Effects of IL-1β inhibition on anemia and clonal hematopoiesis in the randomized CANTOS trial.

"Conflict-of-interest disclosure: J.W., D.L., A.L., H.X., P.S., M.H., D.P.Y., M.T.B., and D.P.S. are employees of Novartis Institute of Biomedical Research. P.L. is a consultant (nonfinancial) to or is involved in clinical trials for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Norvo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron; is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint Therapeutics, Eulicid Bioimaging, Kancera, Kowa Pharmaceuticals, Medimmune, Moderna, Novartis, Olatec Therapeutics, PlaqueTec, TenSixteen Bio, Soley Therapeutics, and XBiotech, Inc; has received research funding from Novartis; is a member of Board of Directors for Soley Therapeutics, TenSixteen Bio and XBiotech, Inc; has financial interest in Soley Therapeutics, TenSixteen Bio and XBiotech, Inc; and had interests reviewed and managed by Brigham and Women’s Hospital and Mass General Brigham in accordance with their conflict of interest policies. P.M.R. has received research grant support from Amarin, Esperion, Kowa, Novartis, Pfizer, and the National Heart, Lung, and Blood Institute; has served as a consultant to Agepha, ANGIOWave, AstraZeneca, Boehringer-Ingelheim, Cardiol Therapeutics CiVi Biopharma, Flame, GlaxoSmithKline, Health Outlook, Horizon Therapeutics, Janssen, Montai Health, New Amsterdam, Novartis, Novo Nordisk, Research Triangle Institute, SOCAR, Uptton, and Zomagen; and receives compensation for service on the Peter Munk Advisory Board (University of Toronto), the Leducq Foundation, Paris, France, and the Baim Institute (Boston, MA)."

"The study was funded by Novartis AG (Basel, Switzerland). P.L. receives funding support from the National Heart, Lung, and Blood Institute (1R01HL134892 and 1R01HL163099-01), the American Heart Association (18CSA34080399), the RRM Charitable Fund, and the Simard Fund."

"Canakinumab, a monoclonal antibody targeting proinflammatory cytokine interleukin-1β (IL-1β), improved hemoglobin levels while preventing recurrent cardiovascular events in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). This cardiovascular (CV) preventive effect was greater in patients with TET2 mutations associated with clonal hematopoiesis (CH). The current proteogenomic analysis aimed to understand the clinical response to canakinumab and underlying proteomic profiles in the context of CH and anemia. The analysis included 4595 patients from the CANTOS study who received either canakinumab or placebo and evaluated multiplexed proteomics (4785 proteins) using SomaScan and targeted deep sequencing for CH mutations. Incident anemia was more common in the presence of CH mutations but reduced by canakinumab treatment. Canakinumab treatment was significantly associated with higher hemoglobin increment in patients with concurrent CH mutations and anemia than patients with CH mutations without anemia or without CH mutations. Compared with those without CH mutations, the presence of CH mutations was associated with proteomic signatures of inflammation and defense response to infection, as well as markers of high-risk CV disease which was further enhanced by the presence of anemia. Canakinumab suppressed hepcidin, proinflammatory cytokines, myeloid activation, and complement pathways, and reversed pathologically deregulated pathways to a greater extent in patients with CH mutations and anemia. These molecular findings provide evidence of the clinical use of IL-1β blockade and support further study of canakinumab for patients with concurrent anemia and CH mutations. This study was registered at www.clinicaltrials.gov as #NCT01327846."