Niacin and Progression of CKD

Niacin is the oldest drug available for the treatment of dyslipidemia. It has been studied extensively and tested in clinical trials of atherosclerotic cardiovascular disease prevention and regression in the general population, but not speciﬁcally in patients with chronic kidney disease (CKD), who are at extremely high re- sidual risk despite current therapy. Despite the current controversy about recent trials with niacin, including their limitations, there may be a place for this agent in select patients with CKD with dyslipidemia. Niacin has a favorable unique impact on factors affecting the rate of glomerular ﬁltration rate decline, including high-density lipoprotein (HDL) particle number and function, triglyceride levels, oxidant stress, inﬂammation and endothelial function, and lowering of serum phosphorus levels by reducing dietary phosphorus absorption in the gastrointestinal tract. These effects may slow glomerular ﬁltration rate decline and ultimately improve CKD outcomes and prevent cardiovascular risk. This review presents the clinically relevant concept that niacin holds signiﬁ-cant potential as a renoprotective therapeutic agent. In addition, this review concludes that clinical in- vestigations to assess the effect of niacin (in addition to aggressive low-density lipoprotein cholesterol lowering) on reduction of cardiovascular events in patients with CKD with very low HDL cholesterol (or those with identiﬁed dysfunctional HDL) and elevated triglyceride levels need to be considered seriously to address the high residual risk in this population. Am J Kidney Dis. 65(5):785-798. ª 2015 by


INTRODUCTION
It is estimated that .10% of the US population 20 years or older has chronic kidney disease (CKD). 1 The condition is progressive and irreversible, and its presence is associated with a high risk of mortality, cardiovascular disease (CVD) morbidity, and a marked increase in health care expenditures. 2 Progression of CKD is associated with increased risk of CVD events and mortality. A recent meta-analysis reported that mortality increases 1.4 times for each 15-mL/min/1.73 m 2 decrease in glomerular filtration rate (GFR) , 45 mL/min/1.73 m 2 . 3 Consequently, current guidelines recommend interventions for prevention of the progression of CKD. The NKF-KDOQI (National Kidney Foundation-Kidney Disease Outcomes Quality Initiative) guidelines 4 advise strict glucose control in diabetes, blood pressure control, and use of drugs providing angiotensin-converting enzyme inhibition or angiotensin-2 receptor blockade. Despite these interventions, there has been limited success in preventing the progression of CKD. The effect of glycemic control on CKD progression was not confirmed in recent large trials. 5,6 The very low optimal blood pressure previously recommended for the prevention of progression of CKD 7 is no longer part of the guidelines in view of a lack of evidence of benefit in terms of CVD events 8 or death. 9 Furthermore, studies have shown that angiotensinconverting enzyme inhibitors and angiotensin-2 receptor blockers decrease GFR decline in patients with proteinuria, 10 but their effectiveness in patients with nonproteinuric CKD has been questioned. 11 Therefore, additional interventions for decreasing the rate of GFR decline are necessary.
Niacin is the oldest drug available for the treatment of dyslipidemia. 12 It has been studied extensively and tested in clinical trials of CVD prevention 13 and reversal of atherosclerosis (see Table 1). Its place in current therapy has to be viewed in the context of its long clinical history of more than half a century and its useful properties shown in basic research studies. Controversy has followed recent reports. Results of 2 recent clinical trials to determine whether niacin confers incremental benefit in patients treated optimally for low-density lipoprotein cholesterol (LDL-C) level reduction resulted in negative outcomes. 14- 16 These trials have cast doubts about the place of niacin in current therapy for cardiovascular risk reduction. The limitations and implications about which types of patients currently may benefit are discussed later in this review. Importantly, we preface this review by indicating that there is a serious unmet need in therapies to slow CKD progression and reduce the high residual risk for CVD. The role of niacin in CKD management has not been the subject of much inquiry and merits attention despite the recent trials. In pharmacologic doses, niacin's effects on lipid and lipoprotein levels are fairly well known, 17 and its pharmacokinetics in patients with CKD have been documented. 18 In experimental animal models of CKD, niacin reduced kidney injury, 24-hour protein excretion, and the rate of GFR decline. 19 The results of 2 recent studies, Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) 15 and Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) 16 have cast doubt on the safety and efficacy of niacin for reducing CVD events in high-risk patients. We believe it is premature to give up on the use of niacin for cardiovascular prevention based on these 2 studies, in which heterogeneous groups of patients may have diluted the benefits in selected populations. Many types of patients were not studied in these trials, as acknowledged by the studies' investigators, and only a few patients with CKD were enrolled.
This review presents the clinically relevant concept that niacin may slow the rate of GFR decline in patients with CKD through its effect on HDL cholesterol (HDL-C), triglycerides, oxidative stress, and phosphate absorption (Fig 1).

NIACIN, TRIGLYCERIDES, HDL CHOLESTEROL, AND CKD
The definition of metabolic syndrome 20 includes elevated serum fasting triglyceride and low HDL-C levels, along with central obesity, hypertension, and impaired fasting glucose level. This definition confers a risk for coronary events, but not more than the sum of its parts. 21 Patients with estimated GFRs (eGFRs) , 60 mL/min/1.73 m 2 are more likely to have metabolic syndrome, 22 and metabolic syndrome also is associated with increased albumin excretion rate (AER). 23 Specifically, a high ratio of triglycerides to HDL-C has an increased prevalence in patients with CKD. [24][25][26] Triglyceride levels commonly are increased in patients with CKD in multivariate analysis whether studied separately 27,28 or combined with central obesity as "hypertriglyceridemia waist." 29 In a recent study, 30 both triglyceride and HDL-C levels were associated independently with CKD.
In most prospective studies, triglyceride and/or HDL-C levels were identified as predictors of the development or progression of CKD whether defined as a GFR threshold, a decrease in GFR, or onset of proteinuria (Table 2). Larger studies also appear more likely to show a positive association between the high triglyceride and/or low HDL-C exposure with the CKD end point.
The mechanism by which high triglyceride and low HDL-C levels increase the risk of CKD progression is not known. Hypertriglyceridemia has been associated with progression of CKD by multiple mechanisms: monocyte activation, glycocalyx degradation, increased permeability of the glomerular filtration barrier, podocyte apoptosis, and mesangial profibrotic changes. 31 The association between HDL-C level and CKD progression is attributed mainly to the fact that HDL particles are one of the main carriers of endogenous antioxidants, and low HDL-C level reflects a deficiency of these important molecules/proteins. Therefore, the total antioxidant defense is diminished irrespective of the capacity for individual HDL particles to carry antioxidants. HDL in patients with CKD is not only reduced, but also dysfunctional. 32,33 Dysfunctional HDL predicts a poor outcome in endstage renal disease (ESRD). 34 Because dysfunctional HDL is characterized by a reduced capacity to transport antioxidants (in addition to reduced reverse cholesterol transport and endothelial function), its association with progression of CKD will be reviewed further. Hence, if high triglyceride and low HDL levels are associated independently with worse outcomes, decreasing triglyceride and elevating HDL-C levels may be indicated for kidney protection.
In addition to statin therapy, drugs commonly used to reduce triglyceride levels and/or increase HDL-C levels are fibric acid derivatives (fibrates, such as fenofibrate and gemfibrozil in the United States), omega-3 fatty acids (HDL neutral), and niacin. New unapproved drugs that increase HDL-C levels include cholesterylester transfer protein (CETP) inhibitors. Two of these drugs (torcetrapib 35 and dalcetrapib 36 ) examined cardiovascular outcomes in patients without CKD and failed to show clinical benefit, raising questions about elevating HDL-C level as a target of therapy to reduce residual cardiovascular risk after statin or LDL-C-based therapy. These drugs have a unique mechanism of action by which cholesterol in HDL is suppressed from transfer to other lipoproteins, thus increasing the cholesterol content in HDL at the possible expense of its removal from the circulation. Despite the controversial mechanism of action of CETP inhibitors, 2 other CETP-inhibitor drugs are in clinical trials (evacetrapib 37 and anacetrapib 38 ), and their potential benefit is unknown. Fenofibrate 39-45 and omega 3 fatty acids 46 have been shown to have a modest renoprotective effect in terms of AER reduction or GFR decline. However, fibrates increase the risk for myopathy and rhabdomyolysis 47 in patients with CKD and thus cannot be considered seriously for reducing residual risk in patients with CKD. The mechanisms of action of all these drugs (CETP inhibitors, fibrates, and omega 3 fatty acids) on triglyceride and HDL concentrations and function are unique and very different from niacin. Study results from one drug should not be extrapolated to another.  The effect of niacin on kidney function and AER has been studied in experimental kidney disease. Cho et al 19,48 reported that niacin-treated partially nephrectomized rats had marked reductions in 24-hour protein excretion and rate of GFR decline. There is no study reporting a similar effect of niacin in humans. However, a case report of a patient with familial lecithin cholesterol acyltransferase deficiency with moderate CKD showed that daily administration of niacin and fenofibrate resulted in a 75% reduction in albumincreatinine ratio and stabilization of serum creatinine level. 49 Conversely, derivatives of niacin, such as niceritrol 50 and nicorandil, 51 have been tested in small clinical trials in patients with CKD and proteinuria. Both drugs have shown a significant reduction in AER when the treated group was compared to the respective control group (untreated and placebo, respectively).
In summary, elevated triglyceride and low HDL-C levels are predictors of increased AER and GFR decline, whereas fenofibrate, a drug used to reduce triglyceride and increase HDL-C levels, has a beneficial effect on AER and GFR in diabetic patients. Additionally, niacin has been shown to be renoprotective in experimental CKD. These data support the need for clinical investigations exploring the potential of niacin for renoprotection in patients with CKD and additionally for identifying the profile of patients who may benefit.

NIACIN, OXIDATIVE STRESS, AND CKD
Progression of kidney disease is associated with a progressive worsening of oxidative stress attributable to an increased level of reactive oxygen species and a decrease in antioxidant defense mechanism. In the past 12 years, multiple reviews have emphasized the role of oxidative stress in different aspects of the pathophysiology of CKD. [52][53][54][55] These reviews explain that oxidative stress is the primary trigger for the inflammation, fibrosis, and impaired endothelial function observed in CKD, and that the level of oxidative stress increases progressively in close association with declining eGFR. Niacin can play a role in ameliorating oxidative stress, inflammation, and endothelial dysfunction.

Oxidative Stress
Oxidative stress has been identified as a major factor in the progression of CKD. This pathogenic pathway is documented through animal studies, in vitro studies, small prospective studies, and randomized clinical trials using antioxidants.
In patients with diabetes, oxidative stress mediates high glucose-induced activation of nuclear factor-kB (NF-kB) and NF-kB-dependent monocyte chemoattractant protein 1 (MCP-1) expression. 56 Upregulation of MCP-1 is considered to be one of the mechanisms Abbreviations and definitions: (1), positive association of exposure with outcome; (2), no significant association found between exposure and outcome; ACEi/ARB, angiotensin-converting enzyme inhibitor or angiotensin-2 receptor blocker; AER, albumin excretion rate; BMI, body mass index; Ca involved in the development and progression of diabetic nephropathy. 57 In early stages of diabetic nephropathy in type 1 diabetes, hyperfiltration is associated with oxidative stress biomarkers independent of age at disease onset, glycated hemoglobin levels, and microalbuminuria. 58 In patients with established CKD, levels of markers of oxidative stress increase and antioxidative enzyme levels decrease as GFR declines. 59 In patients with immunoglobulin A nephropathy, advanced oxidation protein product concentration predicted worse kidney outcomes in multivariate analysis 60 and correlated strongly with the slope of GFR decline over the next 3 to 10 years. 61 In the past 5 years, myeloperoxidase (MPO) has emerged as a main mediator of tissue injury induced by reactive oxygen species [62][63][64][65][66] and as a main pathway for generating dysfunctional HDL. 67 In patients with CKD, MPO is considered to be a primary link between oxidative stress, inflammation, and endothelial dysfunction. 68,69 In mice with CKD, MPO deficiency is associated with decreased levels of inflammatory and profibrotic markers, less proteinuria, and slower course of glomerular lesions. 70 In patients with diabetic nephropathy, MPO is elevated and correlates significantly with albumin-creatinine ratio. 71 MPO levels in patients with CKD are elevated compared with healthy controls, 72 but their association with eGFR has been reported to be both positive 73 and negative. 74 In dialysis patients, MPO levels are more than 20-fold higher than in predialysis patients. 75 In these patients, MPO levels are associated with mortality, cardiovascular events, and reduced kidney function. 76 A study of the gene polymorphism for MPO G-463A showed that the allele G, which is associated with higher MPO levels, also is associated with progression of diabetic nephropathy, expressed as either increased AER or decreased eGFR. 77 Recent research from our laboratory has indicated that niacin significantly decreases the release of MPO by leukocytes and prevents HDL from becoming dysfunctional. 78 In the past 15 years, various attempts were made to decrease antioxidant stress by drug intervention in order to provide renoprotection or cardioprotection for patients with CKD at risk. The agents tested were acetylcysteine 79,80 ; vitamin E, 800 IU/d 81 ; and probucol. 82 A Cochrane analysis reported that antioxidants decreased the progression of CKD. 53 This analysis was based mostly on a 52-week randomized placebocontrolled study, Bardoxolone Methyl Treatment: Renal Function in CKD/Type 2 Diabetes (BEAM). 83 Unfortunately, clinical trials for this antioxidant were discontinued because of safety concerns. 84,85 HDL is one of the main carriers of antioxidants in serum and has impaired antioxidant activity in CKD. 32 In studies of humans, niacin significantly reduced oxidative stress in patients with hypercholesterolemia and low HDL levels. 86 An antioxidant effect of niacin also was demonstrated in cultured human aortic endothelial cells. 87 In this study, niacin decreased mediators of oxidative stress and LDL oxidation, which resulted in reductions in MCP-1 and tumor necrosis factor a (TNF-a), NF-kB activation, and vascular cell adhesion molecule 1 (VCAM-1) levels and secretion. Production of nicotinamide adenine dinucleotide phosphate oxidase enzyme complex and activated reactive oxygen species particles also was inhibited significantly by niacin. 78

Inflammation
As CKD progresses, amplification of oxidative stress is associated with increased inflammatory markers such as C-reactive protein (CRP) and fibrinogen. 88 In the ARIC (Atherosclerosis Risk in Communities) Study, the risk of incident CKD increased with increasing baseline quartiles of white blood cell count and fibrinogen. 89 In other prospective studies, level of CRP, the most commonly used marker of inflammation, predicts doubling of baseline serum creatinine level and/or the onset of ESRD 90 and increase in creatinine level 91 and rate of GFR decline. 92 In the CARE (Cholesterol and Recurrent Events) Study, among survivors of myocardial infarction with CKD, higher baseline CRP and soluble TNF receptor II levels were associated independently with more rapid loss of kidney function. 93 Other biomarkers of inflammation, including TNF receptor I 94 ; circulating matrix metalloproteinases-2, -3 and -9 95 ; and soluble CD40 ligand, 96 have been associated independently with progression of CKD. The anti-inflammatory properties of niacin are mediated in part by the niacin-specific receptor GPR109A 13 and are independent from its lipidmodifying effects. 97,98 In studies of humans, niacin has demonstrated its anti-inflammatory potential by decreasing fibrinogen, 99,100 CRP, 101,102 and soluble CD40 ligand levels. 103

Endothelial Dysfunction
Endothelial dysfunction also increases with progression of CKD. Markers of endothelial dysfunction, such as asymmetric dimethylarginine (ADMA), which is a natural inhibitor of nitric oxide production by the endothelium, 104,105 and von Willebrand factor, 106 have been shown to increase across advancing stages of CKD. Conversely, with progression of CKD, the ability of cultured endothelial progenitor cells to express nitric oxide synthase decreases. 107 Prospective data show that endothelial dysfunction contributes to the deterioration of kidney function. The effect of endothelial dysfunction on progression of CKD was demonstrated by showing that increased acetylcholine-stimulated forearm blood flow, a goldstandard test for endothelial function, is associated independently with decreased eGFR slope. 108 This report is supported by data addressing markers of endothelial dysfunction. Increased levels of soluble VCAM-1 and plasminogen activator inhibitor 1 were reported to be correlated strongly with steeper eGFR decline in patients with type 1 diabetes. 109 In another study in patients with type 1 diabetes, after adjustment for well-known confounders including baseline eGFR, there was a significant increase in risk for ESRD when comparing upper and lower median ADMA levels. 110 Moreover, in patients with mild to moderate nondiabetic CKD, Cox regression analysis revealed that baseline ADMA level was an independent predictor of CKD progression. 111 The effect of niacin on endothelial function was documented in the INEF (Impact of Niacin on Endothelial Function) trial. 112 In this study, extendedrelease niacin treatment improved endothelial dysfunction in patients with coronary artery disease who had low HDL-C levels, but not in those with normal HDL-C levels. In another study, niacin treatment reduced ADMA levels by a clinically significant margin. 113

NIACIN, CKD, AND HYPERPHOSPHATEMIA
Hyperphosphatemia is a non-GFR marker of CKD. The concept that high phosphorus level is associated with the rate of CKD progression was proposed first from dietary and animal studies. 114 In 2006, Schwarz et al 115 showed in male veterans with CKD that higher serum phosphorus concentrations were associated with higher risk of the composite end point of doubling of serum creatinine level or ESRD. Another study 116 reported that increases in phosphorus levels in patients with stage 4 CKD were associated with increases in kidney function decline. Other studies reported that in patients with moderate CKD, higher serum phosphate levels were associated independently with progression to ESRD or death. [117][118][119] Moreover, higher dietary phosphorus burden in the form of higher phosphorus to protein ratio in food is associated with higher mortality in advanced CKD. 120 The slope of GFR decline obtained from prospective data also has been shown to be associated with increasing serum phosphorus levels. 121,122 In patients with normal kidney function, high plasma phosphorus levels are associated with increased likelihood for ESRD outcome. 123 In addition, hyperphosphatemia is associated with overt proteinuria in nondiabetic patients with advanced CKD, 124 and a strong interaction was reported between serum phosphate level and phosphaturia with an antiproteinuric response to a very low-protein diet. 125 These studies provide strong evidence that hyperphosphatemia precedes and predicts the progression of CKD. Although it is assumed that lowering serum phosphorus levels should have a favorable effect on progression of CKD, a retroactive analysis of nondialysis-dependent patients with CKD treated with phosphate binders showed a steeper slope of GFR decline than for untreated patients, 126 and another study showed that phosphorus binders may have a paradoxically deleterious effect on vascular calcification. 127 These data indicate the need for new approaches to address hyperphosphatemia and vascular calcification in CKD.
The phosphorus-reducing properties of niacin and its derivatives, including nicotinamide, were reported first by Shimoda et al. 128 The mechanism of action is attributed to inhibition of type IIb sodium-dependent phosphate cotransporter in the intestinal brush-border membranes. 129 The first report of extended-release niacin use for treatment of hyperphosphatemia in CKD was published in 2006. 130 Subsequently, other authors reported on the phosphorus-lowering effects of niacin or niacin/laropiprant in patients with CKD receiving hemodialysis, non-dialysis-dependent patients with CKD, and patients without CKD (Table 3). All these studies confirmed significant lowering of serum phosphorus levels in treatment arms, which was consistent among subgroups and associated with minimal adverse events. In summary, hyperphosphatemia is associated with an increased rate of GFR loss in CKD, and niacin has been uniformly reported to reduce serum phosphorus concentration.

NIACIN, CKD, AND ATHEROSCLEROTIC CVD
This review is presented at a time when the use of niacin in clinical practice is controversial. The AIM-HIGH study enrolled 3,414 patients with coronary artery disease, low HDL-C levels (men, ,40 mg/dL; women, ,50 mg/dL), high triglyceride levels (.150 mg/dL), and LDL-C level lowered to 40 to 80 mg/dL with simvastatin and ezetimibe if necessary. Study results showed no incremental clinical benefit from the addition of niacin to statin therapy during a 36-month follow-up despite significant improvements in HDL-C and triglyceride levels. A subgroup analysis from the AIM-HIGH trial showed a significant decrease in primary events in 439 patients with triglyceride levels $ 200 mg/dL and HDL-C levels # 32 mg/dL. 131 This finding suggests that the cardioprotective effect of niacin could have been attributable to triglyceride level lowering and/or HDL-C concentration increase, in addition to niacin's other lipid and nonlipid properties. A larger trial, HPS2-THRIVE, compared niacin/laropiprant to placebo in statin-treated patients with atherosclerotic CVD who were recruited without regard for lipid levels and failed to show incremental benefit. 14, 16 These patients had normal HDL-C (mean, 44 mg/dL) and triglyceride levels (mean, 126 mg/dL), and all patients' LDL-C levels in this study were controlled with simvastatin. Patients with this type of lipid profile have not been indicated for treatment with niacin. In addition, by trial design, patients in this study were heterogeneous in terms of racial origin and lipid profiles, so that any subgroup that may have benefitted was diluted by results from the rest of the study cohort.
Because of the limitations of these studies, we believe the clinical benefit and safety of niacin deserves to be investigated further, particularly in patients with CKD. Niacin use in combination with other lipid-lowering drugs consistently has resulted in reversal of atherosclerosis, expressed as increased carotid intima thickness, femoral atherosclerosis, and coronary stenosis. [132][133][134][135] A 2010 meta-analysis reported that niacin significantly reduced major coronary events by 25%, stroke by 26%, and any cardiovascular events by 27%. 136 Another metaanalysis including 9,959 patients showed a 34% reduction in the composite end points of any CVD event and a 25% reduction in major coronary heart disease events. 137 Based on current considerations, we are proposing that a randomized clinical trial of niacin versus placebo on statin background therapy should be undertaken in patients with non-dialysis-dependent CKD with triglyceride levels $ 200 mg/dL and HDL-C levels # 35 mg/dL. Based on numbers provided by the Veterans Administration (VA) database, we approximate that 10% of non-dialysis-dependent patients with CKD would qualify for enrollment based on these HDL-C and triglyceride criteria. In addition, in order to identify additional suitable patients for this study, we may include criteria that patients have elevated CRP levels, endothelial dysfunction, elevated MPO levels, dysfunctional HDL, and/or reduced HDL particle number.
In preparation for this trial, we currently are conducting a retrospective analysis in the VA database of more than 650,000 patients with incident CKD, of whom more than 50,000 were treated with niacin. We aim to explore the safety of niacin in order to further refine the inclusion criteria of our proposed trial. Recent published trials have raised concerns that need to be explored carefully in patients with CKD. In both AIM-HIGH 39 and HPS2-THRIVE, 16 there was a significantly increased risk of nonspecific infection, which is an important complication for patients with CKD. In addition, a significant increase in risk of gastrointestinal bleeding was seen in HPS2-THRIVE, but not in AIM-HIGH. This bleeding has been attributed mainly to the effect of niacin on platelets. 16 Niacin in vitro affects platelet activity by a unique inhibiting effect on aggregation and by stimulating significant prostaglandin release, while major platelet receptor expression remains mostly intact. 138 This niacin effect on platelets is considered to be mild. Moreover, bleeding has not been seen with niacin in other trials. The increased risk of gastrointestinal bleeding found in HPS2-THRIVE raises the question of whether laropiprant (used in this trial and not AIM-HIGH) had a role in this adverse event. Exploring large databases to confirm that niacin is not associated with bleeding complications is essential.
In addition, our group is exploring methods of evaluating HDL function. We believe that niacin's main mechanism of action is altering HDL function, and results from this study may further identify CKD subgroups that will benefit from niacin treatment in conjunction with aggressive LDL-C reduction therapy with statins.

CONCLUSIONS
To our knowledge, the effects of niacin on rate of GFR decline have never been explored in either cohort studies or randomized clinical studies. Niacin has a favorable impact on multiple risk factors affecting the rate of GFR decline, such as HDL concentration and function, triglyceride level, oxidant stress, inflammatory markers, endothelial function, and serum phosphorus level. In addition, recent evidence 135 indicates that niacin may be most effective in reducing cardiovascular events in certain subgroups of statin-treated patients with high triglyceride and very low HDL-C levels, a pattern similar to that seen in patients with CKD. Thus, in patients with CKD, treatment with niacin (in addition to intense LDL-C-lowering therapy) may contribute to lowering the rate of GFR decline and amelioration of atherosclerosis, which is the primary cause of death in these patients. The large body of evidence presented in this review strongly suggests that clinical investigations are needed to assess the effect of niacin (in addition to aggressive LDL lowering) on GFR loss and possibly on reduction of atherosclerosis CVD end points in select groups of patients with CKD; in particular, those with very low HDL-C levels (or identified dysfunctional HDL) and with elevated triglyceride levels who have a very high residual risk and for whom there is no other viable therapy available.