Hypoxia-inducible factor-prolyl hydroxylase inhibitors in treatment of anemia with chronic disease.

Introduction

Anemia of chronic disease (ACD) is regarded as the most frequent clinical issue in chronically ill patients, which is associated with poor health outcomes and substantial economic costs. [ 1 ] It is prevalent in patients with chronic kidney disease (CKD), cancer, chronic infection, and autoimmune diseases. Its pathogenesis is multifactorial, caused largely by an inadequate production of erythropoietin (EPO), iron deficiency, disorders of iron metabolism, and shortening of the half-life of red blood cells (RBC). The mainstay of current management of ACD includes erythropoiesis-stimulating agents (ESAs) administration, iron supplement, and RBC transfusions. [ 2 ] However, several clinical issues, such as hyporesponsiveness to ESAs or defective iron utilization, have been demonstrated. More importantly, the risk of adverse reactions to treatment, such as cardiovascular complications, is increased in these difficult-to-manage patients with ACD. [ 3 , 4 ] Therefore, management of ACD is still a challenging issue.

The elucidation of the hypoxia-inducible factor-prolyl hydroxylase (HIF-PHD) pathway not only extends our knowledge on the understanding of biology of cellular hypoxia, [ 5 ] but also makes it possible to develop the novel therapeutic agents (hypoxia-inducible factor-prolyl hydroxylase inhibitor, HIF-PHI) to correct anemia. [ 6 ] In 2018, roxadustat, the first HIF-PHI, received marketing approval. [ 7 ] Since then, six HIF-PHIs have been successfully completed the clinical trials and received approval in various regions worldwide. Therefore, the discovery of HIF-PHIs has revolutionized the treatment strategy for anemia and promoted us to enter a new era for treating ACD. [ 8 , 9 ] Here, a comprehensive review of the latest advancements in the clinical application of HIF-PHIs was summarized.

Molecular Mechanism of HIF and HIF-PHIs

The HIF-PHD system was discovered as an oxygen-sensitive regulatory pathway that confers adaptive responses of the human body to hypoxia. Accordingly, HIF is composed of two subunits: HIF-α and HIF-β. Under normoxia, proline residue at N-terminus of HIF-α would be hydroxylated by PHD, so that it could be recognized by von Hippel Lindau tumour suppressor (pVHL) and then binds to the E3 ubiquitin ligase, which lead to fast ubiquitin and degradation of HIF-α. Therefore, the expression of HIF maintains at a relative low level. Under hypoxia condition, however, PHD activity is inhibited, leading to decreased hydroxylation of HIF-α; thus, the stably expressed HIF-α translocates from the cytoplasm to the nucleus, where it binds to HIF-β, forming active HIF complex. The complex binds to hypoxia response elements (HREs) in DNA, recruits p300/CREB binding protein (CBP), and then activates the transcription of genes associated with hypoxia adaption, such as erythropoietin ( EPO ), vascular endothelial growth factor a ( VEGFA ), and solute carrier family 2 member 1 ( SLC2A1 ), as well as some other genes, such as divalent metal transporter 1 ( DMT1 ), duodenal cytochrome b ( DCytB ), and transferrin [Figure 1 ]. [ 10 , 11 ]

The HIF-PHI could stabilize HIF expression by inhibiting PHD and preventing N-terminal hydroxylation of HIF-α and subsequent HIF degradation. PHD is a class of Fe 2+ and 2-oxoglutarate (2-OG)-dependent oxygenase. Endogenous cofactor 2-OG is an essential substrate for hydroxylation of PHD. All of HIF-PHIs currently in clinical trials or approved for marketing are designed and developed on the basis of exogenous 2-OG structural analogs, which efficiently act on the 2-OG site to achieve the effect by inhibiting PHD, thereby activating the HIF pathway and initiating downstream pathways of erythropoiesis, including stimulating endogenous EPO production, upregulating the expression of transferrin receptor which increase the absorption and utilization of iron, and reducing the expression of hepcidin so as to release the stored iron to circulation. Therefore, the current clinical development of HIF-PHIs mainly focuses on anemia treatment. [ 10 , 12 ]

Remarkably, FG-4592 became the first HIF-PHI to complete phase III clinical trials and was approved for marketing to treat renal anemia in 2018, with the generic name roxadustat. [ 13 ] In normoxic conditions, roxadustat reversibly inhibits PHD, leading to a transient increase in the expression of HIF and subsequent activation of the HIF pathway. At therapeutic doses, roxadustat primarily increases endogenous EPO expression, upregulates EPO receptor expression, and increases iron absorption, transport, and utilization. These effects make roxadustat a novel treatment option for anemia. [ 14 , 15 ] Up to now, roxadustat has been approved for the treatment of anemia in many countries and regions, such as China, Japan, Chile, South Korea, the European Union, the United Kingdom, etc.

Following the success of roxadustat, a series of HIF-PHIs with different molecular structures were developed. Glaxo Smith Kline (Brentford, UK) developed the pyridine-trione derivative GSK1268863 (daprodustat); Akebia Pharmaceuticals (Cambridge, United States) created the monocyclic pyridine derivative AKB6548 (vadadustat); Cadila Healthcare (Ahmedabad, India) designed the N-alkoxyquinolone derivative ZYAN1 (desidustat), in which the integrity of the carboxylic acid chain is maintained; Japan Tobacco (Tokyo, Japan) produced the triazoline derivative JTZ-951 (enarodustat); and Bayer (Wuppertal, Germany) took a unique approach with BAY85-3934 (molidustat), employing the nitrogen atom in the pyrazole core and the adjacent pyrimidine ring to achieve dual iron chelation, increasing the interaction between the triazole group and the 2-OG binding residue. These compounds have progressed to late-stage clinical trials or have received marketing approval, with recommended dosing regimens of once daily or thrice weekly for the treatment of anemia. [ 16 – 19 ] The landmark trials of HIF-PHIs are showed in Table 1 .

Application of HIF-PHIs in the Treatment of ACD

HIF-PHIs for the treatment of anemia in patients with CKD

Anemia is one of the most common complications of CKD associated with poor outcomes. Inadequate production of EPO from the kidneys, iron deficiency, inflammation, and shortened RBC lifespan is regarded as the main pathogenesis of anemia. [ 20 ] Before the advent of HIF-PHIs, the management of CKD anemia included ESAs administration and iron supplements. However, the management of anemia in CKD patients is often challenging, especially for patients with underlying inflammation, comorbid type 2 diabetes, or malnutrition. [ 21 ] Notably, the introduction of HIF-PHIs with a novel mechanism represents a promising new therapeutic option for these patients.

In 2019, the results of two randomized clinical trials (RCTs) revealed the efficacy and safety of roxadustat in treating anemia among patients with CKD, both in dialysis-dependent (DD-CKD) and non-dialysis-dependent (NDD-CKD) patients. [ 22 , 23 ] In patients on dialysis, the HIF-PHI group demonstrated a greater increase in hemoglobin (Hb) levels than ESA group, with an increase of 0.7 ± 1.1 g/dL, achieving the prespecified non-inferiority endpoint with no significant differences in the safety profile. Importantly, this benefit was consistent irrespective of inflammation status, as indicated by C-reactive protein (CRP) levels—a notable advantage over ESAs, which are less effective under such conditions. Moreover, the efficacy and safety of this HIF-PHI for treating anemia were also evaluated in NDD-CKD patients. The results indicated that in the roxadustat group, Hb levels significantly increased after 8 weeks of treatment, with an increase of 1.9 ± 1.2 g/dL, whereas Hb levels in the placebo group reduced by 0.4 ± 0.8 g/dL. Therefore, the efficacy of roxadustat in increasing Hb levels was significantly superior to that of the placebo group.

On the basis of the aforementioned results, roxadustat became the first approved HIF-PHI globally. In the past five years, roxadustat has demonstrated convincing efficacy and safety in the treatment of renal anemia. Indeed, other HIF-PHIs such as desidustat, daprodustat, and vadadustat are also being clinically validated almost simultaneously. For instance, in 2021, the results of two RCTs reported the efficacy and safety of daprodustat in treating anemia among patients with CKD, both in DD-CKD and NDD-CKD patients. [ 24 , 25 ] Meanwhile, it was found that vadadustat was non-inferior to darbepoetin alfa with correction and maintenance of Hb concentrations in CKD patients. [ 26 , 27 ] In addition, similar results were also obtained in the study of anemia with DD-CKD and NDD-CKD patients by desidustat. [ 28 , 29 ] Collectively, HIF-PHIs appear to open a new door for the treatment of patients with CKD.

Supported by accumulating evidence, HIF-PHIs, such as roxadustat, desidustat, daprodustat, and vadadustat, have been established as novel effective agents in treating anemia with CKD patients. Multiple meta-analyses have shown that HIF-PHIs can effectively increase Hb levels, with efficacy not inferior to ESAs or better to ESAs even more. A comprehensive meta-analysis of 51 RCTs, which included a total of 30,994 CKD patients with anemia, revealed that compared with ESAs, a comparable rate of achieving target Hb levels has been demonstrated in HIF-PHIs and with a potential reduction in transfusion requirements. [ 30 ] Accordingly, compared with placebo, HIF-PHIs not only increased the proportion of patients who reached target Hb levels but also significantly reduced the need for transfusions. [ 30 ] Another network meta-analysis, including 15 clinical trials with a total of 3228 NDD-CKD anemic patients demonstrated that both HIF-PHIs and ESAs increased Hb levels more effectively than placebo did, with no significant difference between HIF-PHIs and ESAs. [ 31 ] A meta-analysis of 26 RCTs including 2804 CKD patients with anemia revealed that roxadustat was more effective at elevating Hb levels than placebo, while there was no significant difference in efficacy between HIF-PHIs and ESAs. [ 32 ] In addition, a meta-analysis of 21 RCTs involving 1408 patients showed that the improvement of Hb level and iron metabolism were significantly higher in the roxadustat group than in the ESA group. [ 33 ] These data demonstrated that HIF-PHIs could significantly ameliorate anemia in patients with CKD, providing a new treatment strategy for anemia in CKD patients.

HIF-PHIs for the treatment of anemia in patients with cancer

Chemotherapy-induced anemia (CIA)

CIA is a common and serious complication of patients with cancer, which is associated with increased morbidity, mortality, and healthcare costs, as well as a decreased quality of life. The primary pathogenesis of CIA is bone marrow suppression induced by chemotherapeutic agents, which directly impair hematopoiesis and decrease EPO production. [ 34 ] This condition even worsens among those with advanced disease and those receiving multiple treatment cycles. In addition, reduced EPO production-mediated by renal function impairment, chemotherapy-induced gastrointestinal side effects, shortened RBC lifespan, and cancer-related inflammation also contribute to anemia. [ 35 ] Current treatment options for CIA include ESAs, RBC transfusions, and iron supplementation, but with the limitations such as insufficient blood resource, injection-related adverse events, and cardiovascular events. Therefore, exploring novel option for the management of CIA is urgent. Fortunately, with the advent of HIF-PHIs, their potential in CIA treatment has garnered extensive clinical attention. [ 36 ]

A phase II, single-arm, open-label study conducted at 15 research centers in the United States evaluated the efficacy of HIF-PHI (roxadustat) in treating CIA in patients with non-myeloid malignancies (2.0 mg/kg for 31 patients; 2.5 mg/kg for 61 patients). [ 37 ] As a result, roxadustat increased Hb from baseline to week 16 by a mean maximum of 2.4 g/dL and 2.5 g/dL in patients starting on 2.0 mg/kg and 2.5 mg/kg doses, respectively. The median time of Hb increase by ≥1 g/dL and ≥2 g/dL was 41 days and 71 days, respectively, in the overall population. Further, of the 31 patients with CRP ≤ ULN at baseline, 74.2% exhibited an Hb increase of ≥2 g/dL during the treatment period. Of the 56 patients with CRP >ULN at baseline, 51.8% exhibited an Hb increase of ≥2 g/dL during the treatment period, suggesting that the significant efficacy of roxadustat in treating CIA in patients with non-myeloid malignancies may be inflammatory status-independent. In addition, the efficacy of roxadustat in correcting Hb could be regardless of tumor type and chemotherapy received.

At the 2023 European Society for Medical Oncology conference, the results from a phase III randomized, open-label, controlled study evaluating the efficacy and safety of HIF-PHI (roxadustat) for the treatment of CIA in patients with non-myeloid malignancies were presented. [ 38 ] The participants were randomly assigned at a 1:1 ratio to either the HIF-PHI group or the recombinant human erythropoietin subcutaneous injection group. In terms of increasing Hb levels, the HIF-PHI group met the predefined non-inferiority threshold. Notably, the proportion of patients who achieved Hb level increases of ≥1.0 g/dL, ≥1.5 g/dL, and ≥2.0 g/dL was greater in the HIF-PHI group than in the recombinant human erythropoietin alpha (rHuEPO-α) group. The median time to the first Hb level increase of 1.5 g/dL and 2.0 g/dL was shorter in the HIF-PHI group than in the rHuEPO-α group by 10 days and 20 days, respectively, and the patient adherence rate was higher (65.4% vs. 39.2%), with a lower transfusion burden. The safety profiles of the two groups were comparable.

Myelodysplastic syndrome (MDS)

MDS is a heterogeneous group of myeloid neoplastic disorders originating from hematopoietic stem cells and manifesting as pathological bone marrow hematopoiesis. About 77% of patients diagnosed with MDS are classified as lower risk (LR-MDS). The primary treatment goal for LR-MDS patients is to improve hematopoietic insufficiency, with anemia being the most common form of cytopenia. More than 90% of patients with MDS have anemia at the time of their diagnosis, and over 60% of patients experience severe anemia at later stages. [ 39 ] Although ESAs treatment and RBC transfusion are the cornerstones of managing LR-MDS, there are inherent adverse clinical and economic consequences. [ 40 ] Therefore, new therapeutic strategies are needed to enhance erythroid response rates and eliminate transfusion dependence in LR-MDS patients.

Recently, the MATTERHORN study, a phase III, randomized, double-blind, placebo-controlled trial, has preliminarily explored the efficacy and safety of HIF-PHI (roxadustat) for treating anemia in patients with LR-MDS. [ 41 ] Interestingly, among the 24 transfusion-dependent LR-MDS patients, 9 patients (37.5%) achieved transfusion independent during the 52-week follow-up period. Meanwhile, 54.2% and 58.3% of patients achieved ≥50% reduction in RBC transfusions during the first 28 weeks and the entire 52-week treatment period, respectively. These results demonstrate the potential of roxadustat in anemia treatment of LR-MDS, which may alleviate the need for high-dose ESA treatments and blood transfusions.

Then, a retrospective analysis published in 2024 enrolling 21 LR-MDS patients evaluated the efficacy and safety of HIF-PHI (roxadustat) for treating anemia in patients with LR-MDS. [ 42 ] Here, the erythroid response criteria proposed by the MDS International Working Group in 2006 was used. The results showed that after 8 weeks of roxadustat treatment, 11 patients (52.38%) responded. Among the 21 patients, 19 presented increased Hb levels after 2 months of treatment, with an increase of 1 g/dL compared with pretreatment levels, and the maximum increase in the Hb level was 5.3 g/dL. The results suggested that roxadustat could correct anemia in LR-MDS patients and may be a treatment option for patients with high EPO levels.

Multiple myeloma (MM)

MM is a myeloid malignant disease characterized by the clonal proliferation of abnormal plasma cells. Anemia and renal insufficiency are two common symptoms of MM and there is no definite therapy for this clinical issue.

Given the outstanding outcomes of HIF-PHIs in treating renal anemia, they are expected to offer a novel approach to the management of anemia in MM patients. One study analyzed the efficacy of rHuEPO injection combined with roxadustat in treating anemia in MM patients. [ 43 ] Participants were randomly assigned into an observation group (rHuEPO injection combined with roxadustat) and a control group (rHuEPO injection) at a 1:1 ratio. The results showed significant improvements in Hb, transferrin saturation (TSAT), serum iron, and total iron-binding capacity (TIBC) levels in both groups after one or three treatment cycles, with the observation group showing significantly higher levels than the control group did ( P <0.05). More importantly, the efficacy of roxadustat in anemia was also evaluated under inflammatory conditions. Interestingly, rHuEPO injection combined with roxadustat could significantly increase in Hb level. Therefore, rHuEPO injection combined with roxadustat may play a synergistic effect on management of anemia in MM patients.

Then, a real-world study published in 2023 by American Society of Hematology evaluated the efficacy of HIF-PHI (roxadustat) in MM patients with renal insufficiency and severe anemia ( n = 98). [ 44 ] The study revealed that the median Hb level change from baseline to weeks 4, 8, and 12 were significantly greater in the roxadustat group than in the control group: 0.55 g/dL vs. 1.70 g/dL ( P <0.001), 1.30 g/dL vs. 3.05 g/dL ( P <0.001), and 2.00 g/dL vs. 4.10 g/dL ( P <0.001), respectively. At week 12, the proportions of MM patients with Hb increases of ≥1 g/dL, ≥2 g/dL, and ≥3 g/dL were 39.7% ( n = 27) vs. 70.0% ( n = 21) ( P = 0.006), 61.8% ( n = 42) vs. 93.3% ( n = 28) ( P = 0.001), and 66.2% ( n = 45) vs. 100% ( n = 30) ( P <0.001), respectively. It is therefore suggested that roxadustat could effectively correct anemia in MM patients with renal insufficiency.

Major Advantages of HIF-PHIs

HIF-PHI is an oral small-molecule compounds that mimics a novel way of utilizing the body’s physiological compensatory mechanisms in response to hypoxia, promoting HIF transcriptional activity. [ 45 ] The data from trials and clinical practice illustrated that HIF-PHIs correct anemia with some distinct advantages.

Stimulating endogenous EPO with physiological level

ESA leads to supra-physiological EPO concentrations; the latter is considered to be associated with increased cardiovascular risk and mortality. Accordingly, one of the most striking superiorities of HIF-PHIs is to stimulate endogenous EPO production in a titratable manner. [ 46 ] Further, EPO with physiological serum concentrations were detected in patients treated with HIF-PHIs. [ 47 ] Thus, it appears that anemia treatment with HIF-PHIs could avoid the potential adverse effects caused by supra-physiological EPO concentrations.

Improving iron metabolism

Patients with chronic diseases often suffer from disorders of iron metabolism, manifesting as either absolute iron deficiency (AID) or functional iron deficiency (FID). It is now widely accepted that systemic iron homeostasis is regulated primarily by hepcidin, which controls iron absorption, release, and distribution by binding to the iron transporter ferroportin. Upon sensing high serum iron levels or inflammation, the liver immediately secretes a large amount of hepcidin, which reduces iron absorption and release, thereby lowering serum iron levels. [ 48 ] Conversely, under conditions of iron deficiency or hypoxia, hepcidin levels are decreased to promote iron absorption and release.

In CKD or cancer patients, chronic inflammation state elevates hepcidin levels to prevent the effective utilization of stored iron, resulting in FID, which is characterized by elevated ferritin levels and decreased TSAT. This condition complicates anemia management, even with high-dose ESAs. [ 49 ] By activating HIF, HIF-PHIs can increase the expression of iron absorption genes such as DMT1 and DCytB and decrease hepcidin levels, thereby improving iron absorption, transport, and utilization [Figure 2 ]. Indeed, a network meta-analysis, including data from 15 clinical trials with a total of 3228 NDD-CKD patients, analyzed and compared the effects of five HIF-PHIs ( vs . ESAs or placebo) on iron metabolism (serum iron, ferritin, hepcidin, and TSAT). [ 32 ] Interestingly, compared with ESAs, HIF-PHIs significantly reduced hepcidin and ferritin levels, increased transferrin levels and TIBC, and decreased TSAT without changing serum iron levels, suggesting that HIF-PHIs increased iron transport and bioavailability. In addition, another network meta-analysis, [ 50 ] which included 26 RCTs with a total of 14,945 dialysis patients, revealed that HIF-PHIs and ESAs significantly increased Hb levels without affecting serum iron levels.

Till now, as the first HIF-PHI drug, roxadustat has been used in clinical anemia therapy for five years in China. Although meta-analyses have demonstrated the ability of roxadustat to significantly reduce the need for intravenous iron supplementation, further research is needed to ascertain whether other HIF-PHIs offer similar benefits and to understand their specific mechanisms of action [Table 2 ].

Being effective in anemia patients with inflammation

Patients with CKD or cancer often exhibit a persistent microinflammatory status. Convincing evidence has demonstrated that microinflammatory state is a key factor contributing to iron utilization disorders and ESA resistance. In anemic patients with high CRP levels, higher ESA doses are required to achieve and maintain target Hb levels, yet the outcomes remain unsatisfactory. [ 51 ]

In the phase III study conducted in China on the treatment of anemia with roxadustat in long-term dialysis patients, in the roxadustat group, similar mean Hb levels were maintained between weeks 23 and 27 (11.3 ± 1.0 g/dL vs . 11.2 ± 0.9 g/dL) regardless of patient CRP levels. [ 22 ] Additionally, the dosages administered to the two subgroups (CRP ≤ ULN and CRP > ULN) were comparable, thereby demonstrating that the efficacy of roxadustat in correcting Hb levels is not adversely affected by the presence of a microinflammatory state. Furthermore, evidence from a meta-analysis of 20 studies including 14,737 dialysis patients was used to assess the performance of six different HIF-PHIs. Among these, only roxadustat showed sufficient evidence to demonstrate its advantage in patients with microinflammation, with maintenance doses regardless of baseline CRP or high-sensitivity CRP (hsCRP) levels. [ 52 ] Therefore, more large-scale clinical studies are needed to investigate the effects of other HIF-PHIs in this context.

Increasing evidence suggests that roxadustat may become an effective and optimized therapeutic option for treatment of CKD anemia patients with microinflammation. However, the exact effect of roxadustat in anemia patients with more serious inflammation (macroinflammation) has yet to be confirmed. In our recent retrospective study including 107 CKD patients, participants were divided into three cohorts according to the baseline hsCRP levels: the non-inflammation group (hsCRP <2 mg/L), the microinflammation group (hsCRP 2–10 mg/L), and the macroinflammation group (hsCRP >10 mg/L). [ 53 ] The results indicated that roxadustat significantly increased Hb levels in all three groups, with no statistically significant differences among the groups ( P >0.05). Moreover, roxadustat significantly reduced ferritin and serum iron levels while increasing TIBC in all three groups, with no statistically significant between-group differences ( P >0.05). More importantly, the effect of anemia correction was not affected by the dose of roxadustat in all three groups, indicating that roxadustat can significantly correct anemia in CKD patients, even in the presence of significant systemic inflammation or iron metabolism disorders.

Prolonging lifespan of RBCs

Patients with ACD often experience persistent (micro)inflammation, which is a key factor affecting the lifespan of RBC. Notably, a cross-sectional observational study in hemodialysis patients revealed that, roxadustat treated patients had a 10.5 days longer median RBC lifespan than patients treated with rHuEPO, indicating that HIF-PHIs may prolong RBC lifespan. [ 54 ]

Others

In addition, the advantages of HIF-PHIs include: easy oral given; beneficial for blood pressure control; maintaining effective for diabetes patients; and potential cholesterol lowering effect. [ 55 , 56 ]

Summary and Outlooks

The discovery of the HIF pathway and the clinical translation of HIF-PHIs have been groundbreaking achievements in medicine over the past 30 years. Encouragingly, it has been demonstrated that HIF-PHIs provide new treatment options for ACD (at least CKD- and tumor-associated anemia) with good efficacy and safety. More importantly, the success of HIF-PHIs in the treatment of anemia related to CKD or cancer provides a novel opportunity for the treatment of anemia, specifically ACD. For instance, HIF-PHIs are being investigated for use in the treatment of postrenal transplant anemia, aplastic anemia, and MM. The great potential for HIF-PHI in the treatment of infections- and autoimmune diseases-related anemia is urgently needed to be investigated. Clearly, more evidence or practice is expected to showcase this mechanistic unique anti-anemia drug in the treatment of ACD, a kind of previously tough clinical issue. In addition, preclinical studies have suggested that HIF-PHI may be a promising treatment strategy for ischemic disease, such as acute kidney injury or stroke. [ 57 – 59 ] Thus, the clinical application potential of the HIF-PHIs needs further study.

Nonetheless, it is worth noting that there are still some issues that need to be clarified. For example, there are still concerns about the safety of HIF-PHIs in tumors, although it has been on the market for five years and no such risk has been observed in CKD patients, [ 60 – 64 ] and there are some mechanisms suggesting that HIF-PHIs may not activate tumor-related genes due to its transiently and intermittently action on HIF. Further, a number of anemic patients complicated with microinflammation, which are hypo-responsive to the conventional ESAs, while previous trials of HIF-PHIs all excluded the patients from the study. Therefore, it is still uncertain whether this group of patients is indicated to use this new type of drugs. Of note, the safety concern regarding cardiovascular and thrombotic events still needs to be assessed as many of the studies done have a shorter follow-up. Clearly, more studies for HIF-PHIs are desperately needed in the future for solving the current unmet need in treatment of ACD.

Funding

This work was supported by the grants from the National Natural Science Foundation of China (Nos. 82230022 and 82030024) and the Natural Science Foundation of Jiangsu Province (No. BK20240212).

Conflicts of interest

None.

Footnotes

Zuolin Li and Lan Shen contributed equally to this work.

How to cite this article: Li ZL, Shen L, Tu Y, Lu S, Liu BC. Hypoxia-inducible factor-prolyl hydroxylase inhibitors in treatment of anemia with chronic disease. Chin Med J 2025;138:1424–1432. doi: 10.1097/CM9.0000000000003470

References

1. Weiss G, Ganz T, Goodnough LT. Anemia of inflammation. Blood 2019;133:40–50. doi: 10.1182/blood-2018-06-856500.

2. Madu AJ, Ughasoro MD. Anaemia of chronic disease: An in-depth review. Med Princ Pract 2017;26:1–9. doi: 10.1159/000452104.

3. Fukuma S Yamaguchi T Hashimoto S Nakai S Iseki K Tsubakihara Y, et al. Erythropoiesis-stimulating agent responsiveness and mortality in hemodialysis patients: Results from a cohort study from the dialysis registry in Japan. Am J Kidney Dis 2012;59:108–116. doi: 10.1053/j.ajkd.2011.07.014.

4. Thavarajah S, Choi MJ. The use of erythropoiesis-stimulating agents in patients with CKD and cancer: A clinical approach. Am J Kidney Dis 2019;74:667–674. doi: 10.1053/j.ajkd.2019.04.022.

5. Yuan X, Ruan W, Bobrow B, Carmeliet P, Eltzschig HK. Targeting hypoxia-inducible factors: Therapeutic opportunities and challenges. Nat Rev Drug Discov 2024;23:175–200. doi: 10.1038/s41573-023-00848-6.

6. Wang Y, Yu X. Stabilizing hypoxia-inducible factor to manage anemia in chronic kidney disease: From basic theory to clinical study. Kidney Dis (Basel) 2024;10:132–142. doi: 10.1159/000536039.

7. Dhillon S. Roxadustat: First global approval. Drugs 2019;79:563–572. doi: 10.1007/s40265-019-01077-1.

8. Li ZL, Wang B, Wen Y, Wu QL, Lv LL, Liu BC. Disturbance of hypoxia response and its implications in kidney diseases. Antioxid Redox Signal 2022;37:936–955. doi: 10.1089/ars.2021.0271.

9. Semenza GL. Regulation of erythropoiesis by the hypoxia-inducible factor pathway: Effects of genetic and pharmacological perturbations. Annu Rev Med 2023;74:307–319. doi: 10.1146/annurev-med-042921-102602.

10. Schödel J, Ratcliffe PJ. Mechanisms of hypoxia signalling: New implications for nephrology. Nat Rev Nephrol 2019;15:641–659. doi: 10.1038/s41581-019-0182-z.

11. Liu BC, Li ZL. Advances in the hypoxia-inducible factor and prolyl hydroxylase inhibitors (in Chinese). Chin J Nephrol 2017;33:951–955. doi: 10.3760/cma.j.issn.1001-7097.2017.12.014.

12. Haase VH. Regulation of erythropoiesis by hypoxia-inducible factors. Blood Rev 2013;27:41–53. doi: 10.1016/j.blre.2012.12.003.

13. Li QY Xiong QW Yao X Liu F Tang X Fu H, et al. Roxadustat: Do we know all the answers? Biomol Biomed 2023;23:354–363. doi: 10.17305/bb.2022.8437.

14. Li ZL, Tu Y, Liu BC. Treatment of renal anemia with roxadustat: Advantages and achievement. Kidney Dis (Basel) 2020;6:65–73. doi: 10.1159/000504850.

15. Ku E Del Vecchio L Eckardt KU Haase VH Johansen KL Nangaku M, et al. Novel anemia therapies in chronic kidney disease: Conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 2023;104:655–680. doi: 10.1016/j.kint.2023.05.009.

16. Locatelli F, Del Vecchio L, Elliott S. The anaemia treatment journey of CKD patients: From epoetins to hypoxia-inducible factor-prolyl hydroxylase inhibitors. Clin Kidney J 2023;16:1563–1579. doi: 10.1093/ckj/sfad105.

17. Stoumpos S Crowe K Sarafidis P Barratt J Bolignano D Del Vecchio L, et al. Hypoxia-inducible factor prolyl hydroxylase inhibitors for anaemia in chronic kidney disease: A clinical practice document by the European Renal Best Practice board of the European Renal Association. Nephrol Dial Transplant 2024;39:1710–1730. doi: 10.1093/ndt/gfae075.

18. Yap DYH McMahon LP Hao CM Hu N Okada H Suzuki Y, et al. Recommendations by the Asian Pacific society of nephrology (APSN) on the appropriate use of HIF-PH inhibitors. Nephrology (Carlton) 2021;26:105–118. doi: 10.1111/nep.13835.

19. Locatelli F Del Vecchio L Esposito C Gesualdo L Grandaliano G Ravera M, et al. Consensus commentary and position of the Italian Society of Nephrology on KDIGO controversies conference on novel anemia therapies in chronic kidney disease. J Nephrol 2024;37:753–767. doi: 10.1007/s40620-024-01937-4.

20. Macdougall IC. Anaemia in CKD-treatment standard. Nephrol Dial Transplant 2024;39:770–777. doi: 10.1093/ndt/gfad250.

21. Raichoudhury R, Spinowitz BS. Treatment of anemia in difficult-to-manage patients with chronic kidney disease. Kidney Int Suppl (2011) 2021;11:26–34. doi: 10.1016/j.kisu.2020.12.006.

22. Chen N Hao C Liu BC Lin H Wang C Xing C, et al. Roxadustat treatment for anemia in patients undergoing long-term dialysis. N Engl J Med 2019;381:1011–1022. doi: 10.1056/NEJMoa1901713.

23. Chen N Hao C Peng X Lin H Yin A Hao L, et al. Roxadustat for anemia in patients with kidney disease not receiving dialysis. N Engl J Med 2019;381:1001–1010. doi: 10.1056/NEJMoa1813599.

24. Singh AK Carroll K McMurray JJV Solomon S Jha V Johansen KL, et al. Daprodustat for the treatment of anemia in patients not undergoing dialysis. N Engl J Med 2021;385:2313–2324. doi: 10.1056/NEJMoa2113380.

25. Singh AK Carroll K Perkovic V Solomon S Jha V Johansen KL, et al. Daprodustat for the treatment of anemia in patients undergoing dialysis. N Engl J Med 2021;385:2325–2335. doi: 10.1056/NEJMoa2113379.

26. Chertow GM Pergola PE Farag YMK Agarwal R Arnold S Bako G, et al. Vadadustat in patients with anemia and non-dialysis-dependent CKD. N Engl J Med 2021;384:1589–1600. doi: 10.1056/NEJMoa2035938.

27. Eckardt KU Agarwal R Aswad A Awad A Block GA Bacci MR, et al. Safety and efficacy of Vadadustat for anemia in patients undergoing dialysis. N Engl J Med 2021;384:1601–1612. doi: 10.1056/NEJMoa2025956.

28. Gang S Khetan P Varade D Chinta VR Mavani S Gupta U, et al. Desidustat in anemia due to dialysis-dependent chronic kidney disease: A phase 3 study (DREAM-D). Am J Nephrol 2022;53:343–351. doi: 10.1159/000523949.

29. Agrawal D Varade D Shah H Nazar A Krishnan J Shukla V, et al. Desidustat in anemia due to non-dialysis-dependent chronic kidney disease: A phase 3 study (DREAM-ND). Am J Nephrol 2022;53:352–360. doi: 10.1159/000523961.

30. Natale P Palmer SC Jaure A Hodson EM Ruospo M Cooper TE, et al. Hypoxia-inducible factor stabilisers for the anaemia of chronic kidney disease. Cochrane Database Syst Rev 2022;8:CD013751. doi: 10.1002/14651858.CD013751.pub2.

31. Yang J, Xing J, Zhu X, Xie X, Wang L, Zhang X. Effects of hypoxia-inducible factor-prolyl hydroxylase inhibitors vs. erythropoiesis-stimulating agents on iron metabolism in non-dialysis-dependent anemic patients with CKD: A network meta-analysis. Front Endocrinol (Lausanne) 2023;14:1131516. doi: 10.3389/fendo.2023.1131516.

32. Wang B Yin Q Han YC Wu M Li ZL Tu Y, et al. Effect of hypoxia-inducible factor-prolyl hydroxylase inhibitors on anemia in patients with CKD: A meta-analysis of randomized controlled trials including 2804 patients. Ren Fail 2020;42:912–925. doi: 10.1080/0886022X.2020.1811121.

33. Liang Q, Li X, Niu Q, Zhao H, Zuo L. Efficacy and safety of roxadustat in chinese hemodialysis patients: A systematic review and meta-Analysis. J Clin Med 2023;12:2450. doi: 10.3390/jcm12072450.

34. Abdel-Razeq H, Hashem H. Recent update in the pathogenesis and treatment of chemotherapy and cancer induced anemia. Crit Rev Oncol Hematol 2020;145:102837. doi: 10.1016/j.critrevonc.2019.102837.

35. Shen L, Lu S. Chemotherapy induced anemia (in Chinese). Chin J Intern Med 2023;62:242–246. doi: 10.3760/cma.j.cn112138-20230110-00011.

36. Bozzini C Busti F Marchi G Vianello A Cerchione C Martinelli G, et al. Anemia in patients receiving anticancer treatments: Focus on novel therapeutic approaches. Front Oncol 2024;14:1380358. doi: 10.3389/fonc.2024.1380358.

37. Glaspy J Gabrail NY Locantore-Ford P Lee T Modelska K Samal V, et al. Open-label, phase 2 study of roxadustat for the treatment of anemia in patients receiving chemotherapy for non-myeloid malignancies. Am J Hematol 2023;98:703–711. doi: 10.1002/ajh.26865.

38. Lu S, Wu J, Jiang J. Roxadustat for chemotherapy-induced anemia in patients with non-myeloid malignancies: A randomized, open-label, active-controlled, phase III study. ESMO, 2023, Abstract#LBA96, Madrid, Spain.

39. Alessandrino EP Amadori S Barosi G Cazzola M Grossi A Liberato LN, et al. Evidence- and consensus-based practice guidelines for the therapy of primary myelodysplastic syndromes. A statement from the Italian Society of Hematology. Haematologica 2002;87:1286–1306.

40. Jabbour E, Kantarjian HM, Koller C, Taher A. Red blood cell transfusions and iron overload in the treatment of patients with myelodysplastic syndromes. Cancer 2008;112:1089–1095. doi: 10.1002/cncr.23280.

41. Henry DH Glaspy J Harrup R Mittelman M Zhou A Carraway HE, et al. Roxadustat for the treatment of anemia in patients with lower-risk myelodysplastic syndrome: Open-label, dose-selection, lead-in stage of a phase 3 study. Am J Hematol 2022;97:174–184. doi: 10.1002/ajh.26397.

42. Lyu Y, Lin ZH, Yang L, Liu H. Efficacy and safety analysis of hypoxia-inducible factor prolyl hydroxylase inhibitors for anemia in low-risk myelodysplastic syndromes patients. Chin J Hematol (in Chinese) 2024;45:290–293. doi: 10.3760/cma.j.cn121090-20230825-00089.

43. Hou J, Wang LL, Yang ML, Wang LJ. Effect of recombinant human erythropoietin injection combined with roxadustat in patients with multiple myeloma renal anemia. Anti-Tumor Pharm 2023;13:751–758. doi: 10.3969/j.issn.2095-1264.2023.06.14.

44. Li SC Han XY Zheng GF He JS Wu WJ Yang Y, et al. The efficacy of roxadustat in multiple myeloma patients with renal insufficiency and anemia: A Real-World Study. Blood 2023;142:4726–4727. (ASH Annual Meeting. Poster 4726). doi: 10.1182/blood-2023-184617.

45. Fu YQ, Tu Y, Liu BC. Research progress on hypoxia-inducible factor prolyl hydroxylase inhibitors for the treatment of renal anemia (in Chinese). Chin J Nephrol 2020;36:726–730. doi: 10.3760/cma.j.cn441217-20191112-00129.

46. Bernhardt WM Wiesener MS Scigalla P Chou J Schmieder RE Günzler V, et al. Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. J Am Soc Nephrol 2010;21:2151–2156. doi: 10.1681/ASN.2010010116.

47. Besarab A Provenzano R Hertel J Zabaneh R Klaus SJ Lee T, et al. Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients. Nephrol Dial Transplant 2015;30:1665–1673. doi: 10.1093/ndt/gfv302.

48. Nemeth E, Ganz T. Hepcidin and iron in health and disease. Annu Rev Med 2023;74:261–277. doi: 10.1146/annurev-med-043021-032816.

49. Weir MR. Managing anemia across the stages of kidney disease in those hyporesponsive to erythropoiesis-stimulating agents. Am J Nephrol 2021;52:450–466. doi: 10.1159/000516901.

50. Chen J Shou X Xu Y Jin L Zhu C Ye X, et al. A network meta-analysis of the efficacy of hypoxia-inducible factor prolyl-hydroxylase inhibitors in dialysis chronic kidney disease. Aging (Albany NY) 2023;15:2237–2274. doi: 10.18632/aging.204611.

51. Karaboyas A Morgenstern H Fleischer NL Vanholder RC Dhalwani NN Schaeffner E, et al. Inflammation and erythropoiesis-stimulating agent response in hemodialysis patients: A self-matched longitudinal study of anemia management in the dialysis outcomes and practice patterns study (DOPPS). Kidney Med 2020;2:286–296. doi: 10.1016/j.xkme.2020.01.007.

52. Zheng Q Zhang P Yang H Geng Y Tang J Kang Y, et al. Effects of hypoxia-inducible factor prolyl hydroxylase inhibitors versus erythropoiesis-stimulating agents on iron metabolism and inflammation in patients undergoing dialysis: A systematic review and meta-analysis. Heliyon 2023;9:e15310. doi: 10.1016/j.heliyon.2023.e15310.

53. Tu Y Li ZL Liu H Tang RN Wang GH Lv LL, et al. Roxadustat on renal anemia with macroinflammation: A retrospective cohort study. Kidney Dis (Basel) 2024;10:193–199. doi: 10.1159/000538372.

54. Yang X Zhao B Wang J Wang L Tao M Lu J, et al. Red blood cell lifespan in long-term hemodialysis patients treated with roxadustat or recombinant human erythropoietin. Ren Fail 2021;43:1428–1436. doi: 10.1080/0886022X.2021.1988968.

55. Sugahara M, Tanaka T, Nangaku M. Future perspectives of anemia management in chronic kidney disease using hypoxia-inducible factor-prolyl hydroxylase inhibitors. Pharmacol Ther 2022;239:108272. doi: 10.1016/j.pharmthera.2022.108272.

56. Mima A. Hypoxia-inducible factor-prolyl hydroxylase inhibitors for renal anemia in chronic kidney disease: Advantages and disadvantages. Eur J Pharmacol 2021;912:174583. doi: 10.1016/j.ejphar.2021.174583.

57. Yang H Wu Y Cheng M Zhang M Qiu X Liu S, et al. Roxadustat (FG-4592) protects against ischaemia-induced acute kidney injury via improving CD73 and decreasing AIM2 inflammasome activation. Nephrol Dial Transplant 2023;38:858–875. doi: 10.1093/ndt/gfac308.

58. Ito M, Tanaka T, Ishii T, Wakashima T, Fukui K, Nangaku M. Prolyl hydroxylase inhibition protects the kidneys from ischemia via upregulation of glycogen storage. Kidney Int 2020;97:687–701. doi: 10.1016/j.kint.2019.10.020.

59. Madai S Kilic P Schmidt RM Bas-Orth C Korff T Büttner M, et al. Activation of the hypoxia-inducible factor pathway protects against acute ischemic stroke by reprogramming central carbon metabolism. Theranostics 2024;14:2856–2880. doi: 10.7150/thno.88223.

60. Singh AK, Wanner C, Wiecek AJ, Blackorby A. MO530: Daprodustat is not associated with an increased risk of cancer: Results from the ASCEND-D and ASCEND-ND trials. Nephrol Dial Transplant 2022;37(Suppl_3):gfac072.012. doi: 10.1093/ndt/gfac072.012.

61. Akizawa T Yamada T Nobori K Matsuda Y Hayashi Y Hayasaki T, et al. Molidustat for Japanese patients with renal anemia receiving dialysis. Kidney Int Rep 2021;6:2604–2616. doi: 10.1016/j.ekir.2021.07.015.

62. Li J, Haase VH, Hao CM. Updates on hypoxia-inducible factor prolyl hydroxylase inhibitors in the treatment of renal anemia. Kidney Dis (Basel) 2022;9:1–11. doi: 10.1159/000527835.

63. Coyne DW Fishbane S Pergola PE Leong R Zhong M Little DJ, et al. Roxadustat is not associated with an increased risk of neoplasm in patients with CKD and anemia. 2020. ASN Annual Meeting. Oral TH-OR04. Denver, USA.

64. Dayan F, Roux D, Brahimi-Horn MC, Pouyssegur J, Mazure NM. The oxygen sensor factor-inhibiting hypoxia-inducible factor-1 controls expression of distinct genes through the bifunctional transcriptional character of hypoxia-inducible factor-1alpha. Cancer Res 2006;66:3688–3698. doi: 10.1158/0008-5472.CAN-05-4564.