Dublin (IE), Cambridge (UK) | 11 January 2018: Inflazome's CSO Dr Luke O'Neill and CEO Dr Matt Cooper publish a letter to the editor in The New England Journal of Medicine (NEJM) today, commenting on the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) by Ridker et al. that found reduced inflammation was associated with reduced cardiovascular risk.
To the Editor: In CANTOS, blocking interleukin-1β reduced the incidence of atherothrombosis and nonfatal stroke, and an additional analysis showed that patients who received the 300-mg dose of canakinumab had a total cancer mortality that was lower by 51% than those who received placebo and a lung-cancer mortality that was lower by 77%.1 The incidence of fatal infection was nearly twice as high in the pooled canakinumab groups as in the placebo group, a finding similar to that observed with the interleukin-1 receptor antagonist anakinra.2 The accompanying editorial by Harrington3 discussed the safety risk of interleukin-1β blockade.
Interleukin-1β is driven by multiple inflammasomes. As an alternative to inhibition of interleukin-1β, precise inhibition of a single inflammasome, NLRP3, is likely to be safer. NLRP3 is implicated in diseases of aging, such as atherosclerosis and neurodegenerative disorders. Selective NLRP3 inhibition will leave other inflammasomes to respond to infection. In addition, at the onset of severe infection, an orally available small molecule could be withdrawn, whereas canakinumab cannot. NLRP3 activation also drives interleukin-18, the clinical targeting of which is also safe.4
CANTOS has advanced our understanding of the clinical relevance of interleukin-1β and the NLRP3 inflammasome. This trial will drive the development and commercialization of an entirely new class of drugs.
References:
- Ridker PM, MacFadyen JG, Thuren T, et al. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet2017;390:1833-1842
- Cabral VP, Andrade CA, Passos SR, Martins MF. Hkerberg YH. Severe infection in patients with rheumatoid arthritis taking anakinra, rituximab, or abatacept: a systematic review of observational studies. Rev Bras Reumatol Engl Ed 2016;56:543-550
- Harrington RA. Targeting inflammation in coronary artery disease. N Engl J Med2017;377:1197-1198
- McKie EA, Reid JL, Mistry PC, et al. A study to investigate the efficacy and safety of an anti-interleukin-18 monoclonal antibody in the treatment of type 2 diabetes mellitus. PLoS One 2016;11:e0150018-e0150018
Read the full article in NEJM here.