Vadadustat — one of three oral agents under development for the treatment of anemia in patients with chronic kidney disease (CKD) — did not meet the prespecified end point for cardiovascular safety but did meet the criteria for target hemoglobin levels in the randomized, global phase 3 PRO₂TECT trials.
In PRO₂TECT-CORRECTION, the hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor was compared with parenteral darbepoetin alfa, an erythropoiesis-stimulating agent (ESA), in 1752 EAS-naïve CKD patients not dependent on dialysis; 1061 were treated in the United States and the majority of the remaining patients was treated in Europe.
In PRO₂TECT-CONVERSION, the two drugs were compared in 1725 CKD patients not dependent on dialysis who were previously treated with an ESA; 1060 were treated in Europe or elsewhere and the remaining patients were treated in the United States.
In a pooled analysis of the two cohorts, there was a difference in the primary end point of major adverse cardiovascular events (MACE) — all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke — between the vadadustat and ESA groups, depending on where the patients were treated.
This could reflect the different target hemoglobin levels in the two trials, suggested investigator Glenn Chertow, MD, from Stanford University in California, during his presentation of the data at Kidney Week 2020.
Target hemoglobin levels reflected clinical practice guidelines in the different regions, so were lower for American participants than for participants treated elsewhere (10 to 11 g/dL vs 10 to 12 g/dL).
In the pooled analysis, the incidence of MACE was higher in the vadadustat group than in the ESA group (hazard ratio [HR], 1.17), as was the rate of all-cause mortality (HR, 1.16), but neither met the prespecified criteria for noninferiority.
The risk for MACE, all-cause mortality, and CV mortality were lower in vadadustat-treated patients in the United States than in those treated elsewhere.
|Hazard Ratios for Cardiovascular Events by Location of Treatment|
|Event||United States, n = 1723||Elsewhere, n = 1748|
There was no difference in the mean change in hemoglobin levels from baseline to weeks 24 to 36 in the vadadustat and darbepoetin groups in the CORRECTION cohort (1.43 vs 1.38 g/dL) or in the CONVERSION cohort (0.41 vs 0.42 g/dL).
There was also no difference in the change from baseline to weeks 40 to 52 for the vadadustat and darbepoetin groups in the CORRECTION (1.52 vs 1.48 g/dL) and CONVERSION cohorts (0.43 vs 0.44 g/dL).
Rates of serious treatment-emergent adverse events were similar in the vadadustat and darbepoetin groups in the CORRECTION cohort (2.6% vs 1.7%) and the CONVERSION cohort (0.5% vs 1.0%). Rates of drug-related adverse events that led to study discontinuation were also similar in the CORRECTION (1.5% vs 0.5%) and CONVERSION cohorts (1.9% vs 0.2%).
"Anemia is a very big problem — even bigger in dialysis patients than in nondialysis patients — as it significantly affects the patient's quality of life," said Jonathan Barratt, MD, PhD, from Leicester General Hospital in the United Kingdom.
It "is a problem on multiple levels" because it increases the risk for cardiovascular disease and potentially hastens the progression of kidney disease, he explained. "It's really important that we treat it, but we've got to do it in the safest way possible."
Anemia management is not as simple as giving an agent to stimulate red blood cell production. First and foremost, patients with anemia need to be managed with some form of iron; sometimes that is enough to boost red blood cell production. However, when iron supplementation does not correct anemia sufficiently, a second agent is needed; to date, that agent has been an ESA.
"We know that with traditional ESAs, if we don't use them properly, they increase the risk of CV disease, which is why we pay particular attention to CV end points in these studies. Previous studies showed us that if we try to make the hemoglobin too high — what we regard as normal — patients have excess CV events," Barratt told Medscape Medical News.
Oral HIF inhibitors "are very exciting and they have real potential, but I think we need to wait for the full peer-reviewed manuscripts to look at what the implications of these studies really are," he said.
There are several reasons why these agents have such potential, he explained. First, the ESAs that have long been used to treat anemia in CKD patients — whether or not they are dependent on dialysis — are all artificial versions of erythropoietin, the production of which is increasingly slowed as patients approach and enter end-stage renal disease.
"The beauty of the HIF stabilizers is that we are not just giving a massive dose of something that is missing, we are giving a drug that modifies the body's biology to allow it to respond in a more physiological way" to stimulate erythropoiesis, he said.
The second "massive" advantage of the HIF stabilizers is that they are oral rather than injectable, as all ESAs are, he added.
But all trials of oral HIF inhibitors must be interpreted with caution until the full data are available for analysis in peer-reviewed publications, Barratt cautioned.
The randomized phase 3 DOLOMITES study that he presented at Kidney Week was also a noninferiority trial that compared roxadustat, another HIF inhibitor, with darbepoetin alfa in CKD patients not dependent on dialysis.
In the per protocol set, with a hemoglobin target of 10 to 12 g/dL, more patients in the roxadustat group than in the darbepoetin group achieved an adequate hemoglobin response during the first 24 weeks of treatment (89.5% vs 78.0%).
This establishes "roxadustat's noninferiority to darbepoetin alfa," Barratt and his colleagues report.
The incidence of treatment-emergent adverse events was comparable in the two treatment groups.
The PRO₂TECT studies were funded by Akebia Therapeutics. The DOLOMITES study was funded by Astellas. Chertow reports receiving consultancy fees from Akebia, Amgen, Ardelyx, Astra Zeneca, Baxter, Cricket, DiaMedica, Gilead, Miromatrix, Reata, Sanifit, and Vertex; having ownership interests in Ardelyx, CloudCath, Durect, DxNow, Eliaz Therapeutics, Outset, Physiowave, and PuraCath; and being a scientific advisor or on the board of directors for Satellite Healthcare, and coeditor of Brenner & Rector's The Kidney. Barratt reports receiving research funding from Astellas.
Kidney Week 2020: American Society of Nephrology Annual Meeting: Abstract TH-OR02, presented October 22, 2020; Abstract FR-OR54, presented October 23, 2020.
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Cite this: Cardiovascular Safety Results for Anemia Drug Disappoint - Medscape - Oct 26, 2020.