ArticleClinical pharmacokinetics2026
Platform Assessment of Concentration-QTc Relationship Across GalNAc-siRNA Molecules.
Article in Clinical pharmacokinetics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 8 registered trials, which are not on this map. Cited by 1 paper.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Phase 1/2, Single-Blind, Placebo-Controlled, Single and Multiple Ascending Dose Safety, Tolerability, Pharmacokinetic and Pharmacodynamics Study of Subcutaneously Administered ALN-GO1 in Healthy Adult Subjects, and Patients With Primary Hyperoxaluria Type 1
A Phase 1, Randomized, Single-Blind, Placebo Controlled, Single-Ascending Dose, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of Subcutaneously Administered ALN-TTRSC02 in Healthy Subjects
ENVISION: A Phase 3 Randomized, Double-blind, Placebo-Controlled Multicenter Study With an Open-label Extension to Evaluate the Efficacy and Safety of Givosiran in Patients With Acute Hepatic Porphyrias
A Phase 1, Randomized, Double-Blind, Placebo-Controlled Single Dose and Active Comparator-Controlled Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneously Administered ALN-AGT01 in Patients With Hypertension
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, 3-Part Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Dose ALN-HSD in Healthy Adult Subjects and Multiple Dose ALN-HSD in Adult Patients With Nonalcoholic Steatohepatitis (NASH)
A Phase 1/2, Randomized, Double-blind, Placebo-controlled, Single Ascending and Multiple Dose Study of the Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of ALN-XDH in Healthy Adult Subjects and Adult Patients With Gout
A Phase 1, Randomized, Double-Blind, Placebo Controlled, Single-Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK), and Pharmacodynamics (PD) of Subcutaneously Administered ALN-TTRSC04 in Healthy Subjects
A Phase 1/2, Randomized, Double-blind, Placebo-controlled, 2-Part Study of the Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of Single Dose ALN-KHK in Overweight to Obese Adult Healthy Volunteers and Multiple Dose ALN-KHK in Obese Patients With Type 2 Diabetes Mellitus (T2DM)
Who cites it
1 citing paper in PubMed.
- The Hidden Cost of QTc Assessment: A Quantitative Weight of Evidence Framework to Eliminate Structural False Positives and Restore the Lost Opportunity Cost of Abandoned Medicines.Clinical pharmacology and therapeutics · 2026Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundGalNAc-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.
methodsTime-matched electrocardiogram (ECG) data and plasma concentration data collected from phase 1/2 studies (N = 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.
resultsGalNAc-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 > 500 ms or a change from baseline > 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 C
conclusionsNo 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. CLINICAL TRIAL REGISTRATION NOS: NCT02797847, NCT04565717, NCT02706886, NCT05256810, NCT03338816, NCT03934307, NCT05661916, and NCT05761301.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.