TRANSLATE-TIMI 70: Vupanorsen significantly lower levels of VLDL-C and remnants

Vupanorsen significantly reduces VLDL-C and remnant cholesterol in proportion to the degree of ANGPTL3 inhibition, according to secondary endpoint data from the TRANSLATE-TIMI 70 trial reported by Dr Nicholas Marston, Brigham and Women’s Hospital, Boston, USA.¹ VLDL-C was reduced by 52-67% at 24 weeks with increasing doses of vupanorsen (SC Q4W: 80, 120, 160 mg; SC Q2W: 60, 80, 120, 160 mg), remnants by 42-59% and TG by 41-57%. ANGPTL3 levels were reduced by 70-95% with increasing vupanorsen doses. VLDL-C reductions were consistent across all subgroups, including by age, sex, BMI, and baseline diabetes, TG levels and statin intensity.

The results build on previously published TRANSLATE-TIMI 70 data showing dose-dependent reductions in non-HDL-C of 22-28% and TG of 41-57%, with more modest reductions in LDL-C and ApoB of 8-16% and 6%-15%, respectively.²

Dr Marston also discussed a further analysis of the safety data showing dose dependent increases in liver enzymes and liver fat that led to the clinical development of vupanorsen in cardiovascular risk reduction and severe hypertriglyceridaemia being halted earlier this year. The additional data show that the ALT increase occurred throughout the dose range but was most prominent at highest doses (2-3-fold increase). AST followed a similar trend but at a somewhat lower level of elevation. The hepatic fat increase was also greatest at higher doses, with an increase of up to 75%.

“Lower doses of vupanorsen or other drugs to inhibit ANGPTL3 synthesis may have an important role in patients with residual dyslipidaemia despite current therapy,” concluded Dr Marston.

In response to questions, he added that the LFT elevation typically occurred after approximately 10 weeks and appeared to persist though data are limited.

References

1. Marston N. Reductions in VLDL and remnant cholesterol through inhibition of ANGPTL3 protein synthesis: an analysis from TRANSLATE-TIMI 70. Presented at the 90^th European Atherosclerosis Society Congress, Milan, Italy, May 22-25 2022, Late Breaker Session 1.
2. Bergmark BA, Marston NA, Bramson CR et al. Effect of Vupanorsen on Non-High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70. Circulation 2022 May 3;145(18):1377-1386

Reportage by Jenny Bryan