{"id":103317,"date":"2025-08-29T02:04:16","date_gmt":"2025-08-29T02:04:16","guid":{"rendered":"https:\/\/www.newsbeep.com\/au\/103317\/"},"modified":"2025-08-29T02:04:16","modified_gmt":"2025-08-29T02:04:16","slug":"marios-georgakis-on-il-6-inhibition-genetics-as-a-tool-for-drug-validation","status":"publish","type":"post","link":"https:\/\/www.newsbeep.com\/au\/103317\/","title":{"rendered":"Marios Georgakis on IL-6 Inhibition, Genetics as a Tool for Drug Validation"},"content":{"rendered":"

Marios Georgakis, a Physician-scientist leading a lab at Universit\u00e4t M\u00fcnchen, shared a post on X<\/a>:<\/p>\n

\u201cI\u2019m often asked how human genetics can be used to validate drug targets.<\/p>\n

In our new Nature Cardiovascular Research paper, we provide an end-to-end framework for IL-6 inhibition<\/p>\n

build a genetic proxy
\ndemonstrate potential for cardiovascular benefit
\nassess expected & unexpected safety signals.<\/p>\n

\"IL-6<\/p>\n

Genetic variation in IL6R, the receptor for IL-6, has long been linked to risk of atherosclerotic cardiovascular disease (ASCVD).<\/p>\n

This has motivated the development of anti-inflammatory therapies targeting IL6 signaling for ASCVD.<\/p>\n

\"Marios<\/p>\n

However, antibodies in development (ziltivekimab by Novo Nordisk, clazakizumab by CSL Behring, pacibekitug by Tourmaline Bio) target IL-6, not its receptor.<\/p>\n

This raises a key translational question:<\/p>\n

Can the genetic evidence for IL6R perturbation be applied to these therapeutics?<\/p>\n

\"Marios<\/p>\n

We screened the IL6 locus to identify variants associated with CRP, a downstream biomarker of IL-6 signaling and the primary endpoint in phase 2 trials of anti-IL-6 therapies.<\/p>\n

This identified 12 moderately correlated variants (r\u00b2 < 0.1) linked to CRP levels.<\/p>\n

Aggregating these 12 variants into a genetic score was associated with lifelong reductions in CRP (up to 24% for the upper vs lower percentile), comparable in magnitude to those observed with an IL6R genetic proxy.<\/p>\n

\"Marios<\/p>\n

All selected variants were non-coding, yet many were associated with IL6 expression in one or more cell types or tissues. This suggests they may modulate downstream signaling by altering IL6 RNA expression.<\/p>\n

\"Marios<\/p>\n

Indeed, most variants showed proportionally concordant effects on circulating IL-6 protein levels, supporting an effect on IL-6\u00a0abundance.<\/p>\n

\"Marios<\/p>\n

Can such a genetic proxy be used to study the effects of pharmacological IL-6 inhibition?<\/p>\n

While phase 3 data are not yet available, phase 2 results from the RESCUE trial (ziltivekimab) provide biomarker evidence.<\/p>\n

When indexed to CRP reduction, the effects of our genetic instrument on 8 tested biomarkers (data leveraged through publicly available GWASs) were highly concordant with ziltivekimab treatment!<\/p>\n

\"Marios<\/p>\n

In other words, our genetic instrument can predict effects on all 8 biomarkers measured in the trial, with a correlation of 0.9 between genetic and trial effects.<\/p>\n

Similarly, the IL-6 genetic proxy showed effects on rheumatoid arthritis and polymyalgia rheumatica, both indications where IL-6 inhibition has proven clinically effective.<\/p>\n

\"Marios<\/p>\n

We then tested associations with cardiovascular endpoints.
Like an IL6R instrument, genetically proxied IL-6 downregulation through IL6 perturbation was associated with lower risk of atherosclerotic outcomes:<\/p>\n

Coronary artery disease (CAD)
\nPeripheral artery disease (PAD)
\nLarge artery atherosclerotic stroke
\nCarotid atherosclerotic plaque<\/p>\n

\"Marios<\/p>\n

These findings were highly consistent in East Asian individuals from Biobank Japan.<\/p>\n

\"Marios<\/p>\n

We also observed interesting metabolic effects:<\/p>\n

an association with a lower risk of type 2 diabetes
\nsignificant changes in lipid profile, mainly increase in HDL particles<\/p>\n

Across multiple metabolomic measurements, the effects were highly consistent with those of an IL6R instrument, indicating convergence downstream of IL-6 signaling<\/p>\n

\"Marios<\/p>\n

The primary safety concern for anti-IL-6 therapies is infection risk.<\/p>\n

In previous work, we have shown that genetically proxied IL6R inhibition increases risk of bacterial infections, consistent with clinical experience with tocilizumab.<\/p>\n

\"Marios<\/p>\n

Interestingly, our IL-6 genetic proxy showed no significant increase in the infection endpoints tested.<\/p>\n

On the contrary, there was even evidence of risk-lowering effects on pneumonia hospitalization.<\/p>\n

\"Marios<\/p>\n

Finally, we performed a phenome-wide association study (PheWAS) in FinnGen to systematically assess whether our IL-6 genetic proxy is associated with any additional outcomes beyond those already studied.<\/p>\n

The main risk-lowering effects of the IL-6 proxy were replicated across:<\/p>\n

cardiovascular and metabolic endpoints
\nautoimmune disease outcomes
\nrespiratory infections (pneumonia, influenza, COPD-related)<\/p>\n

We also observed novel protective associations with:<\/p>\n

depression
\ngallstone disease<\/p>\n

\"Marios<\/p>\n

Regarding side effects, notable and consistent signals included: <\/p>\n

Glaucoma
\n Perinatal and postpartum maternal hemorrhage<\/p>\n

These may be relevant for specific populations and warrant further investigation.<\/p>\n

Thoughts for broader implications:<\/p>\n

1. Often, human genetic studies replicate trial findings retrospectively.<\/p>\n

The results of ZEUS, a phase 3 cardiovascular outcomes trial testing ziltivekimab in patients with ASCVD and high CRP, are expected in 2026.<\/p>\n

I hope this work will provide prospective validation for the use of human genetics to predict trial-relevant clinical outcomes.<\/p>\n

\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

In principle, this framework could be applied to genetically validate any drug target, particularly those developed for chronic, aging-related diseases.<\/p>\n

\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

However, each target and indication has unique nuances that necessitate individual tailored approaches for proper validation.<\/p>\n

A scalable, one-size-fits-all approach risks overlooking important context and already acquired knowledge.<\/p>\n

Great work by Lanyue Zhang, Murad Omarov, and Lingling Xu. Grateful for the partnership with TourmalineBio<\/p>\n

(developing an anti-IL6 antibody) and the collaboration with Pradeep Natarajan.\u201d<\/p>\n

Title: IL6 genetic perturbation mimicking IL-6 inhibition is associated with lower cardiometabolic risk<\/p>\n

Authors: Lanyue Zhang, Murad Omarov, Lingling Xu, Emil deGoma, Pradeep Natarajan, Marios K. Georgakis<\/p>\n

Read the\u00a0Full Article<\/a>\u00a0in Nature.<\/p>\n

\"Marios<\/p>\n

More posts featuring\u00a0Marios Georgakis<\/a>\u00a0on 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…\n","protected":false},"author":2,"featured_media":103318,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[25],"tags":[64,63,336,128],"class_list":["post-103317","post","type-post","status-publish","format-standard","has-post-thumbnail","category-genetics","tag-au","tag-australia","tag-genetics","tag-science"],"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/posts\/103317","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/comments?post=103317"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/posts\/103317\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/media\/103318"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/media?parent=103317"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/categories?post=103317"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/tags?post=103317"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}