{"id":381759,"date":"2025-08-29T04:45:39","date_gmt":"2025-08-29T04:45:39","guid":{"rendered":"https:\/\/www.europesays.com\/uk\/381759\/"},"modified":"2025-08-29T04:45:39","modified_gmt":"2025-08-29T04:45:39","slug":"marios-georgakis-on-il-6-inhibition-genetics-as-a-tool-for-drug-validation","status":"publish","type":"post","link":"https:\/\/www.europesays.com\/uk\/381759\/","title":{"rendered":"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation"},"content":{"rendered":"<p><strong>Marios Georgakis<\/strong>, a Physician-scientist leading a lab at Universit\u00e4t M\u00fcnchen, shared a post on <a href=\"https:\/\/x.com\/MariosGeorgakis\/status\/1960363491937706365\">X<\/a>:<\/p>\n<p>\u201cI\u2019m often asked how human genetics can be used to validate drug targets.<\/p>\n<p>In our new Nature Cardiovascular Research paper, we provide an end-to-end framework for IL-6 inhibition<\/p>\n<ul>\n<li>build a genetic proxy<\/li>\n<li>demonstrate potential for cardiovascular benefit<\/li>\n<li>assess expected &amp; unexpected safety signals.<\/li>\n<\/ul>\n<p><img fetchpriority=\"high\" decoding=\"async\" class=\"alignnone\" src=\"https:\/\/www.europesays.com\/uk\/wp-content\/uploads\/2025\/08\/MariosGeorgakis-800x726.jpeg\" alt=\"IL-6 Inhibition\" width=\"618\" height=\"561\" title=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation 1\"\/><\/p>\n<p>Genetic variation in <strong>IL6R<\/strong>, the receptor for IL-6, has long been linked to risk of atherosclerotic cardiovascular disease (ASCVD).<\/p>\n<p>This has motivated the development of anti-inflammatory therapies targeting IL6 signaling for ASCVD.<\/p>\n<p><img decoding=\"async\" src=\"https:\/\/www.europesays.com\/uk\/wp-content\/uploads\/2025\/08\/mar-800x446.jpeg\" alt=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation\" title=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation 2\"\/><\/p>\n<p>However, antibodies in development (ziltivekimab by Novo Nordisk, clazakizumab by CSL Behring, pacibekitug by Tourmaline Bio) target <strong>IL-6<\/strong>, not its receptor.<\/p>\n<p>This raises a key translational question:<\/p>\n<p><strong>Can the genetic evidence for IL6R perturbation be applied to these therapeutics?<\/strong><\/p>\n<p><b\/><br \/><img decoding=\"async\" src=\"https:\/\/www.europesays.com\/uk\/wp-content\/uploads\/2025\/08\/marr-800x415.png\" alt=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation\" title=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation 3\"\/><\/p>\n<p>We screened the <strong>IL6<\/strong> locus to identify variants associated with<strong> CRP<\/strong>, a downstream biomarker of <strong>IL-6<\/strong> signaling and the primary endpoint in phase <strong>2<\/strong> trials of <strong>anti-IL-6<\/strong> therapies.<\/p>\n<p>This identified <strong>12<\/strong> moderately correlated variants (r\u00b2 CRP levels.<\/p>\n<p>Aggregating these <strong>12<\/strong> variants into a genetic score was associated with lifelong reductions in<strong> CRP<\/strong> (up to<strong> 24%<\/strong> for the upper vs lower percentile), comparable in magnitude to those observed with an<strong> IL6R<\/strong> genetic proxy.<\/p>\n<p><img decoding=\"async\" src=\"https:\/\/www.europesays.com\/uk\/wp-content\/uploads\/2025\/08\/marios.png\" alt=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation\" title=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation 4\"\/><\/p>\n<p>All selected variants were non-coding, yet many were associated with <strong>IL6<\/strong> expression in one or more cell types or tissues. This suggests they may modulate downstream signaling by altering <strong>IL6<\/strong> RNA expression.<\/p>\n<p><img decoding=\"async\" src=\"https:\/\/www.europesays.com\/uk\/wp-content\/uploads\/2025\/08\/marios2-458x800.jpeg\" alt=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation\" title=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation 5\"\/><\/p>\n<p>Indeed, most variants showed proportionally concordant effects on circulating<strong> IL-6<\/strong> protein levels, supporting an effect on IL-6\u00a0abundance.<\/p>\n<p><img decoding=\"async\" src=\"https:\/\/www.europesays.com\/uk\/wp-content\/uploads\/2025\/08\/marios3.jpg\" alt=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation\" title=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation 6\"\/><\/p>\n<p><strong>Can such a genetic proxy be used to study the effects of pharmacological IL-6 inhibition?<\/strong><\/p>\n<p>While phase <strong>3<\/strong> data are not yet available, phase <strong>2<\/strong> results from the RESCUE trial (ziltivekimab) provide biomarker evidence.<\/p>\n<p>When indexed to <strong>CRP<\/strong> reduction, the effects of our genetic instrument on<strong> 8<\/strong> tested biomarkers (data leveraged through publicly available GWASs) were highly concordant with ziltivekimab treatment!<\/p>\n<p><img decoding=\"async\" src=\"https:\/\/www.europesays.com\/uk\/wp-content\/uploads\/2025\/08\/marios4-620x800.jpeg\" alt=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation\" title=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation 7\"\/><\/p>\n<p>In other words, our genetic instrument can predict effects on all <strong>8<\/strong> biomarkers measured in the trial, with a correlation of <strong>0.9<\/strong> between genetic and trial effects.<\/p>\n<p>Similarly, the<strong> IL-6<\/strong> genetic proxy showed effects on rheumatoid arthritis and polymyalgia rheumatica, both indications where <strong>IL-6<\/strong> inhibition has proven clinically effective.<\/p>\n<p><img decoding=\"async\" src=\"https:\/\/www.europesays.com\/uk\/wp-content\/uploads\/2025\/08\/marios5-642x800.jpeg\" alt=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation\" title=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation 8\"\/><\/p>\n<p>We then tested associations with cardiovascular endpoints.<br \/>Like an <strong>IL6R<\/strong> instrument, genetically proxied<strong> IL-6<\/strong> downregulation through <strong>IL6<\/strong> perturbation was associated with lower risk of atherosclerotic outcomes:<\/p>\n<ul>\n<li>Coronary artery disease (CAD)<\/li>\n<li>Peripheral artery disease (PAD)<\/li>\n<li>Large artery atherosclerotic stroke<\/li>\n<li>Carotid atherosclerotic plaque<\/li>\n<\/ul>\n<p><img decoding=\"async\" src=\"https:\/\/www.europesays.com\/uk\/wp-content\/uploads\/2025\/08\/marios6-800x483.jpeg\" alt=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation\" title=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation 9\"\/><\/p>\n<p>These findings were highly consistent in East Asian individuals from Biobank Japan.<\/p>\n<p><img decoding=\"async\" src=\"https:\/\/www.europesays.com\/uk\/wp-content\/uploads\/2025\/08\/marios7-800x259.jpeg\" alt=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation\" title=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation 10\"\/><\/p>\n<p>We also observed interesting metabolic effects:<\/p>\n<ul>\n<li>an association with a lower risk of type 2 diabetes<\/li>\n<li>significant changes in lipid profile, mainly increase in HDL particles<\/li>\n<\/ul>\n<p>Across multiple metabolomic measurements, the effects were highly consistent with those of an <strong>IL6R<\/strong> instrument, indicating convergence downstream of <strong>IL-6<\/strong> signaling<\/p>\n<p><img decoding=\"async\" src=\"https:\/\/www.europesays.com\/uk\/wp-content\/uploads\/2025\/08\/marios8-636x800.jpeg\" alt=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation\" title=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation 11\"\/><\/p>\n<p>The primary safety concern for <strong>anti-IL-6<\/strong> therapies is infection risk.<\/p>\n<p>In previous work, we have shown that genetically proxied <strong>IL6R<\/strong> inhibition increases risk of bacterial infections, consistent with clinical experience with tocilizumab.<\/p>\n<p><img decoding=\"async\" src=\"https:\/\/www.europesays.com\/uk\/wp-content\/uploads\/2025\/08\/marios9-800x519.jpeg\" alt=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation\" title=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation 12\"\/><\/p>\n<p>Interestingly, our <strong>IL-6<\/strong> genetic proxy showed no significant increase in the infection endpoints tested.<\/p>\n<p>On the contrary, there was even evidence of risk-lowering effects on pneumonia hospitalization.<\/p>\n<p><img decoding=\"async\" src=\"https:\/\/www.europesays.com\/uk\/wp-content\/uploads\/2025\/08\/marios10-798x800.jpeg\" alt=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation\" title=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation 13\"\/><\/p>\n<p>Finally, we performed a phenome-wide association study (PheWAS) in FinnGen to systematically assess whether our <strong>IL-6<\/strong> genetic proxy is associated with any additional outcomes beyond those already studied.<\/p>\n<p>The main risk-lowering effects of the <strong>IL-6<\/strong> proxy were replicated across:<\/p>\n<ul>\n<li>cardiovascular and metabolic endpoints<\/li>\n<li>autoimmune disease outcomes<\/li>\n<li>respiratory infections (pneumonia, influenza, COPD-related)<\/li>\n<\/ul>\n<p>We also observed novel protective associations with:<\/p>\n<ul>\n<li>depression<\/li>\n<li>gallstone disease<\/li>\n<\/ul>\n<p><img decoding=\"async\" src=\"https:\/\/www.europesays.com\/uk\/wp-content\/uploads\/2025\/08\/marios11-800x645.jpeg\" alt=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation\" title=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation 14\"\/><\/p>\n<p>Regarding side effects, notable and consistent signals included: <\/p>\n<ul>\n<li> Glaucoma <\/li>\n<li> Perinatal and postpartum maternal hemorrhage<\/li>\n<\/ul>\n<p>These may be relevant for specific populations and warrant further investigation.<\/p>\n<p>Thoughts for broader implications:<\/p>\n<p>1. <b>Often, human genetic studies replicate trial findings retrospectively.<\/b><\/p>\n<p>The results of <b>ZEUS<\/b>, a phase<b> 3<\/b> cardiovascular outcomes trial testing ziltivekimab in patients with <b>ASCVD<\/b> and high <b>CRP<\/b>, are expected in <b>2026<\/b>.<\/p>\n<p>I hope this work will provide prospective validation for the use of human genetics to predict trial-relevant clinical outcomes.<\/p>\n<p>\u00a02. Nearly all data used in this study were publicly available (except the individual-level CRP analysis in UK Biobank that requires submission of an application and payment for access).\u00a0<\/p>\n<p>In principle, this framework could be applied to genetically validate any drug target, particularly those developed for chronic, aging-related diseases.<\/p>\n<p>\u00a03. Large-scale retrospective analyses of target-indication pairs (e.g., Minikel et al, Nature 2024) offer big picture evidence that genetically supported targets are more likely to lead to approved drugs.<\/p>\n<p>However, each target and indication has unique nuances that necessitate individual tailored approaches for proper validation.<\/p>\n<p>A scalable, one-size-fits-all approach risks overlooking important context and already acquired knowledge.<\/p>\n<p>Great work by <b>Lanyue Zhang<\/b>, <b>Murad Omarov<\/b>, and <b>Lingling Xu<\/b>. Grateful for the partnership with TourmalineBio<\/p>\n<p>(developing an anti-IL6 antibody) and the collaboration with <b>Pradeep Natarajan<\/b>.\u201d<\/p>\n<p><b>Title: <\/b>IL6 genetic perturbation mimicking IL-6 inhibition is associated with lower cardiometabolic risk<\/p>\n<p><b>Authors: <\/b>Lanyue Zhang, Murad Omarov, Lingling Xu, Emil deGoma, Pradeep Natarajan, Marios K. Georgakis<\/p>\n<p>Read the\u00a0<strong><a href=\"https:\/\/www.nature.com\/articles\/s44161-025-00700-7\" target=\"_blank\" rel=\"noopener\">Full Article<\/a>\u00a0<\/strong>in Nature.<\/p>\n<p><img decoding=\"async\" src=\"https:\/\/www.europesays.com\/uk\/wp-content\/uploads\/2025\/08\/natureee-800x375.jpg\" alt=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation\" title=\"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation 15\"\/><\/p>\n<p>More posts featuring\u00a0<a href=\"https:\/\/oncodaily.com\/tag\/marios-georgakis\" target=\"_blank\" rel=\"noopener\"><b>Marios Georgakis<\/b><\/a><b>\u00a0<\/b>on OncoDaily.<\/p>\n","protected":false},"excerpt":{"rendered":"Marios Georgakis, a Physician-scientist leading a lab at Universit\u00e4t M\u00fcnchen, shared a post on X: \u201cI\u2019m often asked&hellip;\n","protected":false},"author":2,"featured_media":381760,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[3846],"tags":[267,70,16,15],"class_list":{"0":"post-381759","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-genetics","8":"tag-genetics","9":"tag-science","10":"tag-uk","11":"tag-united-kingdom"},"share_on_mastodon":{"url":"https:\/\/pubeurope.com\/@uk\/115110237591384754","error":""},"_links":{"self":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/posts\/381759","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/comments?post=381759"}],"version-history":[{"count":0,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/posts\/381759\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/media\/381760"}],"wp:attachment":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/media?parent=381759"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/categories?post=381759"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/tags?post=381759"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}