I commonly encounter two questions from patients with chronic kidney disease (CKD) in regards to anemia:
- “How can I avoid taking injections?”
- “Is this anemia treatment safe”
The development of anemia represents a challenging problem in patients with late stage CKD. The last several decades have seen the development of a variety of strategies to treat anemia in CKD. The mechanism is multifactorial and anemia is due to a combination of erythropoietin deficiency and iron deficiency. Iron deficiency in CKD is both an absolute (decreased absorption and increased loss) and functional deficiency (due to hepcidin ‘block’). Right from the discovery of the role of erythropoietin (EPO) in red blood cell production by Allan Erslev in 1953, the search for the ‘magic bullet’ in the therapy of anemia in CKD has been evolving.
Erythropoietin- Recombinant EPO was approved for regular use by the FDA in 1989 and has been considered the ‘standard of care’. The perils and pitfalls of recombinant EPO with regard to serious cardiovascular and cerebrovascular outcomes, thromboembolic events, tumor progression, and increased mortality have been well documented (National Hematocrit Study, TREAT, CHOIR, CREATE). These studies demonstrated that EPO use for anemia in CKD results in decreased blood transfusions and probable improvements in quality of life. However, patients continue to complain about injection frequency and question us about the potential risk of aforementioned adverse effects. Peginesatide, the EPO mimetic peptide, was expected to offset some of these disadvantages, but turned out to be a ‘shooting-star’. Though trials (PEARL and EMERALD) reaffirmed its therapeutic effect, the risk of cardiovascular events remained and reports of fatal anaphylactic reactions were the final nail on the coffin and peginesatide was eventually withdrawn from the market.
Over time, our understanding of the pathophysiology of anemia in CKD has evolved from being focused on EPO deficiency and absolute iron deficiency, to one that acknowledges the significant role of hypoxia inducible factors (HIFs), hepcidin, and functional iron deficiency. Most promising among these newer class of drugs are the HIF stabilizers– prolyl hydroxylase inhibitors (PHI).
Hypoxia Inducible Factor (HIF) – HIF transcription factors are key regulators of cellular activities in response to hypoxia. They consist of an inducible (by hypoxia) α subunit (three isoforms- 1α, 2α, 3α) and constitutively expressed stable β subunit. Posttranslational hydroxylation of the α subunit by prolyl hydroxylase regulates HIF activity. Under conditions of normoxia, prolyl hydroxylase (prolyl hydroxylase domain (PHD)- 1, 2, and 3) hydroxylates the specific prolyl residues subjecting it to von-Hippel-Lindau (vHL) dependent proteolysis (Figure 1). In conditions of hypoxia, the PHDs are inhibited and favor a stable heterodimer which in turn upregulates genes involved in erythropoiesis and angiogenesis. PHD inhibitors/HIF stabilizers serve to increase the levels of HIF and ultimately endogenous erythropoietin production. HIF stabilizers also increase the availability of iron for erythropoiesis possibly by suppressing hepcidin.
HIF stabilizers/Prolyl Hydroxylase Inhibitors (PHIs)- Multiple phase 1 and phase 2 clinical trials have examined PHIs in the treatment of anemia in CKD (they are described and linked to individually below. In addition, a number of phase 3 clinical trials are currently underway. FG-2216 was the first molecule with phase 2 studies showing a positive signal in both healthy volunteers and patients on dialysis.
Roxadustat is a second-generation PHI that was shown in a phase 2 clinical trial to increase hemoglobin concentrations in patients with CKD not yet on dialysis at varying doses. Results from several phase 2 studies of roxadustat show that it is effective in both dialysis dependent and pre-dialysis CKD patients – independent of iron status, CRP level, or dialysis modality. In addition, roxadustat was shown to decrease total cholesterol, reduce hepcidin levels, and improve iron parameters. Importantly, roxadustat administration resulted in improved patient reported outcomes (SF-36 and FACT-AN scores). In order to confirm these findings, large phase 3 clinical studies are underway including a 5-year extension study for safety outcomes.
Daprodustat, another PHI, has been shown to be effective and is well tolerated in phase 2 studies. As much as 1 g/dL increase in hemoglobin was achieved at 4 weeks in a phase 2 study. Though ferritin levels decreased, total iron binding capacity increased and hepcidin remained stable with daprodustat therapy. Results released by GSK from a 52-week phase 3 study from Japan of 271 patients on hemodialysis shows non-inferiority to darbepoetin alfa with good safety profile. The most common adverse events reported were nasopharyngitis, gastrointestinal events and shunt stenosis comparable between both the groups. Results of the global phase 3 study, ASCEND is expected to release in 2020 will establish the efficacy of daprodustat.
Vadadustat (AKB-6548) has been tested in four phase 2 trials to date. The PRO2TECT (in CKD) and INNO2VATE (in CKD on dialysis) are randomized, open-label active controlled phase 3 studies expected to provide results by 2020. FO2RWARD is a global trial examining role of vadadustat in EPO hyporesponsive in patients on dialysis.
Molidustat (BAY 85-3934) is being evaluated in active phase 2 trials. Apart from its benefit on erythropoiesis, it has been shown to reduce blood pressure in animal models. The significance of this finding needs further assessment. A number of similar drugs are in the pipeline in varying stages of development.
All the PHIs uniformly increase hemoglobin levels in animal models, in healthy volunteers, and in patients with both late stage CKD and on dialysis. The differential effects of various PHIs on hepcidin, ferritin, and TSAT values and consequently iron utilization need further evaluation. Animal models have exhibited a reduction in blood pressure with some of these agents while in one roxadustat study the most common adverse event was hypertension (10%) needing antihypertensive dose titration. The pleiotropic effects of HIF activation on vasomotor control, aberrant angiogenesis, inflammation, and fibrosis need further studies as well. Common adverse effects reported were nasopharyngitis and gastrointestinal side effects.
We must keep in mind that it took over a decade of use to understand the shortcomings of EPO, on the subject of cardiovascular outcomes. It is still too early to deliver the verdict on PHIs, as the longest study has only 52 weeks of follow up. Nevertheless, PHIs represent a significant improvement in the treatment of anemia in CKD given the oral administration, efficaciousness thus far, and fewer adverse effects (we hope).
As we wait for an oral therapy for anemia, we are reminded by this quote from Stephen King :
“Hope is a good thing, maybe the best of things, and no good thing ever dies”.
Arunkumar Subbiah, AIIMS, New Delhi
Thanks to Hector Madariaga, Matthew Sparks, Samira Farouk