Pooled Cardiovascular Data on Roxadustat Show No Increased Risk to Patients With CKD

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The risk of major adverse cardiovascular events was comparable with placebo in patients not treated with dialysis who received the investigational drug roxadustat, according to pooled cardiovascular safety data about the first-in-class oral therapy for patients with chronic kidney disease (CKD).

The risk of major adverse cardiovascular events (MACE) were comparable with placebo in patients not treated with dialysis who received the investigational drug roxadustat, according to pooled cardiovascular safety data about the first-in-class oral therapy for patients with chronic kidney disease (CKD).

The highly anticipated results of were presented Friday in a late-breaking session at the American Society of Nephrology Kidney Week 2019 meeting. Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) and works by restoring production of the hormone erythropoietin and improving iron regulation in patients with CDK who are anemic.

Reports on the 3 trials that served as the basis for the pooled results—HIMALAYAS, ROCKIES, and OLYMPUS—will be part of the submission to the FDA and were released Thursday. But what observers really wanted to hear was roxadustat's cardiovascular profile as compared with epoetin alfa or placebo.

The 3 trials looked at 3 different groups of patients. The ROCKIES trial compared roxadustat with epoetin alfa in patients with end-stage renal disease (ESRD) and anemia dependent on dialysis (DD);the OLYMPUS trial compared roxadustat with placebo in patients with CDK who were not on dialysis (NDD); and HIMALAYAS focused on patients with incident dialysis (ID), defined as patients who have been on dialysis for 4 months or less.

MACE includes all-cause mortality, stroke, and heart attack; MACE+ includes MACE, or hospitalization stemming from unstable angina or and congestive heart failure.

Robert Provenzano, MD, associate professor of medicine, Wayne State University, Detroit, Michigan, presented the pooled results.

In NDD patients (4270), risk of MACE, MACE+, and all-cause mortality were comparable with placebo.
In ID patients (1526), roxadustat had a 30% lower risk of MACE and a 34% lower risk of MACE+ compared with epoetin alpha.
For DD patients (3880), there was no increased risk of MACE and all-cause mortality and a lower risk of MACE+ compared with epoetin alfa.

In the pooled DD results, Provenzano broke out MACE+ incidence rates for the 1940 patients receiving roxadustat and the 1940 patients receiving epoetin alfa. They were:

Death: 10.7% for roxadustat versus 12% for epoetin alfa
Myocardial infarction: 5.3% versus 5.6%
Stroke: 2.3% versus 2.6%
Unstable angina: 0.9% versus 1.1%
Congestive heart failure, 6.2% versus 8.6%

Astra Zeneca said the pooled efficacy analyses in the NDD population showed roxadustat demonstrated a statistically significant mean increase from baseline in hemoglobin (Hb) levels, regardless of iron repletion, averaged over weeks 28 to 52 of 1.85 g/dL, compared with 0.13 g/dL with placebo (P <.001).

The pooled efficacy analyses in the DD population showed roxadustat demonstrated a statistically significant mean increase from baseline in Hb levels averaged over weeks 28 to 52 with 1.22 g/dL compared with 0.99 g/dL with epoetin alfa (P <.001).