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In the PRO2TECT program, the investigational agent vadadustat for the treatment of anemia in patients with chronic kidney disease (CKD) not on dialysis showed similar efficacy to darbepoetin alfa, but failed to prove non-inferiority for major adverse cardiac events (MACE).

of Stanford University in California, presented findings on a prespecified regional analysis during a virtual presentation at the recent Kidney Week 2020 Meeting. In this 番茄社区app video, he describes the key results and takeaways.

Following is a transcript of his remarks:

These were two randomized, phase III global trials comparing vadadustat with the darbepoetin alfa active control in patients with non-dialysis-dependent chronic kidney disease.

There were two trials, one in patients who were ESA or erythropoiesis stimulating agent-untreated, also known as a correction phase, and another trial with ESA-treated patients, so these were patients on active therapy with ESAs who were converted to vadadustat. The target hemoglobin concentrations in the U.S. were 10 to 11 g/dL, and outside of the U.S., 10 to 12 g/dL.

The safety analysis was prespecified as a combined analysis across both the ESA-untreated and the ESA-treated trials. They were event-driven, and as I mentioned earlier with respect to the duration of the trial, the trial continued until the requisite number of events were collected.

We aimed for a non-inferiority margin, the upper bound of which was 1.25, and for the efficacy assessment, the lower bound of the 95% confidence limit was 0.75 g/dL in hemoglobin concentration.

We'll proceed with the primary findings. This slide shows the primary endpoint, MACE, defined here as all-cause mortality or non-fatal MI and stroke. Expanded MACE -- which included thromboembolic disease and hospitalized heart failure -- and then all-cause mortality, cardiovascular MACE, and cardiovascular mortality.

If we focus on the top row of MACE, which was the primary endpoint, we can see that the vadadustat versus darbepoetin comparison did not meet the non-inferiority margin of 1.25 with the confidence limits extending beyond that range.

This slide demonstrates, basically, analyses repeated using age as a continuous variable in the Cox model. Again, though, the hazard ratios were attenuated. The 95% confidence limit did not meet the non-inferiority criterion.

To conclude, with respect to cardiovascular safety, vadadustat did not meet prespecified non-inferiority criterion, compared to darbepoetin alfa with respect to cardiovascular safety in patients with anemia and non-dialysis-dependent chronic kidney disease. Many of you probably saw Dr. Eckardt's presentation from the INNO2VATE trials which demonstrated that vadadustat did meet the prespecified non-inferiority criterion in those two trials.

Using age as a continuous variable, the hazard ratio and upper bound of the confidence intervals were attenuated, and as we saw, the cardiovascular risk was similar between the two treatment arms in the U.S., where the hemoglobin target was 10 to 11 g/dL, but was higher in patients randomized to vadadustat in the regions using a higher hemoglobin target of 10 to 12 g/dL.

In terms of efficacy, vadadustat was non-inferior to darbepoetin in maintaining target-range hemoglobin concentrations during both the primary and secondary evaluation periods. Thank you very much for your time and attention.

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