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STOCKHOLM, Sweden — New data on clazakizumab, a monoclonal antibody that targets interleukin-6 (IL-6), and home hemodialysis suggest two possible ways to reduce the high risk of cardiovascular events in people undergoing dialysis, according to a presentation at the 61st Congress of the European Society of Nephrology.
In one study, researchers found that inflammatory markers of cardiovascular events were significantly reduced in patients with end-stage renal disease undergoing dialysis. Cardiovascular risk Home hemodialysis versus peritoneal dialysis.
“In dialysis patients with documented inflammation, clazakizumab significantly reduced inflammatory biomarkers associated with cardiovascular events and albumin“,” lead author Glenn Chartow, MD, MPH, of the Stanford University School of Medicine in Stanford, California, said in a presentation.
The clazakizumab study Simultaneous release in Nature Medicine.
IL-6 Inhibition Testing
End-stage renal disease carries a very high risk of death, with an average adjusted mortality rate of more than 19 percent, more than half of which is related to adverse cardiovascular disease outcomes, Chertow said.
Meanwhile, standard therapies such as lipid-lowering statins have been shown to be largely ineffective in treating these patients.
IL-6 is a central inflammatory cytokine that plays a key role in systemic inflammation in patients undergoing dialysis and is known to be a major contributor to cardiovascular risk in the general population. Chertow and his team theorized that targeting the IL-6 pathway could reduce cardiovascular events and mortality in patients undergoing maintenance dialysis.
Double-blind, randomized phase 2b study POSIBIL6The ESKD trial will enroll 127 patients with cardiovascular disease and/or diabetes who had serological evidence of inflammation at baseline and were undergoing maintenance dialysis between October 2022 and August 2023.
Patients had been on hemodialysis for at least 12 weeks, and the median baseline serum high-sensitivity C-reactive protein (CRP) was 8.3 md/dL. The most common cause of renal failure was diabetes mellitus (71%). The mean age of patients was 62 years, 33% were women, and 46% were non-white.
In the phase 2b dose-finding study, patients were randomly assigned in a 1:1:1:1 ratio to receive up to six intravenous boluses of low (2.5 mg), medium (5 mg), or high (10 mg) doses of clazakizumab (32 patients in each group) or placebo (31 patients) every 4 weeks.
Results at week 12 showed that serum high-sensitivity CRP levels in participants treated with clazakizumab were significantly reduced by 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, serum high-sensitivity CRP levels increased by 19% over the same period in the placebo group.
The rates of normalization of high-sensitivity CRP to less than 2.0 mg/L were 79.2%, 82.1%, and 79.3% of participants in the low-, medium-, and high-dose groups, respectively, compared with 0% in the placebo group.
The reduction in high-sensitivity CRP in the clazakizumab group was rapid and sustained through 24 weeks of follow-up.
Secondary endpoints included significant reductions in downstream biomarkers of IL-6 activity in all clazakizumab groups. Fibrinogenserum amyloid A, secretory phospholipase A2, lipoprotein (all P <.001 compared with placebo).
Of note, the mean increase in serum albumin with clazakizumab was 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 compared with placebo), compared with 0.04 g/dL in the placebo group.
Safety measures
Clazakii was well tolerated, with the most common serious adverse events being serious infections (12.5% in the low-dose group, 9.4% in the medium-dose group, 28.1% in the high-dose group, and 6.5% in the placebo group).
Treatment was discontinued in six patients, including one in the placebo group, because of serious infections.
Persistent grade 3 or 4 thrombocytopenia or Neutropenia.
Consistent with an anti-inflammatory effect, a small increase in total cholesterol was observed in all three clazakizumab groups.
Six deaths occurred, but were similarly distributed across all groups, and none were considered related to clazakizumab.
After the presentation, a member of the audience asked how the infection affected the patients' CRP levels, and Chertow explained that “these patients' CRP levels were slightly elevated, but not consistently elevated.”
He agreed that the issue is important, saying, “We don't want to ignore the possibility that infections could occur as a result of CRP suppression by clazakizumab, so I think we need to be very cautious and use clinical judgment in assessing the risk of infection in patients receiving this drug.”
Improvements in CRP and albumin levels were evaluated as “dramatic”
“All three doses of clazakizumab were much lower than those previously used to treat a variety of immune-mediated diseases,” Cherteau said in his presentation.
“However, despite the extremely low doses of clazakizumab, there was a dramatic reduction in not only CRP but also downstream biomarkers of IL-6 activity, and the effects were sustained over a long period of time,” he said.
The average increase in albumin was particularly notable, Chertow said.
“I've been caring for dialysis patients for 30 years and I've rarely seen a drop in dialysis patients after three months, let alone six months. [have] Elevated serum albumin [to this degree]” he said.
In their paper, Chertow et al. add that increasing albumin is important not only because of the strong association between low serum albumin concentrations and mortality in patients undergoing dialysis, but also because few other controlled interventions have demonstrated the ability to increase serum albumin in this population.
Clazakii is being evaluated in various phase 2 trials in other inflammatory diseases. Rheumatoid arthritis and Psoriatic arthritisThe drug is also currently being studied in the Phase 3 IMAGINE trial for the treatment of chronic active antibody-mediated rejection in kidney transplant patients.
The current phase 2b trial does not include patients undergoing peritoneal dialysis, but the authors plan to include these patients in an ongoing phase 3 trial focusing on the 5 mg dose.
“These are important data showing that hemodialysis patients can benefit from targeted anti-IL-6 therapy,” emphasized study co-author Peter Stenvinkel, MD, PhD, of the Department of Nephrology at Karolinska Institutet, Solna, Sweden.
He explained that statins may not be effective in preventing cardiovascular events in dialysis patients because they have a poor response to these treatments.
“Residual inflammatory risk is likely a major factor determining outcomes in dialysis patients,” Stenvinkel said. Medscape Medical News“Statins do not improve outcomes for these dialysis patients.”
The findings indicate that “targeting residual inflammatory risk may improve outcomes and quality of life for this high-risk patient population,” he said.
“[These are] “This is a very promising sign of a new treatment strategy, which will now be tested in a phase 3 trial,” Stenvinkel added.
Commenting further on the study, Sylvie Shah, MD, of the Department of Nephrology and Nephrology; High blood pressure “Clazakizumab is a promising agent that has been shown to reduce inflammatory markers,” said researchers at the University of Cincinnati in Cincinnati, Ohio.
“Cardiovascular disease is the number one cause of death in dialysis patients, so we hope this treatment will have an impact on their risk of cardiovascular disease.”
Shah, who was not involved in the clakizumab study, noted that a limitation of the study was that “we did not have information about dialysis prescriptions or details of dialysis treatment.”
Home hemodialysis and peritoneal dialysis
Shah was lead author of another study, also presented at the meeting, which found that end-stage renal disease patients who received home hemodialysis had significantly lower rates of cardiovascular events compared with patients who received peritoneal dialysis.
The study included 68,645 patients identified in the U.S. Renal Data System between 2005 and 2018 and linked to Medicare claims.
With a mean follow-up of 1.8 years, home hemodialysis was associated with a slightly lower adjusted risk of cardiovascular events than peritoneal dialysis (hazard ratio 0.011, 0.012, 0.011). [HR]0.92), but home hemodialysis patients had a 42% lower adjusted risk. stroke (HR, 0.58), representing a 17% adjusted risk reduction. Acute coronary syndrome (HR, 0.83) There was no statistically significant risk difference compared with patients receiving peritoneal dialysis. heart failure (HR, 1.05).
On the other hand, with regard to mortality, home hemodialysis was associated with a 22% lower adjusted risk of death from cardiovascular disease (HR, 0.78) and an 8% lower adjusted risk of all-cause mortality (HR, 0.92) compared with peritoneal dialysis.
“Previous studies have shown that home hemodialysis is associated with lower rates of hospitalization for cardiovascular disease, but no studies have looked specifically at incident cardiovascular disease,” Shah said, adding that more research is needed to compare outcomes across forms of home dialysis.
Key factors such as frequency of dialysis could explain the difference, she explained.
“Because home hemodialysis patients undergo more frequent and longer dialysis than peritoneal dialysis, we believe that this improves solute removal and volume removal, leading to better control of parameters related to bone and mineral metabolism, and thus reduces left ventricular volume and mass,” Shah said.
“This reduces the overall risk of developing cardiovascular disease and dying from cardiovascular disease,” she said.
“Clinicians should use this information in shared decision-making and counseling for their kidney disease patients.”
The trial was sponsored by CSL Behring. Chertow serves on the board of directors of Satellite Healthcare, a nonprofit dialysis provider, and Stanford has received grant funding from CSL Behring, the trial's sponsor. Stenwinkel has received honoraria from CSL. Shah has nothing to disclose.
