New Oral Agent for Anemia in CKD Encouraging but Questions Remain

Pam Harrison

July 25, 2019

Roxadustat (AstraZeneca/FibroGen), a new oral agent that stimulates red blood cell production and regulates iron metabolism, is superior to placebo for the treatment of anemia in patients with chronic kidney disease (CKD) not yet receiving dialysis, a new Chinese study indicates.

The oral agent is also noninferior to standard treatment with an erythropoiesis-stimulating agent (ESA) in the correction of anemia in CKD patients undergoing dialysis, a twin study, also conducted in China, suggests.  

Nan Chen, MD, Department of Nephrology, Ruijin Hospital, Shanghai, China, is the lead author of both studies, which were published online July 24 in the New England Journal of Medicine.

Roxadustat is an inhibitor of the prolyl-hydroxylase domain that activates hypoxia-inducible factors (HIF). There are other candidates in this new therapeutic drug class but roxadustat is furthest along in clinical development.

The novel agents treat anemia of CKD "through multiple pathways, beyond increasing erythropoietin levels, by means of effects on inflammation and iron handling, and particularly by decreasing the hepcidin level," explains Joshua Kaplan, MD, Rutgers New Jersey Medical School in Newark, in an accompanying editorial.

However, "adverse events may yet appear when larger, longer trials are completed," he notes, pointing to the OLYMPUS study in nondialysis patients and the ROCKIES trial in dialysis patients.

But if HIF prolyl-hydroxylase inhibitors ultimately fulfill their promise and facilitate normalization of hemoglobin levels in patients with CKD and reduce cardiovascular morbidity related to anemia without the increased risks seen in trials of ESAs, "there might ultimately be a revolution in the treatment of anemia of CKD," Kaplan suggests.

Good but With Caveats; No Data on Long-Term Safety With Roxudustat  

Chen and colleagues explain anemia (defined as a hemoglobin level < 10.0 g/dL) is a complication of CKD associated with increased risks of death and complications. Worldwide, among CKD patients not undergoing dialysis, anemia remains undertreated because of delayed referral to nephrologists and concern about the safety of ESAs.

And anemia is present in more than 90% of patients who undergo dialysis, they write.

Kaplan notes that multiple trials of ESAs have shown, at best, no improvement in outcome, and at worst, increased risks of stroke and death for the treatment of anemia in patients with CKD.

This was demonstrated in the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial and Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).

Such findings "led to lowering of the goals regarding hemoglobin levels in patients undergoing dialysis to a range of 9 to 11 g/dL, and patients with anemia of CKD who were not undergoing dialysis were treated only to reduce the risk of transfusions or to treat symptomatic anemia," he notes.

"Because of inflammation, CKD patients with anemia are unable to access their existing irons stores, which worsens their anemia," Kaplan explained to Medscape Medical News.

Treatment with this new class of agents, while increasing erythropoietin through beneficial effects on inflammation and iron handling, and by decreasing hepcidin levels, nevertheless leads to lower erythropoietin levels than with ESA treatment.

"This is actually a good thing," he observed, because it helps avoid the use of high doses of intravenous iron, "which has been associated with an increased inflammatory state and increased mortality," he further explained.

The two new Chinese trials show "us that roxadustat is effective in treating anemia and accomplishes other things like reducing hepcidin levels," Kaplan says. However, "what they don't establish is long-term safety," he emphasizes.

This issue will be addressed when the full results of the OLYMPUS and ROCKIES trials, exploring the same treatment options in both American and European populations, are reported.

OLYMPUS showed that roxadustat led to statistically significant and clinically meaningful improvement in hemoglobin compared with placebo in 2781 nondialysis-dependent patients in 26 different countries.

Similarly, the ROCKIES study demonstrated significant improvement in hemoglobin compared with epoetin alfa in over 2000 dialysis-dependent patients in 18 different countries.

Topline results from OLYMPUS and ROCKIES were released in December 2018, with a note that the full findings would "be presented at forthcoming medical meetings."

Roxadustat in Nondialysis Patients

With a half-life of approximately 10 hours, roxadustat can be given orally three times a week, say Chen and colleagues, and the intermittent dosing strategy used with roxadustat for the treatment of anemia in patients with CKD was "developed to permit durable maintenance of effect."

In the current trial in nondialysis-dependent patients, a total of 154 CKD patients were randomized in a 2:1 ratio to receive roxadustat or placebo three times a week for 8 weeks in a double-blind manner. This was followed by an 18-week open-label extension during which all patients received roxadustat.

The mean increase in hemoglobin from baseline averaged over weeks 7 through 9 of the 8-week randomized portion of the trial was 1.9 g/dL in the roxadustat group. In the placebo group, hemoglobin decreased by a mean of 4.9 g/dL over the same 8-week interval (P < .001).

The mean reduction from baseline in hepcidin level (associated with greater iron availability) was 56.1 ng/mL in the roxadustat group and 15.1 ng/mL for placebo patients.

Reductions in total cholesterol were also substantially greater in the roxadustat group at 40.6 mg/dL from baseline vs 7.76 mg/dL among placebo controls — a 23% reduction in total cholesterol during the initial 8 weeks of active therapy.

On the other hand, hyperkalemia and metabolic acidosis did occur more frequently with active therapy.

"During the 18-week open phase of the trial, roxadustat was associated with continued efficacy," Chen and colleagues observe. "And hemoglobin levels were maintained during the subsequent 18-week open-label treatment period," they conclude.

Roxadustat in Dialysis Patients

For the Chinese study in dialysis-dependent patients, a total of 305 patients who had received dialysis for at least 16 weeks and who had been on stable doses of epoetin alfa for at least 6 weeks were randomized 2:1 to either roxadustat at a starting dose of 100 to 120 mg, depending on the patient's weight, or to continue on epoetin alfa at the same dose they were already on. Both agents were given three times a week for 6 months.

A total of 256 patients — 162 in the roxadustat group and 94 in the epoetin alfa group — completed the study protocol.

"The use of oral iron therapy was allowed [but] intravenous iron therapy was prohibited except as rescue therapy," the researchers note.

The primary endpoint was the mean change in hemoglobin level from baseline to the average level during weeks 23 through 27.

Roxadustat led to a numerically greater mean increase in hemoglobin of 0.7 g/dL than the comparator agent, epoetin alfa, which increased hemoglobin by a mean of 0.5 g/dL and was statistically noninferior.

Compared with epoetin alfa, roxadustat increased the transferrin level (difference 0.43 g/L), maintained the serum iron level (difference 25 µg/dL), and attenuated decreases in the transferrin saturation (difference 4.2 percentage points).

And at week 27, hepcidin levels had dropped by 30.2 ng/mL in the roxadustat arm compared with only 2.3 ng/mL in the epoetin alfa arm.

Mean changes in both total cholesterol and low-density lipoprotein (LDL) cholesterol levels were again in favor of the oral agent compared with parental ESA.

"The adverse events during treatment that we observed are consistent with those expected in patients undergoing dialysis," Chen and colleagues write.

Hyperkalemia was again reported more often in patients who received roxadustat but further analysis did not reveal any significant changes in mean potassium levels over time or between the two treatment groups.

However, more patients receiving roxadustat discontinued treatment owing to adverse events than those on epoetin alfa.

Oral Drug Would Be More Convenient

Kaplan said the reasons for the increase in hyperkalemia with roxadustat compared with placebo or epoetin alfa in both Chinese trials remains "unclear."

But hyperkalemia has not been reported as an adverse event in phase 2 trials of other HIF prolyl hydroxylase inhibitors, he notes, so it "may be an off-target effect of roxadustat rather than a class effect."

And none of the trials completed to date adequately addresses the issue of whether or not roxadustat can adequately treat patients with ESA-resistant and hyporesponsive anemia more effectively and more safely than current treatment options, he stresses.

Kaplan also wonders whether a drug such as roxadustat might also paradoxically lead to worse outcomes, despite the fact that it increases hemoglobin, a surprising finding that was nevertheless shown in CHOIR and TREAT.

"Agents like roxadustat are able to treat anemia without causing a large rise in erythropoietin levels, so if high levels of erythropoietin were leading to these worse outcomes with the ESAs [in previous trials], then conceivably, roxadustat among others could allow us to normalize hemoglobin and improve outcomes," he said.

And if roxadustat is ultimately approved for anemia, "it is a whole lot more convenient to give patients a pill than it is to schedule them to get their injection so that is going to make clinicians' lives easier and patients' lives better," Kaplan acknowledged.

The study in nondialysis patients was supported by FibroGen and FibroGen (China) Medical Technology Development. The study in dialysis patients was sponsored by AstraZeneca and FibroGen. Kaplan had no relevant financial disclosures.

N Engl J Med. Published online July 24, 2019. Study 1, Study 2, Editorial

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