Inhibition of interleukin (IL)-6 with ziltivekimab reduces multiple biomarkers of inflammation and thrombosis in patients at high atherosclerotic risk with moderate to severe chronic kidney disease (CKD) and elevated C-reactive protein, results of the phase 2 RESCUE trial show.
At 12 weeks, median levels of high-sensitivity C-reactive protein (hsCRP) were reduced by 77%, 88%, and 92% with 7.5 mg, 15 mg, and 30 mg doses of ziltivekimab, respectively, every 4 weeks, compared with a 4% reduction with placebo (P < .0001 for all).
Dose-dependent increases were also seen in the number of patients who achieved both a reduction in hsCRP of at least 50% and an on-treatment hsCRP of less than 2 mg/L (66%, 80%, 93% vs 4%; P < .001 for all).
"The magnitude of change with ziltivekimab on hsCRP was nearly twice as large in RESCUE as that previously observed in CANTOS, where canakinumab resulted in 15% to 20% reductions in event rates," Paul Ridker, MD, MPH, Brigham and Women's Hospital, Boston, said.
The landmark CANTOS trial showed that targeting the IL-1 to IL-6 to CRP pathway of innate immunity with canakinumab (Ilaris), a monoclonal antibody directed at IL-1β, reduced hsCRP by 35% to 40% and reduced the risk for MI, stroke, and cardiac death independent of low-density-lipoprotein (LDL) lowering.
Clinical benefit was greater in those with robust IL-6 reductions, suggesting that IL-6 itself may be the primary target for atheroprotection, Ridker said. Further support has come from recent Mendelian analyses and murine models showing anti-IL-6 receptor antibodies slow atherosclerotic progression.
RESCUE focused on high-risk patients with CKD and an elevated hsCRP because this is a group with considerable unmet clinical need in which IL-6 correlates with the severity of renal impairment and level of atherosclerotic risk, he explained.
The 264 patients with stage 3 to 5 CKD and a hsCRP of at least 2 mg/L were randomly assigned to subcutaneous placebo or ziltivekimab at 7.5 mg, 15 mg, or 30 mg every 4 weeks for up to 24 weeks.
The median estimated glomerular filtration rate was 38 mL/min per 1.73 m2, median hsCRP was 5.7 mg/L, and median IL-6 level was 5.6 pg/mL. The patients' median age was 66 years, and two-thirds were taking statins.
In addition to reductions in the primary endpoint of hsCRP, dose-dependent changes with 7.5 mg, 15 mg, and 30 mg ziltivekimab, compared with placebo, were seen in:
fibrinogen: –25%, –25%, –37% vs –2%
haptoglobin: –30%, –40%, –56% vs –3%
serum amyloid A: –40%, –50%, –42% vs +2%
secretory phospholipase A2: –27%, –41%, –49% vs 0%.
Interestingly, levels of lipoprotein(a) were also lowered (by 16%, 20%, 25% vs 0%). This is "very important because prior IL-6 inhibitors and other IL-6 drugs are known to elevate atherogenic lipids. We did not see that effect with ziltivekimab," Ridker said. The ApoB:ApoA ratio was unchanged (0%, 0%, –5% vs –2%).
Perhaps equally important for cardiologists is the potential for adverse events with anti-inflammatory drugs, particularly IL-6 therapies, he noted. There was no evidence of grade 2, 3, or 4 sustained neutropenia or thrombocytopenia and no alanine aminotransferase or aspartate aminotransferase levels greater than three times the upper limit of normal.
Serious infections were reported in five patients in the placebo group, 11 in the ziltivekimab 7.5 mg group, five in the 15 mg group, and three in the 30 mg group.
"Ziltivekimab is an IL-6 ligand monoclonal rather than an IL-6 receptor inhibitor and it had been hypothesized that that might improve the specificity and therefore reduce the off-target issues and that seems to be holding up here," Ridker told theheart.org | Medscape Cardiology. "It's also a fully human monoclonal, so we had no injection-site reactions."
"This is only a 24-week study and the numbers are relatively small, but the critical thing is we aren't seeing an increase in liver dysfunction or neutropenia or thrombocytopenia compared to placebo," he said. "And the lipids are stable. That's very good news. So all these things point in the right direction that we can now embark on a large-scale outcomes trial."
Novo Nordisk, which snapped up the drug as part of last year's $725 million acquisition of France's Corvida Therapeutics, is backing the double-blind cardiovascular outcomes ZEUS trial, which is evaluating ziltivekimab 15 mg in more than 6000 CKD patients with high-risk features similar to those in the pilot study.
Although the CANTOS results with canakinumab created a stir, its annual price tag of roughly $77,000 limits use outside its orphan drug designation to treat cryopyrin-associated periodic syndromes. Ziltivekimab, however, is being developed by Novo Nordisk specifically for atherosclerosis, Ridker said. "To their credit, they are going after a common disease, so they're going to have to have it appropriated priced."
Nephrologist Joel Topf, MD, Oakland University William Beaumont School of Medicine, Detroit, told theheart.org | Medscape Cardiology that ziltivekimab certainly has biological activity, but outcomes data are necessary to determine whether the "dramatic reductions in IL-6" will translate to better cardiovascular protection.
"I hope so," he added. "My kidney patients have an unacceptably high CV disease burden and, despite great efforts with cardiac catheterization in ISCHEMIA-CKD, implantable cardiac defibrillators in ICD2, and statins in the 4D trial, we have not been able to move the needle."
After the formal presentation, discussant Pradeep Natarajan, MD, Massachusetts General Hospital and Harvard University, Boston, congratulated Ridker on the results, and said: "I love that ZEUS is focusing on patients with CKD, a group with high biomarkers of inflammation, high cardiovascular disease risk, and often excluded from cardiovascular trials, often for competing risks."
Natarajan observed that multiple inhibitors of the NLRP inflammasome are currently available or in development for cardiovascular disease, inhibiting the inflammasome itself or targeting IL-1β or IL-6, and asked about the relative strengths of targeting each of the pathways. "A related question: just like we target cholesterol through multiple different pathways, do you think there will be a role for all these different agents for inflammation?"
Ridker replied that there are oral agents that can attack the upstream NLRP3 that are a few years off in terms of moving into the atherosclerotic space, but they could run the risk of downstream adverse effects. IL-1β was shown to work in CANTOS, but it's predominantly being developed as an oncologic agent because of its huge effects on lung cancer.
"IL-6 is likely to be the fundamental target and probably the target for why IL-1 inhibition in CANTOS worked. And that's why focusing with this drug on IL-6 itself is what our chosen next step is going to be," he said. "But Pradeep, you're absolutely right. At the end of the day, we're going to learn a lot about inflammation biology through these new trials and it's a very exciting time for the cardiovascular community.
"My prediction would be that 5 to 10 years from now, we're going to be giving everybody aggressive lipid lowering and aggressive inflammation lowering. We just have to figure out the right combinations," he said.
The study was sponsored by Corvidia and Novo Nordisk. Ridker reported receiving research grants from Kowa, Novartis, Pfizer, AstraZeneca, the National Heart, Lung, and Blood Institute, and the National Cancer Institute; and serving as a consultant to Corvidia, Novo Nordisk, Inflazome, Novartis, Amgen, Merck, Jansen, Agepha, Flame, and CiviBio. He is also a coinventor on patents that are no longer active related to the use of inflammatory biomarkers in cardiovascular disease and diabetes.
American College of Cardiology 2021 Scientific Session. Presented May 17, 2021.
Lancet. Published online May 17, 2021. Abstract
Medscape Medical News © 2021
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