Investigational Oral CKD-Anemia Agent Effective, Safe

The investigational hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI) daprodustat was safe and as effective as erythropoiesis-stimulating agents (ESAs) for anemia, according to the phase III ASCEND program.

In the first of the two ASCEND trials looking at patients with chronic kidney disease undergoing dialysis, patients treated with oral daprodustat had a mean change in hemoglobin level of 0.28±0.02 g/dL from baseline to weeks 28 through 52, reported Ajay Singh, MBBS, MBA, of Brigham and Women's Hospital in Boston and chair of the ASCEND program's Executive Steering Committee, and colleagues.

Meeting the prespecified noninferiority margin of -0.75 g/dL, patients treated with an ESA saw an average hemoglobin change of 0.10±0.02 g/dL during the trial (difference of 0.18 g/dL, 95% CI 0.12-0.24).

The findings were presented at the American Society of Nephrology's virtual Kidney Week and simultaneously published in the New England Journal of Medicine (NEJM).

Daprodustat also appeared safe for the heart, as there was a 25.2% major adverse cardiovascular event (MACE) rate (374 of 1,487) in the daprodustat group compared with 26.7% in the ESA group (394 of 1,477). Also meeting the prespecified noninferiority margin for daprodustat, this equated to a statistically nonsignificant difference in MACE risk (HR 0.93, 95% CI 0.81-1.07).

There was also a similar rate of other adverse events reported between the two treatment groups, including of esophageal or gastric erosions of special interest.

In the second ASCEND trial -- this time focusing exclusively on CKD patients not undergoing dialysis -- similar outcomes were reported. Also led by Singh, these findings were additionally published in the NEJM.

Also meeting the prespecified noninferiority margin for the primary outcomes, the average change in hemoglobin level from baseline to weeks 28 through 52 was 0.74±0.02 g/dL in the daprodustat group and 0.66±0.02 g/dL in the darbepoetin alfa group (difference of 0.08 g/dL, 95% CI 0.03-0.13).

A similar heart safety profile was seen among this non-dialysis population as well, with a first MACE occurring in 19.5% (378 of 1937 patients) in the daprodustat group and 19.2% (371 of 1,935 patients) in the darbepoetin alfa group -- meeting the prespecified noninferiority margin of 1.25. Likewise, this also translated to a statistically nonsignificant difference in MACE risk (HR 1.03, 95% CI 0.89-1.19).

However in this non-dialysis population, there was a higher rate of cancer-related death or tumor progression or recurrence (3.7% vs 2.5%) and esophageal or gastric erosions (3.6% vs 2.1%) in the daprodustat group.

"As a practicing clinician, I can tell you firsthand that when anemia is left untreated, it contributes to increased morbidity, mortality, and a reduced quality of life," Singh told MedPage Today. "Further, when it's not properly managed, anemia – particularly severe anemia -- could result in exhaustion and an inability to highly function in day-to-day life."

"Today, particularly in the non-dialysis population, anemia is often underdiagnosed and undertreated regardless of the impact it has as a complication of CKD," he explained, adding that today, only 30% of non-dialysis patients are prescribed ESAs who should be, largely due to the method of administration as an injectable. He noted that this often requires administration by a healthcare provider or during dialysis, and also in general can be uncomfortable for patients.

"This creates compliance issues for non-dialysis patients, for which we know treatment is currently underutilized," he underscored. "An oral option that can be as safe and effective as the current standard of care, such as what was found in the ASCEND program with daprodustat, has the potential to be transformative for patient care."

Part of a new class of agents, daprodustat acts as an HIF-PHI to inhibit the oxygen pathway within the body, stimulating endogenous erythropoietin production and thus raising hemoglobin levels. Other investigational HIF-PHIs in this class include desidustat, enarodustat, molidustat, roxadustat, and vadadustat -- none of which are FDA approved.

"Daprodustat is the first agent within the HIF-PHI class to demonstrate clear and consistent efficacy in achieving and maintaining hemoglobin levels, along with no increased CV [cardiovascular] risk compared to the standard of care for patients living with chronic kidney disease, regardless of their dialysis status," Singh pointed out.

The ASCEND clinical program randomized a total of 6,836 patients: 2,964 in the dialysis trial and 3,872 in the non-dialysis trial.

In the dialysis trial, all participants had been undergoing dialysis for at least 90 days (89% on hemodialysis, 11% on peritoneal dialysis), had received an ESA for at least 6 weeks, and had a hemoglobin level between 8.0 and 12.0 g/dL. All participants had a serum ferritin level over 100 ng/mL and a transferrin saturation above 20%. At baseline, the average hemoglobin level was 10.4±1.0 g/dL in the total cohort.

The starting dose of oral daprodustat was dosed according to the participant's prior ESA dose, ranging between 4 and 12 mg daily. Those on hemodialysis were given epoetin alfa and those receiving peritoneal dialysis were given darbepoetin alfa.

In the non-dialysis trial, all participants had stage III-V CKD (majority with stage IV), were not currently receiving dialysis, or were scheduled to start dialysis within 90 days. All also met the hemoglobin and ESA criteria, with a serum ferritin level of more than 100 ng/mL and a transferrin saturation above 20%.

Of the 1,937 participants randomized to daprodustat, the starting dose ranged from 1 to 4 mg daily, according to the baseline hemoglobin level if the patient was not receiving an ESA and according to the ESA dose if the patient was receiving an ESA.

In an accompanying editorial, Patrick Parfrey, MD, of Memorial University of Newfoundland in Canada, compared these trials to the recent phase III program led by Glenn Chertow, MD, MPH, of Stanford University School of Medicine in California, testing vadadustat -- another investigational HIF-PHI agent. Parfrey pointed out that in the trial of vadadustat in non-dialysis patients, there was a modest heart safety signal (HR 1.17, 95% CI 1.01-1.36).

"Whether the vadadustat result occurred by chance or was the result of methodologic problems, or whether it reflects the potential safety of vadadustat, requires further study," Parfrey wrote. He added that while these initial results in the dialysis population are "promising," the adverse events seen in the non-dialysis population "warrant further investigation."

As for the next steps for daprodustat, Singh said: "The goal is to work with the appropriate people, especially regulatory members, for both the FDA and EMA [European Medicines Agency] and the sponsor, GlaxoSmithKline, to get daprodustat into the hands of patients as safely and quickly as possible." (Currently, the agent is approved in Japan.)