It looks like a brutally null result that doesn't leave much room for alternative interpretations. Given the strong genetic support (still holds), I didn't expect it. Genetic variation in both the receptor and the ligand that downregulates the signaling cascade (as captured by CRP, fibrinogen etc) is associated with lower risk of all forms of ASCVD (AMI, CAD, stroke, PAD, carotid plaques). Variants in IL6R pop up in all GWASs for ASCVD phenotypes. Beyond genetics, IL-6 levels are associated with worse CVD outcomes in all epidemiological studies of primary or secondary prevention settings. And in CANTOS, the benefit of canakinumb was restricted to those, who achieved low IL-6 levels. Still, it's an important reminder that no therapy works until we crash-test it in trials. Ofc the setting is important and Novo's choice to go for a CKD population, where mechanisms contributing to CVD are likely different, always felt somewhat weird to me. Signals for incident disease in genetic studies might not work well there. Still, if IL-6 signaling was crucial, I'd expect to see some effect. Definitely, an opportunity to also reflect on the human genetics side of things in drug development. Genetics for sure points to relevant pathways, but clinical development is a different monster. The fact that a pathway is relevant for incident atherosclerosis doesn't mean that targeting it in patients with CKD, who are on aggressive lipid-lowering therapy and 7 other medications would lower MACE. There are interesting examples, where genetics and clinical development deviated, e.g. for factor XI (open.substack.com/pub/thecod…). People who now criticize genetics because "it doesn't always work" should check the <10% success rates of the industry overall. I'll put my thoughts together and write something in the next days/weeks (or after the full results become available). I'd just like to note that very few therapeutic hypotheses have this level of converging support before they proceed to trials (animal studies, human genetics, epidemiology, even indirect trial evidence). So, I find the comments of everyone here, who "always expected the results" based on their gut feelings very interesting.