Issue: March 2020
Disclosures: van Adelsberg, Amedia, Burke, and Houghton report no relevant disclosures. Fishbane and Provenzano report they are principal investigators for AstraZeneca. Wish reports associations with and receiving speaker fees from Keryx Pharmaceuticals, Daiichi Sankyo and Pfizer.
March 12, 2020
12 min read

Hypoxia-inducible factor prolyl hydroxylase inhibitors have emerging role in anemia management

Issue: March 2020
Disclosures: van Adelsberg, Amedia, Burke, and Houghton report no relevant disclosures. Fishbane and Provenzano report they are principal investigators for AstraZeneca. Wish reports associations with and receiving speaker fees from Keryx Pharmaceuticals, Daiichi Sankyo and Pfizer.
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On February 12, the FDA accepted its first new drug application for a hypoxia-inducible factor prolyl hydroxylase inhibitor. The agency has set a Prescription Drug User Fee Act date of Dec. 20, 2020 for final review and approval.

The applicant, FibroGen Inc., is requesting approval for roxadustat for the treatment in both patients who are non-dialysis dependent (NDD) and dialysis dependent (DD). Roxadustat is being co-developed and commercialized in the United States in partnership with AstraZeneca.

“There is significant unmet medical need for patients with anemia of [chronic kidney disease] CKD, who have seen only limited advances in the last 3 decades,” Peony Yu, MD, chief medical officer of FibroGen, said in a statement.

Robert Provenzano, MD, FACP, FASN, a principal investigator in clincial trials for roxadustat, said much still needs to be learned about the benefits and risks of using hypoxia-inducible factor prolyl hydroxylase inhibitors.

Source: DaVita Inc.

The clinical program for roxadustat includes 15 phase 3 trials with more than 10,000 patients worldwide.

Development of roxadustat began 7 years ago, but finding ways to treat the energy-robbing effects of anemia for patients with kidney disease has been going on since the 1960s. Development of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) could be the next chapter in the quest for safe and effective ways to raise hemoglobin levels for patients with kidney disease.

“At the highest level, we have learned a great deal over the last 30 years about managing anemia,” Robert Provenzano, MD, FACP, FASN, associate professor of medicine at Wayne State University and a principal investigator in the clinical trials for roxadustat, told Nephrology News & Issues. “We have an opportunity [with HIF-PHIs] to treat anemia without causing a large pharmacological spike in serum erythropoietin levels like we have seen with epoetin alfa.”

Erythropoietin-stimulating agents (ESAs) have been the mainstay therapy for anemia in both patients with nondialysis dependent-CKD (NDD-CKD) and ESKD. When Amgen Inc. received FDA approval in 1989 for epoetin alfa, patients effected by low hemoglobin now had a drug that could treat their anemia and improve their quality of life.

“It was a game changer,” Jay B. Wish, MD, professor of clinical medicine at Indiana University School of Medicine who has consulted with pharmaceutical companies developing HIF-PHIs, told Nephrology News & Issues. “ESAs took the place of the missing hormone; it was like replacing insulin for a diabetic.”

A normal Hb level for male patients is 14 g/dL to 18 g/dL; for female patients, 12 g/dL to 16 g/dL. Prior to ESAs, hemoglobin for patients on dialysis hovered around 7 g/dL, he said.


Ongoing clinical trials for HIF-PHIs from a number of pharmaceutical companies (see Table) have shown these are more efficient than ESAs in raising hemoglobin – and have proven effective among patients who are resistant to current anemia therapy. Delivered in pill form vs. ESAs that use IV or subcutaneous delivery, HIF-PHIs for patients with NDD-CKD and patients with ESKD may offer other advantages.

Steven Fishbane, MD, chief of nephrology at Northwell Health in Great Neck, New York, and a primary investigator in AstraZeneca’s OLYMPUS and ROCKIES trial, told Nephrology News & Issues, “With this class of drugs, the fact that they are oral medications is important. It is difficult to offer [current] anemia drugs to CKD patients and PD patients. Phase 2 and 3 studies also showed that these medications have positive iron effects, and they work well with patients who have elevated C-reactive protein levels. Those are areas we want to explore.”

“We have evidence with roxadustat that it is effective in treating anemia in CKD,” Provenzano said. “In addition, there was evidence that roxadustat preserved renal function in CKD patients, along with a reduction in cardiac-related events. There is still a lot left to be done” to understand the benefits, he said.

Wish agreed that results from the trials look promising, but said, “The downside to HIF stabilizers is that we don’t know the long-term effects of the stimulation of hundreds, if not thousands, of genes related to the cellular response to a hypoxic state, which is what HIF stabilizers are simulating. Of greatest concern is angiogenesis, which may accelerate diabetic retinopathy and tumor growth, and fibrosis, which may affect many organs, including kidneys, lungs, heart and the liver,” he said.

Mechanism of action

HIF-PHIs work differently than ESAs. Once kidneys begin to fail, so does the production of erythropoietin, resulting in anemia. Recombinant erythropoietin is produced by cloning the gene for erythropoietin, which when administered to patients stimulates the bone marrow to produce more red blood cells.

Steven Fishbane

HIF-PHIs act by blocking the normal degradation of HIF alpha which, now stabilized, can translate the gene for endogenous EPO production.

“It is hypothesized that the consistent but noncontinuous low-level stimulation of HIF by these agents improves erythropoiesis while minimizing some of the undesirable downstream effects of continuous HIF stimulation,” Nupur Gupta, MD, and Wish wrote in a 2017 article detailing the mechanisms of HIF-PHIs.


HIFs also aid in improving iron utilization.

“EPO production induced by HIF leads to the production by erythroblasts of erythroferrone, which limits the gene expression of liver hepcidin. These functions of HIF complement its effect on erythropoiesis by coordinating EPO-stimulated [red blood cell] RBC production with increased available iron,” they wrote.

Clinical trials for HIF-PHIs

Presentations at ASN Kidney Week in November 2019 by principal investigators for AstraZeneca, Akebia Therapeutics, FibroGen and GSK showed that, when compared to epoetin alfa, HIF-PHIs were more effective in raising hemoglobin levels for NDD-CKD and in both incident and prevalent ESKD patients.

Data presented from AstraZeneca’s ROCKIES trial, which included prevalent patients on both hemodialysis and peritoneal dialysis, showed use of roxadustat led to greater increases in hemoglobin levels compared to use of epoetin alfa.

“These data demonstrated that roxadustat effectively increased hemoglobin levels for patients with anemia from chronic kidney disease, including those who were inflamed. Patients who experience chronic inflammation are often more difficult to treat than the overall chronic kidney disease patient population, emphasizing the need for new treatment options,” Fishbane said.

Specifically, roxadustat improved hemoglobin levels from baseline in this subgroup of patients identified by elevated high-sensitivity C-reactive protein (greater than 5 mg/L). Chronically inflamed patients can represent up to 10% of [a] dialysis clinic’s patient population, Wish said.

Steven K. Burke

Likewise, use of roxadustat did not show any higher risk for cardiovascular events, according to pooled data presented at ASN Kidney Week. Provenzano and colleagues compared roxadustat for patients with stages 3 to 5 NDD-CKD to placebo and to epoetin alfa in dialysis-dependent patients. Key safety endpoints were time to major adverse cardiovascular event (MACE), which was defined as all-cause mortality, stroke and myocardial infarction; and time to MACE+, defined as MACE and unstable angina that required hospitalization and congestive heart failure requiring hospitalization. They also assessed efficacy by hemoglobin and rescue therapy, which was blood transfusion, IV iron and ESAs.

For patients with CKD who received roxadustat, researchers found the risk of MACE, MACE+ and all-cause mortality was comparable to patients in a placebo group. Prevalent dialysis patients had a lower risk of MACE+ and did not have increased risk of MACE or mortality compared to epoetin alpha-treated patients. Importantly, incident dialysis-dependent patients demonstrated a 30% lower risk of MACE and 34% lower risk of MACE+ and showed a trend toward lower mortality. All patients who received roxadustat required fewer transfusions.


“Cardiovascular safety was demonstrated in all study populations,” Provenzano said.

Akebia Therapeutics’ two global phase 3 studies – PRO2TECT (patients with NDD-CKD) and INNO2VATE (patients on dialysis) – for its HIF-PHI vadadustat are underway with a combined 7,436 patients. Results are expected by the second quarter of 2020 for INNO2VATE and by mid-2020 for PRO2TECT, subject to the accrual of MACE, company officials told Nephrology News & Issues.

“In both the PRO2TECT and INNO2VATE phase 3 programs, the primary efficacy endpoint is the mean change in hemoglobin between baseline and the primary evaluation period. Both the PRO2TECT and INNO2VATE programs include the primary safety endpoint of the assessment of MACE, with a comparison of vadadustat to darbepoetin alfa,” the company said.

Last year, the company announced positive top-line results from two phase 3 active-controlled pivotal studies that evaluated vadadustat in Japanese patients with anemia due to CKD. Each study, one in patients with NDD-CKD and one in hemodialysis-dependent patients, met its primary endpoint.

Nangaku and colleagues from the University of Tokyo School of Medicine, and colleagues from Akebia’s Japanese marketing partner, Mitsubishi Tanabe Pharma Corporation, offered details on the phase 3 study in an abstract presented at ASN Kidney Week. In the trial, NDD-CKD patients were randomized to either vadadustat (n=151) or darbepoetin alfa (DA)(n=153). After an initial vadadustat dose of 300 mg daily, doses were adjusted within 150 mg to 600 mg to achieve and maintain target hemoglobin (Hb) of 11 g/dL to 13 g/dL. The vadadustat regimen “was associated with significant increases in total iron-binding capacity and decreases in hepcidin from baseline to week 24, not found in the DA group ... [vadadustat] was effective as DA in controlling Hb within the target range in both conversion and correction patients without new safety concerns, indicating the usefulness of [vadadustat] for treating anemia in Japanese NDD-CKD patients.”

Steven K. Burke, MD, senior vice president and chief medical officer for Akebia, told Nephrology News & Issues that the company has reviewed the results from the Japanese studies that show a slower, more gradual hemoglobin ascent vs. ESAs.

“We’ll know more details on the dialysis population when we evaluate the data from the U.S. clinical trialsin the second quarter of this year,” Burke said.

Janet van Adelsberg

Researchers also tested the impact of moderate hepatic impairment on vadadustat. In another abstract presented at ASN Kidney Week, Chavan and colleagues reviewed the results from a phase 1 study that evaluated vadadustat with a dose of 450 mg in patients aged 18 to 70 years old with moderate hepatic impairment compared with those who have normal hepatic function. In the 16 enrolled participants who completed the study, “moderate hepatic impairment did not significantly impact vadadustat systemic exposure,” the researchers wrote. “A single dose of 450 mg vadadustat was generally well tolerated by participants with both normal and moderately impaired hepatic function.”


GSK’s HIF-PHI, called daprodustat, has undergone clinical studies in Japan, and the company has submitted an NDA in that country with approval estimated in the second half of 2020. The company’s ASCEND-D and ASCEND-ND are both cardiovascular events driven studies from the global phase 3 program in patients on dialysis and non-dialysis.

“We currently estimate [to see results] during 2022,” Janet van Adelsberg, MD, vice president of GSK research and development, told Nephrology News & Issues. “We have a large clinical development program with more than 8,000 patients that includes 3 phase 2 and 5 phase 3 studies currently ongoing to support regulatory filings in Europe, the U.S. and other countries across the world. The program has robust cardiovascular outcomes studies comparing daprodustat to standard of care erythropoietin [darbepoetin and epoetin], one in dialysis patients [both hemodialysis and PD] and one in patients with anemia of CKD who are not on dialysis.

“Efficacy and safety will be assessed in the spectrum of anemic CKD patients, including patients new to dialysis,” van Adelsberg said. “The program will provide information on how to initiate treatment in patients not yet on anemia treatment and how to switch from rhEPO to daprodustat. We have a placebo-controlled study to demonstrate efficacy and to explore the quality of life benefit of treating anemia with daprodustat.”

In an abstract presented at ASN Kidney Week, Hamano and colleagues from Osaka University Graduate School of Medicine and GSK presented data that reviewed the safety of daprodustat with a focus on ocular-, cardiovascular- and cancer-related adverse events (AEs). The results were compared to AEs among patients with NDD-CKD who received ESAs.

“The principal outcomes were frequencies of a subset of the predefined AEs of special interest (AESIs): ocular (proliferative retinopathy, macular edema, choroidal neovascularization), cardiovascular (all-cause death, myocardial infarction, stroke, heart failure, thromboembolic events, thrombosis of vascular access) and cancer (cancer-related mortality and tumor progression and recurrence) related AEs, and ophthalmological findings by ophthalmologists during treatment,” the researchers wrote.

Results showed that, in patients with NDD-CKD, the incidence of ocular-, cardiovascular-, and cancer-related AEs between daprodustat and ESAs were similar. “The incidence of ophthalmological findings were 11% vs. 10% in (NDD-CKD) patients and 6% vs. 8% in HD patients.

Jay B. Wish

“Daprodustat showed no new safety concerns in these predefined AESIs in these clinical studies, but further investigation will be needed,” they wrote.

Other companies developing HIF-PHIs are also showing positive results. In a paper published in the American Journal of Nephrology, trial results for patients with NDD-CKD receiving Japan Tobacco Company’s enarodustat vs. patients receiving placebo or an ESA “showed that enarodustat was associated with decreases in hepcidin and ferritin and increased total iron binding capacity,” the authors wrote. The company filed an NDA in Japan in November 2019.


Results from phase 2 trials with Bayer’s molidustat showed the HIF-PHI was associated with increases in mean hemoglobin levels of 1.4g/dL to 2 g/dL.

“In the DIAGLOGUE 2 study (n=124), hemoglobin levels were maintained within the target range after switching to molidustat, with an estimated difference in mean change in hemoglobin levels between molidustat and darbepoetin treatments of up to 0.6g/dL,” Macdougall and colleagues wrote. “Molidustat was generally well tolerated, and most adverse events were mild or moderate in severity.”

If these are sustainable, benefits of HIF-PHIs beyond the efficacy of raising hemoglobins – reduced iron use, fewer blood transfusions, a lower risk of MACE, even a slowdown in the progression of kidney disease – could offer a better therapy for patients. “From what we saw of the trial results with roxadustat, we werepleased,” John Houghton, AstraZeneca’s global medicines leader for roxadustat, told Nephrology News & Issues. “The reduction in the cardiovascular risk was demonstrated in the trials presented, along with the drop in the number of red blood cell transfusions. It was interesting to also see some benefit of lowering iron requirements in the trials compared to ESAs,” he said.

Real-world application

Adrian Amedia, the executive vice president for North Central Pennsylvania Dialysis Clinics in Boardman, Ohio, uses Roche’s mircera ESA to treat anemia in his 225 in-center and home dialysis patients. He has saved 25% in drug costs after switching from Amgen’s aranesp. However, he said he is open to trying HIF-PHIs when they come on the market.

“We have always been an early adopter because we are nimble and can make changes quickly,” he told Nephrology News & Issues. “I can see a big advantage for the oral therapy for home and CKD patients. “

In their recent surveys, Spherix Global Insights found while some nephrologists are intrigued by HIF-PHIs, others feel ESAs have a long history of working effectively and changing to a new class of drug is not necessary (see Bottom Line).

“ESAs remain a good drug,” Wish said. “If it isn’t broken, some nephrologists may believe, don’t fix it.”

Houghton recognized the value and contribution ESAs have made in kidney care and acknowledged much still has to be learned about HIF-PHIs. “ESAs are still the standard of care, but as always with innovation, every now and again a game changer comes along,” he said. “Essentially what we are doing with roxadustat is limiting the body’s natural response to hypoxia – like climbing up the mountain, we are mimicking that with a pill. I think the science here is exciting.” – by Mark E. Neumann


Disclosures: van Adelsberg, Amedia, Burke, and Houghton report no relevant disclosures. Fishbane and Provenzano report they are principal investigators for AstraZeneca. Wish reports associations with and receiving speaker fees from Keryx Pharmaceuticals, Daiichi Sankyo and Pfizer.