Among patients not on dialysis, the experimental anemia treatment failed the phase-3 safety test for non-inferiority, they reports in the New England Journal of Medicine.
The findings come from two studies known as PRO2TECT, which looked at patients who were not on dialysis, and INNO2VATE, which studied patients who were on dialysis.
Both tests showed that vadadustat was not inferior when it came to correcting the anemia, regardless of dialysis status.
But it's the safety that has caused the most concern.
"The data are convincing that vadadustat is effective in increasing hemoglobin concentrations in both dialysis-dependent and non-dialysis-dependent populations but are less convincing with respect to safety," writes Dr. Adeera Levin of the University of British Columbia, in Vancouver, Canada, in a linked editorial.
Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor. Darbepoetin is an erythropoiesis stimulating agent.
PRO2TECT compared the two drugs in 3,476 patients with anemia. The volunteers who received vadadustat were 17% (95% confidence interval, 1% to 36%) more likely to die, develop a heart attack or experience a stroke than were patients treated with darbepoetin alfa, sold under the brand name Aranesp by Amgen.
Specifically, death or major cardiovascular events (MACE) occurred in 22.0% of vadadustat recipients versus 19.9% of those treated with darbepoetin alfa. Each MACE component - stroke, heart attack and all-cause death - was more frequent with vadadustat.
Every subgroup favored darbepoetin alfa.
When the team added in hospitalizations for either heart failure or a thromboembolic event into the mix of bad outcomes, the hazard ratio was 1.11 (95% CI, 0.97 to 1.27).
Both groups showed a comparable rate of progression in their kidney disease.
"Analysis of events in the current trials revealed that the higher risk that was observed among patients who had been randomly assigned to the vadadustat group than among those in the darbepoetin alfa group was due largely to an excess of nonfatal myocardial infarctions and a higher incidence of death from noncardiovascular causes," write Dr. Glenn Chertow of Stanford University School of Medicine in Palo Alto, California, who worked on both studies.
"We could not identify a reason for the excess in noncardiovascular deaths," they add.
After Akebia, which financed both trials, announced on September 3 that vadadustat had failed to meet the main safety goal in the test, the company's stock fell 70%.
INNO2VATE, with 3,923 participants with anemia and incident or prevalent dialysis-dependent chronic kidney disease, showed a rate of death, heart attack or stroke of 18.2% with the experimental drug versus 19.3% with darbepoetin alfa, a non-significant 4% reduction.
Target ranges for hemoglobin concentrations varied by country. But 43.6% of vadadustat patients were within their country-specific target range between weeks 24 to 36 compared with 56.9% of patients getting darbepoetin alfa. At weeks 40 to 52, the respective percentages were 39.8% and 41.0%.
From weeks 24 to 36, 1.3% of vadadustat patients received a red-cell transfusion versus 1.8% in the comparison group. The trend flipped during weeks 40 to 52, when the transfusion rates were 2.4% and 0.7%.
The company announced the positive findings for its INNO2VATE trial on May 5.
Dr. Chertow did not respond to two emailed requests for an interview.
SOURCES: https://bit.ly/2QWNSDX and https://bit.ly/3erI8u3 The New England Journal of Medicine, online April 28, 2021.
By Reuters Staff
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