**7. Potential and investigational agents**

#### **7.1 Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs)**

Also, they are called HIF stabilizers. The major transcription factor for the EPO gene, HIF, was discovered in 1992. This was followed by the creation of HIF stabilizers. Their action process is via the HIF-prolyl hydroxylase domain (PHD) pathway through stimulation of transcription of EPO gene resulting in increased endogenous EPO levels. Anemia-induced tissue hypoxia leads to HIF system stimulation. Intranuclear dislocation of HIF-alpha is followed by its binding to HIF-B to form a functional dimer that binds to hypoxia-response elements on DNA. Eventually, HIF induces the expression of genes regulating erythropoiesis and iron metabolism in a wide range of tissues. HIF activity and degradation are regulated by PHD proteins. They are oxygen-sensitive hydroxylase enzymes. Their activity decreases during conditions of hypoxia. Development of CKD leads to HIF dysregulation with reduced EPO production. HIF-PHIs enhance the physiologic response to hypoxia through suppression of PHD leading to endogenous EPO production with Hb overshoots less than ESA therapy. HIF-PHIs have direct and indirect beneficial effects on iron deficiency, either absolute or functional type. Directly, HIF-PHIs regulate iron homeostasis proteins, for example, duodenal cytochrome B, ferroportin, transferrin, and divalent metal-ion transporter 1. Indirectly, HIF-PHIs have suppression action on hepcidin (via erythroferrone, the main hepcidin-erythroid regulator), leading to a possible increase in iron availability [56, 57].

Agents of this novel class included in clinical trials are: daprodustat, vadadustat, and raxadustat; all are used orally.

The safety and efficacy of the HIF PHI daprodustat were evaluated in a trial of 2964 patients on dialysis over 2.5 years (average hemoglobin 10.4 g/L) who were randomly given daprodustat (dose range from 4 to 24 mg daily, according to ESA dose) or injectable ESA (epoetin alfa hemodialysis patients or darbepoetin alfa for peritoneal dialysis patients). The average change in Hb concentration was 0.28 g/dL with daprodustat therapy and 0.10 g/dL with ESA therapy. Rates of adverse cardiovascular events, a composite of death, nonfatal myocardial infarction, and stroke, were similar between the treatment groups (25.2 versus 26.7% for daprodustat and epoetin alfa,

#### *Hyporesponsiveness to Erythropoietin-Stimulating Agents: Possible Solutions DOI: http://dx.doi.org/10.5772/intechopen.109988*

respectively), as were the rates of other adverse events. The efficacy of another dosing of daprodustat was studied in a 52-week trial in which 407 patients on hemodialysis were randomly assigned to daprodustat (dose range from 2 to 48 mg) thrice weekly with dialysis or to epoetin alfa; the average change in Hb concentration and rates of adverse events were similar between the treatment groups.

The efficacy and safety of vadadustat have been studied in comparison to Darbepoetin alfa in hemodialysis patients in a trial of 3554 patients who were randomly assigned to receive vadadustat 150–600 mg or darbepoetin alfa. to target Hb of 10 to 11 g/dL in patients of the United States and 10 to 12 g/dL in patients from other countries. Iron was given to all participants targeting transferrin saturation (TSAT) >20 percent and serum ferritin >100 ng/mL. Between weeks 40 and 52, prevalent dialysis patients assigned to vadadustat were less likely to maintain target Hb (44 versus 51 percent), although rates of red cell transfusion were similar (2.0 vs. 1.9% of prevalent dialysis patients). Findings from a similar trial of 369 incident patients on dialysis showed comparable results.

Collectively, data of patients from both trials, rates of mortality (13.0 vs. 12.9%, nonfatal stroke (1.3 vs. 1.9%), hospitalization for heart failure (3.9 vs. 4.0%), and nonfatal myocardial infarction (3.9 vs. 4.5%) were comparable. Other adverse events, for example, hypertension, diarrhea, and pneumonia, were lower in the vadadustat group; both among prevalent (55 vs. 58%) and incident (50 vs. 57%) dialysis patients [58, 59].

Similar findings have been obtained from smaller studies of roxadustat in comparison to findings of studies of daprodustat and vadadustat [60].

As roxadustat is a selective activity ligand for thyroid hormone receptor B; with its similar structure to T3, it can suppress TSH release.

These agents have gained acceptance for clinical use in Europe, China, Japan, and Chile but not yet in the United States.

Long-term follow-up is required for concerns like increased risk of cancer, cardiovascular events, thrombosis, and deterioration of diabetic retinopathy, among others [61–63].

#### **7.2 Experimental combination of ESA and thrombopoietin**

The use of ESA and thrombopoietin in combination to treat EPO-resistant anemia in otherwise healthy rats was suggested based on the ability of thrombopoietin to stimulate self-renewal of stem cells and correct depletion of erythroid precursor cells [64].

#### **7.3 l-carnitine**

Dialysis patients are in a state of chronic carnitine deficiency, associated with fatty acid and other organic acid metabolic disturbances. Observational studies showed a relation between elevated ERI and low l-carnitine. However, other studies did not show evidence of beneficial effects regarding oxidative stress and inflammation in hemodialysis patients [65].

#### **7.4 Pentoxifylline**

It has anti-inflammatory effects through inhibition of the production of TNFalpha and IFN-gamma. This was shown with oral pentoxifylline given to dialysis patients hyporesponsive to ESA therapy with a resulting significant improvement of Hb levels in a small open-label study. However, CRP levels were not changed. Further studies did not support the clinical utility of pentoxifylline in anemic dialysis patients [66].
