Inhibition of interleukin (IL) -6 with ziltivekimab reduces multiple biomarkers of inflammation and thrombosis in patients with high to moderate to severe atherosclerotic risk chronic kidney disease (CKD) and elevated C-reactive protein, phase 2 results RESCUE test show.
At 12 weeks, median levels of high-sensitivity C-reactive protein (hsCRP) were reduced by 77%, 88%, and 92% with ziltivekimab doses of 7.5 mg, 15 mg, and 30 mg, respectively. every 4 weeks, compared with a 4% reduction with placebo (Pg <.0001 for all).
Dose-dependent increases were also observed in the number of patients who achieved both a reduction in hsCRP of at least 50% and an hsCRP in treatment of less than 2 mg / L (66%, 80%, 93). % vs 4%; Pg <.001 for all).
“The magnitude of the change with ziltivekimab to hsCRP was almost twice as large in RESCATE as observed previously in CANTOS, where canakinumab resulted in 15% to 20% reductions in event rates, ”said Paul Ridker, MD, MPH, Brigham and Women’s Hospital, Boston.
The milestone CANTOS the trial showed that targeting the IL-1 to IL-6 pathway of CRP of innate immunity with canakinumab (Ilaris), a monoclonal antibody directed to IL-1β, reduced hSCRP by between 35% and 40% and reduced the risk of MI, stroke, and cardiac death independent of low-density lipoprotein (LDL) reduction.
The clinical benefit was greater in those with robust reductions in IL-6, suggesting that IL-6 itself could be the primary target of atheroprotection, Ridker said. Recent ones have given more support Mendelian analysis and murine models showing antibodies against the IL-6 receptor with slow atherosclerotic progression.
RESCUE focused on high-risk patients with CKD and elevated hsCRP because it is a group with considerable unmet clinical need in which IL-6 correlates with the severity of renal failure and the level of risk. atherosclerotic, he explained.
The 264 patients with 3- to 5-stage CKD and an 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 estimated average glomerular filtration rate was 38 ml / min per 1.73 m2, mean hsCRP was 5.7 mg / L and mean IL-6 level was 5.6 pg / mL. The mean age of the patients was 66 years and two-thirds were taking statins.
In addition to reductions in the primary endpoint of hsCRP, dose-dependent changes were observed with 7.5 mg, 15 mg, and 30 mg of ziltivekimab compared with placebo at:
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, lipoprotein (a) levels were also reduced (16%, 20%, 25% versus 0%). This is “very important because previous inhibitors of IL-6 and other IL-6 drugs are known to raise atherogenic levels. lipids. We didn’t see this effect with ziltivekimab, ”Ridker said. The ApoB: ApoA ratio did not change (0%, 0%, –5% vs. –2%).
Perhaps equally important to cardiologists is the potential for adverse events with anti-inflammatory drugs, especially IL-6 therapies, he noted. There were no sustained grade 2, 3 or 4 tests neutropenia or thrombocytopenia and there are no levels of alanine aminotransferase or aspartate aminotransferase above three times the upper limit of normal.
Serious infections were reported in five patients in the placebo group, 11 in the 7.5 mg ziltivekimab group, five in the 15 mg group, and three in the 30 mg group.
“Ziltivekimab is an IL-6 monoclonal ligand rather than an IL-6 receptor inhibitor and it has been hypothesized that this could improve specificity and therefore reduce problems outside the goal and that seems to stay here, ”Ridker said. theheart.org | Cardiology Medscape. “It’s also a completely human monoclonal, so we had no reaction at the injection site.”
“This is just a 24-week study and the numbers are relatively small, but most importantly, we don’t see an increase in liver dysfunction or neutropenia or thrombocytopenia compared to placebo,” he said. “And lipids are stable. That’s good news. So all of these things point in the right direction that we can now undertake a large-scale test of results.”
Novo Nordisk, which withdrew the drug as part of last year’s $ 725 million acquisition from the French Corvida Therapeutics, supports the ZEUS trial of double-blind cardiovascular outcomes, which evaluates ziltivekimab 15 mg in more than 6,000 patients with CKD with high-risk characteristics similar to those in the pilot study.
Although the results of CANTOS with canakinumab created a stir, its annual price of approximately $ 77,000 limits the use outside the orphan drug designation to treat periodic syndromes associated with cryopyrin. Ziltivekimab, however, is being developed by Novo Nordisk specifically for atherosclerosis, Said Ridker. “On their credit, they’re going to look for a common disease, so they’re going to have to have a proper price.”
Said nephrologist Joel Topf, Ph.D. from William Beaumont School of Medicine at Oakland University, Detroit theheart.org | Cardiology Medscape that ziltivekimab certainly has biological activity, but outcome data are needed to determine whether “dramatic reductions in IL-6” will result in better cardiovascular protection.
“I hope so,” he added. “My kidney patients have an unacceptably high CV disease burden and despite the great efforts made with cardiac catheterization ISCHEMIA-CKD, implantable cardiac defibrillators a ICD2, and statins in Test in 4D, we could not move the needle “.
After the formal presentation, speaker Pradeep Natarajan, MD, Massachusetts General Hospital and Harvard University, Boston, congratulated Ridker on the results and said, “I love that ZEUS focuses on patients with CKD, a group with elevated biomarkers of ‘inflammation, high risk of cardiovascular disease, and often excluded from cardiovascular trials, often because of competitive risks’.
Natarajan noted that several NLRP or developing inflammasome inhibitors are currently available 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: In the same way that we target cholesterol through multiple different pathways, do you think there will be a role for all of these different agents for inflammation?”
Ridker responded that there are oral agents that can attack the NLRP3 upstream that are a few years off in terms of moving into the atherosclerotic space, but that could run the risk of adverse effects downstream. IL-1β has been shown to function in CANTOS, but is mainly developed as an oncological agent due to its enormous effects on lung cancer.
“IL-6 is probably the primary goal and probably the goal of why IL-1 inhibition worked in CANTOS. And that’s why we focus with this drug on IL itself. -6 is what will be our next chosen step, “he said. dit. “But Pradeep, you’re absolutely right. After all, we’ll learn a lot about the biology of inflammation through these new trials and it’s a very exciting time for the cardiovascular community.
“My prediction would be that in five or ten years we will offer everyone aggressive lipid reduction and aggressive inflammation. We just need to figure out the right combinations,” he said.
The study was sponsored by Corvidia and Novo Nordisk. Ridker reported that he had received research grants from Kowa, Novartis, Pfizer, AstraZeneca, the National Heart, Lung and Blood Institute, and the National Cancer Institute; and acting as a consultant to Corvidia, Novo Nordisk, Inflazome, Novartis, Amgen, Merck, Jansen, Agepha, Flame and CiviBio. He is also a co-inventor of patents that are no longer active related to the use of inflammatory biomarkers in cardiovascular disease and diabetes.
Scientific Session of the American College of Cardiology 2021. Presented May 17, 2021.
Lancet. Published online May 17, 2021. Summary