Trio of trials supports roxadustat for CKD-anaemia

Roxadustat improves haemoglobin levels vs placebo and epoetin alfa, with similar  safety profile, in 8,000 patients with chronic kidney disease (CKD)-related anaemia on- and off-dialysis, according to a pooled efficacy and CV safety analyses of roxadustat, spanning over 13,000 patient exposure years.

Anaemia is a frequent complication of CKD. The findings from three pivotal trials support roxadustat as the first-in-class oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) for CKD-anaemia.

“We, clinical nephrologists know that dialysis patients are not created equal. There are CKD levels 1 through 5, with different physiological requirements, [as well as] dialysis-incident vs prevalent patients, and how they react [to treatment]. Morbidity and mortality are also different,” said first author Associate Professor Roberto Provenzano of Wayne State University in Detroit, Michigan, US during his presentation at ASN Kidney Week 2019. “These are unique populations and these studies pooled all of our knowledge on treating anaemia in each of them.”

CV safety holdup in study populations

Cardiovascular (CV) safety was demonstrated with roxadustat in all study populations. There was no increase in the risk of major adverse CV events (MACE, defined as a composite of all-cause mortality, stroke, and myocardial infarction) nor in MACE+ (defined as heart failure or unstable angina requiring hospitalization), and all-cause mortality with roxadustat in nondialysis-dependent patients vs placebo.

In incident (newly initiated) dialysis patients, there was a 30 percent lower risk of MACE and a 34 percent lower risk of MACE+ with roxadustat. There was also a trend  towards lower all-cause mortality risk relative to epoetin alfa, which is currently the standard of care for erythropoietin-deficient anaemia in most patients with CKD,  said Provenzano.

Dialysis-dependent patients receiving roxadustat also had a lower risk of MACE+ and no increased risk of MACE or all-cause mortality vs those treated with epoetin alfa.

From bench to bedside

Roxadustat is approved in China for the treatment of anaemia in CKD patients, regardless of whether they require dialysis. In Japan, roxadustat is indicated for the treatment of patients with CKD-anaemia on dialysis. Following results of the pooled efficacy and CV safety analyses, US FDA filing for approval is expected at yearend.  “This is one of the rare opportunities to watch an agent go from bench to bedside,” said Provenzano.

Roxadustat works by mimicking the body’s natural response to low oxygen and physiologically stimulating red blood cell production. Across three trials of non-dialysis dependent patients, roxadustat significantly improved haemoglobin levels vs placebo, regardless of iron depletion levels at baseline. In the dialysis group, roxadustat achieved higher mean haemoglobin increases vs epoetin alfa, particularly in inflamed patients, said Provenzano.

3 trials, 13 patient exposure years

Overall, the pooled analysis included 4,277 patients not on dialysis and 3,880 patients on dialysis for a total of 6,194 and 7,059 patient exposure years, respectively. [ASN Kidney Week 2019, abstract FR-OR131] Among the nondialysis patients, 42 percent had baseline eGFRs <15; 40 percent were iron deficient. Dialysis-dependent patients were well-balanced between the intervention and standard of care arms, with similar baseline mean haemoglobin levels (9.63 vs 9.67), TSAT (33 vs 32.7), and ferritin (608.6 vs 602.2 ng/mL), Provenzano reported.

Aside from the differences in the rate of MACE, MACE+, and all-cause mortality were also looked into.

Non-dialysis patients on roxadustat had a nearly identical risk for all three safety outcomes vs placebo (hazard ratios [HRs], 1.04–1.08). Incident dialysis patients had a reduced risk of MACE (HR, 0.70, 95 percent confidence interval [CI] 0.51-0.96) and MACE+ (HR, 0.66 95 percent CI, 0.50-0.89), while prevalent dialysis patients had a lower risk for MACE+ vs epoetin alfa (HR, 0.86, 95 percent CI, 0.74-0.98), Provenzano reported.

HIMALAYAS:  Roxadustat in patients newly started on dialysis

Among 1,043 incident-dialysis patients on treatment between 2 weeks and ≤4 months in the HIMALAYAS trial, roxadustat was noninferior and superior to epoetin alfa in improving haemoglobin levels from baseline to the levels averaged across weeks 28–52 vs epoetin alfa (-2.57 vs -2.36). The proportion of patients achieving a haemoglobin response was also similar between groups (88.2 percent vs 84.4 percent), Provenzano reported. [ASN Kidney Week 2019, abstract TH-0RO21]

 “This is an important patient group – they just survived CKD, they just got started on dialysis, they’re sick, scared, and their mortality is high as they transition through the first year of dialysis,” said Provenzano. “And in HIMALAYAS, patients on roxadustat required less iron use during the trial, and the treatment remained superior to epoetin alfa even when patients were iron-depleted or inflamed at baseline.”

HIMALAYAS pooled with other roxadustat phase III dialysis studies for CV safety analyses.

ROCKIES: A trial in dialysis-dependent patients

In the ROCKIES trial of 2,133 patients with anaemia receiving peritonial or haemodialysis, the mean haemoglobin change from baseline to the levels averaged across weeks 28–52 was significantly higher with roxadustat given thrice weekly vs epoetin alfa (+0.77 vs +0.68 g/dL; p=0.036), with an initial dosing effect that leveled out over the course of the 52 weeks, reported co-author Dr Steven Fishbane from the Feinstein Institutes for Medical Research at Northwell Health in Great Neck, New York, US. [ASN Kidney Week 2019, abstract TH-ORO22]

The proportion of time patients had haemoglobin levels of at least 10 g/dL between weeks 28 and 52 was also significantly higher in the roxadustat group (79 percent vs 76 percent for epoetin alfa; p=0.045).

“It is a momentous occasion to be able to look for the first time at the effects of inhibiting the HIF system pharmacologically,” he said. “Roxadustat increased haemoglobin as effectively in dialysis patients with anaemia as epoetin alfa; it increased haemoglobin more effectively in those with inflammation, required significantly less intravenous iron use, and lowered hepcidin to a greater extent,” Fishbane said.

Common adverse events with roxadustat were generally similar with those of epoetin alfa and commonly found in dialysis-dependent patients.

OLYMPUS: Roxadustat in non-dialysis dependent CKD and anaemia

In the OLYMPUS trial of 2,781 patients with stage 3, 4, or 5 CKD and anaemia but not on dialysis, roxadustat demonstrated superior haemoglobin change from baseline to the averaged levels across weeks 28–52 vs placebo (+1.75 vs +0.40; p<0.001). Haemoglobin response was also significantly higher with roxadustat (77 percent vs 8.5 percent for placebo; p<0.001). [ASN Kidney Week 2019, abstract TH-ORO23]

“This was regardless of iron repletion or inflammation.  In the population we worry about most, the inflamed population which is to my sense the biggest cause of hyporesponse in 2019, roxadustat works quite well,” Fishbane said. “Roxadustat also reduced the need for rescue therapy, including RBC transfusion.”

Of note, more patients on placebo (n=800) discontinued treatment earlier than on roxadustat (n=499), particularly  those with move advanced CKD; 38 percent of patients on placebo started dialysis.

New treatment option for CKD-anaemia

“The pooled CV safety and efficacy data,  support roduxastat’s potential as an important new treatment option for patients with anaemia from CKD who have seen little-to-no innovation in decades,” said Provenzano. “Roxadustat efficacy and safety will continue to be studied in a phase IV trial.”