Current treatment practices for anemia in patients with chronic kidney disease and future opportunities with hypoxia‑inducible factor prolyl hydroxylase inhibitors: a narrative review
Mercedes Kile1 · Patcharaporn Sudchada2
Abstract
Purpose To investigate current treatment practices for anemia in patients with chronic kidney disease (CKD), issues sur- rounding current treatment practices, and the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) that are currently in clinical trials.
Summary Treatment of anemia in patients with CKD has traditionally included iron supplementation and erythropoiesis- stimulating agents (ESAs). However, due to adverse cardiovascular (CV) events and hypo-responsiveness to ESA therapy, new agents are currently in clinical trials to treat anemia in patients with CKD. The HIF-PHIs stimulate erythropoiesis and regulate iron metabolism and are attractive alternatives to iron supplementation and ESAs.
Keywords Chronic kidney disease · Anemia · Iron · ESA · Hypoxia-inducible factor prolyl hydroxylase inhibitors
Background
Chronic kidney disease is kidney damage associated with a decline in the glomerular filtration rate (GFR) and albu- minuria. Over its disease course, chronic kidney disease (CKD) can result in many complications, including anemia [1]. Anemia in CKD is commonly associated with reduced erythropoietin production and reduced survival of red blood cells [2]. It has also been attributed to a dysfunction in iron metabolism, where excess levels of hepcidin play a role [3, 4].
Once a patient develops Stage 3 CKD, anemia becomes more common, and the incidence increases as the CKD stage progresses [5]. Therefore, the guidelines recommend screening for anemia once a patient develops Stage 3 CKD, with the frequency of monitoring increasing as the CKD
stage progresses [1, 2, 5]. Furthermore, erythropoietin levels should not be considered for an anemia diagnosis in patients with CKD [2, 5]. A patient is diagnosed with anemia once the hemoglobin concentration is less than 13 g/dL in men and 12 g/dL in women [1]. Anemia can result in morbidities, including increased cardiac output, left-ventricular hyper- trophy, and decreased immune response [2]. If anemia is left untreated, it can lead to a further decrease in the over- all quality of life and an increased risk of necessary blood transfusions, cardiovascular (CV) events, hospitalizations, and mortality [3, 4].
This review reflected upon the current treatment prac- tices for anemia in patients with CKD, including iron sup- plementation and erythropoiesis-stimulating agents (ESAs), across different guidelines, and commented on a new class of medications, the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs), which are currently in clinical trials.
[email protected] Mercedes Kile
[email protected]
cal trial data was noted.
Current treatment practices
1School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA
2Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand
The current treatment options available for anemia in CKD are iron supplementation and ESAs, and treatment recom- mendations are sorted by guideline in Table 1.
ESA therapy is individualized by patient, and availability and cost play a role in this decision [1, 2, 5]. Transfusions are reserved for patients who have severe blood loss or hypo- responsiveness to ESA therapy due to its association with infections and sensitization [1–4].
When starting an ESA in a patient, the initial dose is determined by factors like the patient’s baseline hemoglobin (Hb) concentration, weight, laboratory values, and the rate of decline in hemoglobin concentration [1, 2, 5]. Patients should have their hemoglobin monitored frequently and dose adjustments should be individualized. Guidelines sug- gest monthly monitoring upon initiating ESA therapy when patients on dialysis are on maintenance therapy and every
3months when patients not on dialysis are on maintenance therapy [1, 2, 5].
When treating anemia in patients, the guidelines recom- mend to not exceeding a Hb concentration of 11.5 g/dL to 12 g/dL in patients with CKD [1–3, 5]. In contrast, the National Kidney Foundation–Kidney Disease Outcomes Quality Initiative (KDOQI) commentary group supported the recommendation from the United States-Food and Drug Administration (US-FDA) which is now specified that ESAs dosing should be reduced or interrupted if the Hb level exceeds 11 g/dL. The treatment of anemia in CKD with ESA therapy should be considered risk and benefits for the individual patient since insufficient evidence is available to support Hb concentration targeted between 11 and 11.5 g/
dL [6].
Long-term safety profiles of ESA therapy have been shown that there is an increased risk of adverse outcomes, such as CV disease, when using ESAs and iron therapy to correct hemoglobin concentration [3].
Future treatment practices
While current treatment options for anemia in CKD do improve the quality of life for a patient, they are associated with adverse events. ESA treatment is not recommended in patients with a history of stroke or malignancy, and they have been associated with adverse CV events like hyper- tension and thromboembolism, especially when the hemo- globin concentration exceeds 11.5 g/dL to 12 g/dL [1–5]. Additionally, some patients experience resistance or hypo- responsiveness to ESA therapy [1–3, 5]. This resistance or hypo-responsiveness is correlated with increased morbidity and mortality [2]. Furthermore, the adverse effects with iron supplementation are thought to be associated with impaired immune function and increased oxidative stress [4]. There- fore, there has been a push to develop new treatment options for patients with CKD and anemia.
A new class of medications, HIF-PHIs, is currently in clinical trials as an alternative therapy option for anemia
in CKD. Medications in the class include daprodustat, desidustat, molidustat, roxadustat, and vadadustat. Table 2 outlines the current clinical trial status of each medication and Table 3 provides an overview of available published
phase III clinical trial data. This class of medication helps to stimulate erythropoiesis, improve the bioavailability of iron, and decrease hepcidin levels, all of which can increase hemoglobin concentrations [7–9]. Differences in the iron
repletion status of patients across trials were noted. Some trials required that participants were iron replete, while oth- ers required that participants were iron deficient [3].
Roxadustat (FG‑4592)
Roxadustat is being developed by FibroGen/Astellas/Aztra- Zeneca, and it is currently in phase III clinical trials. Phase II clinical trials in both dialysis and non-dialysis CKD patients showed increased erythropoietin levels and hemoglobin con- centrations and decreased hepcidin levels [10]. Furthermore, statistically significant increases in hemoglobin were found with thrice weekly dosing, and short-term iron supplementa- tion was not needed in this population, even though roxadus- tat was studied in participants who were not iron replete [3]. Roxadustat was shown to be well tolerated and did not show any increase in CV events or mortality [4]. The most com- mon adverse events were hypertension and reduced TSAT levels [3]. This year, 3 phase III clinical trials, 1 in non-dial- ysis patients and 2 in dialysis patients, have been published.
The Chen et al.’s trial was a randomized, open-label, active-controlled, phase III trial investigating the efficacy and safety of roxadustat compared to epoetin alfa in patients on dialysis in China [11]. Patients were included in the study if they were between the ages of 18 and 75, had end-stage renal disease on dialysis for at least 16 weeks, received stable doses of epoetin alfa for at least 6 weeks, and had a mean hemoglobin concentration of 9–12 g/dL. There were 305 patients enrolled into the study, and they were randomized in a 2:1 ratio to oral roxadustat and parenteral epoetin alfa, respectively. Patients randomized to the oral roxadustat group received starting doses of 100 mg if they weighed between 45 and 60 kg and 120 mg in patients if they weighed more than 60 kg. Doses were given three times a week and were adjusted to maintain a hemoglobin concen- tration between 10.0 and 12.0 g/dL. Patients randomized to the parenteral epoetin alfa group continued their previous doses. Additionally, oral iron supplementation was permit- ted; however, IV iron supplementation was prohibited unless it was needed as rescue therapy. To account for noninferi- ority, the “lower boundary of the 95% confidence interval for the treatment difference in the change in hemoglobin level had to be greater than or equal to – 1.0 g per decili- ter” [11]. The primary outcome was the mean change in hemoglobin concentration from baseline to the average level from weeks 23 to 27. Roxadustat resulted in a greater mean change in hemoglobin concentration from baseline than epoetin alfa (0.7 ± 1.1 g/dL vs. 0.5 ± 1.0 g/dL, respectively) and was statistically noninferior (difference 0.2 ± 1.2 g/dL; 95% confidence interval, – 0.02 to 0.5) Additionally, roxa- dustat was able to maintain serum iron levels compared to epoetin alfa (difference 25 μg/dL; 95% confidence interval, 17 to 33). Notable adverse events were higher incidences of hyperkalemia and metabolic acidosis in the roxadustat group and hypertension in the epoetin alfa group.
The second Chen et al.’s trial was a randomized, double- blind, placebo-controlled, phase III trial investigating the efficacy of roxadustat compared to placebo in patients not on dialysis in China [8]. Patients were included in the study if they were between the ages of 18 and 75, had CKD stages 3–5, were not undergoing dialysis, had not been receiving ESA therapy, and had two recent hemoglobin concentrations between 7.0 g/dL and 10.0 g/dL. There were 154 patients enrolled into the study, and they were randomized in a 2:1 ratio to oral roxadustat or placebo, respectively. Patients ran- domized to the oral roxadustat group received starting doses of 70 mg if they weighed between 40 and 60 kg and 100 mg if they weighed more than 60 kg. Doses were given three times a week and were adjusted to maintain a hemoglobin range between 10.0 to 12.0 g/dL. Patients randomized to the placebo group received their doses in the same man- ner. Additionally, IV iron supplementation was prohibited unless it was needed as rescue therapy. The primary out- come was the mean change in hemoglobin concentration from baseline to the average level from weeks 7 to 9. Roxa- dustat had a mean change in hemoglobin concentration from baseline of 1.9 ± 1.2 g/dL and placebo had a mean change in hemoglobin concentration from baseline of – 0.4 ± 0.8 g/dL with a statistically significant difference of 2.2 g/dL (95% confidence interval, 1.9 to 2.6; p < 0.001). Furthermore, serum iron remained stable in the roxadustat group. Nota- ble adverse events were higher incidences of hyperkalemia and metabolic acidosis in the roxadustat group compared to placebo.
The Akizawa et al.’s trial was a randomized, open- label, non-comparative, phase III trial investigating the efficacy and safety of roxadustat in patients on peritoneal dialysis (PD) in Japan [9]. Patients were randomized into two groups, the ESA-naïve group and the ESA-converted group. Patients in the ESA-naïve group were included in the study if they were over the age of 20, had end-stage renal disease on peritoneal dialysis, had not been receiv- ing ESA therapy within 6 weeks of prescreening, had two recent hemoglobin concentrations below 10.5 g/dL, and a TSAT greater than or equal to 5% or serum ferritin greater than or equal to 30 ng/mL. Patients in the ESA-converted group were included in the study if they were over the age of 20, had end-stage renal disease on peritoneal dialysis, had received ESA therapy for more than 8 weeks before prescreening and after the initiation of PD, had two recent hemoglobin concentrations between 10 g/dL and 12 g/dL, and a TSAT greater than or equal to 20% or a serum fer- ritin greater than or equal to 100 ng/mL. There were 56 patients enrolled into the study, and they were randomized into the 2 groups. Patients randomized to the ESA-naïve group received either 50 mg or 70 mg of roxadustat.
Patients randomized to the ESA-converted group received either 70 mg or 100 mg of roxadustat. Doses were given 3 times a week and were adjusted to maintain a hemoglobin concentration between 10.0 and 12.0 g/dL. Additionally, oral iron supplementation was permitted; however, IV iron supplementation was prohibited unless it was needed as rescue therapy. The primary outcome was the rate at which the hemoglobin concentration was maintained at 10 to 12 g/dL at weeks 18 to 24. In the ESA-naïve group, 92.3% maintained an average hemoglobin concentration of 10.0–12.0 g/dL (95% confidence interval, 64.0–99.8) and 74.4% maintained the aforementioned hemoglobin concentration in the ESA-converted group (95% con- fidence interval, 58.8–86.5). Furthermore, serum iron remained stable in this study. Notable adverse events include nasopharyngitis, back pain, catheter site infec- tion, diarrhea, and vomiting. While three patients in the ESA-naïve group and five patients in the ESA-converted group reported serious adverse events (i.e., peritonitis, rhabdomyolysis due to interaction with pravastatin and roxadustat, palpitations, muscle weakness, pruritis, and dyspepsia), there were no adverse events that resulted in death.
Another Phase III trial by Akizawa T et al. was a 24-week, double-blind, double-dummy study evaluating whether roxadustat was not inferior to or as effective as to darbepoetin alfa for hemodialysis-dependent CKD anemia in Japanese patients [12]. A total of 303 stable Japanese patients on hemodialysis previously treated with ESA were randomized either to oral roxadustat three times weekly or to darbepoetin alfa injections once weekly, titrating doses to maintain hemoglobin between 10 and 12 g/dl. Change of average Hb from baseline to weeks 18–24, proportion of patients with hemoglobin between 10–12 g/dl (maintenance rate at weeks 18–24), and iron parameters as well as safety assessment were determined. The results showed that roxadustat was equally effective as darbepoetin in maintaining hemoglobin within target levels. The difference between roxadustat and darbepoetin alfa in ∆Hb18–24 was - .02 g/dl (95% confidence inter- val, - 0.18 to 0.15) and the average hemoglobin at weeks 18–24 with roxadustat was 10.99 g/dl (95% confidence interval: 10.88–11.10). In addition, there was slightly difference of proportion of patients with hemoglobin between 10 and 12 g/dl (maintenance rate) at weeks 18–24 (roxadustat: darbepoetin alfa; 95.2%:91.3%). Naso- pharyngitis, shunt stenosis, diarrhea, contusion, and vom- iting were common adverse events. New or worsening retinal hemorrhage was 32.4% with roxadustat and 36.6% with darbepoetin alfa [12]. These data support another effective alternative medicine to injectable ESA agents for dialysis-dependent CKD anemia.
Vadadustat (AKB‑6548)
Vadadustat is being developed by Akebia Therapeutics, and it is currently in phase III clinical trials for CKD stages 3 and 4. Phase II clinical trials showed that once daily dosing increased and maintained hemoglobin concentration while reducing ferritin levels [3, 10, 13]. Additionally, vadadus- tat was associated with a reduction in hepcidin, which is indicative of improved iron metabolism [3]. There were no serious drug-related adverse effects associated with vadadus- tat [3]. Furthermore, no Phase III clinical trials have been published.
Molidustat (BAY 85‑3934)
Molidustat is being developed by Bayer, and it is currently in development for phase III clinical trials. Phase II clinical trials showed that molidustat could be a potential alterna- tive for treatment of anemia in both non-dialysis CKD and dialysis-dependent CKD, showing increased endogenous erythropoietin production and Hb concentrations within the target range [3, 14–17]. The effect of molidustat on mean Hb levels was similar to that of darbepoetin or epo- etin in these populations and was well tolerated for up to 36 months [14–17]. It can also increase iron availability in CKD patients who are not on dialysis [18, 19]. In addition, molidustat has a similar adverse event profile to placebo, where the most common adverse events were infections, gastrointestinal disorders, vascular disorders, and renal and urinary disorders [3, 14–16].
Daprodustat (GSK1278863)
Daprodustat is being developed by GlaxoSmithKline, and it is currently in phase III clinical trials. The Xie et al. conducted a meta-analysis [20] of 4 phase II clinical trials [21–25] to compare the efficacy and safety of daprodustat with placebo in 447 anemic patients with CKD stage 3–5 and dialysis. Patients received doses of daprodustat rang- ing from 0.5 mg to 100 mg/day for 4 weeks. This analysis found that, in short term, daprodustat might improve ane- mia in CKD patients and improve iron utilization without increasing adverse events [20]. Adverse events of dapro- dustat observed in these trials were nausea, dyspepsia, and abdominal pain, and were possibly associated with higher doses which 60% of patients who received 100 mg dapro- dustat experienced adverse events [20]. Therefore, high doses of daprodustat should be used with caution [20]. Similar findings were reported in recent phase II clini- cal trial in hemodialysis patients comparing daprodustat to placebo during 29 day-treatment period [26]. The trial reported a dose-dependent of daprodustat between 10 and 30 mg three times a week (TIW) could increase in Hb and initially maintained Hb levels in patients switched from rhEPO or its analogs [26]. Daprodustat was generally well tolerated and raised no new safety concerns at doses up to 30 mg TIW [26]. Another phase II trial investigated the short-term safety and efficacy of daprodustat (1, 2,
4mg) to achieve a target hemoglobin in patients with ane- mia of CKD stage 3–5 comparing to recombinant human EPO (rhEPO) in a 24-week period [27]. Daprodustat was fond to be effectively achieved target hemoglobin levels in recombinant human EPO (rhEPO)-naïve participants and maintained target hemoglobin levels in rhEPO users and daprodustat was well tolerated with the CKD popula- tion [27].
These phase II clinical trials showed that daprodustat increased and maintained hemoglobin concentrations with positive effects on iron metabolism through decreased hep- cidin levels [3, 10, 20–28]. Daprodustat was well tolerated, with nausea being the most common adverse event for CKD patients [3, 10, 20–27]. These findings supported continued development of daprodustat to treat anemia of CKD. One phase III clinical trial was published this year to investigate long-term efficacy and safety of daprodustat.
The Tsubakihara et al.’s trial was an open-label, non- comparative, phase III trial investigating the efficacy and safety of daprodustat in patients on hemodialysis in Japan who were not using ESAs [29]. Patients were divided into two groups, the newly started dialysis group and the main- tenance dialysis group. Patients were included in the study if they were over the age of 20, had hemoglobin concentra- tions between 8 and 10 g/dL, serum ferritin greater than 100 ng/mL, TSAT greater than 20%, were new to dialysis (started < 12 weeks before screening) and never used an ESA or were on maintenance dialysis (started > 12 weeks before screening) and had not received ESA therapy within 8 weeks before screening. There were 28 patients enrolled into the study, 11 patients in the newly started dialysis group, and 17 patients in the maintenance dialysis group. Patients received 4 mg of daprodustat once daily for 4 weeks and the dose was adjusted every 4 weeks up to 24 weeks to maintain a hemo- globin concentration between 10.0 and 12.0 g/dL. Addition- ally, oral iron supplementation was permitted; however, IV iron supplementation was prohibited during the screening and first 4 weeks, but could be given between weeks 4 and 24. The primary outcomes were the change in hemoglobin concentration from baseline at week 4 and the number of patients by hemoglobin concentration change from base- line at week 4. From baseline to week 4, the mean change in hemoglobin concentration was 0.79 g/dL (95% confi- dence interval, 0.53–1.05). Eighty-six percent of patients experienced an increase between 0 and 2.0 g/dL in the first 4 weeks. The mean serum levels of ferritin, TSAT, and hep- cidin decreased, while TIBC increased during the course of the study. Notable treatment-related adverse events were blood cholesterol decrease and erythema. Serious adverse events included shunt occlusion and device dislocation [29].
Desidustat
Desidustat is being developed by Zydus Cadila, and it is currently in phase II clinical trials. A phase I clinical trial showed that desidustat was safe and tolerated in healthy par- ticipants, and a phase II trial has shown increases in hemo- globin concentration compared to placebo [30]. The most common treatment-related adverse events were abdominal pain, vomiting, and headache. There were no serious adverse events associated with this phase II trial.
Limitations
Between the 5 phase III published trials for roxadustat and daprodustat, a limitation is the small and homogenous sam- ple sizes. Further phase III clinical trials are necessary to assess efficacy and safety of roxadustat and daprodustat in a more generalized population. Additionally, while iron supplementation was permitted in these trials, there was no standardization in regard to iron levels and ability to sup- plement with iron across the trials. Considering many of these medications are still in phase III clinical trials, more studies with efficacy and safety information in heterogenous populations are needed to apply the results to the general population.
Conclusion
The HIF-PHIs appear to be promising treatment alternatives to ESAs that may be associated with fewer adverse CV out- comes and fewer incidences of hypo-responsiveness. Once larger scale clinical trials occur with more heterogenous populations, there will be better insight into the safety and efficacy of this new potential treatment of anemia in patients with CKD.
Acknowledgements This work was investigator initiated. No funding was provided for support. M. Kile was a candidate of Doctor of Phar- macy at the School of Pharmacy, University of Wisconsin-Madison.
Authors’ contribution PS conceived, supervised, and conducted the review. PS and MK conduct the review and wrote the initial draft of the paper. PS review and edited the paper.
Compliance with ethical standards
Conflict of interest The authors (PS and MK) declare that they have no potential conflict of interest regarding the publication of the paper.
Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors.
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