Phase 2b trial evaluating ANGPTL3 antisense meets primary endpoint
It was reported that the dose-ranging study with the investigational antisense therapy vupanorsen (IONIS-ANGPLT3-LRX) has met its primary endpoint. Vupanorsen significantly reduced non-HDL-c at all doses at 24 weeks compared to placebo in subjects with elevated non-HDL-c and triglycerides (TG). In addition, vupanorsen significantly reduced TG and ANGPTL3 at all doses at 24 weeks compared to placebo.
Most common adverse events were injection site reactions, which occurred most often with the highest dose of vupanorsen. Most common laboratory abnormalities were increases in ALT and AST, primarily with the highest doses. Some doses of vupanorsen were associated with an increase in hepatic fat fraction at week 24 compared to placebo. There were no serious adverse events (SAEs) related to treatment and incidence of SAEs was similar between the 2 treatment groups.
The TRANSLATE-TIMI 70 (TaRgeting ANGPLT3 with an aNtiSense oLigonucleotide in AdulTs with dyslipidEmia) was a global multicenter, double-blind, placebo-controlled, dose-ranging phase 2b study, which enrolled 286 subjects (≥40 years) with dyslipidemia (elevated non-HDL-c and TG) on a stable dose of statin. Doses of vupanorsen given were either 80, 120 or 160 mg every 4 weeks, of 60, 80, 120 or 160 mg every two weeks via subcutaneous injection. Primary endpoint was percentage change from baseline in non-HDL-c at week 24. Efficacy, safety, tolerability and pharmacokinetics of vupanorsen were assessed in the trial.
Vupanorsen has been designed to reduce the production of ANGPTL3, a key regulator of triglyceride and cholesterol metabolism in the liver. People with a genetic deficiency of ANGPLT3 have reduced levels of LDL-c and TG, and a lower risk of T2DM and CVD.
Phase I study results showed that vupanorsen reduced dose-dependently ANGPLT3, TG, LDL-c and non-HDL-c and total cholesterol with a good safety and tolerability profile. A phase 2a study showed that vupanorsen met the primary endpoint of reductions in TG levels compared to placebo with a good safety and tolerability profile.