Ziltivekimab reduces biomarkers of inflammation, thrombosis in kidney disease

Reuters Health - 04/06/2021 - Ziltivekimab, a human monoclonal antibody directed against the IL-6 ligand, reduced biomarkers of inflammation and thrombosis in patients with chronic kidney disease (CKD) at high cardiovascular risk in a placebo-controlled, phase 2 trial.

The RESCUE trial demonstrated that targeting the IL-6 ligand "has large effects on multiple critical biomarkers related to inflammation and thrombosis and that the approach appears to be safe, albeit in a modestly sized 24-week trial," Dr. Paul Ridker of Brigham and Women's Hospital in Boston told Reuters Health by email.

"The critical issue," he said, "is that the RESCUE data have directly resulted in the launch of a new 6,000 participant cardiovascular outcomes trial known as ZEUS (Ziltivekimab Cardiovascular Outcomes Study) that will address whether or not this novel anti-inflammatory approach can reduce major adverse cardiovascular event rates."

ZEUS will enroll patients similar to those in RESCUE, he said. "This group has substantial unmet clinical need, is often excluded from major cardiovascular outs-comes trials, yet is a group where the inflammatory process is of greater relative importance than that of cholesterol."

As reported in The Lancet and at the American College of Cardiology's 70th Annual Scientific Session on May 17, the RESCUE trial enrolled 264 adults in clinical sites across the US with moderate-to-severe chronic kidney disease, and high-sensitivity C-reactive protein (hsCRP) of at least 2 mg/L.

Participants received subcutaneous ziltivekimab 7.5 mg, 15 mg, or 30 mg or placebo every four weeks up to 24 weeks. The primary outcome was percentage change from baseline in hsCRP after 12 weeks of treatment with ziltivekimab compared with placebo.

At 12 weeks after randomization, median hsCRP levels were reduced by 77% in the 7.5 mg group, 88% in the 15 mg group, and 92% in the 30 mg group, compared with 4% in the placebo group.

Effects were stable over the 24-week treatment period, and dose-dependent reductions were also seen for fibrinogen, serum amyloid A, haptoglobin, secretory phospholipase A2, and lipoprotein(a).

Ziltivekimab was well tolerated and did not affect the total cholesterol to high-density lipoprotein cholesterol ratio.

No serious injection-site reactions, sustained grade 3 or 4 neutropenia or thrombocytopenia were reported.

Dr. Ridker said, "My prediction is that, 10 years from now, virtually all patients with atherosclerosis will be receiving a combination of aggressive lipid-lowering and aggressive inflammation-lowering therapies."

Dr. Anne Tybjaerg-Hansen of the University of Copenhagen, coauthor of a related editorial, commented in an email to Reuters Health, "Lipoprotein(a) levels increase in the earliest stages of kidney impairment even before GFR decreases, and GFR is inversely associated with plasma lipoprotein(a) levels."

"Therefore, in patients with CKD, a 25% lowering of lipoprotein(a), as observed in the RESCUE trial, might contribute to a reduction in atherothrombotic events in these patients, despite no apparent overall improvement in eGFR or urine albumin-to-creatinine ratio in the present study."

Major strengths of the study, she said, "are that the population selected were patients at high cardiovascular risk with CKD and increased high-sensitivity CRP, reflecting a group in whom IL-6 levels correlate with severity of renal impairment and level of atherosclerotic risk."

"Limitations," she noted, "include the small sample size, the modest duration of the trial, and the restriction of the study sites to the US."

Novo Nordisk affirmed in an email to Reuters Health, "Based on the results of the phase 2 trial, Novo Nordisk is planning to progress investigational ziltivekimab to a large-scale phase 3 cardiovascular outcomes trial to further assess its potential benefit in people with atherosclerotic cardiovascular disease, advanced CKD and high levels of inflammation. The trial will initiate in the second half of 2021.

The study was originally sponsored by Corvidia Therapeutics and, subsequent to a takeover, by Novo Nordisk. Four coauthors were employees of the former, four are employees of the latter, and two coauthors received fees from the companies.

SOURCE: https://bit.ly/3wYdUql and https://bit.ly/3z5h9Os The Lancet, online May 17, 2021.

By Marilynn Larkin



Posted on 4 June 202115 June 2021