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Through hepatic targeting and silencing of the <jats:italic>TMPRSS6<\/jats:italic> gene, SLN124 increases endogenous hepcidin synthesis. This is the first clinical report of an siRNA targeting a component of iron homeostasis. This first\u2010in\u2010human, phase 1 study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of SLN124 (1.0, 3.0, and 4.5\u2009mg\/kg) in healthy volunteers. Twenty\u2010four participants were randomized in three sequential cohorts of eight subjects, each to receive a single dose of either SLN124 or placebo (6:2 randomization), administered subcutaneously. There were no serious or severe adverse events, or discontinuations due to adverse events, and most treatment\u2010emergent adverse events were mild, including transient mild injection site reactions, resolving without intervention. SLN124 was rapidly absorbed, with a median <jats:italic>t<\/jats:italic><jats:sub>max<\/jats:sub> of 4\u20135\u2009h across all treatment groups, and largely eliminated from plasma by 48\u2009h. Plasma concentrations increased in a greater than dose proportional fashion between treatment groups. In all SLN124 groups, a dose\u2010related effect was observed across iron metabolism markers, and across erythroid markers, SLN124 resulted in increased plasma hepcidin levels, peaking around Day 29, and consequent dose\u2010related sustained reductions in plasma iron and transferrin saturation with decreased reticulocyte production, MCHC, and MCV. Results suggest duration of action lasting up to 56\u2009days after a single SLN124 dose, on hepcidin and hematological parameters of iron metabolism (serum iron and TSAT).<\/jats:p>","DOI":"10.1002\/ajh.27015","type":"journal-article","created":{"date-parts":[[2023,7,27]],"date-time":"2023-07-27T12:03:50Z","timestamp":1690459430000},"page":"1425-1435","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["SLN124, a GalNAc conjugated 19\u2010mer siRNA targeting <i>tmprss6<\/i>, reduces plasma iron and increases hepcidin levels of healthy volunteers"],"prefix":"10.1002","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3000-9359","authenticated-orcid":false,"given":"John B.","family":"Porter","sequence":"first","affiliation":[{"name":"University College Hospitals  London 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