Review

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Emerging drugs for chronic kidney disease Sergio Stefoni†, Giuseppe Cianciolo, Olga Baraldi, Mario Iorio & Maria Laura Angelini

1.

Background

2.

Medical need

3.

Existing treatment

4.

Market review

5.

Current research goals and

S.Orsola University Hospital, Department of Experimental, Diagnostic and Speciality Medicine, Dialysis, Nephrology and Trasplantation Unit, Bologna, Italy

scientific rationale 6.

Competitive environment

7.

Expert opinion

Introduction: Chronic kidney disease (CKD) is a worldwide health problem. Despite remarkable headway in slowing the progression of kidney diseases, the incidence of end-stage renal disease (ESRD) is increasing in all countries with a severe impact on patients and society. The high incidence of diabetes and hypertension, along with the aging population, may partially explain this growth. Currently, the mainstay of pharmacological treatment for CKD, aiming to slow progression to ESRD are ACE inhibitors and angiotensin II receptor blockers for their hemodynamic/antihypertensive and anti-inflammatory/antifibrotic action. However, novel drugs would be highly desirable to effectively slow the progressive renal function loss. Areas covered: Through the search engines, PubMed and ClinicalTrial.gov, the scientific literature was reviewed in search of emerging drugs in Phase II or III trials, which appear to be the most promising for CKD treatment. Expert opinion: The great expectations for new drugs for the management of CKD over the last decade have unfortunately not been met. Encouraging results from preliminary studies with specific agents need to be tempered with caution, given the absence of consistent and adequate data. To date, several agents that showed great promise in animal studies have been less effective in humans. Keywords: albuminuria, bardoxolone, chronic kidney disease, end stage renal disease, endothelin receptor antagonist, paricalcitol, renin-angiotensin-aldosterone system Expert Opin. Emerging Drugs (2014) 19(2):183-199

1.

Background

Kidney disease is defined as abnormal kidney structure or function that can occur abruptly and either be resolved or become chronic. When kidney disease progresses to a chronic state, it can evolve into end-stage renal disease (ESRD), a condition of chronic kidney failure that requires replacement therapy, such as dialysis or transplantation. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative classifies the severity of chronic kidney disease (CKD) in five stages based on the level of kidney function, irrespective of diagnosis [1]. Recently, the Kidney Disease Improving Global Outcome (KDIGO) recognized six criteria for CKD: i) albuminuria (albumin excretion rate ‡ 30 mg/24 h; albumin-to-creatinine ratio (ACR) ‡ 30 mg/g [‡ 3 mg/mmol]); ii) urine sediment abnormalities; iii) electrolyte and other abnormalities due to tubular disorders; iv) abnormalities detected by histology; v) structural abnormalities detected by imaging; and vi) history of kidney transplantation. KDIGO defined CKD as abnormalities of kidney structure or function present for > 3 months, with implications for health; the CKD classification is based on cause, glomerular filtration rate (GFR) category and albuminuria category.

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KDIGO chose a threshold of GFR £ 60 ml/min/1.73 m2 (GFR categories G3a--G5) for > 3 months and a threshold for ACR > 30 mg/g to indicate CKD [2]. This approach encompassing cause and severity, as expressed by the level of GFR and the level of albuminuria, links CKD to risks of adverse outcomes, including mortality and kidney failure. The incidence and prevalence of CKD differ substantially across countries and regions but have reached epidemic proportions everywhere [3-5]. Prevalence is estimated to be 8 -- 16% worldwide [6]. In the USA, the incident rate of ESRD (adjusted for age, gender and race), stable since the year 2000, decreased by 3.8 % in 2011 to 357 per million population [7]. A review of 26 studies showed a prevalence of CKD ranging from 23.4% to 35.8% in patients over 64 years. Bearing in mind the progressive aging of the general population, renal disease should thus be considered a public health priority [8-10]. Diabetes, hypertension and an aging population are the leading causes of CKD in all developed and many developing countries while glomerulonephritis and unknown causes are more common in Asia and sub-Saharan Africa [11-13]. According to the 2010 US Renal Data System Annual Data Report, the commonest cause of CKD and kidney failure is type 2 diabetes, which in the USA, accounted for 153 incident cases of ESRD per million population in 2009 (> 22% of the incident patients), while hypertension and glomerulonephritis account for 99 cases and 23.7 cases per million population, respectively [3]. Obesity is a major and rapidly increasing health problem: obese patients with high blood pressure (BP) have a threefold increased risk of CKD [14-16]. In addition, neoplasia, greater exposure to environmental toxins, infections (e.g., hepatitis C, tuberculosis, HIV, and parasitic infection) and the increased use of nephrotoxic agents (e.g., analgesics and radiological contrast media) might contribute to the increase in CKD [3,17,18]. Despite recognition that it is an important public health issue, awareness of CKD remains low: generally < 20% are aware even at more advanced stages and in developed nations. In the USA, < 5% of people with an eGFR < 60 ml/min per 1.73 m2 were aware of having CKD [19]. Nephrological referral and therapeutic strategies depend on the need to recognize and estimate the risk of progression towards kidney failure [20-22]. There are several modifiable and initiating factors that influence the likelihood and rate of CKD progression: the degree of albuminuria, the cause and family history of kidney disease, ongoing exposure to nephrotoxic agents, high salt intake, obesity, hypertension, diabetes mellitus, dyslipidemia, age, race, ethnicity, ACE gene polymorphism and low birthweight. Among these nontraditional factors, recent studies have identified some emerging progression factors for CKD, such as asymmetric dimethylarginine (ADMA), fibroblast growth factor 23 (FGF23), phosphate, parathyroid hormone (PTH) 184

and sympathetic hyperactivity (Figure 1). As some of these risk factors are modifiable, they should be actively identified and treated: this might have an impact on long-term outcomes, including cardiovascular (CV) condition, quality of life and progression of CKD. There is general consensus that albuminuria is a powerful and independent risk factor for kidney and cardiovascular disease (CVD). Albuminuria is defined as the elimination of urinary albumin excretion above 30 mg per 24 h, equivalent to 30 mg/g creatinine in a single sample. Traditionally collection of 24-h urine samples is the commonest way of quantitatively evaluating proteinuria, but several reports have complained of poor patient compliance. Besides, when the GFR is stable, protein excretion is fairly constant throughout the day, suggesting that one might as well measure the ratio of albumin to creatinine in an ‘untimed’ spot urine specimen. The KDOQI guidelines recommend evaluating urinary ACR (the ratio between milligrams of albumin per gram of creatinine or milligrams of albumin per millimol of creatinine) for diagnosis and follow-up in adults with CKD [1]. When the ACR is elevated (> 500 mg/g, which corresponds to proteinuria > 500 mg/day), it is highly recommended to evaluate the protein-to-creatinine ratio (PCR) in spot urine samples as a predictor of quantitation of proteinuria. The reasons for the apparent link between proteinuria and the progressive decline in kidney function are still not completely understood, but it is likely that proteinuria might be a marker of the severity of kidney disease, or even nephrotoxic in its own right, as proteinuria is known to induce tubular inflammation and interstitial fibrosis. This finding is the pathophysiological prerequisite for using ACE inhibitors (ACEI) and angiotensin II receptor blockers (ARBs) in CKD as both classes of agents are effective in lowering BP and reducing proteinuria [23].

2.

Medical need

Failure to recognize CKD in the early stages leads to underestimating its complications, just as late referral of people with advanced CKD leads to worse dialysis outcomes. In addition, there is growing evidence that people with CKD have an increased risk of acute kidney injury, which is also associated with poor outcome and may accelerate progression of kidney failure [24,25]. If CKD is detected early, the associated complications can be delayed or even prevented through appropriate interventions such as antihypertensive drugs, better glycemic control, treatment of mineral bone disorders and anemia, statins and lifestyle interventions such as weight reduction, decreased fructose and salt intake and stopping smoking. Furthermore, timely detection of people at earlier stages of CKD, with appropriate management and earlier referral, could lead to both clinical and economic benefits [26].

Expert Opin. Emerging Drugs (2014) 19(2)

Emerging drugs for chronic kidney disease

Progression risk factors in CDK patients Traditional risk factor Diabetes High salt intake

Non-traditional risk factor Abnormal mineral and bone metabolism (FGF 23, PTH, Phosphate)

Age Hypertension

ACE gene polymorphism

Degree of albuminuria

Dyslipidemia Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Maastricht on 06/11/14 For personal use only.

Obesity

ADMA

Sympathetic overactivity

RAAS

Smoking Genetics

Race and ethnicity Endothelin

AGEs Low birth weight

CKD progression

Figure 1. Traditional and nontraditional risk factors involved in CKD progression. ADMA: Asymmetric dimethylarginine; AGEs: Advanced glycation end products; CKD: Chronic kidney disease; FGF 23: Fibroblast growth factor 23; PTH: Parathyroid hormone; RAAS: Renin--angiotensin--aldosterone system.

Delaying progression prolongs health and saves lives at a much lower cost than renal replacement therapy (RRT) [27]. Early diagnosis of renal disease based on proteinuria and/or reduced GFR would also make it possible to intervene and reduce the high risk of CV events. CKD is above all a risk factor for CVD; likewise, CVD may promote CKD, resulting in a vicious cycle. This association between CVD and renal disease is present from the earliest stages of CKD. The high CV risk derives from the observation that CKD patients are not only exposed to traditional risk factors (most notably diabetes and hypertension) but also to nontraditional factors, including activation of the renin--angiotensin-aldosterone system (RAAS), endothelin-1 (ET-1), endothelial dysfunction, mineral metabolism disorders, increase in ADMA, activation of sympathetic tone, inflammation and oxidative stress and hemodynamic disturbances (Figure 1). All of the above lead to a specific form of arterial remodeling, which contributes to the development of CVD. Arterial calcification is the main, though not the only, event involved in the arterial remodeling process and is strongly linked to mineral metabolism abnormalities associated with CKD [28]. 3.

Existing treatment

CKD represents an increasing burden on the worldwide healthcare system. Treatment of CKD aims to slow progression to ESRD and allow time to prepare for dialysis or transplantation. Whereas the symptoms of progressive renal failure develop slowly, the mainstay of therapy is usually early nephrological referral, a

proper dietary approach and management of risk factors, such as hypertension and proteinuria, which can accelerate kidney injury by multiple pathways. The exposure of renal tubular cells to protein induces chemokine expression and complement activation. The release of pro-inflammatory and chemoattractant cytokines causes inflammatory cells to infiltrate the interstitium and lead to fibrogenesis. Tubulointerstitial injury is one of the key factors in renal damage progression, which is why proteinuria may provide a link between glomerular and tubule-interstitial pathology, but the exact nature of the relationship between proteinuria and progressive renal injury remains a topic of debate [29-31]. There is substantial evidence that upregulation of RAAS plays a key role in the development and progression of CKD and CVD. ACEI and ARBs are standard drugs for primary hypertension and have been shown to reduce proteinuria and retard the progression of renal function; they are understood to be beneficial agents in this setting through hemodynamic/antihypertensive action and anti-inflammatory/antifibrotic action [32,33]. In the endocrine RAAS system, renin release is the first step leading to cleavage of angiotensinogen into angiotensin I, which is converted into angiotensin II (Ang II) by ACE. Ang II activates AT1 receptors, resulting in aldosterone production and reabsorption of sodium and water. Ang II is a potent vasoconstrictor peptide involved in the development of glomerular hypertension, which causes hemodynamic changes associated with an increase in glomerular capillary pressure, progressive proteinuria and glomerulosclerosis. Aldosterone and renin-receptor seem to be pathophysiologically involved in CV and renal damage via local proinflammatory and profibrotic effects [34,35].

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RAAS is now recognized as a pro-inflammatory and pro-fibrotic mediator: Ang II activates NF-kB, upregulates adhesion molecules, and may directly stimulate proliferation of lymphocytes [36,37] and interacts with TGF- b1 inducing extracellular matrix proteins, such as type I procollagen, fibronectin and collagen type IV [37]. The result of these actions is a local inflammatory environment within the kidney, the heart and the vasculature [38]. All in all, it is clear that RAAS plays a central role in the pathogenesis of progressive renal and CV injury through multiple hemodynamic and nonhemodynamic mechanisms. In the Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study, designed to prove or disprove the olmesartan effect on delaying the onset of microalbuminuria in 4447 normoalbuminuric patients with type 2 diabetes and CV factors, a positive outcome was demonstrated, but more CV deaths were observed in patients on active therapy than placebo. As in another study, a trend toward higher CV mortality was observed in patients withpre-existing coronary heart disease who had the most significant BP reduction [39]. ACE and ARBs were combined to obtain more complete blocking of RAAS; during the RAAS blockade, Ang II levels increase considerably, contributing to Ang II generation via non-ACE pathways (‘Ang II-escape’); similarly, ‘aldosterone escape’ and a reactive rise in renin levels occurs when Mineralcorticoid Receptor Antagonists and renin inhibitor aliskiren are used. These compensatory responses at different levels do not provide full blockade of RAAS cascade. Chronically increased Ang II activation worsens diseases such as heart failure and renal disease [40,41]. The major limitation of these drugs is the compensatory rise in renin levels due to the disruption of the feedback inhibition of renin production. High renin clogging increases the risk of Ang II-dependent and -independent organ damage, which may limit the efficacy of RAAS inhibition and may be the cause of the resistance to therapy sometimes seen with the use of ACEI and/or ARBs (Figure 2). Clinical studies have demonstrated that dual blockade with ACEI/ARBs reduces BP and proteinuria more effectively than single therapy, especially when the proteinuria baseline is high [42,43]. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) reported the effects of dual blockade with ACE/ARB on the renal end point in patients with CKD [44]. As in other studies, despite less albuminuria and significantly greater BP reduction, dual renin--angiotensin system inhibition did not improve CV or renal outcomes compared with monotherapy, yet had a concomitant increased risk of hyperkalemia, renal impairment and hypotension [45]. Moreover, an increased death rate from CV causes was observed among patients with known coronary heart disease (if the systolic BP was below 120/80 mmHg) during the time of dual therapy [46]. 186

In the ONTARGET study, the benefit of dual therapy in decreasing the risk of CKD has only been shown in patients with overt proteinuria; thus any potential benefit from ACEi/ARBs appears to be related to the specific risk profile of the population studied [47-50]. Recently, the Veterans Affairs Office of Research and Development (VA NEPHRON-D), a multicenter trial to assess the effect of combining losartan and lisinopril compared with losartan alone on the progression of kidney disease in 1850 patients with diabetes and overt proteinuria, showed an increased risk of serious adverse effects in patients treated with dual therapy [51]. The study was stopped early, primarily on account of safety concerns due to increased rates of acute kidney injury (HR with combination therapy 1.7, 95% CI 1.3 -- 2.2, p < 0.001) and hyperkalemia (HR 2.8, 95% CI 1.8 -- 4.3, p < 0.001). These results need to be tempered by the fact that this cohort of patients was a high-risk population, but it does seem that there may be a point in the RAAS cascade beyond which further blockade is unsafe and without additional benefits. The results of the VA NEPHRON-D trial are broadly consistent with those of ONTARGET and also with the Aliskiren Trial Type 2 Diabetes Using Cardiorenal Endopoints (ALTITUDE), a trial designed to compare aliskiren, a direct renin inhibitor, versus placebo, added to either ACEI or ARBS in patients with type 2 diabetes and CKD or CV disease or both. In December 2011, ALTITUDE was stopped prematurely on the recommendation of its Data Monitoring Committee due to increased incidence of hypotension, hyperkalemia, renal complications and nonfatal stroke in the aliskiren arm [52]. Likewise, from a cardiologic point of view, RAAS blockade with combination therapy was widely believed to reduce CV morbidity and mortality, and it became a cornerstone of CV pharmacotherapy. Nevertheless, in the Valsartan in Acute Myocardial Infarction trial, a total of 14,723 patients with acute myocardial infarction and heart failure and/or dysfunction randomly received valsartan, valsartan + captopril or captopril. No difference between treatment arms was found for the incidence of death or CV events [53]. Very recently, the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT), designed to evaluate the effect of in-hospital initiation of aliskiren or placebo in addition to standard therapy in patients with worsening chronic heart failure and reduced left ventricular function, failed to obtain a significant effect on the primary combined end point (CV mortality and heart failure rehospitalization at 6 months) [54]. In nearly all these studies, albuminuria was significantly reduced, but often surrogate end points fail to match the clarity of hard outcome end points. 4.

Market review

Although the need to treat chronic kidney failure with dialysis and/or kidney transplantation arises in only 1% of people

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Emerging drugs for chronic kidney disease

Renal injury

Proximal tubule cells

Interstitium

Vessel

T lymphocyte

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Proteinuria Nephrotoxins Obstruction Metabolic Immune Hemodynamic

Macrophage Apoptosis

IL-6 MCP-1 RANTES IL-8 TNF-α Other cytokines

Myofibroblast

ECM EMT ACEI or ARB or renin inhibitor

Figure 2. Compensatory renin overproduction and Ang II increase following therapy with RAAS inhibitors in CKD patients. Adapted by permission from Macmillan Publishers Ltd [98]. ACEI: Angiotensin-converting enzyme inhibitor; Ang I: Angiotensin I; Ang II: Angiotensin II; ARB: Angiotensin II type 1 receptor blocker; AT1R: Angiotensin II type 1 receptor; CKD: Chronic kidney disease; ECM: Extracellular matrix; EMT: Epithelial to mesenchymal transition; RAAS: Renin--angiotensin--aldosterone system; RANTES: Regulated on Activation Normal T cell Expressed and Secreted; RAS: Renin--angiotensin system.

with CKD, it remains the most expensive of chronic diseases, apart from significantly reducing lifespan. The costs of dialysis and transplantation consume disproportionate amounts of healthcare budgets in many countries [55,56]. Furthermore, we must consider that CKD usually comes with other comorbidities, such as diabetes and congestive heart failure. These disorders involve an enormous burden of economic costs, whether direct (specialist care and hospital outpatient) or indirect (costs related to the lack of employment and reduced productivity). The most obvious social disadvantage of CKD is the enormous financial cost and loss of productivity associated with advanced kidney disease. For instance, many developed nations spend > 2 -- 3% of their annual healthcare budget providing treatment for ESRD, whereas the population with ESRD represents approximately 0.02 -- 0.03% of the total population [3,57]. Quantifying the cost of CKD is challenging due to the numerous variables implied. The subgroup of patients with ESRD obviously has a bigger cost impact on the healthcare system in all countries. Yet the economic burden associated with milder forms of CKD is huge: more than twice the total cost of ESRD. In the USA, monthly costs associated with managing CKD alone are $1250, and > $3000 per month if diabetes and heart

failure are present, while anemia increases the expense by $5800 on average per patient per year [58]. Smith et al. assessed that patients with CKD have a greater total cost of care compared with age- and gender-matched controls, even after controlling for CKD-related comorbidities. This suggests that, with increasing development of CKD, the burden to patients and the healthcare system could well worsen. In the USA, CKD patients account for 9.8% of the total Medicare population > 65 years of age: the Medicare expenditure of this population exceeded $60 billion in 2007 versus $25 billion for ESRD and represented 27% of the total Medicare budget (only slightly less than the cost of treating diabetes and heart failure). In the USA, patients with ESRD involve an annual cost per person of around $66,000, ranging from $26,000 for transplant patients to $77,000 for those on hemodialysis treatment. These analyses included hospitalizations, outpatient visits, laboratory results and pharmacy utilization. However, the economic cost is expected to increase in comorbid patients if a multidisciplinary approach to CKD is applied. This situation is even worse in most developing nations, where ESRD constitutes a ‘death sentence’, as RRT is often unavailable or unaffordable: nearly one million people die of ESRD each year in developing nations [59].

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Last but not least, not only is there a high financial cost of ESRD care but also the ‘true cost’ of ESRD, in terms of quality of life, goes beyond the cost of therapy. Delaying progression to ESRD will probably have an impact on patient morbidity and mortality, as well as preventing the cramping of quality of life that is associated with ESRD. These are all good reasons why intervention to delay progression of CKD to ESRD is so important. Clearly, then, a drug able to prevent or delay progression to ESRD would significantly reduce healthcare expenses worldwide. Moreover, there would be a high number of patients who could benefit from such a drug considering that in 2012 in the USA, ACEI were prescribed for CKD to the tune of almost $20 million.

widespread and continued use of ACEI and ARBs both in the USA and worldwide over the last two decades, most estimates suggest that the progression of CKD to ESRD has continued, almost unabated, in CKD patients around the world [64-66]. The following sections review the scientific literature in search of emerging drugs, in Phase II or III trials, that appear to be most promising in the treatment of CKD. We focused our attention on: . bardoxolone methyl: an oral antioxidant inflammation

modulator . paricalcitol: a selective vitamin D receptor (VDR)

activator . avosentan and atrasentan: endothelin (ET) receptor

5. Current research goals and scientific rationale

Regardless of what is shown in several animal experimental models, regression of CKD is rare in humans. Actually, the primary aims of all therapies currently available for human CKD are both to slow the progression of CKD and to prevent CVD, the principal cause of morbidity and mortality in the CKD population [60]. The main approaches to slowing the rate of CKD progression are treatment of the underlying disease, if possible; treatment of reversible causes of renal failure, which, if identified and corrected, may result in the recovery of renal function; and treatment of secondary factors that are predictive of progression, such as elevated BP and proteinuria, when the renal damage has already occurred. Multiple studies in animals and humans have shown that progression of a variety of CKDs may be largely due to secondary hemodynamic and metabolic factors, rather than the activity of the underlying disorder. It is no wonder that the best therapeutic strategies currently available for CKD focus primarily on optimizing and maximizing RAAS blockade, particularly in patients with diabetic nephropathy, the leading cause of ESRD worldwide [23]. More agents have been tested in human and animal studies in diabetic nephropathy than in any other chronic renal disease. A review of the scientific literature shows that current research is primarily directed at discovery of potential new therapies and harnessing drugs approved for other diseases to slowing the progression of CKD. But, as shown in the following sections, few of the emerging therapies aimed at slowing the progression of renal disease have been tested on humans. 6.

Competitive environment (Table 1)

Current renoprotection paradigms generally depend on the use of ACEI and/or ARBs, but on the whole, these agents have proved to be imperfect [61-63]. Despite the extensive, 188

antagonists . pyridoxamine dihydrochloride: a metabolic derivative of

pyridoxal phosphate (vitamin B6), an inhibitor of advanced glycation . pirfenidone: a compound with antifibrogenic, antiinflammatory and antioxidant properties . sulodexide: a heterogenous group of sulfated glycosaminoglycans (Figure 3).

Bardoxolone Bardoxolone methyl is the prime member of a new antioxidant inflammation modulator drug class. Bardoxolone methyl and other antioxidant inflammation modulators activate the nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 (Nrf2-Keap1) system that regulates 250 antioxidant and detoxification genes, improves endothelial function and maintains kidney structure and function [67-69]. This system is one of the most critical cytoprotective mechanisms acquired in vertebrates in the course of evolution. Nrf2/Keap1 regulates the transcription of antioxidant and cytoprotective genes through direct Nrf2 binding to responsive elements in the promoter region of target genes or via Keap1-induced NF-kB inhibition. The association between oxidative stress and inflammation with progression of CKDs directed attention toward bardoxolone methyl and its analogues, potent Nrf2/Keap1 inducers, as a potential way of renoprotective intervention [70-73]. The net result is an inhibition of immune-mediated inflammation at tissue level, which may protect against end-organ damage. Nevertheless, despite the presence of oxidative stress and inflammation, which should have induced Nrf2 activation, the diseased kidneys paradoxically had impaired Nrf2 activity and reduced expression of its target gene products. Inability to limit oxidative stress because of Nrf2 deficiency possibly contributed to enhancing NF-kB activation and inflammation in the experimental diseased kidney. The anti-inflammatory effect of bardoxolone methyl might prevent or delay the decline in kidney function. In a randomized double-blind placebo-controlled trial, 227 patients were randomly assigned to 6.1

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Table 1. Competitive environment table. Compound

Company

Structure

Indication

Stage of development

Mechanism of action

Bardoxolone methyl

Reata Pharmaceuticals

Oleana-1,9(11)-dien28-oic acid, 2-cyano3,12-dioxo-, methyl ester

Phase III

Paricalcitol

Abbott

Transcription factor Nrf2 stimulant Reducing agent Apoptosis stimulant Vitamin D agonist

Avosentan

Novartis

Phase III

Endothelin A receptor antagonist

Atrasentan

Abbott

Symptomatic antidiabetic; urological; anticancer; other

Phase III

Endothelin A receptor antagonist Angiogenesis inhibitor

Pyridoxamine dihydrochloride

BioStratum

Glycosylation inhibitor

Alfa Wassermann

Symptomatic antidiabetic; urological; ophthalmological Anticoagulant; hypolipemic/ Antiatherosclerosis

Phase III

Sulodexide

19-Nor-9,10-secoergosta5,7,22-triene-1,3,25-triol, (1a,3b,7E,22E)- [CAS] N-[6-Methoxy5-(2-methoxyphenoxy)2-(4-pyridinyl)-4-pyrimidinyl]-5-methyl2-pyridinesulfonamide 3-Pyrrolidinecarboxylic acid, 4-(1,3-benzodioxol5-yl)-1-[2-(dibutylamino)2-oxoethyl]-2-(4methoxyphenyl)-, (2R,3R,4S)- [CAS] 4-(aminomethyl)5-(hydroxymethyl)2-methylpyridin-3-ol (glucurono-2-amino)2-deoxyglucoglycan sulfate

Anticancer, other; hepatoprotective; antiarthritic, other; immunosuppressant Hormone; urological; anticancer, hormonal Symptomatic antidiabetic; urological

Phase III

Pirfenidone

GNI

Formulation, other; respiratory; anti-inflammatory; radio/chemoprotective; symptomatic antidiabetic; urological

Phase II

Lipase clearing factor stimulant Glycosaminoglycan stimulant Fibroblast growth factor antagonist TGF-b1 antagonist TNF-a antagonist P38 kinase inhibitor Collagen inhibitor

2(1H)-Pyridinone, 5-methyl-1-phenyl-

placebo or bardoxolone methyl for 52 weeks. The study investigated the effect of three oral doses (25, 75, 150 mg once daily) of bardoxolone methyl on eGFR in patients with CKD and type 2 diabetes. The eGFR (primary end point) showed a significant improvement in the group receiving bardoxolone methyl [74]. When compared with placebo, treatment with bardoxolone methyl in addition to standard therapy increased the eGFR by 5 -- 10 ml/min. However, the fact aroused concern. First, bardoxolone methyl has a similar structure to cyclopentenone prostaglandins that have been shown to cause renal vasodilatation, so that bardoxolone methyl may cause afferent arteriolar dilatation and increase intraglomerular pressure [75]. This hemodynamic effect is the opposite of ACEI and could prove unfavorable in the long term: it may result in short-term hyperfiltration, which predisposes to accelerated renal function loss and progression of nephropathy in the long term. These observations have been confirmed by the fact that patients receiving bardoxolone methyl had a slight increase in ACR [76-79]. It is conceivable that the effects of bardoxolone methyl on the kidney are much more complex than previously thought. Reisman et al.

Phase II

demonstrated that bardoxolone methyl-induced albuminuria may result from the downregulation of megalin, a protein involved in the tubular reabsorption of albumin and lipidbound proteins [80]. Administration of bardoxolone methyl to cynomolgus monkeys significantly decreased the protein expression of renal tubular megalin, which inversely correlates with ACR. This effect is consequent on the marked induction of Nrf2 targets by bardoxolone. Moreover, daily oral administration of bardoxolone methyl to monkeys for 1 year did not lead to any adverse effects on renal histopathological findings but did reduce serum creatinine (sCr) and blood urea nitrogen, as observed in patients with CKD. Moreover 4 weeks after discontinuation of the drug, a reduction in eGFR and ACR was noticed. Ding et al. further explored the potential mechanisms by which bardoxolone methyl increases GFR in rats following short-term administration: the drug attenuated the decrease in GFR and the contraction of cultured mesangial cells in response to Ang II [81]. To better clarify the role of bardoxolone methyl, a multinational, multicenter, double-blind, randomized, placebo-controlled Phase III study was designed. In June 2011, the Bardoxolone

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Bardoxolone

Pyridoxamine Dihydrochloride Renal vasodilatation

Downregulation of megalin and cubilin

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Nrf2

Sulodexide AGEs, scavenging of reactive carbonyl species

Reabsorption of albumin and lipidbound proteins

Activation of antioxidant and detoxification genes

CKD progression

Production and activity of TGF-β Renin transcription antiproliferative and antifibrotic effect Nephrin upregulation NFκB activity

Pirfenidone

Glycosaminoglycan of glomerular basement membrane

Afferent arteriolar vasoconstriction

Podocyte and mesangial dysfunction Renal inflammation oxidative stress

ETA-receptor

Paricalcitol

ET-antagonism

Figure 3. Main effects of emerging drugs on CKD treatment. CKD: Chronic kidney disease; ET: Endothelin; ETA: Endothelin A.

Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes, the Occurrence of Renal Events (BEACON) trial with hard end points began. It set out to determine whether long-term administration of bardoxolone methyl, on a background of standard therapy, including RAAS inhibitors, safely reduced renal and cardiac morbidity and mortality [82]. Approximately 2500 patients were recruited. The primary end point was time-to-first occurrence of ESRD or CV death. Unfortunately in October 2012, the trial was halted after an excess of serious adverse events and mortality were found in the group. More specifically, a total of 96 patients in the bardoxolone methyl group were hospitalized for heart failure or died of heart failure compared with 55 in the placebo group. The mechanism linking bardoxolone methyl to heart failure is unknown. The early termination of the trial ruled out any conclusion as to the effect on ESRD events [83]. Paricalcitol Paricalcitol (19-Nor-1a,25-dihydroxyvitamin D2) is a synthetic analog of calcitriol, the metabolically active form of vitamin D. It is approved for oral and intravenous use in the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure [84]. Its biological actions are mediated through binding of the VDR, a member of the nuclear receptor family of transcription factors, which 6.2

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results in the selective activation of vitamin D-responsive pathways [85]. Paricalcitol suppresses PTH synthesis and secretion, having less effect on serum levels of calcium and phosphorus than vitamin D. Furthermore, the possible pleiotropic role of this analog of calcitriol can be supported by the presence of VDR in a wide variety of tissues [86]. A potential link between paricalcitol and proteinuria reduction had first been identified in three double-blind, randomized, placebo-controlled studies in CKD stage 3 and 4 patients with secondary hyperparathyroidism. The subjects enrolled in these three studies (94 oral paricalcitol patients and 101 placebo patients) had tests for dipstick urinalysis at the beginning and end of the study. The results showed that more paricalcitol-treated patients had a reduction in dipstick proteinuria compared with placebo. One limitation of these studies was the detection of proteinuria by automated dipstick and not by spot urinary PCR or ACR [87]. Previous experimental studies in uremic rats had in turn suggested that paricalcitol can reduce albuminuria and slow the progression of renal insufficiency via mediation of the TGF-b signaling pathway. This effect was amplified when BP was controlled via RAAS blockade [88]. In the VITAL study, a multicenter placebo-controlled double-blind trial, 281 patients with type 2 diabetes and albuminuria were enrolled. All patients had been receiving stable

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doses of ACEI or ARBs for 3 months or more. They were assigned (1:1:1) by computer-generated randomization sequence to receive 24 weeks treatment with placebo, 1 µg/ day paricalcitol or 2 µg/day paricalcitol together with their usual treatment for diabetes and CV protection. The primary measure of efficacy was the percentage change in geometric mean ACR from baseline to the last measurement during treatment. Change in geometric mean ACR was higher in the combined paricalcitol groups than in the placebo group, with a between-group difference of -15% (95% CI -28 to 1; p = 0.071). Also, it seemed to have a dose--response relation with paricalcitol: in the 1 µg group, the between-group difference versus placebo was --11% (95% CI -27 to 8; p = 0.23), while in the 2 µg group the between-group difference versus placebo was -18% (95% CI -32 to 0; p = 0.053). These results showed that 24-week treatment with 2 µg paricalcitol daily reduced residual albuminuria particularly in patients with high dietary sodium intake [89]. Paricalcitol seems to have several action mechanisms for the lowering of albuminuria because activation of the VDR intervenes in pathways with well-known associations with renal and vascular progressive disease. Accumulated clinical and mainly experimental data suggest that in the context of kidney disease, VDR activators exert their renoprotection through suppression of renin transcription [90-94], suppression of TGF-b and macrophage infiltration [95,96], antiproliferative effects, antifibrotic effects [95,97,98], nephrin upregulation and reduced NFkB activity [90,99]. VDR activation also attenuates systemic and renal inflammation, reducing renal fibrosis and glomerulosclerosis [100]. ET receptor type A antagonist The ET system is a family of 21 amino acid peptides with powerful vasoconstrictor and pressor properties. Three different isopeptides, ET-1, ET-2 and ET-3, are known, each with distinct gene and tissue distributions. ET-1 is the predominant isoform expressed in vasculature, and its overall actions are to regulate renal salt and water reabsorption and to increase BP and vascular tone. Renal and extrarenal effects work via activation of two receptor subtypes: endothelin receptor type A and B (ETAR, ETBR). Inhibition of ETBR may have been responsible for the fluid overload found in clinical trials with the dual ET antagonist bosentan and the more ETAR selective antagonist darusentan [101,102]. Experimental data suggest antifibrotic as well as antiproteinuric effects of ETAR blockade [103]. Plasma ET1 is increased in CKD patients and correlates with urinary albumin excretion and severity of renal function impairment. ETAR but not ETBR blockade seems to exert a protective renal effect on CKD patients. ETAR activation promotes podocyte and mesangial dysfunction, renal inflammation, and oxidative stress, leading to proteinuria and glomerulosclerosis [104,105]. Hence, the still unanswered questions are whether all clinically available ET antagonists inhibit ETBR at higher dosages and which dosage of the corresponding ET antagonist can be regarded as selective. Interest in ET 6.3

receptor blockade was recently renewed because of the encouraging results of studies on BP (darusentan) and diabetic nephropathy (avosentan) [106,107]. Avosentan and atrasentan are ETAR-selective antagonists tested in diabetic nephropathy in addition to standard ACEI/ARBs therapy. Avosentan Avosentan is a competitive ETAR (ETAR:ETBR blockade 300:1). In a dose-finding safety/efficacy Phase IIb trial (286 patients), avosentan was administered at doses of 5-10-25 and 50 mg/day versus placebo in patients with diabetic nephropathy already treated with standard ACEI/ARBs therapy for 12 weeks [107]. Drug safety and tolerability was shown to be acceptable; the most frequent adverse event was peripheral edema mainly with the highest dosages. Relative to baseline, all avosentan dosages decreased the mean relative urinary albumin excretion rate (UAER) compared with placebo. Median relative UAER decreased with all avosentan dosages compared with placebo. Creatinine clearance and BP were unchanged at 12 weeks. In a Phase III clinical study (ASCEND), the effect of avosentan on progression of overt diabetic nephropathy was evaluated in a multicenter, multinational, double-blind, placebocontrolled trial. The study enrolled 1392 patients on standard ACEI/ARBs therapy, or a combination thereof, randomly assigned to avosentan 25 or 50 mg/day or placebo [108]. The composite primary outcome was the time of doubling sCr, ESRD, or death. The clinical trial was stopped after an average of about 4 months’ follow-up for serious adverse events in avosentan groups, in particular, an excess of CV events, mainly congestive heart failure, pulmonary edema and fluid overload. There were no statistically significant differences for the primary outcomes among the three groups. The decrease in eGFR was slightly greater in the avosentan 50 mg/day group compared with placebo, both at 3 and 6 months, with no significant findings for avosentan 25 mg/day. In both avosentan groups, the median ACR (secondary outcome) significantly declined. Although administration of avosentan at the dosages of 25 and 50 mg/day was associated with symptoms of fluid overload, the slight weight gain in the ASCEND study (approximately 0.5 kg over 6 months with avosentan) may be explained not only by fluid retention but also by fluid redistribution. However, in previous studies with a shorter followup and carried out on patients with less advanced renal disease, the supposed effects of avosentan on fluid balance were seen mainly at dosages > 5 mg/day and were not found to be life threatening. It may be that at dosages of 25 -- 50 mg, avosentan is less selective for ETAR and thus caused sodium and water retention and peripheral vasodilation with a potential fluid shift from the intravascular to extravascular space. 6.3.1

Atrasentan Atrasentan is a highly selective ETAR antagonist (ETAR: ETBR blockade 1800:1). 6.3.2

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A randomized, double-blind, placebo-controlled Phase IIa clinical trial evaluated the safety and efficacy of atrasentan in reducing residual albuminuria in subjects with type 2 diabetic nephropathy who had been receiving stable doses of ACEI or ARBs. Eighty-nine patients were randomly assigned to receive four treatments: atrasentan at doses of 0.25 -- 0.75 -- 1.75 mg/day or placebo for 8 weeks. The study included patients with an eGFR > 20 ml/min per 1.73 m2 and ACR between 100 and 3000 mg/g [109]. The ACR-lowering effect, which occurred early after drug initiation, was sustained throughout the treatment period for the 0.75 mg/day and 1.75 mg/day doses but was not significant in the lowest dose group. Although both of the effective doses were associated with significant lowering of BP, the major effect of atrasentan on ACR reduction was independent of the BP change. The finding that eGFR did not change during treatment suggests that ETAR antagonism of efferent vasoconstriction may not be the dominant mechanism for its albuminuria-lowering effect. There was a significant excess of adverse events in the 1.75 mg/day group, related to fluid overload/fluid redistribution, while 0.75 mg/day provided an acceptable balance between efficacy and adverse effects. The advantage of atrasentan may be the higher selectivity for ETAR, which may translate into reduced inhibition of ETBR-mediated sodium retention. Some of the questions about the use of ET antagonists may be answered by the study called ‘SONAR’ (Study of Diabetic Nephropathy with Atrasentan), a Phase III clinical trial currently recruiting participants, which has as primary outcomes time to the first occurrence of a component of the composite renal end point: doubling of sCr, or the onset of ESRD in subjects with type 2 diabetes on treatment with ACEI/ ARBs, with eGFR 25 -- 75 ml/min/1.73 m2 and proteinuria. In this study, to avoid the risk related to fluid overload, BNP levels < 200 mg/l were among the inclusion criteria [110]. Pyridoxamine dihydrochloride High levels of advanced glycation end products (AGEs) are present in diabetic patients; experiments in animal models suggest that AGEs cause direct injury to the mesangial cells and podocytes as they upregulate gene expression of collagen and TGF-b1 in diabetic glomerular lesions. AGEs mediate their action by receptor-dependent or -independent mechanisms. The receptors for AGEs are expressed on podocytes, and inhibition of their activity reduces the expression of TGF-b, mesangial expansion, and basement membrane thickening. Thus, inhibition of AGE formation seems to be an attractive therapeutic option that may alter the pathogenesis and delay the progression of diabetic kidney disease. Pyridoxamine dihydrochloride is an efficient inhibitor of AGEs and glycoxidative reactions in various biological systems. Furthermore, pyridoxamine dihydrochloride is a chemical scavenger of pathogenic reactive carbonyl species and has also been shown to inhibit formation of advanced lipoxidation end

products during lipid peroxidation reactions. These biochemical characteristics suggest the possibility that pyridoxamine dihydrochloride may be a novel agent targeting several pathogenetic pathways involved in the progression of diabetic kidney disease. Several preclinical studies in rat models of diabetic nephropathy have demonstrated oral pyridoxamine dihydrochloride to be efficient in preserving renal function. Two Phase II clinical studies were conducted in patients with mild-to-moderate type 1 and type 2 diabetic nephropathy, and the results were subjected to a post hoc analysis by Williams et al. [111]. This study demonstrated that pyridoxamine is safe and tolerated in patients suffering from diabetic nephropathy (types 1 and 2) at doses of 50 or 250 mg twice daily. However, pyridoxamine appeared to have a significant effect in reducing the slope of creatinine change from baseline compared with placebo. Although pyridoxamine did not affect urine albumin excretion, it significantly reduced the plasma AGE level compared with the placebo group. Lewis et al. enrolled 317 patients suffering from diabetic nephropathy (type 2) with macroalbuminuria and a PCR at least 1200 mg/g in a Phase IIb clinical trial and randomly assigned them to oral (150 mg or 300 mg twice daily) or placebo in addition to only one ACEI or ARB [112]. The purpose of the study was to determine whether 1 year of therapy with pyridoxamine dihydrochloride delayed the progressive loss of renal function. The trial failed to detect any effect by pyridoxamine on the progression of sCr at 1 year. However, secondary analysis in the patient subgroup with better preserved renal function at baseline (lowest tertile sCr) showed a significantly lower increase of creatinine in both treatment groups versus placebo. The same pharmaceutical company that led this last study announced in 2011 that it had reached an agreement with the FDA on the design of a new Phase III program (to date this has not yet been registered) to evaluate pyridoxamine in diabetic nephropathy patients using a surrogate end point that includes sCr changes after 1 year as predictive of progression to ESRD.

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Sulodexide Sulodexide is a highly purified mixture of glycosaminoglycans mainly composed of low-molecular-weight heparin sulfate (80 ± 8%) and dermatan sulfate (20 ± 8%) [113]. In clinical practice, it is used for the prophylaxis and treatment of thromboembolic diseases such as deep vein thrombosis. Sulodexide differs from other glycosaminoglycans, such as heparin, in having a longer half-life and a reduced effect on systemic clotting and bleeding [114]. The achieved plasma oral sulodexide concentration is low, but components of sulodexide have an average molecular weight of approximately 9 kDa and therefore are freely filterable at the glomerulus, exposing the structural components of the glomerular capillary wall to these anionic molecules. A series of small studies have reported that orally administered sulodexide was capable of decreasing urine albumin excretion rates in patients with diabetic nephropathy [115-119]. 6.5

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This renal disease is associated with a decrease in the glycosaminoglycan composition of the glomerular basement membrane, particularly heparin sulfate. The loss of glomerular basement membrane integrity may aggravate proteinuria and accelerate the progression of renal disease. Starting from the hypothesis that sulodexide was capable of interfering with the abnormal biochemistry of the glomerular capillary wall in the diabetic state, particularly with respect to heparin sulfate content, after conducting a previously reported pilot study, the Collaborative Study Group (CSG) undertook two multinational, randomized, double-blind, placebocontrolled trials using sulodexide in patients with type 2 diabetes. The first study, sulodexide microalbuminuria (SunMICRO) trial, was conducted in patients with preserved renal function and microalbuminuria [120]. The study enrolled 1056 participants with type 2 diabetes mellitus, a sCr level < 1.5 mg/dl and microalbuminuria defined as ACR of 35 -- 200 mg/g in men and 45 -- 200 mg/g in women. Moreover, all the subjects had been receiving the highest US FDA-recommended dose of an ACEI or ARBs for at least 120 days. The primary end point was normoalbuminuria (ACR < 20 mg/g and a decrease > 25%) or 50% decrease in baseline ACR. But at the end of a 26-week maintenance period, orally administered sulodexide at a dose of 200 mg/day failed to decrease urine albumin excretion compared with placebo in patients with type 2 diabetic nephropathy and microalbuminuria. An equally negative result concerning a possible renoprotective effect by sulodexide was found by Packham et al. in the sulodexide macroalbuminuria (Sun-MACRO) trial, which evaluated the renoprotective effects of sulodexide in patients with type 2 diabetes, renal impairment, and significant proteinuria (900 mg/day) already receiving maximum therapy with ARBs [121]. The patients were randomized to receive sulodexide 200 mg/day or placebo. The primary end point was a composite of doubling of baseline sCr, development of ESRD, or sCr 6.0 mg/d. The study planned to enroll 2240 patients over approximately 24 months but was terminated prematurely because after 1029 person-years of follow-up no significant differences between sulodexide and placebo were detected. Pirfenidone Pirfenidone is an oral compound with antifibrotic properties. Although its action mechanism is not fully understood, it inhibits production and activity of TGF-b [122]. Due to its antifibrotic effects, pirfenidone has been tested in numerous disorders such as idiopathic pulmonary fibrosis, myelofibrosis, primary sclerosing cholangitis, and multiple sclerosis. In animal models of glomerulosclerosis, 12-week treatment with pirfenidone reduced renal cortical collagen accumulation and had a positive effect on renal function but did not affect proteinuria [123,124]. The major clinical trial on this topic was performed on 77 patients with diabetic nephropathy [125]. This was a randomized double-blind placebo-controlled trial 6.6

investigating the effect on eGFR variations, in a 12-month follow-up, of two oral doses of pirfenidone (1200 mg and 2400 mg daily) versus placebo. After 54 weeks, there was a significant improvement in eGFR in patients assuming 1200 mg of pirfenidone, while no statistically significant differences were found among the 2400 mg group or the placebo group. Moreover, no statistical differences were found in the secondary end points: ACR and urinary TGF-b level. Failure to decrease albuminuria is similar to what was observed in a recent open-label clinical study of pirfenidone in patients with advanced focal segmental glomerulosclerosis, suggesting that the treatment was associated with a reduction in the rate of renal function decline without attenuating albuminuria. The urine levels of TGF-b were not significantly affected by pirfenidone; this may be due to the wide variability of TGF-b urine levels and/or the small sample size. The lack of hard end points, such as hemodialysis initiation and CV death, was the major limitation of the study. The lack of differences in ACR is also relevant. On the other hand, the high dropout rate in the 2400 mg group, mainly due to gastroenteral side effects, could be the reason why statistically significant eGFR improvement was not observed. 7.

Expert opinion

The increasing use of treatments aimed at attenuating progressive CKD, most notably metabolic control and BP treatment with ACEI and ARBs in almost all forms of CKD, has coincided with a plateau in the incidence of ESRD in the USA over the past few years [7]. However, a constant incidence rate at over 100,000 per year cannot be a source of satisfaction. The current mainstay in the treatment of proteinuric nephropathy, RAAS blockade, although undoubtedly effective, does not completely resolve the problems of proteinuria and CKD progression: in many patients, either the lowering of proteinuria is incomplete or a secondary increase in proteinuria (escape) occurs. Likewise, the long-term benefit from a dual-therapy combination of RAAS-blocking drugs remains to be ascertained: it has been examined in various CKD and CVD conditions, generally enhancing the therapeutic effects on several end points such as proteinuria and BP. The most evident advantages derived from administration of these drugs have been obtained in proteinuric nephropathies, such as chronic glomerulonephritis and diabetic nephropathy, where they have become the treatment of choice. In this case, the dual therapy should be used judiciously and restricted to patients with residual proteinuria despite maximal monotherapy RAAS blockade, with close monitoring of BP and kidney function. Furthermore, in more advanced stages of CKD, RAAS blockade fails to halt completely the progressive loss of GFR. Considering the incomplete efficacy of RAAS blockade,

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it is necessary to find new drugs that could either exert a complementary action to ACEI and ARBs or act on other pathophysiological processes involved in the progression of renal damage. However, the great expectations of new drugs for CKD management over the last decade have been disappointing. In addition, there is considerable economic loss for pharmaceutical companies resulting from the failure of these studies. However, the negative and/or inconclusive results of the recent trials based on new drugs for the treatment of CKD do not justify a nihilistic attitude, but on the contrary should spur to a number of methodological correctives. If it is true that in order to assess the efficacy of new drugs in the treatment of CKD it is necessary to target hard end points (that for CKD being the risk of RRT or death), all this makes such trials complex and expensive in view of the slowly evolving nature of CKD. No less problematic is the utility of surrogate outcomes. For many years, a change in albuminuria has generally been believed to be a suitable surrogate for assessing kidney disease progression, as well as the efficacy of treatment with ACEI and ARBs [126,127]. However, several recent studies, including ONTARGET [44] and ROADMAP [39], have shown favorable effects on albuminuria but detrimental effects on kidney failure and CV outcomes, while the BEAM [74] study showed favorable effects on kidney function with increased albuminuria. Until the nephrological community finds a reproducible, minimally invasive and reliable biomarker that can predict outcomes to a high degree of accuracy, we must continue to rely on albuminuria and changes in GFR as our end points, imperfect and at times contradictory as they may be. One further point of reflection is the early termination of the trials respectively based on bardoxolone (BEACON) [82,83] and sulodexide [120]. The BEACON trial was terminated prematurely in October 2012 based on the recommendation of the Independent Data Monitoring Committee ‘for safety concerns due to excess serious adverse events and mortality’. In total, 57 out of the 2185 patients who had been randomized either to bardoxolone methyl or to placebo died at that time for reasons that have not yet been disclosed by Reata Pharmaceuticals. No published studies on the effects of bardoxolone in animal models of type 2 diabetic nephropathy were available before the BEAM trial [74]. Furthermore, the results of some experimental studies made with bardoxolone methyl analogue RTA 405 have provided unexpected negative results such as: i) increase in serum alanine aminotransferase and aspartate aminotransferase, and in liver weight in association with notable histological changes; and ii) proteinuria, glomerulosclerosis, and tubular damage [70]. These results emphasize once again the need to perform experimental animal studies to provide important insights not only into pathogenetic

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mechanisms but also into unexpected side effects. Here one notes that the early termination of the SUN-MACRO trial [121] based on sulodexide was made by the sponsor for lack of a surrogate outcome signal, not by the Data and Safety Monitoring Committee for safety or efficacy concerns. However, it could be said that the goals set by the investigators were too ambitious in wishing to demonstrate the utility of sulodexide in diabetic nephropathy. High expectations originating from preliminary studies with specific agents such as bardoxolone need to be tempered with caution, given the absence of consistent and adequate data. To date, several agents that showed great promise in animal studies have been less effective in humans. On the basis of currently available studies, it is reasonable to assume that in the first place paricalcitol can be a powerful aid in the slowing of CKD. ET receptor antagonists could likewise find a clinical application with the use of selective molecules such as atresantan at dosages that reduce the risk of also inhibiting ETBR and hence the risk of side effects such as fluid overload, especially in patients with cardiac dysfunction. This feature is analogous to that of ibopamine, which, at a low dosage, slows the progression of renal failure [128], while at higher dosages it increases the mortality rate in patients with moderate-tosevere heart failure [129]. For emerging therapeutic strategies to find clinical application, they should be more effective than RAAS inhibition or bring additional benefits. To achieve disease regression, such drugs will need to be able to reverse the pathological hallmarks of CKD, including cell proliferation, inflammation, atrophy, and fibrosis. Although many strategies are effective at reversing proliferation and inflammation, few are effective at reversing atrophy and fibrosis. In addition, successful drugs will need to be shown to reverse the hard end points such as decline in GFR, need for dialysis and mortality, and not just show effects on surrogate markers of disease progression such as proteinuria. Finally, the longterm efficacy and safety of any new therapies will need to be demonstrated in large-scale trials before such new therapies can be introduced into common clinical practice.

Acknowledgment We are grateful to Helen Spiby for her kind linguistic collaboration.

Declaration of interest This research was supported in part by the University of Bologna, project ‘Ricerca fondamentale orientata’. Principal investigator: S Stefoni, 2013. The authors declare no other conflict of interest.

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Affiliation

Sergio Stefoni†1, Giuseppe Cianciolo2, Olga Baraldi2, Mario Iorio2 & Maria Laura Angelini2 † Author for correspondence 1 Professor, S.Orsola University Hospital, Department of Experimental, Diagnostic and Speciality Medicine, Dialysis, Nephrology and Trasplantation Unit, Via Massarenti, 9, Bologna, 40138, Italy E-mail: [email protected] 2 S.Orsola University Hospital, Department of Experimental, Diagnostic and Speciality Medicine, Dialysis, Nephrology and Trasplantation Unit, Via Massarenti, 9, Bologna, 40138, Italy

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Emerging drugs for chronic kidney disease.

Chronic kidney disease (CKD) is a worldwide health problem. Despite remarkable headway in slowing the progression of kidney diseases, the incidence of...
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