TRANSLATE-TIMI 70: Primary endpoint met but safety concerns for vupanorsen

Vupanorsen, an investigational angiopoietin-like protein 3 (ANGPTL3) inhibitor, reduced non-high-density lipoprotein (non-HDL) cholesterol levels in patients with elevated cholesterol who were treated with statins. However, injection site reactions and elevated levels of liver enzymes were common and increased with dose.

 The multicentre, double-blind, placebo-controlled, phase 2b TRANSLATE-TIMI 70 trial (NCT04516291) randomised 286 patients with non-HDL cholesterol levels ≥100 mg/dL and triglyceride levels of 150 to 500 mg/dL who were treated with statins to subcutaneous vupanorsen (80, 120, or 160 mg every 4 weeks; 60, 80, 120, or 160 mg every 2 weeks) or placebo (n=44) [1]. The primary endpoint was the placebo-adjusted percentage change from baseline in non-HDL cholesterol at week 24. Dr Brian Bergmark (Brigham and Women’s Hospital, MA, USA) presented the findings of the trial, which were simultaneously published in Circulation [1,2].

At week 24, vupanorsen significantly outperformed placebo with regard to reductions in non-HDL cholesterol from baseline across all vupanorsen doses, with reductions ranging from 22.0% to 27.7% (P<0.001). Similarly, treatment with vupanorsen resulted in reduced levels of triglycerides after 24 weeks, ranging from 41.3% for the lowest dose to 56.8% for the highest dose (all P<0.001). Furthermore, modest and mostly non-significant reductions were observed in LDL cholesterol levels (up to 16.2%) and apolipoprotein B100 (ApoB) levels (up to 15.1%) in participants on vupanorsen.

Although the authors did not report significant issues with renal function or platelet count in participants on vupanorsen, injection site reactions and >3x elevations of the liver enzymes alanine aminotransferase and aspartate aminotransferase were reported in 33.3% and 44.4%, respectively, of the participants who had received a high dose of vupanorsen. Moreover, a dose-dependent increase was observed in hepatic fat fraction of up to 76%.

"Vupanorsen reduced non-HDL cholesterol at all doses studied in a statistically significant way and cut triglyceride levels in half,” said Dr Bergmark. “However, the effect of vupanorsen on lipids was less than hoped for and important safety concerns were observed. Nonetheless, we did find out some information that may be relevant for future studies and agents targeting this pathway or adjacent metabolic pathways through similar mechanisms.”

1. 
   
   1. Bergmark BA, et al. Effect of Vupanorsen on Non-High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70. Abstract 405–10, ACC 2022, 2–4 April, Washington DC, USA.
   2. Bergmark BA, et al. Circulation. 2022;145(18):1377–86.

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Posted on 15 June 202224 June 2022