Archived Virtual Seminar: IL-1 blockade in heart disease

About this Seminar

The intracellular sensing protein termed NLRP3 (for NACHT, LRR, and PYD domains-containing protein 3) forms a macromolecular structure called the NLRP3 inflammasome. The NLRP3 inflammasome plays a major role in inflammation, particular in the production of interleukin-1b (IL-1b). IL-1b is the most studied of the IL-1 family of cytokines, including 11 members among which IL-1a and IL-18.  Dr. Abbate will summarize pre-clinical and clinical findings supporting the key pathogenetic role of the NLRP3 inflammasome and IL-1 cytokines in the formation, progression and complications of atherosclerosis, in ischemic (acute myocardial infarction, AMI), and non-ischemic injury to the myocardium (myocarditis)  and the progression to heart failure (HF).  He will also review the clinically available IL-1 inhibitors, although not currently approved for a cardiovascular indications, and discuss other IL-1 inhibitors, not currently approved, as well as oral NLRP3 inflammasome inhibitors currently in clinical development. Canakinumab, IL‑1b  antibody, prevented the recurrence of ischemic events in patients with prior AMI in a large phase III clinical trial including 10,061 patients world-wide. Phase II clinical trials show promising data with anakinra, recombinant IL-1 receptor antagonist, in patients with ST segment elevation AMI or HF with reduced ejection fraction. Anakinra also improved outcomes in patients with pericarditis and it is now considered standard of care as second line treatment for patients with recurrent/refractory pericarditis. Rilonacept, a soluble IL‑1 receptor chimeric fusion protein neutralizing IL-1aand IL-1b, has also shown promising results in a phase II study in recurrent/ refractory pericarditis. In conclusion, there is overwhelming evidence linking the NLRP3 inflammasome and the IL-1 cytokines with the pathogenesis of cardiovascular diseases. The future will likely include targeted inhibitors to block the IL‑1 isoforms, and possibly oral NLRP3 inflammasome inhibitors, across a wide spectrum of cardiovascular diseases.

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