New renal anemia drugs: is there really anything new on the horizon?

Abstract

Anemia has remained one of the most characteristic and visible manifestations of chronic renal failure for over 150 years. The pathogenesis of anemia of chronic kidney disease (CKD) is multifactorial with inadequate production of erythropoietin being the leading factor. The development of recombinant human erythropoietin (epoetin) in the late 1980s was a milestone in treatment of renal anemia. Despite new drugs, our ‘good old friend' erythropoietin-stimulating agents are our everyday life in nephrology practice. It seems that peginesatide would not become a new approach for treating anemia of CKD patients, but rather a falling star. Several new strategies for treating the anemia of CKD are currently being investigated in clinical trials, including prolyl hydroxylase inhibitors and modulators of hepcidin activity, but their role in the management of this condition remains to be established. As shown by the expert in this review, we have to take into account not only the safety and convenience of administration but also cost-effectiveness, while biosimilars are consequently knocking at the doors of dialysis units more and more, particularly in Europe.

Keywords::

• chronic kidney disease
• dialysis
• erythropoietin
• peginesatide
• renal anemia

Anemia has remained one of the most characteristic and visible manifestations of chronic renal failure for over 150 years. Typically, it is a normocytic and normochromic anemia with normal cellularity of bone marrow. The pathogenesis of anemia of chronic kidney disease (CKD) is multifactorial with inadequate production of erythropoietin (EPO) being the leading pathogenetic cause. Iron deficiency is not directly related to CKD, although it is often observed in CKD patients. It became clear that besides iron, EPO would be the desirable approach to treat renal anemia. However, making therapeutic EPO available was much more problematic than making insulin available for diabetics, and it was not until the advent of recombinant DNA technology that this became possible. The development of recombinant human erythropoietin (epoetin) in the late 1980s was a milestone in treatment of renal anemia, liberating many dialysis patients from lifelong regular blood transfusions with all its consequences. As epoetins (α and β) have a fairly short half-life of ∼ 6 – 8 h, requiring frequent injections, and two strategies including either attachment of an extra two carbohydrate chains to the therapeutic protein hormone to make darbepoetin-α or a large PEGylation chain to make C.E.R.A were introduced to prolong the circulating half-life of peptide. In the very elegant review in the current issue of Expert Opinion on Emerging Drugs [1], rationale for anemia treatment were provided as well as use of first and second generation of EPOs were discussed. Other strategies for enhancing erythropoietic activity have been investigated as a means of generating future treatments for anemia [2]. Peginesatide, a peptide-based agent with no structural homology with native or recombinant EPO but sharing the same biological and functional characteristics, was approved by FDA in 2012. During clinical studies, its safety profile appeared to be safe, except the potential increase in the risk of safety end-point events in CKD patients not on dialyses. Unfortunately, soon after launch, unexpected toxicity including anaphylaxis, which can be life-threatening, or fatal, was identified. As a consequence Affymax, Inc. and Takeda Pharmaceutical Co. Ltd., along with the US FDA are informing the public of a voluntary recall of the entire lot of peginesatide injections in the user level [3]. These post marketing serious hypersensitivity reactions have completely changed the scenario and urgently need in-depth clarification. This promising drug seems to have prematurely finished its prospects and instead of rising, became a falling star [4].

Future strategies include stabilization of hypoxia-inducible factor (HIF), by orally active inhibitors of the prolyl hydroxylase enzyme, EPO gene therapy, modulators of hepcidin activity and inhibition of GATA-2. The advent of orally bioavailable small-molecule erythropoietin stimulating agents (ESAs) such as HIF stabilizers in the development of novel anti-anemia therapies expands the list of potential ESA as doping techniques. The anti-anemia drug candidates FG-2216, FG-4592, GSK1278863, AKB-6548 and BAY85-3934e entered the stage of clinical trials [5]. As nicely presented in the review [1], EPO is part of a widespread system of hypoxia-inducible gene expression mediated by HIFs [6]. HIFs are composed of one of two oxygen-regulated α-subunits (HIF-1α and HIF-2α) that form heterodimers with a constitutive HIF-β subunit. HIF-2α is the isoform responsible for regulation of EPO [7]. Molecular oxygen regulates stability and transcriptional activity of HIF-α. Stabilization of HIF achieved by inhibition of prolyl hydroxylation paved the way for development of new orally active anti-anemia drugs, however, as suggested in the review, with some potentially harmful effects on angiogenesis and glucose metabolism [8]. In the published Phase I study, an orally active prolyl hydroxylase inhibitor, FG-2216, stabilized HIF independent of oxygen-availability in 12 hemodialysis patients, 6 of whom were anephric, and in 6 healthy volunteers [9]. These data demonstrated that pharmacologic manipulation of the HIF system can stimulate endogenous EPO production and indicate that deranged oxygen sensing – not a loss of EPO production capacity – caused renal anemia [9]. In addition, this compound, FG-2216, has been reported to decrease hepcidin expression [10]. Another prolyl hydroxylase inhibitor, FG-4497, has been shown to stabilize HIF-1α and HIF-2α, increasing the expression of Epo mRNA and several other hypoxia-regulated mRNAs in cultured cells and in vivo and elevating serum Epo and blood hematocrit values in mice and rats without apparent toxicity [10]. It was also reported that FG-4497 plays a role in the regulation of EPO production, hepcidin expression and erythropoiesis [11]. Potential role of prolyl hydroxylase inhibitors in treating anemia of CKD patients include their oral administration, ability to modulate other genes involved in erythropoiesis. In addition, they downregulate hepcidin production, which might be clinically relevant in patients resistant to conventional ESA therapy. Stabilization of HIF with subsequent transcription of the Epo gene might lead to increase in EPO levels above a certain threshold, which might prove safer than administering high concentrations of ESA in a pharmacologic manner. However, we should be aware that upregulation of other hypoxia-sensitive genes as well as those engaged in glucose regulation and angiogenesis might be unpredictable. Upregulation of vascular endothelial growth factor may facilitate tumor growth but, on the other hand, it results in the cautiousness of prescribing ESA to patients with history of malignancy.

The main function of recently described hepcidin is homeostatic regulation of iron metabolism and mediation of host defense and inflammation [12]. In an experimental model, Sasu et al. [13] reported that suppression of hepcidin mRNA improved anemia in a mouse model of inflammation and high-affinity antibodies neutralized hepcidin and increased hemoglobin levels in hepcidin knockout mice. Thus, anti-hepcidin antibodies may be an effective treatment for inflammatory anemia. Potential therapies downregulating hepcidin may include mimicking soluble hemojuvelin, inhibition of bone morphogenetic protein (BMP) receptor-dorsomorphin, interruption of IL-6 activation (tocilizumab-neutralizing antibody to IL-6, approved for rheumatoid arthritis, ameliorates anemia in Castleman's disease), inhibition of STAT3 – curcumin and others. On the other hand, modulation of hepcidin activity may be associated with some risks: inhibition of hepcidin may increase the risks of infection/inflammation, as well as tumor growth, stabilization of HIF in some studies enhances tumor growth, interruption of BMP (particularly BMP-6) may result in calcification of tissues (including peritoneum) and interruption of the binding of hepcidin to ferroportin may enhance iron absorption and mobilization [14].

As reviewed elegantly, GATA family of transcription factor may also be considered a new class of anti-anemia drugs in future. K7174 inhibited GATA-2-mediated negative regulation for EPO gene, which might contribute to the amelioration of anemia induced by inflammatory cytokines in mice [15]. In vitro and in vivo analyses suggested that K7174 may suppress hepcidin expression, at least in part, through modulating GDF15 expression. Thus, other hepcidin-lowering agents [16], including K7174 or perhaps orally administrable K11706 [17] might be another therapeutic option in anemia in the future. Last, but not least, new potential drug could be sotatercept (ACE-011). This activin receptor type IIA (ActRIIA) ligand trap is a novel, recombinant, fusion protein comprising the extracellular domain of human ActRIIA linked to the Fc portion of human immunoglobulin G1 that binds several members of the transforming growth factor (TGF)-β superfamily [18]. Sotatercept, originally developed to increase bone mineral density, was noted with serendipity to have robust effects on erythropoiesis. The mechanisms underlying the beneficial effects of ACE-011 on red cell production remain unknown. Ligands of the TGF-β superfamily and activin-receptor signaling play an important role in erythropoiesis. It was reported that sotatercept was generally safe and well tolerated, and elicited clinically significant, dose-dependent increases in hemoglobin, hematocrit and red blood cell counts that persisted up to 4 months. The effect of sotatercept on hemoglobin was dose-limiting. Sotatercept also increased bone mineral density and biomarkers of bone formation. The sotatercept serum exposure–dose relationship was linear, with a mean terminal half-life of ∼ 23 days [18]. Finally, EPO gene therapy is presented in this very interesting and updated review [1].

We started our journey a long time ago, when the first suggestion was made by Richard Bright that the kidney might be involved in erythropoiesis. He described, in 1835, the association between ‘anemia' and ‘kidney dysfunction'. Then, at the beginning of the twentieth century, Carnot and Deflandre reported that serum from an anemic donor rabbit injected into a normal rabbit resulted in increased erythropoiesis. Almost half a century later, Erslev proposed that plasma from anemic rabbits containing a factor capable of stimulating erythropoiesis could have a potential as a therapeutic approach. In 1957, Jacobson, Goldwasser and others showed that the kidney was the source of this substance. Exactly 20 years later, Miyake et al isolated the hormone from urine of patients with aplastic anemia and named it EPO. Owing to the progress in biotechnology, the gene was isolated and cloned. Fast-track of EPO from bench to bedside became a milestone in the therapy of renal anemia, enabling avoidance of blood transfusion with secondary hemochromatosis and human leukocyte antigen sensitization. A new era for nephrologists struggling with end-stage kidney patients with all their problems has just begun. Despite new drugs, our ‘good old friend' EPO-stimulating agents are our everyday life in nephrology practice. It seems that peginesatide would not become a new approach for treating anemia of CKD patient but rather a falling star. Several new strategies for treating the anemia of CKD are currently being investigated in clinical trials, including prolyl hydroxylase inhibitors and modulators of hepcidin activity, but their role in the management of this condition remains to be established. As shown by the expert in this review we have to take into account not only the safety and convenience of administration but also cost-effectiveness, while biosimilars are knocking at the doors of dialysis units more and more consequently, particularly in Europe.

Declaration of interest

The author states no conflict of interest and has received no payment in preparation of this manuscript.