Roxadustat — the furthest-advanced agent from a new oral drug class for treating anemia in patients with chronic kidney disease (CKD) — has now shown efficacy and safety in a sextet of phase 3 trials that collectively randomized more than 8000 patients worldwide, including patients who were dialysis dependent as well as patients who had not yet progressed to dialysis.
Roxadustat’s efficacy was “demonstrated across the progression of CKD” compared with placebo in nondialysis-dependent patients, and compared with epoetin alfa (Epogen, Procrit) in dialysis-dependent patients, said Robert Provenzano, MD, and colleagues in a poster presented at the National Kidney Foundation’s Spring Clinical Meetings (SCM21).
Next up for roxadustat (Evrenzo) is a US Food and Drug Administration advisory committee meeting scheduled for July to assess whether the drug merits approval as the first agent from the class of oral hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI).
The drug class takes advantage of a normal regulatory pathway that boosts hemoglobin production in response to hypoxia by increasing endogenous erythropoietin, improving iron availability, and reducing hepcidin. Five agents in the HIF-PHI class are already on the market in Japan or China, including roxadustat. In Europe, an application for approval of roxadustat for the treatment of anemia of CKD in patients both on dialysis and not on dialysis was filed for review in May 2020
Overall Favorable Efficacy and Safety as an Outpatient Treatment
“It looks like these agents have an overall favorable efficacy and safety profile,” said Steven N. Fishbane, MD, chief of the Division of Kidney Diseases and Hypertension at both Northshore University Hospital in Manhasset and Long Island Jewish Medical Center, New York.
Speaking during SCM21, he voiced the promise for using the orally delivered drugs as outpatient treatment, an opinion shared by Volker H. Haase, MD, who spoke during the same session.
“Having an oral anemia drug would certainly be an advantage, especially given some of the logistical issues of taking care of anemia in the outpatient setting,” commented Haase, a nephrologist and professor at Vanderbilt University in Nashville, Tennessee.
But the encouraging data collected on roxadustat and other agents in the HIF-PHI class go beyond their route of administration.
These drugs “increase both erythropoietin and iron at the same time, producing a more balanced effect that is vastly different from what we currently do” when treating patients with either of the two approved erythropoietin-stimulating agents (ESAs), epoetin alfa and darbepoetin alfa (Aranesp), both delivered by injection, explained Fishbane, a coauthor of the poster presented at SCM21.
HIF-PHI agents mobilize stored iron, giving them the “remarkable” ability to be as effective for raising hemoglobin in patients who are not iron replete, as well as in those who are.
Another distinction from the ESAs is that HIF-PHI agents can be effective in patients with higher levels of inflammation marked by higher C-reactive protein (CRP) levels, Fishbane said.
Roxadustat Data From Six Phase 3 Trials
The analysis combined six separate phase 3 trials and included 4277 patients with nondialysis-dependent CKD and 3890 who were dialysis dependent, including a subset of 1530 who began dialysis 2 weeks to 4 months before randomization to roxadustat or epoetin alfa (defined as recent-onset dialysis).
Among patients who were not dialysis dependent, treatment with roxadustat three times weekly produced a sustained rise in hemoglobin from baseline that averaged about 1.6 g/dL higher than patients who received placebo.
Among dialysis-dependent patients, roxadustat increased hemoglobin from baseline by about 1 g/dL, similar and noninferior to controls who received epoetin-alfa, note Provenzano and coauthors in their poster. Roxadustat treatment also significantly reduced the need for iron treatment and blood transfusions and reduced volume-related adverse events compared with controls, reported Provenzano, a Detroit-area nephrologist, and colleagues.
Results from additional studies that have been reported at meetings but are not yet fully published showed no statistically significant difference in the rate of major adverse cardiovascular events (MACE) with roxadustat compared with controls in patients who were either dialysis dependent or nondependent, said Fishbane.
He highlighted that this lack of a significant impact on MACE persisted after adjusting the data based on a clarification issued by FibroGen, one of the companies developing roxadustat, in April 2021.
Investigators published the MACE outcome for the subset of 1530 patients who began dialysis immediately before randomization. The analysis showed that treatment with roxadustat was associated with a significant reduction in MACE compared with controls treated with epoetin alfa as well as noninferior efficacy.
However, the analysis, published in Kidney International Reports in December 2020, is being retracted, a spokesperson for Elsevier, the journal’s publisher, told Retraction Watch this week, noting that the “authors will be given the opportunity to resubmit a corrected version.”
MACE Increased With Vadadustat
This contrasts with recently published results for another HIF-PHI agent, vadadustat (Vafseo, Akebia Therapeutics), as reported by Medscape Medical News, which showed noninferior efficacy compared with darbepoetin-alfa in nearly 3500 randomized patients with nondialysis-dependent CKD in the PRO2TECT studies, but a significant 17% relative increase in MACE.
Results from a comparison of vadadustat with darbepoetin alfa in 3923 dialysis-dependent patients published at the same time, in the INNO2VATE trials, showed a different result: vadadustat was noninferior to the active comparator for both MACE safety and efficacy.
Currently, unresolved concerns remain about the long-term safety of roxadustat and other HIF-PHIs for other potential adverse effects including risk for triggering cancers, such as neuroendocrine tumors, causing pulmonary hypertension, or producing thromboembolic events, proangiogeneic effects, or progression of CKD, said Haase.
The roxadustat trials were sponsored by FibroGen, AstraZeneca, and Astellas Pharma, the companies developing this drug. The PRO2TECT and INNO2VATE trials of vadadustat were funded by Akebia Therapeutics and Otsuka, the companies developing this drug. Fishbane has been a consultant to and received research funding from Akebia, AstraZeneca, FibroGen, and MegaPro Biomedical. Haase has been an advisor to Akebia, AstraZeneca, FibroGen, Incyte, and Rockwell Medical.
SCM21. Abstract 173. Presented April 6, 2021.
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