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STOCKHOLM, Sweden — New data on clazakizumab, a monoclonal antibody targeting interleukin-6 (IL-6), and home hemodialysis suggest the potential of two ways to reduce the high risk for cardiovascular events in people receiving dialysis, according to presentations at the 61st European Renal Association Congress.

In one study, researchers found important reductions in inflammatory markers of cardiovascular events in people with end-stage kidney disease undergoing dialysis. A separate analysis showed a lower cardiovascular risk with home hemodialysis vs peritoneal dialysis. 

"In patients undergoing dialysis with documented inflammation, clazakizumab resulted in a robust reduction in inflammatory biomarkers that are associated with cardiovascular events and increased albumin," said first author Glenn Chertow, MD, MPH, of Stanford University School of Medicine in Stanford, California, in one presentation.

The clazakizumab study was concurrently published in Nature Medicine.

Testing IL-6 Inhibition

End-stage kidney disease is associated with an exceptionally high risk for mortality, with average adjusted death rates exceeding 19% and more than half of those deaths related to adverse cardiovascular outcomes, Chertow said. 

Meanwhile, standard therapies, including lipid-lowering statins, have shown little benefit in treatment for those patients.

IL-6 is known to be a central inflammatory cytokine playing a key role in the systemic inflammation in patients undergoing dialysis and a key contributor to cardiovascular risk in the general population. Chertow and his team theorized that targeting the IL-6 pathway could reduce cardiovascular events and possibly mortality in patients receiving maintenance dialysis.

For the double-blind, randomized phase 2b POSIBIL₆ESKD trial, 127 patients with cardiovascular disease and/or diabetes receiving maintenance dialysis with serologic evidence of inflammation at baseline were enrolled between October 2022 and August 2023.

The patients had been on hemodialysis for at least 12 weeks and their median baseline serum high-sensitivity C-reactive protein (CRP) was 8.3 md/dL. The most common cause of kidney failure was diabetes (71%). The patients had a mean age of 62 years; 33% were women, and 46% were non-White.

For the phase 2b dose-finding study, patients were randomly assigned in a 1:1:1:1 ration to receive either a low (2.5 mg), medium (5 mg), or high dose (10 mg) of clazakizumab (32 participants in each group) or placebo (31 participants) via intravenous bolus every 4 weeks for up to 6 doses.

The results at week 12 showed that participants treated with clazakizumab had substantial reductions in serum high-sensitivity CRP level of 89% in the low-dose clazakizumab group, 92% in the medium-dose group, and 93% in the high-dose group (all doses P <.0001 compared with placebo).

In contrast, the serum high-sensitivity CRP level increased over the same period by 19% in the placebo group.

Normalization of high-sensitivity CRP to levels < 2.0 mg/L was achieved in 79.2%, 82.1%, and 79.3% of participants in the low-, medium-, and high-dose groups, respectively, vs 0% of the placebo recipients.

The decreases in high-sensitivity CRP in the clazakizumab group were rapid and were maintained throughout 24 weeks of follow-up. 

For secondary outcomes, all clazakizumab groups showed significant reductions in the downstream biomarkers of IL-6 activity, including fibrinogen, serum amyloid A, secretory phospholipase A2, and lipoprotein (all P <.001 compared with placebo).

Notably, mean increases in serum albumin level with clazakizumab were 0.28 g/dL in the low-dose group, 0.25 g/dL in the medium-dose group, and 0.21 g/dL in the high-dose group (all P <.01 vs placebo), compared with 0.04 g/dL in the placebo group.

Safety Measures

Clazakizumab was well tolerated, with the most common serious adverse events being serious infection (12.5% in the low-dose group, 9.4% in the medium-dose group, and 28.1% in the high-dose group vs 6.5% in the placebo group).

Serious infections led to discontinuation of treatment in six patients, including one in the placebo group. 

There were no reports of sustained grade 3 or 4 thrombocytopenia or neutropenia.

Consistent with an anti-inflammatory effect, small increases in total cholesterol were observed in all three clazakizumab groups.

Six deaths occurred; these were similarly distributed across all groups, and none were considered to be related to clazakizumab. 

Asked by an audience member following his presentation about how the infections affected patients' CRP levels, Chertow explained that "there were some elevations in the CRP in those patients, but not consistently."

He agreed that the issue is important: "I think we have to be very cautious and use our clinical judgment in terms of evaluating the risk of infection in patients receiving this drug, because we would hate to ignore an infection as the result of CRP has been suppressed by clazakizumab."

CRP, Albumin Improvements Called 'Dramatic'

"All three doses of clazakizumab were much lower than doses previously used in the treatment with the drug in a variety of immunological diseases," Chertow said in his talk.

"Yet, even with these quite low doses of clazakizumab, there was dramatic reduction, not only in CRP but in the downstream biomarkers of IL-6 activity, that was sustained over time," he said.

The mean increases in albumin were especially remarkable, Chertow said.

"I've been caring for patients on dialysis for the better part of 30 years, and I very rarely even over the course of 6 months let alone 3 months [have] seen an increase in the serum albumin [to this degree]," he said.

In their paper, Chertow and colleagues add that the increase in albumin is important "not only because of the strong association between low serum albumin concentrations and mortality in patients receiving dialysis, but also because few other controlled interventions have demonstrated the ability to increase serum albumin in this population."

Clazakizumab has been evaluated in a variety of other phase 2 studies in other inflammatory diseases, including rheumatoid arthritis and psoriatic arthritis, and the drug is currently also being studied in the phase 3 IMAGINE trial of the treatment of chronic active antibody-mediated rejection in kidney transplant recipients.

Although the current phase 2b study did not include patients receiving peritoneal dialysis, the authors expect to include those patients in the phase 3 trial, which is moving ahead with a focus on the 5-mg dose.

Peter Stenvinkel, MD, PhD, of the Division of Renal Medicine at Karolinska Institutet in Solna, Sweden, who was a co-author on the study, underscored that "these are important data showing that hemodialysis patients benefit from targeted anti–IL-6 treatment." 

He explained that statins may not be of benefit in patients on dialysis in preventing cardiovascular events owing to a compromised response to those therapies.

"Residual inflammatory risk is likely a major determinant of outcome in dialysis patients," Stenvinkel told Medscape Medical News. "Statins do not improve outcomes in these dialysis patients."

The study results indicate that "targeting that residual inflammatory risk may improve outcomes and improve quality of life in this high-risk patient group," he said.

"[These are] very promising signals of a novel treatment strategy that now will be tested in a phase 3 trial," Stenvinkel added.

Further commenting on the research, Silvi Shah, MD, of the Division of Nephrology and Hypertension at the University of Cincinnati, Cincinnati, Ohio, said that "clazakizumab is a promising drug that has shown a reduction in inflammatory markers." 

"I remain hopeful that it can impact cardiovascular disease risk in dialysis patients, with cardiovascular disease being the leading cause of mortality in dialysis patients."

Shah, who was not involved in the clazakizumab study, noted that limitations include that "we did not have information on dialysis prescriptions and dialysis treatment details."

Home Hemodialysis vs Peritoneal Dialysis

Shah was first author on another study, also presented at the meeting, that found significantly lower rates of cardiovascular events in patients with end-stage kidney disease treated with home hemodialysis compared with those receiving peritoneal dialysis. 

The study included 68,645 patients identified in the United States Renal Data System and linked Medicare claims between 2005 and 2018.

With a mean follow-up of 1.8 years, home hemodialysis was associated with a slightly lower adjusted risk for cardiovascular events than peritoneal dialysis (hazard ratio [HR], 0.92). However, the home hemodialysis patients had as much as a 42% lower adjusted risk for stroke (HR, 0.58), and a 17% lower adjusted risk for acute coronary syndrome (HR, 0.83) vs those receiving peritoneal dialysis, with no statistically significant difference in risk for heart failure (HR, 1.05). 

In terms of mortality, home hemodialysis was meanwhile associated with 22% lower adjusted risk for cardiovascular death (HR, 0.78) and 8% lower adjusted risk for all-cause death (HR, 0.92) compared with peritoneal dialysis. 

"Previous studies showed a lower rate of cardiovascular hospitalizations with home hemodialysis; however, no study has specifically examined cardiovascular events," Shah said, adding that further studies also need to compare outcomes by home dialysis modalities.

Key factors, including the frequency of dialysis, could explain the differences, she explained.

"We believe home hemodialysis patients receive more frequent and longer dialysis than peritoneal dialysis, which results in better solute clearance and better volume removal, therefore resulting in better control of parameters associated with bone and mineral metabolism and reduction in left ventricular volume and mass," Shah said.

"This eventually lowers the risk of cardiovascular events and overall cardiovascular death," she said. 

"Clinicians should use this information in shared decision-making and counseling of patients with kidney disease." 

The trial was sponsored by CSL Behring. Chertow has served on the Board of Directors of Satellite Healthcare, a nonprofit dialysis provider, and Stanford University has received a grant from the trial sponsor, CSL Behring. Stenvinkel has received honoraria from CSL. Shah had nothing to disclose.