Lack of QT Prolongation for 2′-O-Methoxyethyl-Modified Antisense Oligonucleotides Based on Retrospective Exposure/Response Analysis of Ten Phase 1 Dose-Escalation Placebo-Controlled Studies in Healthy Subjects

The potential of QT prolongation of ten 2'-O-methoxyethyl-modified (2'-MOE) antisense oligonucleotides (ASOs) was evaluated retrospectively via exposure/response (ER) analysis using data from Phase 1 clinical studies in healthy subjects. All Phase 1 studies were double-blind, placebo-controlled, single and multiple ascending dose studies designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of the ASOs in healthy subjects. The active doses in these studies ranged from 50 to 450mg administered by subcutaneous (SC) injection in single and multiple ascending dose cohorts. Two of the ten studies also included 2-h intravenous (IV) infusions up to 600mg. Electrocardiogram (ECG) measurements were performed at baseline and selected time points (including T-max). The correlation betweenQTcF intervals corrected for baseline (Delta QTcF) and the mean time-matched placebo (Delta Delta QTcF) with PK plasma exposure when available was evaluated using a linear mixed-effects approach. There was no evidence for QTc prolongation associated with increasing plasma concentrations in healthy subjects, including exposures with treatment up to 450mg administered SC or 600mg by IV infusions, and concentrations that are 4-20 times the C-max of the therapeutic dose, as assessed by both Delta QTcF and Delta Delta QTcF. The ER analysis of the relationship between drug plasma concentration and Delta Delta QTcF showed that the slope of the regression line was close to zero, and the upper bound of the 90% confidence interval at twice the mean observed (or predicted) C-max (2 x C-max) of the clinical therapeutic dose (ie, the highest clinically relevant plasma concentration) was well below 10ms for all 10 compounds evaluated. Therefore, no concentration-dependent effect on QT prolongation was observed for any one of the ten 2'-MOE ASOs evaluated in Phase 1 studies. These results confirmed that 2'-MOE ASOs, as a chemical class, do not cause QT prolongation at clinically relevant dose levels.