- Welcome to peer-to-peer discussions. I'm Juan Carlos Kaski, professor of cardiovascular science at St George's University of London. And my guest today is Dr. Peter Libby, senior physician at Brigham and Women's Hospital, and professor of medicine at Harvard Medical School in Boston. Professor Libby is a living legend in the field of inflammation and atherosclerosis. His work has been cited 250,000 times. So that's awesome. And for those who are interested in figures such as h-index, his h-index exceeds the 240 mark. So Peter, thank you very much for finding the time to join us today to discuss targeted anti-inflammatory therapy and cardiovascular outcomes in patients.

- It's great to be with you.

- Peter, may I start by asking you, how has your work on biological models of inflammation and atherogenesis informed the search for anti-inflammatory drugs?

- Well, we have a great deal of in vitro and animal experimentation evidence that supports inflammation as a driver of atherosclerosis and there's a very concordant biomarker data from humans that led us down the path of trying to target inflammation in atherosclerosis.

- What's the reason why your research and the consequent development of therapeutic agents focused mainly on the NLRP3 inflammasome, IL-6, IL-1 beta? What's the rationale behind that?

- Well, I started working on cytokines in vascular disease back in the 1980s, and that was when interleukin 1 beta was characterised as a protein and then finally, molecular cloning by Charles Dinarello. We were able to show that vascular cells could be induced to produce these cytokines known as interleukins. The very name, interleukin, suggests that they mediated conversations between leukocytes, and we actually got a lot of pushback from the immunology community when we said, wait a minute. Human vascular wall cells such as endothelial cells and muscle cells could be induced by inflammatory stimuli to make these cytokines. And we then found that interleukin 1 can induce its own gene expression, a positive feedback loop, and then that IL-1 can induce interleukin 6, another amplification loop. What we didn't discover was the inflammasome, which has the apparatus that senses danger, including a bunch of disease-relevant stimuli such as cholesterol crystals or hypoxia and turns on the enzyme that can take pro-inactive IL-1 beta and convert it to the active form. So we actually worked out a pathway where IL-1 beta can induce interleukin 6, which induces the acute phase response, which includes the production of fibrinogen the precursor of clots and plasminogen activator inhibitor, the major blocker of our own fibrinolytic system. So when we have activation of this pathway, inflammasome to IL-1 beta to IL-6, we have a perfect storm that sets the stage for thrombosis and thrombus accumulation because of impaired fibrinolysis.

- So the experimental basis is very strong. The hypothesis is absolutely interesting. But what is the evidence we have that anti-inflammatory therapies are actually doing something good to patients?

- Well, together with Dr. Paul Ridker, my clinical research partner, we instigated and conducted a study, the Canakinumab Antithrombotic Outcome Study, CANTOS, and that target in interleukin 1 beta, which I'd been working on for several decades, providing the fundamental basis of the study and we took people who had stable coronary artery disease, chronic coronary artery disease after myocardial infarction, and who had some inflammation that was residual despite being on a full menu of our secondary prevention therapies and allocated them randomly to a monoclonal antibody that blocks interleukin 1 beta or a control, and found that there was a decrease in cardiovascular events. So that was the first trial that actually showed that all of this ferment about inflammation in the laboratory and all the biomarker studies in humans actually correlated with human disease.

- I'm afraid that the time allocated to our discussion is almost finished now, but I have a burning, last, very brief question. What is the direction we go in in terms of researching anti-inflammatory drugs in ischemic heart disease? Is the IL-6, so the monoclonal, is there something else in the pipeline?

- Right. So we can go upstream to the inflammasome, and there is a number of programmes that are now exploring neutralising the inflammasome, which generates active IL-1 beta, which generates IL-6. So we have this pathway and all levels of that pathway merit investigation. And the great privilege that I've had in my scientific career and medical career is starting at the most fundamental level and pushing, pushing, pushing until we get therapeutics across the finish line to help our patients. I'm wearing scrubs today because I'm on call and I've always had one foot in the laboratory, one foot in the clinic, and that really keeps me motivated and curious.

- Fabulous, and Peter, thank you very much, not only for having found the time to join me today, but also for the amount of really fundamental work you have done in this field, which is actually having very good results and actually helping our patients live a better life. Thank you very much.

- Thank you.