin sensitivity enhancing effective amount.” What consti about 50. In various embodiments K. (ET) is not greater than tutes such an effective amount will depend on the particular about 5 nM, not greater than about 2 nM, not greater than 35 selective ET receptor antagonist used, on the individual sub about 1 nM, not greater than about 0.5 nM or not greater than ject, on the dosage form and route of administration used and about 0.2nM. In various embodiments K. (ET)/K,(ET) is at on other factors, and can be readily determined by one of skill least about 100, at least about 200, at least about 500 or at least in the art without undue experimentation based on the disclo about 1000. Sure herein. Any dose that is effective for enhancing glycemic Suitable selective ET receptor antagonists can be identi 40 control and/or insulin sensitivity, up to a maximum that is fied by one of ordinary skill from literature on Such antago tolerated by the subject without unacceptable adverse side nists, based on the disclosure herein, but a non-limiting list of effects, can be administered. Illustratively for darusentan, Such antagonists includes ambrisentan, atrasentan, avosen such a dose is likely to be about 1 to about 600 mg/day, for tan, BMS 193884, BQ-123, CI-1020, claZosentan, darusen example about 5 to about 450 mg/day or about 10 to about 300 tan, edonentan, S-0139, SB-209670, sitaxsentan, TA-0201, 45 mg/day. Higher or lower doses can be useful in specific cir tarasentan, TBC 3711, tezosentan, YM-598, ZD-1611 and cumstances. Useful doses of other selective ET receptor ZD-4054, as well as salts, esters, prodrugs, metabolites, tau antagonists are doses that are therapeutically equivalent to tomers, racemates and enantiomers thereof. Such a dose of darusentan. In one embodiment, the selective ET receptor antagonist comprises darusentan ((+)-(S)-2-(4,6-dimethoxy-2-pyrim The desired daily dosage amount can be administered in 50 any suitable number of individual doses, for example four idinyl)oxy-3-methoxy-3,3-diphenylpropionic acid). This times, three times, twice or once a day. With a dosage form compound has the formula having appropriate controlled release properties, a lower fre quency of administration may be possible, for example once every two days, once a week, etc. In one embodiment, the selective ET receptor antagonist O is administered according to a therapeutic regimen wherein dose and frequency of administration and duration of therapy OH O-CH are effective to lower blood glucose level by at least about 10 HC-O N mg/dl and/or to lower HbA level by at least about 0.5 per centage points. O K / In another embodiment, the selective ET receptor antago N nist is administered according to a therapeutic regimen O-CH wherein dose and frequency of administration and duration of therapy are effective to achieve a goal preprandial blood 65 glucose level of about 80 to about 120 mg/dl., a goal bedtime Riechers et al. (1996) J. Med. Chem. 39:2123-2128 blood glucose level of about 100 to about 140 mg/dland/or a reported that 2-(4,6-dimethoxypyrimidin-2-yloxy)-3-meth goal Hb A level not greater than about 7%. US 8,623,819 B2 10 Benefits of the present method may not be evident imme meanx100. A diurnal ABP pattern having a day/night ABP diately upon initiating a therapeutic regimen as described ratio of less than about 10% is sometimes referred to as a herein. In particular, it can take some time for it to become “non-dipping ABP. evident that progression of a complication of diabetes Such as The patient receiving therapy according to a method of the diabetic neuropathy has been slowed. It is therefore contem invention can be a patient exhibiting resistance to a baseline plated that administration of a selective ET receptor antago antihypertensive therapy with one or more drugs. A "baseline nist will in some cases continue for an extended period of antihypertensive therapy herein means a therapeutic regi time, typically at least about 1 month, more typically at least men comprising administration of one or more drugs, not about 3 months. Duration of therapy in some embodiments including a selective ET receptor antagonist, with an objec 10 tive (which can be the primary objective or a secondary objec can be at least about 1 year, at least about 5 years, or for as tive of the regimen) of lowering blood pressure in the patient. long as needed, which can be lifelong (i.e., from a time of Each drug according to the regimen is administered at least at initiation of treatment for substantially the remainder of the a dose considered by an attending physician to be adequate patient’s life). In one embodiment duration of therapy is from for treatment of hypertension, taking into account the particu a time of diagnosis of diabetic nephropathy (whether incipi 15 lar patient’s medical condition and tolerance for the drug ent or overt) at least to a time of progression of the diabetic without unacceptable adverse side-effects. An "adequate’ nephropathy into end-stage renal disease. In some situations dose as prescribed by the physician can be less than or equal the method of this embodiment will be successful in prevent to a full dose of the drug. A “full dose is the lowest of (a) the ing progression of the disease to end-stage; in Such situations highest dose of the drug labeled for a hypertension indication; the treatment can be continued indefinitely. For example, (b) the highest usual dose of the drug prescribed according to administration of the selective ET receptor antagonist can JNC 7, BHD-IV, ESH/ESC or WHO/ISH guidelines; or (c) continue for as long as a therapeutic benefit is provided the highest tolerated dose of the drug in the particular patient. thereby and any adverse side effects thereof remain commen A baseline antihypertensive therapy illustratively com Surate with the therapeutic benefit. prises administering one or more and/or one or more Selective ET receptor antagonists are known to be useful 25 antihypertensive drugs selected from (a) angiotensin convert as antihypertensive agents. Thus practice of the present ing enzyme inhibitors and angiotensin II receptor blockers, method is likely to provide a benefit not only in glycemic (b) beta- blockers, (c) calcium channel control and/or insulin sensitivity as outlined above, but an blockers, (d) direct vasodilators, (e) alpha-1-adrenergic additional benefit in lowering blood pressure. As hyperten receptor blockers, (f) central alpha-2-adrenergic receptor 30 agonists and other centrally acting antihypertensive drugs, sion is an important feature of both diabetic nephropathy and and (g) aldosterone receptor antagonists. Optionally drugs of metabolic syndrome, these benefits can be mutually reinforc still further classes can be included in the baseline therapy. ing. A patient who is “resistant to a baseline antihypertensive Any one or more measures of blood pressure can be low therapy is one in whom hypertension is failing to respond ered by a method as described herein, including SBP and/or 35 adequately or at all to the baseline therapy. Typically, the DBP as determined, for example, by sphygmomanometry. patient receiving the baseline therapy is failing to reach an SBP and/or DBP can be measured, for example, in a sitting or established blood pressure goal, as set forth for U.S. patients, ambulatory patient. for example, in JNC 7 or comparable standards in other coun A “trough sitting SBP or DBP is measured at a time point tries (e.g., BHD-IV, ESH/ESC or WHO/ISH guidelines). when serum concentration of a drug or drugs administered 40 Illustratively, the JNC 7 goal in a patient having a complicat according to a method of the invention is expected to be at or ing condition Such as diabetes and/or chronic kidney disease close to its lowest in a treatment cycle, typically just before is <130 mmHg SBP and <80 mmHg DBP. administration of a further dose. Illustratively, where the drug Patients resistant to a baseline antihypertensive therapy, or drugs are administered once a day at a particular time, for especially such a therapy involving a plurality of drugs, example around 8 am, trough sitting systolic or diastolic 45 clearly represent a very challenging population for treatment. blood pressure can be measured at that time, immediately Typically in Such patients, increasing dosages of the baseline before the daily administration. It is generally preferred to therapy are not an option because of resulting adverse side measure trough sitting SBP or DBP at around the same time effects; furthermore this approach is often ineffective in pro of day for each Such measurement, to minimize variation due viding a desired lowering of blood pressure. to the natural diurnal blood pressure cycle. 50 A clinically meaningful lowering of blood pressure can be A “24-hour ambulatory” SBP or DBP is an average of obtained in such patients by use of a selective ET receptor measurements taken repeatedly in the course of a 24-hour antagonist Such as darusentan. A reduction of at least about 3 period, in an ambulatory patient. mmHg in any blood pressure parameter can be considered A“maximum diurnal SBP or DBP is a measure of highest clinically meaningful. SBP or DBP recorded in a 24-hour period, and often reflects 55 Accordingly, in one embodiment of the present invention, the peak of the natural diurnal blood pressure cycle, typically a method for enhancing glycemic control and/or insulin sen occurring in the morning, for example between about 5am sitivity and for lowering blood pressure in a patient exhibiting and about 11 am. Commonly, a second peak occurs in the resistance to a baseline antihypertensive therapy comprises evening, for example between about 5 pm and 10 pm. Such a administering to the patient a selective ET receptor antago bimodal waveform diurnal ABP pattern may be especially 60 nist, for example darusentan, at a dose and frequency effec characteristic of resistant hypertension. tive to provide a reduction of at least about 3 mmHg in trough A common feature of resistant hypertension is a nighttime sitting SBP and/or DBP. 24-hour ambulatory SBP and/or (defined herein as 2200 to 0600) mean systolic ABP that is DBP, and/or maximum diurnal SBP and/or DBP. less than about 10% lower than the daytime (defined hereinas In patients exhibiting resistance to a baseline antihyperten 0600 to 2200) mean systolic ABP. The parameter herein 65 sive therapy with one or more drugs, administration of termed “day/night ABP ratio’ expressed as a percentage is darusentan adjunctively with these same drugs is Surprisingly calculated as (daytime mean-nighttime mean)/daytime well tolerated. Accordingly, in another embodiment of the US 8,623,819 B2 11 12 present invention, a method for enhancing glycemic control sion. By definition herein, in general accordance with JNC 7. and/or insulin sensitivity and for lowering blood pressure in a Such a patient exhibits resistance to an antihypertensive regi patient exhibiting resistance to a baseline antihypertensive men of at least three drugs including a diuretic. In one therapy with one or more drugs comprises administering embodiment, the patient having resistant hypertension exhib darusentan to the patient adjunctively with said one or more its resistance to a baseline antihypertensive therapy that com drugs. prises at least the following: While in certain embodiments the selective ET receptor (1) one or more diuretics; and antagonist, for example darusentan, can be administered (2) two or more antihypertensive drugs, selected from at alone, i.e., in monotherapy, it is contemplated that in most least two of the following classes: cases combination therapy, for example but not necessarily 10 (a) ACE inhibitors and angiotensin II receptor blockers; with one or more drugs of the baseline therapy to which the (b) beta-adrenergic receptor blockers; and patient has proved resistant, will be desirable. However, a (c) calcium channel blockers. benefit of the administration of darusentan can be that, at least In some cases, the patient is resistant to an even more in some circumstances, it can permit dose reduction, or even comprehensive baseline therapy, further comprising, for elimination, of at least one of the drugs in the baseline 15 example, one or more direct vasodilators, alpha-1-adrenergic therapy. blockers, central alpha-2-adrenergic agonists or other cen Particularly when used at a full dose, many baseline anti trally acting antihypertensive drugs, and/or aldosterone hypertensive therapy drugs can have undesirable, in some receptor antagonists. cases clinically unacceptable or even dangerous, adverse side While in one embodiment the selective ET receptor effects. antagonist is administered orally, the invention is not limited For example, especially at full doses, potassium-sparing to any route of administration, so long as the route selected diuretic drugs can be associated with increased risk of hyper results in effective delivery of the drug so that the stated kalemia and related disorders. Overuse of loop diuretics can benefits are obtainable. Thus administration of the darusentan cause depletion of sodium resulting in hyponatremia and/or can illustratively be parenteral (e.g., intravenous, intraperito extracellular fluid volume depletion associated with hypoten 25 neal, Subcutaneous or intradermal), transdermal, transmu sion, reduced GFR, circulatory collapse, and thromboembo cosal (e.g., buccal, Sublingual or intranasal), intraocular, lic episodes. Further, loop diuretics can cause ototoxicity that intrapulmonary (e.g., by inhalation) or rectal. Most conve results in tinnitus, hearing impairment, deafness and/or ver niently for the majority of patients, however, the selective tigo. diuretics, similarly to loop diuretics, can have ET receptor antagonist is administered orally, i.e., per os adverse effects related to abnormalities of fluid and electro 30 (p.o.). Any Suitable orally deliverable dosage form can be lyte balance. Such adverse events include extracellular vol used for the selective ET receptor antagonist, including ume depletion, hypotension, hypokalemia, hyponatremia, without limitation tablets, capsules (solid- or liquid-filled), hypochloremia, metabolic alkalosis, hypomagnesemia, powders, granules, syrups and other liquids, etc. hypercalcemia and hyperuricemia. Thiazide diuretics can Most antihypertensive medicines are suitable for once a also decrease glucose tolerance, and increase plasma levels of 35 day administration, and this is true also of darusentan. Thus, LDL cholesterol, total cholesterol, and total triglycerides. particularly where darusentan is being administered in Angiotensin converting enzyme (ACE) inhibitors are asso adjunctive therapy with one or more other antihypertensive ciated with cough and increased risk of angioedema. Beta drugs, it is generally most convenient to administer the adrenergic receptor blockers are associated with increased darusentan once a day in a dose as indicated above. risk of bronchospasm, bradycardia, heart block, excess nega 40 Most typically, where the patient has clinically diagnosed tive inotropic effect, peripheral arterial insufficiency and resistant hypertension, the selective ET receptor antagonist Sometimes male impotence. Calcium channel blockers are is administered adjunctively with (1) one or more diuretics; associated with increased risk of lower limb edema. Further and (2) two or more antihypertensive drugs, selected from (a) information on adverse events associated with antihyperten ACE inhibitors and angiotensin II receptor blockers; (b) beta sive drugs can be found, for example, in standard reference 45 adrenergic receptor blockers; and (c) calcium channel block works such as Goodman & Gilman's The Pharmaceutical ers. Each of these diuretic and antihypertensive drugs is typi Basis of Therapeutics, 13th ed. cally administered at an adequate to full dose. One of skill in In situations such as those outlined immediately above, the art can readily identify a suitable dose for any particular dose reduction or elimination of a baseline therapy drug per diuretic or from publicly available mitted by use of darusentan can result in a reduced risk or 50 information in printed or electronic form, for example on the incidence of adverse events by comparison with the baseline internet. therapy alone without such dose reduction or elimination. Mention of a particular diuretic orantihypertensive drug in Adjunctive' administration of darusentan (or other selec the present specification and claims will be understood, tive ET receptor antagonist) in the present context means except where the context demands otherwise, to include phar that the darusentan is administered concomitantly with a 55 maceutically acceptable salts, esters, prodrugs, metabolites, baseline hypertensive therapy as defined above, with or with racemates and enantiomers of the drug, to the extent that Such out dose reduction of one or more drugs in the baseline salts, esters, prodrugs, metabolites, racemates or enantiomers therapy. For example, darusentan can be administered exist and are therapeutically effective. adjunctively with an adequate to full dose of each of the drugs Examples of drugs useful in combination or adjunctive in the baseline therapy. In adjunctive therapy, the dose and 60 therapy with a selective ET receptor antagonist, for example frequency of darusentan administration is, in one embodi darusentan, or as a component of a baseline antihypertensive ment, effective in combination with the baseline therapy to therapy are classified and presented in several lists below. provide a reduction of at least about 3 mmHg in trough sitting Some drugs are active at more than one target; accordingly SBP and/or DBP. 24-hour ambulatory SBP and/or DBP and/ certain drugs may appear in more than one list. Use of any or maximum diurnal SBP and/or DBP. 65 listed drug in a combination or adjunctive therapy of the A method of the present invention is especially beneficial invention is contemplated herein, independently of its mode where the patient has clinically diagnosed resistant hyperten of action. US 8,623,819 B2 13 14 A suitable diuretic can illustratively be selected from the isosorbide following list: Kiowa Hakko KW 3902 Organomercurials mannitol chlormerodrin muZolimine chlorothiazide perhexyline chlorthalidone -Aventis SR 121463 meralluride ticrynafen mercaptomerin Sodium triamterene mercumatilin sodium la mercurous chloride 10 In some embodiments, the diuretic if present comprises a mersalyl thiazide or loop diuretic. Thiazide diuretics are generally not Purines preferred where the patient has a complicating condition Such pamabrom as diabetes or chronic kidney disease, and in Such situations a protheobromine loop diuretic can be a better choice. theobromine 15 Particularly suitable thiazide diuretics, for example for use Steroids with darusentan, include chlorothiazide, chlorthalidone, CaO. hydrochlorothiazide, indapamide, metolaZone, polythiazide oleandrin and combinations thereof. Particularly suitable loop diuretics spironolactone include bumetanide, furosemide, torsemide and combina Sulfonamide Derivatives tions thereof. acetazolamide A suitableACE inhibitor can illustratively be selected from ambuside the following list: aZosemide bumetanide butazolamide 25 chloraminophenamide ceronapril clofenamide clopamide clorexolone enalapril disulfamide 30 ethoXZolamide eosinopril furosemide mefruside methazolamide piretanide 35 torsemide moveltipril tripamide Xipamide and Analogs althiazide 40 bendroflumethiazide Sampatrilat benzthiazide benzylhydrochlorothiazide buthiazide trandolapril chlorthalidone 45 Particularly suitable ACE inhibitors, for example for use cyclopenthiazide with darusentan, includebenazepril, captopril, enalapril, fosi cyclothiazide nopril, lisinopril, moexipril, perindopril, quinapril, ramipril, ethiazide trandolapril and combinations thereof. fenduizone A suitable angiotensin II receptor blocker can illustratively hydrochlorothiazide 50 be selected from the following list: hydroflumethiazide indapamide methylclothiazide irbesartan metolaZone losartan paraflutizide 55 polythiazide quinethaZone teclothiazide trichloromethiazide A Suitable beta-adrenergic receptor blocker can illustra Uracils 60 tively be selected from the following list: aminometradine AC 623 Unclassified acebutolol amiloride alprenolol Biogen BG 9719 atenolol chlorazanil 65 amoSulalol ethacrynic acid arotinolol etozolin atenolol US 8,623,819 B2 15 16 befunolol Dihydropyridine Derivatives betaxolol amlodipine bevantolol aranidipine bisoprolol barnidipine benidipine bopindolol cilnidipine efonidipine bucumolol elgodipine bufetolol felodipine bufuralol isradipine bunitrolol 10 lacidipine bupranolol lercanidipine butidrine hydrochloride manidipine butofilolol nicardipine carazolol nifedipine 15 nilvadipine carteolol nimodipine carvedilol nisoldipine celiprolol nitrendipine cetamolol NZ 105 cloranolol Piperazine Derivatives dilevalol cinnarizine esmolol dotarizine indenolol flunarizine labetalol lidoflazine landiolol 25 lomerizine levobunolol Unclassified mepindolol bencyclane metipranolol etafenone metoprolol fantofarone moprolol 30 perhexyline nadoxolol Particularly suitable calcium channel blockers, for nebivolol example for use with darusentan, include amlodipine, dilt nifemalol iazem, felodipine, isradipine, nicardipine, nifedipine, nisol nipradillol 35 dipine, Verapamil and combinations thereof. oXprenolol Optionally, one or more additional antihypertensive drugs can be administered. These can be selected, for example, from pindolol direct vasodilators, alpha-1-adrenergic receptor blockers, practolol central alpha-2-adrenergic receptor agonists and other cen pronethalol 40 trally acting antihypertensive drugs, and aldosterone receptor propranolol antagonists. Sotalol A suitable direct vasodilator can illustratively be selected sulfinalol from the following list: talinolol amotriphene tertatolol 45 benfurodil hemisuccinate tilisolol benziodarone timolol chloracizine toliprolol chromonar clobenfurol Particularly suitable beta-adrenergic receptor blockers, for 50 clonitrate example for use with darusentan, include acebutolol. cloricromen atenolol, betaxolol, bisoprolol, carvedilol, labetalol, meto dilaZep prolol, nadolol, penbutolol, pindolol, propranolol, timolol droprenilamine and combinations thereof. efloxate A suitable calcium channel blocker can illustratively be 55 erythrityl tetranitrate selected from the following list: etafenone Arylalkylamines fendiline bepridil hexestrol bis(B-diethylaminoethyl ether) clentiazem hexobendine diltiazem 60 hydralazine fendiline isosorbide dinitrate gallopamil isosorbide mononitrate mibefradil itramin tosylate prenylamine khellin Semotiadil 65 lidoflazine terodiline mannitol hexanitrate Verapamil minoxidil US 8,623,819 B2 17 18 nitroglycerin Illustrative NEP inhibitors, some of which are also ACE pentaerythritol tetranitrate inhibitors, include: pentrinitrol candoxatril perhexyline CGS 26582 pimethylline MDL 100173 prenylamine omapatrilat propatyl nitrate trapidil sinorphan tricromyl thiorphan trimetazidine 10 Z13752A trolnitrate phosphate Illustrative prostanoids include: Visnadine beraprost Particularly suitable direct vasodilators, for example for cicaprost use with darusentan, includehydralazine, minoxidiland.com epoprostenol binations thereof. 15 iloprost A Suitable alpha-1-adrenergic receptor blocker can illus PGE tratively be selected from the following list: PGI2 (pro stacyclin) amosulalol NS-304 arotinolol treprostinil carvedilol Illustrative PDE5 inhibitors include: dapiprazole sildenafil tadalafil ergoloid mesylates Vardenafil fenspiride Other drugs that can be useful in combination or adjunctive idaZOXan 25 therapy with darusentan or in a baseline antihypertensive therapy can illustratively be selected from the following labetalol unclassified list: ajmaline monatepil alfuzosin 30 Alteon ALT 711 nicergoline y-aminobutyric acid atrial natriuretic tamsulosin aZelnidipine teraZosin tolazoline 35 bosentan budralazine Particularly suitable alpha-1-adrenergic receptor blockers, bufeniode for example for use with darusentan, include carvedilol, dox bunaZosin aZosin, labetalol, prazosin, teraZosin and combinations 40 cadralazine thereof. It is noted that, of these, carvedilol and labetalol also carmoxirole function as beta-adrenergic receptor blockers. CD3400 A Suitable central alpha-2-adrenergic receptor agonist or chloride other centrally acting antihypertensive drug can illustratively cicletanine be selected from the following list: 45 ciclosidomine clevidipine debrisoquin denitronipradillol desacetylalacepril methyldopa 50 diazoxide dihydralazine A Suitable aldosterone receptor antagonist can illustra endralazine tively be selected from the following list: CaO. 55 floseduinan eplerenone spironolactone , N-cyano-N'-4-pyridinyl-N'-(1.2.2-trimethyl Still further classes of drugs that can be useful in combi propyl)-, monohydrate nation or adjunctive therapy with darusentan or in a baseline antihypertensive therapy include vasopeptidase inhibitors, 60 NEP (neutral endopeptidase) inhibitors, prostanoids (particu larly oral prostanoids), PDE5 (phosphodiesterase type 5) inhibitors, nitrosylated compounds and oral nitrates. LBI 45 Illustrative vasopeptidase inhibitors include: levcromakalim fasidotril 65 omapatrilat magnesiocard Sampatrilat mebutamate US 8,623,819 B2 19 20 (g) a central alpha-2-adrenergic receptor agonist or other normopresil centrally acting drug selected from the group consisting 2-oxazolamine, N-(dicyclopropylmethyl)-4,5-dihydro of clonidine, guanabenz, guanadrel, guanfacine, meth (2E)-2-butenedioate yldopa, moxonidine, reserpine and combinations thereof, and (h) an aldosterone receptor antagonist selected from the pentamethonium bromide group consisting of canrenone, eplerenone, Spironolac tartrate tone and combinations thereof. pheniprazine More particularly, the selective ET receptor antagonist, 10 more specifically darusentan, can be administered in combi pildralazine nation or adjunctive therapy with one or more of (a), (b), (c) pinacidil and (d) above, optionally further with one or more of (e), (f), piperoxan (g) and (h). protoveratrines 15 Still more particularly, the selective ET receptor antago 3.5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl nist, more specifically darusentan, can be administered in 4-(3-nitrophenyl)-, methyl 1-(phenylmethyl)-3-pyrrolidinyl combination or adjunctive therapy at least with (a) and any ester two of (b), (c) and (d). raubasine As in the case of the selective ET receptor antagonist, the rescimetol one or more drugs constituting the baseline antihypertensive therapy and optionally administered in combination with the rillmenidine selective ET receptor antagonist can be delivered by any Suitable route of administration. Generally, such drugs are Sodium niroprusside Suitable for oral administration, and many are Suitable for 25 once a day oral administration. Thus in one embodiment at Takeda TAK 536 least one of the diuretic or antihypertensive drugs in the TBC 3711 baseline therapy is orally administered once a day. In a par tetrahydrolipstatin ticular embodiment, all drugs in the baseline therapy are 1,4-thiazepine-4(5H)-acetic acid, 6-1-(ethoxycarbonyl)- orally administered once a day. According to this embodi 3-phenylpropylamino-tetrahydro-5-oxo-2-(2-thienyl) 30 ment, it will generally be found convenient to administer all drugs in the regimen, i.e., the selective ET receptor antago todralazine nist as well as the baseline therapy drugs, orally once a day. Fixed-dose combinations of two or more drugs can be trimethaphan camsylate achieved in many cases by coformulation of the drugs in a tyrosinase 35 single dosage unit Such as a tablet or capsule. For example, coformulations of various drugs useful in a baseline antihy pertensive therapy as defined herein are available, including: In one embodiment, the selective ET receptor antagonist, amiloride-l-hydrochlorothiazide; more specifically darusentan, is administered concomitantly amlodipine--benazepril; (e.g., in combination or adjunctive therapy) with one or more 40 atenolol--chlorthalidone; of benazepril--hydrochlorothiazide: (a) a diuretic selected from the group consisting of chlo bisoprolol--hydrochlorothiazide; rothiazide, chlorthalidone, hydrochlorothiazide, inda candesartan-hydrochlorothiazide; pamide, metolaZone, polythiazide, bumetanide, furo captopril--hydrochlorothiazide: semide, torsemide and combinations thereof; 45 enalapril--felodipine; (b) an ACE inhibitor selected from the group consisting of enalapril--hydrochlorothiazide: benazepril, captopril, enalapril, fosinopril, lisinopril, eprosartan--hydrochlorothiazide; moexipril, perindopril, quinapril, ramipril, trandolapril fosinopril--hydrochlorothiazide: and combinations thereof, and/or an angiotensin II irbesartan+hydrochlorothiazide: receptor blocker selected from the group consisting of 50 lisinopril--hydrochlorothiazide; candesartan, eprosartan, irbesartan, losartan, olm losartan+hydrochlorothiazide: esartan, tasosartan, telmisartan, Valsartan and combina methyldopa--hydrochlorothiazide; tions thereof; metoprolol--hydrochlorothiazide; (c) a beta-adrenergic receptor blocker selected from the moexipril--hydrochlorothiazide: group consisting of acebutolol, atenolol, betaxolol, biso 55 nadolol--hydrochlorothiazide; prolol, carvedilol, labetalol, metoprolol, nadolol, penb olmesartan--hydrochlorothiazide; utolol, pindolol, propranolol, timolol and combinations propranolol--hydrochlorothiazide: thereof; quinapril--hydrochlorothiazide; (d) a calcium channel blocker selected from the group reserpine--chlorothiazide; consisting of amlodipine, diltiazem, felodipine, israd 60 reserpine--chlorthalidone; ipine, nicardipine, nifedipine, nisoldipine, Verapamil reserpine--hydrochlorothiazide; and combinations thereof; spironolactone--hydrochlorothiazide; (e) a direct vasodilator selected from the group consisting telmisartan+hydrochlorothiazide; of hydralazine, minoxidil and combinations thereof; timolol--hydrochlorothiazide; (f) an alpha-1-adrenergic receptor blocker selected from 65 trandolapril--Verapamil; the group consisting of carvedilol, doxazosin, labetalol, triamterene--hydrochlorothiazide; and prazosin, teraZosin and combinations thereof; Valsartan+hydrochlorothiazide. US 8,623,819 B2 21 22 It will be understood that combination or adjunctive thera Particularly suitable antidiabetics, for example for use with pies as indicated above, while of particular benefit in patients darusentan, include , , , insu having resistant hypertension, are not limited to such patients. lins, , , , , Hypertension (whether resistant or not) is a common feature and combinations thereof. of most complications of diabetes, including both diabetic 5 nephropathy and metabolic syndrome, and it is contemplated For a subject with metabolic syndrome, a selective ET that combination or adjunctive therapies of a selective ET receptor antagonist can be administered in combination or receptor antagonist with one or more antihypertensive drugs adjunctive therapy with one or more additional agents other than selective ET receptor antagonists can be useful in selected from antidiabetics (for example as listed above), many diabetic patients having these complications. antihypertensives (for example as listed above), anti-obesity Another kind of combination oradjunctive therapy that can 10 agents and antidyslipidemics. be useful according to the present invention includes a selec Suitable anti-obesity agents include anorexics, CB1 recep tive ET receptor antagonist and one or more additional tor blockers and lipase inhibitors. antidiabetic agents other than selective ET receptor antago A suitable anti-obesity agent can illustratively be selected nists. Such additional antidiabetic agents can, for example, be from the following list: selected from alpha-glucosidase inhibitors, , exen 15 dins, hormones and analogs thereof, , Sulfony aminorex lurea derivatives and . amphetamine A suitable antidiabetic can illustratively be selected from benzphetamine the following list: chlorphentermine Biguanides clobenzorex clortermine metformin cyclexedrine dextroamphetamine Hormones and Analogs Thereof diethylpropion 25 N-ethylamphetamine insulin fenbutrazate fenfluramine fenproporex levophacetoperane insulin glulisine 30 maZindol mefenorex methamphetamine pramlintide norpseudoephedrine Derivatives orlistat 35 pentorex phendimetrazine phenmetrazine phentermine phenylpropanolamine glimepiride 40 rimonabant Sibutramine Particularly suitable anti-obesity agents, for example for glisoxepid use with darusentan, include benzphetamine, methamphet glyburide amine, orlistat, phendimetrazine, phentermine, rimonabant, glybuthiazole 45 Sibutramine and combinations thereof. glybuzole Suitable antidyslipidemics include bile acid sequestrants, glyhexamide cholesterol absorption inhibitors, fibrates, HMG CoA reduc glymidine tase inhibitors (statins), nicotinic acid derivatives, and thyroid hormones and analogs thereof. 50 A suitable antidyslipidemic can illustratively be selected tolcyclamide from the following list: Thiazolidinediones Bile Acid Sequestrants pioglitaZone cholestyramine resin rosiglitaZone colesevelam 55 colestilan Unclassified colestipol acarbose polidexide exenatide Fibrates bezafibrate 60 binifibrate ciprofibrate nateglinide clinofibrate clofibrate clofibric acid 65 etofibrate fenofibrate gemfibrozil US 8,623,819 B2 23 24 pirifibrate packaging ("common presentation”). As an example of co ronifibrate packaging or common presentation, a kit is contemplated simfibrate comprising, in separate containers, darusentan and at least theofibrate one drug useful in combination or adjunctive therapy with HMG CoA Reductase Inhibitors darusentan, for example an antidiabetic, antihypertensive, atorvastatin anti-obesity agent or antidyslipidemic. In another example, cerivastatin darusentan and at least one drug useful in combination or fluvastatin adjunctive therapy with darusentan, for example an antidia lovastatin betic, antihypertensive, anti-obesity agent or antidyslipi pitavastatin 10 demic, are separately packaged and available for sale inde pravastatin pendently of one another, but are co-marketed or rosuvastatin co-promoted for use according to the invention. The separate simvastatin dosage forms can also be presented to a patient separately and Nicotinic Acid Derivatives independently, for use according to the invention. acipimox 15 A further embodiment of the present invention provides a aluminum nicotinate method for treating a complex of comorbidities in an elderly niacin (nicotinic acid) diabetic human Subject. This method comprises administer niceritrol ing to the Subject a selective ET receptor antagonist in com OXiniacic acid bination or adjunctive therapy with Thyroid Hormones and Analogs Thereof (a) at least one additional agent that is (i) other than a dextrothyroxine selective ET receptor antagonist and (ii) effective in etiroXate treatment of diabetes and/or at least one of said comor thyropropic acid bidities other than hypertension, and optionally Unclassified (b) at least one antihypertensive other than a selective ET acifran 25 receptor antagonist. avasimibe An “elderly subject is as defined hereinabove. A “comorbidity” is a disease condition present in the sub detaXtran ject in addition to diabetes, that adds to the deleterious effects eicosapentaenoic acid of the diabetes on the subject and/or affects the choice of eZetimibe 30 therapy. Comorbidities can arise secondarily from the diabe meglutol tes or from other comorbidities, or may arise independently. melinamide Among comorbidities commonly occurring in an elderly dia omega-3 acid ethyl esters betic patient population are, illustratively, insulin resistance, Y-oryZanol chronic kidney disease, hypertension, dyslipidemia, obesity, pantethine 35 cardiac insufficiency and sleep apnea. pirozadil A “complex” of comorbidities is defined herein as the policonasol presence of at least two such comorbidities, in addition to the probucol underlying diabetes. In some embodiments the Subject pre B-sitosterol sents with at least three, or even four or more, such comor Sultosilic acid 40 bidities. For example, in metabolic syndrome, a Subject can tiadenol exhibit diabetes with insulin resistance, hypertension, dys torcetrapib lipidemia and obesity. Xenbucin “Treating in the present context includes alleviating Particularly suitable antidyslipidemics, for example for use symptoms, enhancing glycemic control and/or insulin sensi with darusentan, include atorvastatin, colesevelam, 45 tivity, arresting, slowing, retarding or stabilizing progression eZetimibe, fenofibrate, fluvastatin, lovastatin, niacin, rosuv of a condition or a physiological or morphological marker astatin, simvastatin and combinations thereof. thereof, and/or improving clinical outcome, for example as It is further contemplated that the selective ET receptor measured by quality of life, incidence or severity of adverse antagonist can itself have useful antidyslipidemic activity, for cardiac events, time to end-stage renal disease or Survival example secondary to its activity in enhancing glycemic con 50 time. trol and/or insulin sensitivity. The selective ET receptor antagonist can illustratively be When a selective ET receptorantagonist is used in adjunc selected from those mentioned hereinabove. In one embodi tive therapy with one or more additional antidiabetics, anti ment the selective ET receptor antagonist comprises hypertensives, anti-obesity agents and/or antidyslipidemics, darusentan, for example at dosage amounts and frequencies the selective ET receptor antagonist and at least one addi 55 of administration, by routes of administration and dosage tional antidiabetic, antihypertensive, anti-obesity agent and/ forms, and for duration of treatment as indicated hereinabove. or antidyslipidemic can be administered at different times or Several of the comorbidities mentioned above as occurring at about the same time (at exactly the same time or directly in elderly diabetic patients have been individually reported in one after the other in any order). The selective ET receptor the literature (including literature cited herein) to be mediated antagonist and the at least one antidiabetic, antihypertensive, 60 by ET-1 and/or to be treatable with a selective ET receptor anti-obesity agent and/orantidyslipidemic can be formulated antagonist. However, it has not hitherto been proposed to in one dosage form as a fixed-dose combination for adminis simultaneously address a complex of comorbidities of diabe tration at the same time, or in two or more separate dosage tes in an elderly patient by treatment with a selective ET forms for administration at the same or different times. receptor antagonist Such as darusentan; nor has it been pro Separate dosage forms can optionally be co-packaged, for 65 posed to combine Such treatment, in adjunctive or combina example in a single container or in a plurality of containers tion therapy, with one or more additional agents effective in within a single outer package, or co-presented in separate treatment of diabetes and/or at least one of said comorbidities US 8,623,819 B2 25 26 other than hypertension. Given the spectrum of effects of of situations, not limited to methods described herein. How selective ET receptor antagonists but without being bound ever, a combination of this embodiment can be especially by theory, it is believed that the selective ET receptor antago useful for treating a complex of comorbidities in an elderly nist (e.g., darusentan) component of Such adjunctive or com diabetic human subject as described above. bination therapy can contribute in a Substantial way to clinical The selective ET receptor antagonist and the at least one improvement in each of a plurality of comorbidities, for antidiabetic, anti-obesity or antidyslipidemic agent can be example Supplementing the effect of, co-acting with, or per present in the combination in two or more separate dosage mitting dose reduction (with potential benefits in reducing forms, permitting administration at the same or different adverse side-effects) in at least one additional agent. How times. Such separate dosage forms can be formulated with ever, even without such contribution by the selective ET 10 receptor antagonist to more than one comorbidity, the adjunc one or more pharmaceutically acceptable excipients for tive or combination therapy of the present embodiment brings administration via the same or different routes. In a particular great benefit to the elderly diabetic patient by enabling a embodiment all agents in the combination are formulated for complex of comorbidities, as seen for example in diabetic oral administration; in an even more particular embodiment nephropathy or metabolic syndrome, to be simultaneously 15 all agents are formulated for once-daily oral administration addressed. and can be administered at the same time each day. Where a The at least one additional agent that is (i) other than a treatment regimen includes administration of a plurality of selective ET receptor antagonist and (ii) effective in treat drugs, as in the present instance, there are great benefits in ment of diabetes and/or at least one comorbidity other than convenience and compliance in standardizing route, fre hypertension can comprise, for example, one or more antidia quency and timing of administration in this way. betics, anti-obesity agents and/or antidyslipidemics, includ As indicated hereinabove, separate dosage forms can ing any such agents listed hereinabove. For example, one or optionally be co-packaged, for example in a single container more agents selected from acarbose, exenatide, glimepiride, orina plurality of containers within a single outer package, or , metformin, nateglinide, pioglitaZone, pramlintide, co-presented in separate packaging, for example as a kitcom rosiglitaZone, benzphetamine, methamphetamine, orlistat, 25 prising, in separate containers, a selective ET receptor phendimetrazine, phentermine, rimonabant, Sibutramine, antagonist and at least one antidiabetic, anti-obesity or anti atorvastatin, colesevelam, eZetimibe, fenofibrate, fluvastatin, dyslipidemic agent. The kit can optionally comprise separate lovastatin, niacin, rosuvastatin, simvastatin and combinations labeling information for each agent, or a single product label thereof can be administered in adjunctive or combination having information on the therapeutic combination as a therapy with a selective ET receptor antagonist, for example 30 darusentan. whole. In another example, the selective ET receptorantago Antihypertensive(s) optionally additionally present in the nist and the at least one antidiabetic, anti-obesity or antidys adjunctive or combination therapy can comprise, for lipidemic agent are separately packaged and available for sale example, agents of any class listed hereinabove, including independently of one another, but are co-marketed or co diuretics, ACE inhibitors, angiotensin II receptor blockers, 35 promoted for use according to the invention. The separate beta-adrenergic receptor blockers, calcium channel blockers, dosage forms can also be presented to a patient separately and direct vasodilators, alpha-1-adrenergic receptor blockers, independently, for use according to the invention. central alpha-2-adrenergic receptor agonists and other cen In another embodiment, the selective ET receptor antago trally acting antihypertensive drugs, aldosterone receptor nist and the at least one antidiabetic, anti-obesity or antidyS antagonists, vasopeptidase inhibitors, NEP inhibitors, pros 40 lipidemic agent are coformulated with one or more pharma tanoids, PDE5 inhibitors, nitrosylated compounds, oral ceutically acceptable excipients in a single pharmaceutical nitrates and renin inhibitors, or combinations of agents from composition as a fixed-dose combination. one or more than one such class. For example, where the A pharmaceutical composition comprising the selective Subject has clinically diagnosed resistant hypertension as one ET receptor antagonist, the at least one antidiabetic, anti of the comorbidities, the adjunctive or combination therapy 45 obesity or antidyslipidemic agent, and one or more pharma can comprise administration of at least one diuretic and at ceutically acceptable excipients is itself a still further least two antihypertensives selected from at least two of (a) embodiment of the present invention. ACE inhibitors and angiotensin II receptor blockers, (b) beta In a therapeutic combination or pharmaceutical composi adrenergic receptor blockers and (c) calcium channel block tion of the invention, the selective ET receptor antagonist CS. 50 can illustratively be selected from those mentioned herein Illustratively antihypertensives for use in the method of the above. In one embodiment the selective ET receptor antago present embodiment can be selected from chlorothiazide, nist comprises darusentan, for example in a dosage amount as chlorthalidone, hydrochlorothiazide, indapamide, metola set forth hereinabove. Zone, polythiazide, bumetanide, furosemide, torsemide, The combination or composition can comprise at least one benazepril, captopril, enalapril, fosinopril, lisinopril, moex 55 antidiabetic, for example selected from alpha-glucosidase ipril, perindopril, quinapril, ramipril, trandolapril, cande inhibitors, biguanides, exendins, hormones and analogs Sartan, eprosartan, irbesartan, losartan, olmesartan, tasosar thereof, meglitinides, Sulfonylurea derivatives and thiazo tan, telmisartan, Valsartan, acebutolol, atenolol, betaxolol. lidinediones. In a particular embodiment the selective ET bisoprolol, carvedilol, labetalol, metoprolol, nadolol, penb receptor antagonist comprises darusentan and the at least one utolol, pindolol, propranolol, timolol, amlodipine, diltiazem, 60 antidiabetic is selected from acarbose, exenatide, glime felodipine, isradipine, nicardipine, nifedipine, nisoldipine, piride, insulins, metformin, nateglinide, pioglitaZone, pram Verapamil and combinations thereof. lintide, rosiglitaZone and combinations thereof. A still further embodiment of the present invention pro The combination or composition can comprise at least one vides a therapeutic combination comprising a selective ET anti-obesity agent, for example selected from anorexics, CB1 receptor antagonist and at least one antidiabetic, anti-obesity 65 receptor blockers and lipase inhibitors. In a particular or antidyslipidemic agent other than a selective ET receptor embodiment the selective ET receptor antagonist comprises antagonist. Such a combination can have utility in a number darusentan and the at least one anti-obesity agent is selected US 8,623,819 B2 27 28 from benzphetamine, methamphetamine, orlistat, phendime EXAMPLES trazine, phentermine, rimonabant, Sibutramine and combina tions thereof. The following examples are merely illustrative, and do not The combination or composition can comprise at least one limit this disclosure in any way. Reference is made in the antidyslipidemic, for example selected from bile acid seques examples to statistical analysis. Such reference is made in the trants, cholesterol absorption inhibitors, fibrates, HMG CoA interest of full disclosure and does not constitute admission reductase inhibitors, nicotinic acid derivatives, and thyroid that statistical significance is a prerequisite for patentability hormones and analogs thereof. In a particular embodiment of any claim herein. the selective ET receptor antagonist comprises darusentan and the at least one antidyslipidemic is selected from atorv 10 astatin, colesevelam, eZetimibe, fenofibrate, fluvastatin, lov astatin, niacin, rosuvastatin, simvastatin and combinations Example 1 thereof. For example, the combination or composition can comprise a selective ET receptor antagonist such as darusen 15 Summary tan, a cholesterol absorption inhibitor Such as eZetimibe, and The following is a protocol for a Phase II double blind an HMG CoA reductase inhibitor (statin) such asatorvastatin, placebo-controlled randomized study to investigate the safety fluvastatin, lovastatin, rosuvastatin or simvastatin. and the hemodynamic effects of three-week oral applications The combination or composition comprises, in one of different doses of darusentan on top of standard medication embodiment, a selective ET receptor antagonist, at least one in congestive heart failure patients. antidiabetic and at least one anti-obesity agent. Objectives The combination or composition comprises, in another The primary objective of this study was to assess the tol embodiment, a selective ET receptor antagonist, at least one erability and safety profile of three-week oral applications of antidiabetic and at least one antidyslipidemic. different doses of darusentan on top of established standard The combination or composition comprises, in yet another 25 medicinal treatments in patients Suffering from advanced embodiment, a selective ET receptor antagonist, at least one chronic congestive heart failure NYHA functional class III. anti-obesity agent and at least one antidyslipidemic. Secondary objective was the assessment of the short-term The combination or composition comprises, in a still fur effects of three-week darusentan treatment on hemodynamic ther embodiment, a selective ET receptor antagonist, at least parameters by means of SWANGANZ floating catheteriza one antidiabetic, at least one anti-obesity agent and at least 30 tion and thermodilution. one antidyslipidemic. Methodology According to any embodiment mentioned above, the com This was a multinational, multicenter, prospective, double bination or composition optionally further comprises at least blind, placebo-controlled, randomized clinical trial. one antihypertensive. The at least one antihypertensive can 35 After a pre-investigational eligibility check, double-blind comprise, for example, one or more agents of any class listed treatment was started for a period of three weeks, followed by hereinabove or a combination of agents from more than one a one-week double-blind follow-up period. Such class. The safety and hemodynamic effects of three different An illustrative combination or composition of the inven dosages of darusentan were consecutively studied, starting tion comprises: 40 with darusentan at 30 mg or placebo. The following dosages (a) darusentan as a selective ET receptor antagonist; of 300 mg followed by 100 mg were selected after reviewing (b) one or more of: the results and experiences gleaned from evaluating the safety (i) at least one antidiabetic selected from acarbose, data of at least 15 patients who completed the entire three exenatide, glimepiride, insulins, metformin, nateglin week dosing period. ide, pioglitaZone, pramlintide, rosiglitaZone and com 45 Patients binations thereof; To obtain at least 24 evaluable patients per treatment group, (ii) at least one anti-obesity agent selected from benz it was expected to include a total number of 120 patients into phetamine, methamphetamine, orlistat, phendimetra the study. Actually, 157 patients were randomized (30 mg: Zine, phentermine, rimonabant, Sibutramine and com n=36; 100 mg. n=39; 300 mg. n=49; placebo: n=33). binations thereof, and/or 50 Male and female patients were selected based on the fol (iii) at least one antidyslipidemic selected from atorvas lowing profile: aged 18 years or older who needed to undergo tatin, colesevelam, eZetimibe, fenofibrate, fluvastatin, SWANGANZ floating catheterization for diagnostic reasons lovastatin, niacin, rosuvastatin, simvastatin and com with clinical CHF signs of at least three months duration and binations thereof, and 55 for any underlying cause (except for primary organic valvular (c) at least one antihypertensive selected from chlorothiaz heart disease), present or recent history of NYHA functional ide, chlorthalidone, hydrochlorothiazide, indapamide, class III and presenting with a left ventricular ejection frac metolaZone, polythiazide, bumetanide, furosemide, tion less than or equal to 35%, assessed by means of echocar torsemide, benazepril, captopril, enalapril, fosinopril, diography or isotope Ventriculography within seven days lisinopril, moexipril, perindopril, quinapril, ramipril, 60 prior to investigational procedures. Continuation in the study trandolapril, candesartan, eprosartan, irbesartan, losar was only possible, if at baseline pulmonary capillary wedge tan, olmesartan, tasosartan, telmisartan, Valsartan, ace pressure (PCWP) was more than equal to 12 mmHg and butolol, atenolol, betaxolol, bisoprolol, carvedilol, labe cardiac index (CI) was less than or equal to 2.6 l/min/m. talol, metoprolol, nadolol, penbutolol, pindolol, Test Product, Dose, Mode of Administration and Duration of propranolol, timolol, amlodipine, diltiazem, felodipine, 65 Treatment isradipine, nicardipine, nifedipine, nisoldipine, Vera Tablets containing 30 mg, 100 mg or 300 mg darusentan. pamil and combinations thereof. Medication was taken orally once a day for 3 weeks US 8,623,819 B2 29 30 Reference Therapy, Dose, Mode of Administration and Dura -continued tion of Treatment Matching placebo tablets taken orally once a day for 3 Glucose Levels weeks. Visit Visit Visit Visit Visit Visit Criteria for Evaluation: 5 1 2 3 4 5 6 Side Effects 1. Efficacy Patient NFA 116 121 NAA NAA NAA Sensations of Heat Changes in hemodynamic parameters from baseline focus- 190 (3) ing on CI (1/min/m), and PCWP (mmHg). Furthermore, Head cephalgia (3) pharmacokinetic parameters and neurohormone plasma lev- 10 AnginaSubjective Pectoris feelings (3) els were assessed. of unrest (3) 2. Safety Sleep Disturbance Adverse events, changes in Systemic blood pressure, heart (3) rate, ECG and clinical laboratory parameters were measured. Angina Pectoris Statisticala1S1Ca MethodCO S 15 withSensations Dyspnoea of (3) All treated patients were included in the safety analysis. Abdominal Efficacy was analyzed primarily according to the intention- Pressure (3) to-treat principle. Continuous data were described by statis- rent N/A 97 92 N/A N/A N/A CHF worsening (4) tical characteristics (n), mean, standard deviation, minimum, Patient NFA 127 141 NAA NAA 104 Acute Left Heart 1' quartile, median, 3' quartile, maximum, number of miss- 216 Failure (5) ing values) for each time point, as well as for changes from 2O Decreasing Plueral baseline. For categorical data and adverse events, frequency Effusion and percentage were given. For the two primary efficacy 288Patient 8O 6S NAA NA NA 88 None Listed parameters CI (1/min/m) and PCWP (mm Hg), analysis-of covariance models were calculated. Side Effect Relationship to Drug Results: 25 S. During the course of this study blood glucose levels 3-Possible (mg/dl or mmol/l) were determined at patient visits. Only 4-Unlikely fasting blood glucose levels are shown below. “N/A is used Non-survivorrelated patients whose mordity was deemed to have an unlikely or unrelated where either blood glucose level was not examined or the 30 relationship to darusentan by the clinician have been omitted. laboratory test was performed when the patient was not fast ing. Example 2 Summary 3s Hypertension clinical studies conducted over the last decade have indicated that proper control of systolic blood Glucose Levels pressure (SBP) is equally as important as diastolic blood Visit Visit Visit Visit Visit Visit pressure (DBP) control in relationship to cardiovascular and 1 2 3 4 5 6 Side Effects renal outcomes; and SBP is more difficult to control than Patient N/A 156 N/A N/A N/A 139 Increasing of DBP. especially in patients over 50 years of age. Despite 18S Dyspnoea (3) treatment with multiple antihypertensive drugs at therapeutic Increase of Body doses, a Substantial number of patients, especially those with Wight f diabetes mellitus (diabetes) and/or chronic kidney disease Diuresisecreaseo (3) (CKD), do not reach guideline-recommended blood pressure Patient NFA 11.4 8.6 6.4 11.1 5.2 Hyperglycemia (5) 45 goals. 152 Face Rush (3) The following is the protocol for a phase 3 randomized, E. s double-blind, placebo-controlled, multi-center, parallel s s ( (80 group study to evaluate the efficacy and safety offixed doses Better Exercise of darusentan in Subjects with resistant systolic hypertension Tolerance (2) receiving combination therapy with three or more antihyper tensive drugs, including a diuretic.

LIST OF ABBREVIATIONS ABPM Ambulatory blood pressure monitoring EC Independent ethics committee ACEI Angiotensin converting enzyme inhibitor gM Immunoglobulin M AE Adverse event ND Investigational New Drug application ALT Alanine aminotransferase NR International normalized ratio ANCOVA Analysis of covariance RB Institutional review board ARB Angiotensin receptor blocker Kg Kilograms AST Aspartate aminotransferase K; Inhibition constant AUC Area-under-the-curve LDH Lactate dehydrogenase AV Atrioventricular LDL Low density lipoprotein BMI Body mass index LFT Liver function test BNP b-type LH Luteinizing hormone BP Blood pressure LLN Lower limit of normal BUN Blood urea nitrogen LV Left ventricular CCB Calcium channel blocker LVIDD Left ventricular internal diastolic diameter US 8,623,819 B2

-continued

LIST OF ABBREVIATIONS Cmax Peak plasma concentration m? Meters squared CHF Chronic heart failure MDRD Modification of Diet in Renal Disease CFR Code of Federal Regulations ng Milligrams CKD Chronic kidney disease min Minutes CNO Certificate of non-objection mL Milliliters CRF Case report form mmHg Millimeters of mercury DBP Diastolic blood pressure 9. Micrograms dL Deciliters nM Nanomolar DMC Data Monitoring Committee NOTEL No toxic effect level ECG Electrocardiogram NOAEL No observed adverse effect level eGFR Estimated glomerular filtration rate NSAIDs Non-steroidal anti-inflammatory drugs ET1 Endothelin-1 P450 Cytochrome P450 ET Endothelin A receptor PDC Premature Discontinuation ET Endothelin B receptor PDE Phosphodiesterase ERA Endothelin receptor antagonist PHI Protected health information FDA Food and Drug Administration PK Pharmacokinetic FSH Follicle stimulating hormone O Peros (orally) 9. Grams PT Prothrombin time GCP Good clinical practice PTT Partial thromboplastin time GDC Global Data Collection qd Once daily GGT Gamma glutamylaminotransferase RBC Red blood cell HbA. Glycosylated hemoglobin RHTN Resistant hypertension HDL High density lipoprotein SADR Serious adverse drug reaction HIPAA Health Insurance Portability and Accountability Act SAE Serious adverse event HR Heart rate SaO. Arterial oxygen Saturation IB Investigator's Brochure SBP Systolic blood pressure ICD Implantable cardioverter defibrillator SCir Serum creatinine ICF Informed Consent Form SSRIs Selective serotonin reuptake inhibitors ICH International Conference on Harmonization SUSAR Suspected unexpected serious adverse event t1/2 Elimination half-life TCA Tricyclic antidepressants TG Triglycerides TSH Thyroid stimulating hormone UACR Urinary albumin-to-creatinine ratio ULN Upper limit of normal WBC White blood cell

METHODS 35 All potential subjects will be classified with regard to dia betes and CKD as part of the Screening process. Diabetic Patients Subjects must have a documented diagnosis of Type 2 diabe Approximately 352 subjects will be randomized to one of tes prior to Screening, and all screened subjects will be evalu three doses of darusentan (50. 100 or 300 mg po qd) or 40 ated for the presence of CKD according to the following placebo in a ratio of 7:7:7:11 at approximately 160 investi- definition: (i) reduced excretory function with an eGFR <60 gative S1tes in North and South America, Europe, New mL/min/1.73 m and/or (ii) the presence of albuminuria in a Zealand, and Australia. spot urine sample (>200 mg/g22.60 mg/mmol creatinine). Eligible sub ects will include men and women, 35-8O years Antihypertensive therapy must include: old, treated with full doses of three or more antihypertensive 45 A diuretic, preferably a thiazide; and drugs, including a diuretic, with RHTN as defined by con- Two or more drugs from at least two of the following temporary clinical guidelines for the treatment of hyperten- classes of antihypertensive agents: sion 1.2. Subjects with diabetes and/or CKD must have a ACEIS, ARBs, and/or renin inhibitors SBP>130 mmHg at Screening to be eligible for study entry, so Sh k All other subjects must have a SBP of >140 mmHg. SBP at a-TOCKCS S creen1ng must bee <180

STUDY VISIT

1 2 3a 3b 4 S 6 7 8 9 10a 10b Study Week Random. 14 -2 D1 D 2 2 4 6 8 10 12 D1 D 2 UV Assessments

Informed consent Review Inclusion X X Exclusion criteria Medical history demographics ConMed assessment X X X X X X X X X X Adverse Event X X X X X X X X X X aSSeSSnent Trough sitting standing X X X X X X X X X X BP and HR Full physical examination X X Abbreviated physical X X X X X X X X X examination Measure body weight X X X X X X X X X X 2-lead ECG X X X X Echocardiogram Ambulatory BP Oil Off Oil Off Monitoring Health Economics Questionnaire Obtain vital status' Laboratory Tests

Chemistry X X X X X X Hematology X X X X X X Urine sample X X6 X6 X6 X6 X X6 Fasting Blood Collection" X, S S X X X X

Biomarker plasma X X sample Women only:

Serum pregnancy test X 3-hCG urine pregnancy X test Men only:

Hormone analysis X X Semen analysis S8 (x) S8 (x) Warfarin-treated Subjects only:

Coagulation X X Study Drug

Collect study drug? assess X X X X X X X X X10 compliance Register study visit X X X X X X X X X X X X US 8,623,819 B2 40 -continued

STUDY VISIT

1 2 3a 3b 4 S 6 7 8 9 10a 10b Study Week Random. 14

-4 -2 D1 D 2 2 4 6 8 10 12 D1 D 2 UVI

Randomization X Dispense study drug X11 X12 X X X X X X X10 UV = Unscheduled Visit; 'An echocardiogram must be obtained during the Screening Period or within 3 months prior to Screening. However, historical echocardiograms must report predefined criteria necessary to determine subject eligibility, A Health Economics Questionnaire will be completed by all screened subjects. "All randomized subjects must be contacted to assess vital status at or shortly after the time of the last subject visit and again for the purposes of Global Data Collection. The chemistry panel performed at Screening will include measurements of immunoglobulinM (IgM), thyroid stimulation hormone (TSH) and glycosylated hemoglobin (HbA), TSH and HbA will be used to evaluate subject eligibility, Spoturine collection for subjects with clinically significant albuminuria (230 mgg 3.39 mgimmol creatinine) at Screening, 'S = Schedule. Fasting Blood Collection-Baseline may occur at Placebo Run-in (Visit 2) or within 2 weeks after that visit, but not at the Randomization Visit (Visit 3). Fasting Blood Collection-End of Study (EOS) for all subjects may occur within the 2 weeks following the Week 12 Visit (Visit 9), but not during the Week 14 Visit (Visit 10). Schedule a semen sample collection within 2 weeks prior to or during Randomization (Visit 3a), Schedule a post-baseline semen sample collection within 2 weeks prior to or during the Week 14Visit (Visit 10a). 'Coagulation labs will be completed for subjects receiving warfarin (Coumadin) or warfarin-like anticoagulants, "If down-titration of study drug occurs at an unscheduled visit, collection of study drug, assessment of compliance, and dispensation pf study drug should also be performed. 'Single-blind, placebo study drug will be dispensed to all eligible subjects at the visit. 'Randomized, double-blind treatment begins for all eligible subjects,

Primary Efficacy Endpoints Trough plasma concentrations of darusentan and its The co-primary endpoints are the change from baseline to metabolites: Week 14 in trough sitting SBP and trough sitting DBP as Statistical Methods measured by sphygmomanometry. 30 Secondary Endpoints Change in SBP and DBP from baseline to Week 14 will be The following secondary endpoints will be assessed during tested with analysis of covariance, using stratification factors this study: (comorbidity status and race) and baseline blood pressure as covariates. Proportion at goal blood pressure will be tested Change from baseline to final measurement in mean with logistic regression, using the same covariates. The last 24-hour SBP measured by ABPM 35 observation during double blind therapy will be used for Change from baseline to final measurement in mean analyses. 24-hour DBP measured by ABPM The percent of subjects who reach SBP goal after 14 weeks Adjustment for multiple comparisons for the primary end of treatment, defined as follows: points of change in SBP and DBP will use the fallback Subjects with diabetes and/or CKD must reach a SBP 40 method. First, SBP will be compared between the 300 mg goal of <130 mmHg dose and placebo at the nominal alpha level of 0.04. If this is All other subjects must reach a SBP goal of <140 mmHg significant, DBP will be compared between the 300 mg dose Change from baseline to Week 14 in eGFR and placebo at the nominal level of 0.04. From this point, the Measures of Interest fixed sequence procedure will be followed, requiring signifi The following measures of interest will be examined: 45 cance on an endpoint before allowing testing of the following Change from baseline in the following ABPM measures: endpoint, and testing all comparisons at the same level. If the Mean hourly ambulatory SBP and DBP over a 24-hour 300 mg dose was significant at the 0.04 level for both SBP and monitoring period DBP, the tests will be reported at the 0.05 level; otherwise the tests will be reported at the 0.01 level. These comparisons will Mean trough ambulatory SBP and DBP 50 Mean peak ambulatory SBP and DBP be, in order, the 100 mg dose compared to placebo for SBP Mean trough/peak ratio then DBP, and the 50 mg dose compared to placebo for SBP Mean daytime ambulatory SBP and DBP and then DBP. Continuous secondary endpoints will be Mean nighttime ambulatory SBP and DBP handled analogously. Mean daytime/nighttime ratio: 55 Assuming a difference in placebo-adjusted change from Change from baseline to Week 14 in pulse pressure mea baseline of 8 mmHg in trough SBP for each darusentan dose Sured by sphygmomanometry; and a standard deviation of 15 mmHg, 121 subjects random Change from baseline in selected biomarker concentra ized to placebo and 77 subjects randomized to each dose of tions; darusentan will provide 85-90% power to detect a difference Change from baseline in glycosylated hemoglobin 60 between placebo and any individual darusentan dose, and (HbA), fasting plasma glucose, serum lipid profile, 95% power to find at least one dose of darusentan that is serum insulin, serum C-peptide, serum C-reactive pro different from placebo. tein, and waist circumference; It is expected that treatment of a human Subject, for Change from baseline in urinary albumin-to-creatinine example a human Subject having diabetic nephropathy and/or ratio (UACR) in a subset of subjects with clinically 65 metabolic syndrome, in accordance with the foregoing pro significant albuminuria (i.e. >30 mg/g 3.39 mg/mmol tocol will produce an enhancement in glycemic control and/ creatinine in a spot urine sample); or insulin sensitivity. US 8,623,819 B2 41 42 References 7. The method of claim 1, wherein the angiotensin convert 1 Chobanian AV. Bakris GL, Black HR, Cushman WC, ing enzyme inhibitor is selected from the group consisting of Green LA, Izzo J. L., Jr. et al. Seventh report of the Joint alacepril, benazepril, captopril, ceronapril, cilazapril, dela National Committee on Prevention, Detection, Evaluation, pril, enalapril, enalaprilat, eosinopril, fosinopril, imidapril, and Treatment of High Blood Pressure. Hypertension 2003: lisinopril, moexipril, moveltipril, omapatrilat, perindopril, 42(6):1206-1252. 2 2003 European Society of Hypertension-European quinapril, ramipril, sampatrilat, spirapril, temocapril, tran Society of Cardiology Guidelines for the Management of dollapril, and combinations thereof. Arterial Hypertension. J Hypertens 2003: 21(6):1011-1053. 8. The method of claim 1, wherein the angiotensin II recep All patents and publications cited herein are incorporated tor blocker is selected from the group consisting of cande by reference into this application in their entirety. 10 Sartan, eprosartan, irbesartan, losartan, olmesartan, tasosar The words "comprise", "comprises', and "comprising” are tan, telmisartan, Valsartan and combinations thereof. 9. The method of claim 1, wherein the method further to be interpreted inclusively rather than exclusively. comprises administering a thiazide diuretic selected from the What is claimed is: group consisting of althiazide, bendroflumethiazide, benzthi 1. A method for delaying progression of diabetic nephr 15 opathy in a human subject in need of treatment for diabetic azide, benzylhydrochlorothiazide, buthiazide, chlorothiaz nephropathy comprising: ide, chlorthalidone, cyclopenthiazide, cyclothiazide, ethiaz administering to the subject atrasentan or a salt thereof, and ide, fenduizone, hydrochlorothiazide, hydroflumethiazide, a dose of at least one of an angiotensin converting enzyme indapamide, methyclothiazide, metolazone, paraflutizide, inhibitor or an angiotensin II receptor blocker, and polythiazide, quinethazone, teclothiazide, trichlormethiaz wherein the method delays the progression of diabetic ide, and combinations thereof. nephropathy. 10. The method of claim 1, wherein the method further 2. The method of claim 1, wherein the method further comprises administering a loop diuretic selected from the comprises reducing incidence or severity of adverse cardiac group consisting of bumetanide, furosemide, torsemide and eventS. combinations thereof. 3. The method of claim 1, comprising administering the 25 11. The method of claim 1, wherein the diabetic nephropa dose of the angiotensin converting enzyme inhibitor orangio thy is overt diabetic nephropathy. tensin II receptor blocker at an adequate dose labeled for a 12. The method of claim 1, comprising administering the hypertension indication. atrasentan or a salt thereof for a period of at least about 3 4. The method of claim 1, comprising administering the months. dose of the angiotensin converting enzyme inhibitor orangio 30 13. The method of claim 1, comprising administering the tensin II receptor blocker at a highest dose labeled for a atrasentan or a salt thereof for as long as a therapeutic benefit hypertension indication. is provided thereby and any adverse side effect thereof remain 5. The method of claim 1, comprising administering the commensurate with the therapeutic benefit. dose of the angiotensin converting enzyme inhibitor orangio 14. The method of claim 1, comprising administering the tensin II receptor blocker at a highest usual dose prescribed 35 atrasentan or a salt thereof concomitantly with the angio according to Joint National Committee on Prevention, Detec tensin converting enzyme inhibitor oran angiotensin II recep tion, Evaluation, and Treatment of High Blood Pressure (JNC tor blocker. 7), British Hypertensive Society (BHD-IV), European Soci 15. A method for extending the time to end-stage renal ety of Hypertension/European Society of Cardiology (ESH/ disease or chronic kidney failure in a human subject in need of ESC) or World Health Organization/International Society of 40 treatment comprising: administering to the subject atrasentan Hypertension (WHO/ISH) guidelines. or a salt thereof, and a dose of at least one of an angiotensin 6. The method of claim 1, comprising administering the converting enzyme inhibitor or an angiotensin II receptor dose of the angiotensin converting enzyme inhibitor orangio blocker, and wherein the method extends the time to end tensin II receptor blocker at a highest tolerated dose in the stage renal disease or chronic kidney failure. human subject.