- Hello, I'm Peter Libby from Boston's Brigham and Women's Hospital and the Harvard Medical School. And it's my pleasure to speak about Inflammation in Chronic Kidney Disease, Targeting Interleukin-6. These are my competing interests, I do not accept any personal payment from pharma or device companies. We focus on interleukin-6 because it is the apex of a biological pathway from the inflammasome, which is a dangerous signalling supermolecular structure within the cell, that activates pro interleukin-1 beta, and pro IL-18 to their active forms, providing an amplification loop, because IL-1 can induce its own gene expression. In turn, IL-1 can induce large amounts of interleukin-6, which goes to the liver and signals the acute-phase response, pouring out fibrinogen, the precursor of clots, and the major inhibitor of our own clot-busting system, plasminogen activator inhibitor-1. We've known for over two decades, thanks to the work of my colleague, Dr. Paul Ridker, that interleukin-6 levels in blood independently predict first-ever cardiovascular events. We also have very strong human genetic evidence that those who carry variants that interfere with the function of interleukin-6 signalling not only have a decrease in the biomarker of inflammation, C-reactive protein, but also a decrease in cardiovascular events; strong human genetic evidence that interleukin-6 is causal in cardiovascular disease. That led to the design of a phase II trial, called RESCUE, of interleukin-6 inhibition with a monoclonal antibody that neutralises interleukin-6 ligand in patients with high cardiovascular risk. This was a double-blind, placebo-controlled, dose-ranging study. The protocol is shown here. It's a typical phase II dose-ranging study, and the primary endpoint was C-reactive protein decrease. This is a biomarker of inflammation. And you see at the highest dose tested, that there was an over-90% decrease in C-reactive protein. As you see in panel B, this was sustained for many weeks. This very promising phase II result led to the design and the initiation of a large-scale phase III outcome trial known as ZEUS, for Ziltivekimab Cardiovascular Outcomes Trial. Why chronic kidney disease? Because as all practising cardiologists know, this is a great population with unmet medical need. They have very high cardiovascular risk, and it's a particularly special biological state because LDL is much less important. This is one of the only populations in which statin therapy has not proved clinically beneficial. And in work which Dr. Ridker will present at the American College of Cardiology meeting in Washington, DC, in April of 2022, an analysis of our CANTOS trial shows that C-reactive protein is a much stronger correlate of cardiovascular events than LDL itself. So we really have to focus on the cardiovascular risk in this population, and colchicine, which is an established anti-inflammatory agent of use in patients in secondary prevention is relatively contraindicated in chronic kidney disease. So it's a very exciting time, because we're going to have, perhaps, a test of another tool to decrease inflammation in atherosclerosis in this particularly vulnerable population. Thank you very much for your attention.