Background <p>GalNAc-conjugated short interfering RNAs (GalNAc–siRNAs) lack a biologically plausible mechanism for QT/QTc prolongation based on their unique physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties. Nevertheless, regulatory agencies require characterization of QTc effects via either a thorough QT (TQT) study or a concentration–QTc (C–QTc) analysis using early-phase data. This manuscript summarizes platform-level experience across eight GalNAc–siRNAs to assess QTc prolongation risk via C–QTc analysis.</p> Methods <p>Time-matched electrocardiogram (ECG) data and plasma concentration data collected from phase 1/2 studies (<i>N</i> = 686), involving healthy subjects and/or patients receiving single ascending doses of study drug or placebo, were used for C–QTc analysis for eight GalNAc–siRNAs. For each drug, individual and mean change from baseline in placebo-corrected values of Fridericia corrected QT interval (∆ΔQTcF) were assessed over time. Linear regression analysis evaluated the relationship between plasma concentrations of parent/metabolite and ∆ΔQTcF. A concentration-dependent QTc effect was defined as an increase of ≥ 10 ms in the upper bound of the 90% confidence interval (CI) for predicted ∆∆QTcF at the clinically relevant exposures. As per International Council for Harmonisation (ICH) E14 guidance, categorical analyses of QTcF interval data were also performed.</p> Results <p>GalNAc–siRNAs demonstrated similar pharmacokinetics with rapid absorption and short plasma half-lives, with concentrations typically declining to below quantifiable levels within 24–48 h. Across the eight GalNAc–siRNAs, there were no dose-dependent increases in ∆∆QTcF over time. No subject had a QTcF interval &gt; 500 ms or a change from baseline &gt; 60 ms. Slopes of the linear regression of concentration versus ∆∆QTcF were close to zero, and the upper bound of 90% CI for ∆∆QTcF values at mean <i>C</i>_max values of the highest doses tested was well below 10 ms.</p> Conclusions <p>No concentration-dependent increase in QTcF was observed with multiple GalNAc–siRNA molecules across diverse targets and indications, confirming that GalNAc–siRNAs are highly unlikely to pose a QT prolongation risk. Hence, dedicated TQT studies are not necessary for the molecules in this platform and assessment of C–QTc relationships from early clinical studies up to maximum feasible clinical doses, which might be less than twofold of the likely therapeutic dose, is sufficient to assess the QT liability.</p> Clinical trial registration nos. <p>NCT02797847, NCT04565717, NCT02706886, NCT05256810, NCT03338816, NCT03934307, NCT05661916, and NCT05761301.</p>