GSK’s Daprodustat Comes Out Strong for CKD-Related Anemia, But What About its Heart Safety Profile?

GlaxoSmithKline (GSK) unveiled positive safety and efficacy data for its oral anemia drug daprodustat from five pivotal trials for the drug last week. The drug was evaluated for the treatment of both dialysis and non-dialysis patients with anemia stemming from chronic kidney disease (CKD). The topline results hold even more significance after the rejection of AstraZeneca and FibroGen’s oral anemia med roxadustat by the US Food and Drug Administration (FDA) in August.

Data from the trials demonstrated that daprodustat improved, or maintained, hemoglobin levels within target range without increasing cardiovascular risk when compared to standard of care, according to GSK.

The trials are part of GSK’s Phase III ASCEND (Anaemia Studies in Chronic Kidney Disease: Erythropoiesis via a novel prolyl hydroxylase inhibitor Daprodustat) program for daprodustat, and interim results from the studies were presented at the American Society of Nephrology’s Kidney Week 2021. The results were also published in the New England Journal of Medicine at the same time. Two of the five trials focused on non-dialysis (ASCEND-ND) and dialysis (ASCEND-D) patients, and detailed data from these trials was shared at the nephrology meeting.

In a press release, GSK said “the positive primary efficacy and safety results confirm the potential for daprodustat to be a new oral treatment for patients with anaemia due to chronic kidney disease (CKD) in both non-dialysis and dialysis settings.”

The ASCEND program enrolled over 8,000 patients who were treated with daprodustat for just over four years.

Related: GSK’s Dostarlimab Wins FDA Approval for dMMR Endometrial Cancer

What is Daprodustat?

Daprodustat is an investigational oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI). It was developed based on Nobel Prize-winning findings of how cells sense and adapt to oxygen availability.

In the ASCEND trials, Daprodustat was comparable to Amgen’s Aranesp (darbepoetin alfa), an erythropoiesis-stimulating agent (ESA), with respect to heart safety. Darbepoetin alfa is a synthetic version of the hormone erythropoietin, which is made in the kidneys and stimulates the production of red blood cells (RBC), or erythrocytes. Kidney dysfunction in CKD leads to impaired production of the hormone, particularly in more advanced disease.

A major issue with ESAs is their associated cardiovascular risks, and HIF-PHIs have not been faring much better, especially in non-dialysis populations. AstraZeneca’s Roxadustat was knocked down by the FDA over issues of heart safety and Akebia Therapeutics’ vadadustat demonstrated heart risks even greater than those of ESAs, particularly in non-dialysis patients. Roxadustat was also flagged by the FDA for an increased risk of blood clots.

Cardiac Safety Profile for Daprodustat

In the ASCEND-D trial for daprodustat, the risk of time to first major adverse cardiovascular event (MACE) was similar between daprodustat and darbepoetin alfa (25.2 percent versus 26.7 percent, respectively). Importantly, in the non-dialysis population, the risk of time to first MACE remained similar between daprodustat and the ESA (19.5 percent and 19.2 percent, respectively).

With the latest trial data, GSK’s daprodustat becomes the first HIF-PHI to find success for kidney disease anemia, irrespective of the dialysis status of patients, and with cardiovascular risks similar to those of ESAs.

There was some confusion over the so-called “on-treatment” MACE analysis, which included events that occurred when the drug was started and 28 days after the last dose. Results of that analysis showed that the risk of first MACE was 40 percent higher for the drug compared with darbepoetin alfa, with rates of 14.1 percent for daprodustat and 10.5 percent for darbepoetin alfa.

However, in another study published simultaneously in the New England Journal of Medicine, the investigators noted that on-treatment analyses could confound the data, as they didn’t account for the different dosing intervals for the two drugs, which led to different observation periods. Upon accounting for the varying dosing schedules, the results were “more consistent with the results of the primary analysis,” the researchers said.

Market Size and Regulatory Pathway

“Over 700 million people suffer from chronic kidney disease worldwide, and an estimated 1-in-7 of these patients suffers from anaemia. Grounded in research based on Nobel Prize-winning science, we believe these data show daprodustat has the potential to transform the treatment landscape for these patients, many of whom have limited treatment options today,” said Dr. Hal Barron, chief scientific officer and president, R&D, GSK, in the statement from the company.

Currently, GSK’s daprodustat is only approved in Japan (as Duvroq) for patients with renal anemia. GSK said the new data will be used to support its regulatory filings with health authorities around the world.