Rates of MACE, serious AEs, similar between oral therapy and ESAs

Daprodustat, an oral hypoxia-inducible factor prolyl hydroxylase (HIF PH) inhibitor proved non-inferior to conventional erythropoietin stimulating agents (ESA) for the treatment of anemia in chronic kidney disease (CKD), whether or not patients were on dialysis, two separate phase III international studies found.

In the ASCEND-D trial, a total of 2,964 patients were randomized to either daprodustat or the injectable ESA epoetin alfa if receiving hemodialysis or darbepoetin alfa if receiving peritoneal dialysis.

Hemoglobin levels were then tracked from baseline to weeks 28 through 52.

The mean change in hemoglobin at study endpoint was 0.28 g/dL in the daprodustat group and 0.10 g/dL in the ESA group, a between-group difference of 0.18 g/dL (95% CI, 0.12-0.24), meeting the prespecified noninferiority endpoint, Ajay Singh, MB, Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues reported in The New England Journal of Medicine.

At a median follow-up of 2.5 years, 25.2% of patients in the daprodustat arm and 26.7% of patients in the ESA arm had experienced a major adverse cardiovascular event (MACE), another prespecified noninferiority endpoint, investigators also noted, at a hazard ratio of 0.93 (95% CI, 0.81-1.07).

In the ASCEND-ND study, a total of 3872 CKD patients not undergoing dialysis were again randomized to daprodustat or darbepoetin alfa.

In this study, the mean change in hemoglobin levels from baseline to weeks 28 through 52 was 0.74 g/dL in the daprodustat group versus 0.66 g/dL in the darbepoetin alfa group, a between group difference of 0.08 g/dL (95% CI, 0.03-0.13), again meeting the prespecified noninferiority endpoint, Singh and colleagues again reported in the same issue of The New England Journal of Medicine.

During a median follow-up of 1.9 years, 19.5% of patients treated with daprodustat and 19.2% of patients in the ESA group experienced a first MACE at a HR of 1.03 (95% CI, 0.89-1.19), again meeting the prespecified noninferiority endpoint.

“We found that oral delivery of daprodustat worked just as well as conventional therapy, increasing and maintaining hemoglobin levels among non-dialysis patients and maintaining levels among patients on dialysis, and was just as safe,” Singh said in a statement.

“This could usher in a new way of treating people with kidney disease, avoiding injections while stimulating the body to produce red blood cells [so o]ral treatment has the power to be transformative for patient care,” he added.

In ASCEND-D, patients with CKD had a baseline hemoglobin level of between 8 and 11.5 g/dL while in ASCEND-ND, baseline hemoglobin levels were between 8 to 10 g/dL in patients not receiving an ESA or 8 to 11 g/dL among those already receiving an ESA.

The mean baseline hemoglobin level in the dialysis cohort was 10.4 g/dL while the mean baseline hemoglobin level in non-dialysis patients was similar in both treatment groups.

In ASCEND-D, serious adverse events (AEs) were documented in 52.2% of the daprodustat group compared with 50.7% in the ESA group. In the ASCEND-ND study, 43.9% of patients treated with daprodustat and 36.4% of those treated with the ESA also experienced a serious AE, as investigators pointed out.

Thus, the safety profile of daprodustat appeared to be similar to that of an ESA, as no unexpected safety concerns were identified, Singh and colleagues suggested.

However, in an editorial commenting on the use of HIF-PHIs for the treatment of anemia in CKD, Patrick Parfrey, MD, Memorial University of Newfoundland, St. John’s Newfoundland, noted that the treatment of anemia in patients with non-dialysis dependent CKD is more complicated, because treatment with an ESA may cause harm and the benefits of such treatment are uncertain.

He also cautioned that in theory, activation of the HIF pathway by the HIF-PHIs may promote the development of cancer.

Indeed, in the ASCEND-ND trial, “investigators observed a higher incidence of cancer-related death or tumor progression or recurrence in the daprodustat group (3.7%) than in the darbepoetin alfa group (2.5%),” Parfrey pointed out—a signal that was not observed in ASCEND-D where rates of cancer-related death or tumor progression or recurrence were very similar (3.2% and 3.5%, respectively).

Furthermore, in the non-dialysis CKD study, more esophageal or gastric erosions were seen in the daprodustat group at 3.6% compared with 2.1% in the ESA group—a signal that was again not seen in dialysis-dependent patients.

“The safety of HIF-PHIs from the cancer perspective will require longer follow-up,” the editorialist cautioned, and concluded: “Initial results in patients with DD-CKD are promising but in patients with NDD-CKD, questions about indications and safety warrant further investigation.”

As both the authors and the editorialist pointed out, most patients with CKD who are on maintenance dialysis have anemia as do many patients with CKD who are not yet dialysis-dependent.

Treatment of anemia with an ESA is effective but as a class of agents, the ESAs have been linked to an increased risk of stroke, myocardial infarction (MI), vascular access thrombosis, and tumor progression or death when targeting treatment to a normal hemoglobin level of between 13 and 14 g/dL: thus, cautious use of the ESAs is recommended.

As an oral alternative to ESAs, the HIF-PHIs are a new class of compounds that stabilize HIF, which in turn stimulates endogenous erythropoietin, increasing hemoglobin levels in patients with CKD.

  1. Daprodustat, an oral treatment for anemia, was as safe and effective as conventional erythropoietin stimulating agents (ESAs) in patients with chronic kidney disease (CKD), both on and not on dialysis.

  2. Rates of major adverse cardiovascular events and other serious adverse events were roughly equivalent between oral daprodustat and conventional ESAs.

Pam Harrison, Contributing Writer, BreakingMED™

Both studies were supported by GlaxoSmithKline.

Singh reported stock in Gilead Sciences and consulting work for GlaxoSmithKline.

Parfrey reported personal fees from Akebia, outside the submitted work.

Cat ID: 127

Topic ID: 81,127,730,127,448,192,925,540