Modest effect on apoB and key safety findings with ASO targeting ANGPTL3 mRNA

Effect of Vupanorsen On Non-high-density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol – TRANSLATE-TIMI 70

Presented at ACC.22 by Brian Bergmark, MD (Boston, MA, USA)

Introduction and methods

Angiopoietin-like protein 3 (ANGPTL3) inhibits lipoprotein lipase (LPL) and other lipases. People with loss-of-function variants in ANGPTL3 have been reported to have lower levels of lipids. A monoclonal antibody directed against ANGPTL3 (evinacumab) has been approved as treatment option in patients with homozygous familial hypercholesterolemia.

Vupanorsen is a second-generation antisense oligonucleotide (ASO) targeting ANGPTL3 mRNA in the liver that has a potential role in the reduction of CV risk. This was investigated in the TRANSLATE-TIMI 70 trial.

The TRANSLATE-TIMI 70 trial enrolled adults on stable statin therapy with non-HDL-c ≥ 100 mg/dL and triglyceride levels 150-500 mg/dL. Participants were randomized to placebo or 7 different dosing schedules (80 mg Q4W, 120 mg Q4W, 160 mg Q4W, 60 mg Q2W, 80 mg Q2W, 120 mg Q2W, 160 mg Q2W).

The primary endpoint was percentage change in non-HDL- from baseline to week 24. Secondary endpoints were percentage change in triglycerides, LDL-c, apoB and ANGPTL3. Safety outcomes included hepatic fat fraction, ALT/AST, renal function, and platelet count.

Results

• Placebo-adjusted percentage change at week 24 in non-HDL-c ranged from -22.0 to 27.7 with different dosing schedules of vupanorsen (P<0.001 for all when compared to placebo).
• There were strong reductions in ANGPTL3 (range: 69.9 to 95.2%) and TG (range: 41.3 to 56.8%), whereas reductions in LDL-c (range: 7.9 to 16.0%) and ApoB (range: 6.0 to 15.1%) were more modest.
• There were more frequent injection site reactions in the vupanorsen groups, including any injection site reactions and recall.
• Liver enzyme elevations were more frequently observed at the higher total monthly doses of vupanorsen.
• A dose-related increase in hepatic fat fraction was seen with vupanorsen.

Conclusion

In the TRANSLATE-TIMI 70 trial, vupanorsen significantly reduced non-HDL-c and triglyceride levels at all doses, but other lipid parameter were only reduced at certain doses and apoB was only modestly reduced. There were key safety and tolerability findings with vupanorsen.

The authors concluded that this trial emphasizes the importance of rigorous evaluation of new therapies and may provide mechanistic insights.

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The findings of this study were simultaneously published in Circulation. Watch the video about this study